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Gadi Rennert: Okay. Well, I'll take the next 15 minutes
trying to run you through an Israeli program which actually comes from a slightly different
angle. It's going to be the experience of implementing personalized medicine program
within an HMO-like organization, a non-for-profit organization.
Okay. Let's go for here. Okay, so just couple minutes on the Israeli Health System. We are
-- it's, again, like what we heard before in Belgium, or we know from the U.K. and other
-- Canada and other -- it's a health system where there's full coverage of the whole Israeli
population, only that the service here is provided by four providers, say HMO-like.
They're non-for-profit, and the people in the country have the freedom to move between
the providers every three or six months, and, actually, the providers only compete on a
level of service. And, you know, length of lines -- of waiting lines, and things like
that because the content of the services provided is dictated by the government, and it's fixed
for all the HMOs.
Okay, so once every year there's a process that updates the services basket, but -- and
says what will be included and whatnot. But once it's included, all four providers provide
the same service on the same items, and everything is free of charge, or with a very tiny co-pay.
So, we have four services, and I'm going to talk today about the program of Clalit, which
is the largest one covering about close to 60 percent of the population, and with about
a thousand primary care clinics, about 30 to 100 primary care physicians, seven general
hospitals that belong to Clalit. But the insurees of Clalit can go into any other hospital in
the country. So these are just hospitals that are -- specifically belong to the organization.
In a sense, at least for the Americans, it's kind of a Kaiser Permanente-type of organization
size wise, and -- but it's not for profit.
Okay, so -- and the interesting thing is that we all pay our health insurance to the government.
We do not pay to the provider. There's no financial contract between us and the provider,
and the government disperses the funding between the different providers according to various
parameters. Okay. Now when the -- when the organization that Clalit -- I mean, that organization,
HMO, whatever we call it -- decided to move on towards the subject of genomic medicine,
personalized medicine, whatever name you give it, they approached us.
We were then active as the National Cancer Control Center of the organization, of the
HMO, and we had a large team -- a disciplinary team of a variety of professions. We had quite
a large lab. We had -- we were involved in a lot of research with tens of thousands of
participants. We had a biobank of more than 400,000 samples -- a variety of samples, and
we had experience with a lot of genetic testing -- research-based genetic testing.
So it made sense to come to us as an expert group and suggest that we try and develop
a program for the HMO on these grounds. We also have the clinical counseling service,
and we have very large series of carriers; some of them are a reflection of the fact
that the Israeli -- especially the Ashkenazi population -- is a founder population, so
you get a lot of mutations and -- so you really reach very large numbers.
So, in -- as a whole, we were a facility that was right in place with a lot of hands-on
experience in the genetic aspects of research and large-scale research. So, we were approached.
I just want to show that within our studies -- that's one of our studies -- our corrective
cancer study, and that's the first 5,000 participants in the study, et cetera. We were in a stage
-- at that -- when we started designing things, we were at a stage of really separating populations
very clearly and very dramatically.
Within Israel, you see the Ashkenazi population here in black. You see the Sephardi population
in red. These are the Jewish populations. You see the Arab population in blue. In light
blue is an Arabic sect that are the Druze. It's interesting. We got an influx of non-Arab
-- Christians who were non-Arab. We have Arab Christians. And non-Arab Christians that came
in, especially from the Russian Republics in recent years, and you see they're here
in green in between. So it's very interesting to see the separation. A paper that showed
similar data came out from Duke. Was it David Ginsburg, right?
Male Speaker: [inaudible]
Gadi Rennert: Goldstein. Sorry, Geoff. Sorry.
[laughter]
Male Speaker: He would have taken credit for it --
Male Speaker: He's not taking credit for it.
[laughter]
Gadi Rennert: I'm allowed to do that mistake, you know,
see. In any case -- in any case, David Goldstein that's a paper that he did, and he, again,
could separate very, very clearly the Jewish population here from the Druze population,
Palestinian population, and Bedouin population, and here is like the U.S. population.
