International Experience Part 2: Discussion
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International Experience Part 2: Discussion


Juan Lertora:
And I will begin making a brief comment. We’ve been talking about implementation in terms
of pharmacogenomics. I just want to mention that for the last couple of years, the NIH
Clinical Center has been offering HLA genotyping when abacavir, carbamazepine, and now phenytoin
and allopurinol are prescribed by practitioners in the NIH Clinical Center. My colleague Dr.
Barry Goldspiel, who is acting — rather deputy director of pharmacy, co-chairs the Pharmacogenomics
Subcommittee with me, and Dr. Bill Flegel in the Department of Transfusion Medicine
is in charge of the actual HLA genotyping implementation. So I just wanted to mention
that the Clinical Center is, in fact, moving in that direction. It is required for abacavir;
otherwise, it is a recommendation, and clinicians may decide on an individual-patient basis
whether or not to order a test at any given time. So with that, again, this is open for
general discussion. Teri Manolio:
If I could just make a — make a comment, building a bit on what Steve described, it
seems as though, Steve, you have a system that — you know, you’ve got data collection
forms; you’ve got the software. It shouldn’t be all that difficult to transport that to
other systems. And so — recognizing that Cerner is not the most penetrant nationwide,
but still, it’s one that’s fairly standard. So you know, recognizing that, that’s not
your mandate to do, how could we facilitate that happening, if that would be a useful
thing to happen, in other systems? Male Speaker:
Well, I think we would be perfectly willing to share the forms. I mean, the institution
paid for the development of the systems through a contract with Cerner, so it’s the institution’s.
I mean, the whole goal was to come up with a system that would allow, if there were to
be a cutaneous adverse drug reaction network — I mean, I was only thinking in the context
of pediatrics because that’s really what our focus is, but if there were ever funding
for a network, we wanted to be able to participate in the network by having everything in place.
And we would be more than willing to share, you know, whatever we can that would facilitate
this occurring at more institutions, wherever. So what does it take? I guess it takes probably
a medical IT person at a given hospital or system to tweak it or engineering — I don’t
— I don’t — I don’t — I don’t know. But it was our medical informatics team working
with the Cerner employees who walk around with Children’s Mercy Hospital ID badges
on to make it happen, and that’s the extent of my knowledge. Marc Williams:
Yeah, Marc Williams, Geisinger, unfortunately living in this world. So, you know, these
things are conceptually simple, but actually realizing them is incredibly difficult because
what usually happens is that they do get billed as one-offs, and so they will work in Cerner,
but they won’t transport necessarily even to other Cerners. And so I think the strategy
would be to take advantage of I think what is a little bit of momentum that’s gathering
as a result of the GM7 Meeting and the IOM EHR Action Collaborative Meeting where people
are saying we really have to solve this generalizability issue and we have to use some of the standards
that are available that are going to be — all certified EHRs are going to have, like a fast
health care, interoperable resources, and those sorts of things. So I think that as
we develop a strategy, assuming that we want to move this forward, that this is, you know,
creating a network, creating standardized data entry, and those sorts of things, engaging
with the informatics community to build the resource such that it would be, at least in
theory, interoperable with any certified electronic health record, not integrated within it but
sitting on top of it and able to communicate with it, would be a desirable approach. But
it’s difficult to do that without sort of a national perspective because the — at the
individual level it just doesn’t move in a generalized way, so it’s very challenging. Teri Manolio:
Although, as we’ve — as we’ve talked about, it’s a big country. And trying, I
think, to do this on a national level, I mean, eventually it could happen, and yet you’d
like to take advantage of sort of willing partners early on and if there were, you know,
at least a handful of hospitals that wanted to partner and then those could grow and those
could grow broader. Maybe, Josh, you wanted to comment on that? Josh Denny:
Yeah, I was just thinking that, you know, I think it is great to have these interoperable
standards, and I think we need to continue to shoot for them and, you know, certain — there
have been some great demonstration projects like SMART and things like that that can run
across each of these apps; you can put across different smart enabled EHRs. But you know,
optimally, to be effective, it’s got to be integrated within the EHR in a way that
sort of fits all the standard workloads people are used to. And I do think, as long as, you
know, you have standard outputs and think about what those outputs look like, then the
work you’ve done in Cerner to design a form that works well on the data elements you want
to collect could be properly mapped to something that looks similar in Epic. I know we could
probably do something similar, for instance, in our EHR, and — of course, ours is Homegrown,
so we have the ability to sort of do what — you know, kind of, whatever we want. But
the — but I think those elements, if you standardize the outputs you could cross them
across different systems. And I — Marc is completely right that, you know, what works
in one Cerner doesn’t necessarily work in another Cerner, same with Epic et cetera,
but it gives you a great head start. It’s a lot easier to adapt code that’s in one
Cerner to another Cerner application. So I would think that model is a good step forward. Marc Williams:
The thing that I would — I completely agree with what Josh has said, but I think what
you really want to do is you want to have an eye on ultimately where you want to be
so that you don’t create — you can create something that works with a small amount of
partners, but if you create it in such a way that it only works with that small number
of partners and doesn’t have a vision for extensibility, that’s not a good outcome
either. It’s a lot of resources that ultimately won’t get you to where you want to go. So
I think it — you know, starting with a smaller group of cross-multiple EHR systems and demonstrating
that it can work will then lower the energy barrier to extend it more broadly if that’s
the direction that things want to go. We had talked yesterday at our breakout — and we’ll
here about this — about whether or not, you know, even something within groups that are