So, populations separately, if we were talking about population certification and need to
know the genetics of certain populations where you operate your medical system, this is clearly
a case where it shows that you need to have a lot of information about that.
Our colleague from Kuwait talked before about Arab populations. We actually have tons of
data on the genetics of various Arab populations just because we're doing all -- most of our
studies in northern Israel, and that's where most of the Israeli-Arab population resides.
So, a lot of genetics, a lot of non-genetics later on that that could be of help to groups.
Family history was mentioned before. We put a lot of emphasis in trying to introduce family
history into our medical records. Every activity that we do on a national level, we try to
collect data on that. So, for example, here you see the result -- the reporting of the
family history of breast cancer among Jews, Christian Arabs, Muslim-Arabs, Druze, in women
who came in to have a mammogram, okay. So these are the reports of a million women,
okay, in a tiny country; we only have 4 million women in the whole country. There are a million
women reported on family history. The same thing with every screening activity; everything
we do, we make sure to incorporate family history data into our databases. Not only
that, we push it into the doctor's computers, and all the doctors are computerized on the
same system.
So we push it in, and the next step that we took only recently, was we identified first-degree
family relatives through the population register, and pushed the -- their information of family
history into their medical records without disclosing who the family case is because
you then run into all this -- all the privacy issues. But we pushed -- we really are trying
to push this data wherever we can, and we have registers on many other diseases. We
also run large registers of cardiovascular diseases and others, so we can really push
in a lot of information this way.
In any case, so we set up to build a program -- an organized program, really a committed
organized program, and there were issues of policy, of education, and provision of service.
And in policy, first thing was to get the commitment of the management; that's always
the toughest part. You're always talking in words of cost effectiveness. And when you
compete only on quality of care -- because there's no, you know, there's no other grounds
for competition in our system -- you want to be innovative. You be to -- you want to
show up as a modern service. You want to -- I mean, all these women -- all these words kind
of excite the CEO, okay. So this is what you come and sell. You try to say that you'll
provide better health and you'll be cost effective.
The contents were defined as dealing with molecular medicine to -- for risk reduction,
for disease detection, for efficient treatment, and for prognosis determination.
Finances are always a big issue. These are, you know, all these technologies are very
costly, and also the fact that they are outdated before they actually hit your bench is also
a major issue.
We had to struggle with issues of homebrewed testing versus commercial kits. We decided
to go for homebrewed testing wherever we could. And for example, just because, you know, a
founder mutation panel for Ashkenazi Jews in the U.S. would be $500 to $700; in our
lab it's about $40. And I've done about 50,000 of them, so, I mean, so wherever we can. But
when you do home brew, you have to invest in R&D because otherwise you cannot rely on
the development of a kit of others; a lot of legal and ethical issues. Yes, of course,
entry into databases, and everything is computerized in our system; it's a big issue.
Education: We invested a lot in education of the medical teams. We are aware of the
fact that they are scared, terribly scared, by this whole field, and many times, confused.
This is an illegible language for you, but that's like our Caerus [spelled phonetically]
brochure, which tells the doctors -- and it's actually aimed at the primary care level -- to
say, you know, what is the disease we're talking about? What drugs will be influenced by it?
The gene: What tests are we going to do? What's a gene-test interaction? What's a population
variability? And the gene, what is the clinical evidence? Who should be tested, and what should
you do with the answer of the test? Okay, so this is kind of a -- and we have it for
numerous, many, many different tests.
Provision of service: We established an expert team of geneticists, and pharmacogeneticists,
and pharmacologists, and a variety of physicians who are at the service of all the doctors
of our organization. They want to ask somebody -- they have a phone call. They can ask about
whether to order the test, what to do with the test result, what the test is about, and
everything they want. So there's a support group. And there's a centralized lab, as much
as we can. We're not limiting it to the centralized lab, but the centralized lab takes most of
it all and does most of the tests. I'll skip these long lists of genes that we are able
to do.
This is one panel that we gave in, and we are starting to operate now, the TruSeq on
our MiSeq. And just as an example, doing EGFR testing in lung cancer tissue, we could report
close to 2,000 tests within about a year of activity because we, as a centralized lab,
get the samples from all the hospitals. In Israel, we can say how many were positive.
We can say what is the distribution of the mutations just by being centralized and being
with good databases. We just have all the data right there.
We can look at, similarly, at ALK, which follows a negative EGFR, and, again, see the proportion
in our population that are positive. We can see, if we want to look at the whole picture
of lung cancer, that 33 percent will be EGFR mutated, 25 KRAS, et cetera, et cetera.
And, again, I mean this is critical data for our decision making with regards to treatment.
We can look at multiple mutations in a tumor, okay, to see what's mutually exclusive and
what's not. We can look at survival patterns here that people with EGFR mutations and without
EGFR mutations. So, the EGFR mutate are doing better, but are they doing better because
of treatment, or are they doing better just because the mutations gives them an advantage?
Well, no, if you have the mutation, but you're not treated, you are in blue. You are like
without the mutation.
So the advantage is really only if you are mutated and you get -- and you receive the
TKIs to treat the mutation. Similarly, with ALK, we could show the differences in here.
If you have ALK mutation, you're really faring badly. We were even able -- because we have
all the pharmacy data -- everything is computerized, every single element in the system.
So we could actually look, if you had an ALK mutation, but you wrongly received TKIs, what
would happen? And also, if you did not have the ALK mutation and you received Crizotinib,
what would happen? And we can see that it's actually of no value. I mean, so it's true
that Crizotinib should be reserved only for TKI -- for ALK mutated, and that TKIs should
be reserved only for EGFR mutated. You know, you can show it with rather big numbers of
information. So, I mean, that's -- to conclude, I mean, it's a centralized program, and we
think that the centralized program is a good approach as a -- whoops. Already?
[laughter]
I think I still have a second.
[laughs] Okay. Can you bring it back? Okay, anyway, we think that our centralized program
has its advantages, and by having big volumes, you can really make sure that you have very
good high-quality control for your tests. You can make sure that your turnaround of
the -- of response of results will be fast and quick. And you have tons of data that
actually come to a central database where you can control and see the stuff.
I wanted to acknowledge the team. You are not going to see the picture of all the team
members. But any case, this is just an example of how to try -- in a very organized manner
-- take something from A to B and -- under the responsibility of the organization. So
this is really covering a whole population. Thank you very much.
[applause]
Mary Relling: Mary Relling, St. Jude. So, you showed the
incredible ancestral diversity that you have in your population related to race and ethnic
groups. Do you have any examples of a variant that's actionable in one group and not actionable
in another? Either somatically-acquired or inherited?
Gadi Rennert: No.
Mary Relling: Dan --
Gadi Rennert: So I have, so I have all these specific --
Mary Relling: -- I'm still here.
Male Speaker: Well, that's fine --
[laughter]
Mary Relling: No, that's okay.
Male Speaker: Okay.
Mary Relling: Dr. Roden's [inaudible] --
Gadi Rennert: No. I mean because you are asking whether
it's actionable or not, and you're referring to the result of the action to show that something
worked in this group and did not, although the two groups had the same mutation.
Mary Relling: Right. I mean, I think there's a lot of examples
of things that are very --
Male Speaker: That's a different question.
Mary Relling: -- actionable that have a functional --
Gadi Rennert: Right.
Mary Relling: -- consequence. It's a little bit difficult
to say that they're non-actionable in another group -- another rare ancestral group -- when
they're known to have a functional consequence. They may be less important.
Gadi Rennert: Or non-existent. So for example --
Mary Relling: Now that's a different situation.
Gadi Rennert: Yeah.