participating in the Sentinel program could potentially utilize something like this, which
again, would have a lot more oomph behind it if we could pull something like that off. Teri Manolio:
Well, and maybe, if I can just make one quick comment in response to that, you know, what
we seem to be talking about is not — at least doesn’t sound like research. And so, you
know, for NIH, this would be a — kind of a tall mountain to climb. On the other hand,
you made the very good point that then it provides the infrastructure on which you can
do research, so then we’d be interested. So is it possible to sort of leverage this
with the variety of patient safety initiatives that are ongoing? And I’ll turn to our FDA
friends to help us to know who the people are to engage. I would think AHRQ, to some
degree, our agency for Health Care Research and Quality and potentially the CDC. But I
don’t know, so I don’t know if, Mark or others, if you want to comment. Mark Avigan:
I don’t have a very specific answer, but there are a lot of stakeholders in the government
who are interested in this. And actually, the deputy secretary of health had recently
convened a report, which I sat on as a steering committee member, to look at various aspects
around three areas of safety events and how to leverage informatics systems and so on
to improve both the research aspect but also the patient management aspect, and they brought
in some IT specialists. AHRQ was one of the groups that was involved, all — right across
the across the whole government, actually. So we can find out who are the people to go
to, but I think that the vision here is to have a system in place, an informatics system
in place, which you can use both for patient management so that it’s early recognition
of events and interventions, the research aspects, and then the public health aspect,
so that’s sort of the three-cornered hat. And if you — and if you really do it right,
over time, you build a network so that it becomes basically for these rare events especially,
you know, sort of, you know, encompasses, hopefully, the whole health care system or
as much as possible. The other aspect — and Dr. Hoofnagle’s
going to talk about this — is that besides the data elements, which are important to
accumulate, you really do need a clinical brain to look at individual cases. You need
this kind of causality analysis, which also has its own methodology, so that when patients
are being seen at the bedside by the clinicians, they’re actually calling what those cases
actually are, and there needs to be a system in place where, in addition to data analysis,
there’s a kind of smart narrative which has its own consistency across the system
where the narrative synthesizes what the patient actually had and what the expert brain thought
the diagnosis was. So FDA has a lot of experience with this as an issue, is how not only to
get information bits but to actually get the differential diagnosis, the causality analysis,
the phenotype, and so on. So you still need that as part of it. The collection and documentation
— and this will be especially important for genomics — where when you start doing whatever
your case-controlled studies designs are, you want to have the confidence that the cases
that you accrue to do genomic analysis on are bona fide cases, that they are not something
else, because otherwise, you will not have a good research platform. Josh Denny:
I just want to say other group to talk to would be ONC. Juan Lertora:
Other questions or comments? Male Speaker:
Yeah. No, a comment. One problem we can come to diffuse and get all ADRs. When this meeting
is focused on a very serious one that does call for research, you know, type of investment.
One thing about these forms that we are very involved with, is that they can be used to
calculate causality scores, severity scores, to put these things in context, including
— you can include what we call a completant [spelled phonetically] score, which basically
you have enough data to decide are the cases too confusing to consider. Because when you
take all ADRs, a lot of them aren’t as clear cut as the ones that get presented at these
meetings. They’re a mess. We have patients that are taking 25 drugs, so not much you
can do with that. So, these types of scores can be built into these systems and you can
give an output to the person who puts it in. It can even include a recommendation like,
“do HLA typing” or something like that. But we have been unsuccessful in getting people
to actually submit things to us through these types of computerized systems. Female Speaker:
I would just like to raise a question, a challenge for us is polypharmacy. You know, on average,
patients are leaving the hospital with eight different medications. So it really makes
the association very complicated, and I think there are some areas here for research and
how to approach that difficult problem. Teri Manolio:
Maybe just to change the topic a bit, Cynthia, you commented when you presented that educating
your clinicians was a key part of the effectiveness of your initiative and that the way you did
that was through a letter to them, pre and post. And I just can’t imagine that our
physicians would pay attention to a single letter. So there was probably more than that
— Cynthia Sung:
That’s — no. Yes, that’s right. I mean, it was really that the director of medical
services said this is now standard of care. That’s what made the difference. We had
— in 2009, we came out with a newsletter which summarized what was going on in the
research validating, you know, reporting the 1502, and there was no change at all in the
carbamazepine SJS. So it was really convincing at the ministry of health level, and telling
people this is now your, basically like your clinical practice guideline, and I think we’ve
been feeling more and more that it’s really getting these kinds of recommendations into
the clinical practice guidelines that are really the way to go. No, they don’t listen
to — they don’t read drug labels. Teri Manolio:
And in terms of clinical practice guidelines, we’re fortunate, I think, to have the Clinical
Pharmacogenomics Implementation Consortium, or CPIC, that is developing guidelines, but
they’re not a professional society, and so what you’d like is a professional society
to say, you know, this is our standard of care, and we heard yesterday that one of the
challenges with carbamazepine is that there are multiple specialties that prescribe it,
so you don’t have a single specialty, but is there some way to unify those or approach
at least the major ones. I mean, I think you identified, you know, several that are likely
to be prescribing this and maybe kind of target them that way. Cynthia Sung:
Well, yes, one of the HSA staff, you know, presented at the Singapore Epilepsy Society.