Mary Relling: Now the problem --
Gadi Rennert: No, but that's very surprising to ask that
we have, you know, within the Jewish population, you know, we could find the 185delAG whatever
BRCA in Ashkenazi Jews also in Iraqi Jews, which are completely a different area, but
in none of the North African Jews. So --
Mary Relling: But then you don't --
Gadi Rennert: Right.
Mary Relling: -- need to know someone's ancestry in order
to interpret the results --
Gadi Rennert: Right.
Mary Relling: -- by clinical context for the patient. So
we're all very interested in this diversity --
Gadi Rennert: Yeah.
Mary Relling: -- but does it really affect the way that
we give advice to patients and act on it clinically?
Gadi Rennert: Not before we test it.
Male Speaker: So I have a very specific question about a
germline variant, and that's the D36Y variant in VKORC1. Do you -- so one question was --
Gadi Rennert: In where?
Male Speaker: In VKORC1, so the warfarin gene.
Gadi Rennert: Okay.
Male Speaker: So one of the questions I actually had was
whether you have a focus only on the tumor genome, or whether there's a --
Gadi Rennert: We've done --
Male Speaker: -- germline as well.
Gadi Rennert: No. We're definitely doing germline testing
too. I've done thousands of VKORC1 as part of a -- you know, I mean research based, because,
again, we are constantly involved in R&D. We have to -- because we have to -- if this
comes up to be an important gene, we have to be ready to supply --
Male Speaker: So there --
Gadi Rennert: -- the service nationwide.
Male Speaker: -- so there is Israeli data that suggests
that there's a --
Male Speaker: -- five -- there's a five percent or a rare,
non-synonymous variant in VKORC1 that confers relative or absolute warfarin resistance.
So these patients take -- instead of taking 5 milligrams a day, take 15 milligrams a day,
and I'm just wondering whether you have encountered that one and whether that is an implementable
variant --
Gadi Rennert: We probably will not encounter it -- I mean,
specific in our lab, because otherwise I would known about it. But I do know that we tested
for the whole, you know, cardiovascular panel including, you know --
Male Speaker: So the cardiovascular panels have to include
this one. I would have thought they had to include this one because this is an Ashkenazi
variant.
Gadi Rennert: Right. Okay. Sorry.
Male Speaker: No, no, no, no, I mean, I just --
Gadi Rennert: [laughs]
Male Speaker: -- you know, you're the one who delivers the
services not me, so. I hope -- I was hoping that that was going to be an answer to Mary's
question: a variant that is ancestry specific and actionable, but maybe I'm not -- maybe
I don't know enough about it.
Gadi Rennert: That's not her -- her question was if I can
find it in one ethnic group -- in two ethnic groups, but it's actionable in one and not
in the other. That is a tricky one. Because, I mean, finding it in --
Mary Relling: You're right. That was a [inaudible].
Gadi Rennert: Yeah.
[laughter]
Teri Manolio: Dan was wrong.
I wanted to ask you about the data that you showed on Crizotinib not being effective in
the EGRF negatives, which is what one would expect. You would think that those would be
unimportant data, but actually in talking with our Centers for Medicare and Medicaid
Services, one of the things that they find is that physicians will do these tests and
will give the drug anyway, even if it's negative. You may have the same thing happen in your
place because it's the best choice.
Gadi Rennert: You see, that's why it happened. I mean how
would --
Teri Manolio: How would you otherwise have it?
Gadi Rennert: Theoretically, it should be sequential.
Teri Manolio: Right.
Gadi Rennert: You have the mutation. You're eligible for
the drug.
Teri Manolio: Correct.
Gadi Rennert: Now many patients elect to use the drugs prior
to whatever.
Teri Manolio: Anyway --
Gadi Rennert: And that's -- how we can show -- I mean otherwise
I would not have had anybody --
Teri Manolio: Exactly.
Gadi Rennert: -- [inaudible].
Teri Manolio: So I wanted to say was, you know, a) we need
to get physicians to actually follow-up and act based on the tests that they do; but that's
one issue. Another is that it's very helpful to have that kind of evidence because actually
some of the ways that our Centers for Medicare and Medicaid Services, CMS, makes decisions
on payment is not necessarily on having evidence of benefit, but just having some influence
on medical care. So it doesn't necessarily have to have an evidence.
Gadi Rennert: It's been written up.
Teri Manolio: Great. Great.
Gadi Rennert: It's number 28 --
Teri Manolio: So, and yeah, and so just letting others know
that those kinds of data are very helpful. And they said, "If you have any evidence that
things don't work, we want to know that," so, that would be great.
Male Speaker: Maybe I'll ask the -- or make the last comment.
What I heard you describe was an incredibly powerful system for evidence generation. You
describe it as a centralized means of providing quality service provision, but you've got
the genomic data, the pharmacy data, the outcome data, and because you're an HMO, you have
obviously the cost data. So, to me, this would seem like the perfect system to do what is
thematic in this meeting to really begin to generate evidence at scale. Do you want to
comment on that? Or do you disagree or -- and --
Gadi Rennert: Oh, wow. That's a really powerful statement
on a perfect system, but --
[laughter]
Gadi Rennert: No. But, no, it is very powerful. I have to
admit it's very powerful, and actually a lot of different agencies are making use of our
data. Like now we're happy to have the FDA ask us questions about certain drugs, not
the genomics of drugs, but like, you know, side effects and stuff like that whenever
the issues come up, we can immediately, you know, query our databases. And this is an
immense database. I mean, it has billions of points of entry. So it's actually quite
powerful to handle. But yes, I mean, it's special.
The only thing that worries me a little bit, when we do our work, is to what extent is
it generalizable? That's the only issue. I mean if we are really genetically different,
to what extent is it -- is that the case, and because it really, I mean, I -- naturally
I don't have the time to show a million examples. But, you know, I mean, like, we have half
the lung cancer rate per same smoking than non-Jews.
Now it's true in Israel and it's true in New York. If you compare -- Jews and non-Jews
in New York in studies with 10,000, 15,000 participants, big studies, and, you know,
with all the effort to find the genetics of that including whole -- no, not whole -- I
mean, yeah, whole genome sequencing and everything. We can't put a finger on what's happening,
okay.
So there's a lot of issues. And the question is really to what extent is it generalizable,
you know, because some -- there are many issues, you know. I mean, like BRCA genes, very common
in our system. Does anybody know why -- if the benefits is 50 percent, why do two women
with the same mutation, one gets a cancer and one does not? I mean, 100 women, 50 get
it, 50 do not. Why?
Teri Manolio: So --
Gadi Rennert: I mean CIMBA -- the CIMBA Consortium is trying
to answer this question for 10 years. No answer.
Teri Manolio: So you're mention of the BRCA gene makes me
channel Heidi again, and just raise the issue of it's been very difficult in the U.S. to
get data on sequence variation in BRCA1 because all the data are locked up in a proprietary
database. But there are efforts to try to either, you know, liberalize -- or liberate
some of those data or report them individually. But are you guys working on BRCA1 sequence
variants depositing them somewhere; making them available with phenotype information?
Because it would be critically important, I think.
Gadi Rennert: Frankly, the answer is no, and it's "no" because
we're so spoiled. We have the founder mutations. We don't need to look at variants.
Teri Manolio: Oh I see.
Gadi Rennert: We just go directly for the founders. So we
don't sequence. We're going to start sequencing now because we have enough reason to do it,
but actually --
Teri Manolio: Yeah. When you do, yeah, please.
Gadi Rennert: [laughs]
Teri Manolio: Please deposit the data --
Gadi Rennert: Yeah. Although we have tons of variants in
other genes, cancer-related, you know, Lynch syndrome gene.