So even here today, there’s no neurologist, right, in this meeting, so — unless I’m
wrong– Teri Manolio:
Not around the table. We do have neurology colleagues from Neurology Institute. Cynthia Sung:
Oh, okay, yes. But I think we need to reach out to the disciplines that are actually prescribing
the drugs. That’s where they’ll influence the decision whether or not to do the test. Elizabeth Phillips:
In Taiwan, one of the initial interventions that helped was actually targeting off-label
use of carbamazepine. Is off-label use a problem in Singapore? Because I guess that also speaks
to the issue of the cohesiveness of the providers you’d be speaking to in terms of how to
prescribe carbamazepine and the constituency groups that would be involved. Cynthia Sung:
Yeah, I’m not familiar enough. I do know it’s used by dentist a fair amount, but,
you know– but I think that’s in the label, neuralgia. Yeah so, as far as inappropriate
use, this came up yesterday with allopurinol, that a lot of the cases we see is just being
used for asymptomatic hyperuricemia, and that is not in the indication, but uric acid is
standardly measured in these health screens and then when it’s just a little bit bumped
people start getting, taking allopurinol, and I think if we eliminated that population,
we could get, even without genotyping, we could get some impact on the cases. Lars French:
I have just one comment. Mr. Leeder, I liked your presentation a lot and think one challenge
is definitely getting as many patients into these documentation systems, but another is
harmonizing the system so we’re using all the same and guaranteeing the quality of the
data. And your comment on rash, which is, for dermatologists, really a problem and getting
that sorted out and your comment on phenotyping, good phenotyping, is really something that
I think is important because those like Munir or others who are doing genotyping experiments
afterwards, I mean, if they want clean results, they have to be sure that the phenotypes are
correct in these systems, and that’s a challenge. Teri Manolio:
I should just mention that Dr. French has just joined us for our second day. We very
much appreciate you coming from Geneva. Welcome. Male speaker
So maybe two or three random thoughts. In terms of
support — Teri Manolio:
Can you step closer to the mic? Male Speaker:
Oh, sorry. In terms of support for these kinds of projects, national registries and work
thereof, remember PCORI, the Patient Centered Outcome Research Institute. This could be
a really interesting project for them. And then thinking about patient-centered kinds
of programs, I think yesterday it was mentioned, the idea of social media and engaging patients
through programs like PatientsLikeMe and other social media programs. You’ve already heard
how important this is to actual patients and patient’s families. Homegrown grassroots
registries could be potentially much more powerful than top down approaches as much
as we think we know about this problem. The last comment, a little bit different than
the first two, we’ve heard a lot about, over the course of the last day, what’s
the offending drug. There are polypharmacy chart reviews that take hours and hours to
try to figure all of this out, and then I’ve also heard, I think Terry [spelled phonetically]
mentioned yesterday, that maybe there’s this common pathway that we should be thinking
much more about. And with, again sequencing of HLA, which again is possible and will become
better and better, maybe we don’t need to worry so much about what the offending agent
is. We should be thinking about HLA essentially as the main offender genetically. And as many
of you know, there are various kinds of statistical tests, burden tests, aggregate tests that
might be very useful in essentially determining overall what is the role of fine variation
in HLA with regard to Steven Johnson Syndrome, really irrespective of the offending agent. Juan Lertora:
Thank you. Marc, you have another? Marc Williams:
Yes, this is just in response to Terry’s questions about guidelines, one clarification
and then a comment. The CPIC guidelines presume that you have the genomic information in hand
and provide guidelines about what to do with the information. They don’t actually provide
guidelines about who to test and who not to test. So that is of some relevance in a situation
where we’re really talking about should we test or not test. The second thing is again
in my role as what blanket over the last two days [laughs]. I would just once again point
out that, at least in the United States, there’s been a fair amount of scholarship that shows
that creating a clinical guideline does not in fact rapidly change practice, unfortunately.
Some of it is because the guidelines are frequently constructed in such a way that they’re not
adequately explicit. They would say things like, “should consider” or make what we
would refer to in the informatics world as weasel words, and so it really gives clinicians
a lot of latitude. But again, the role the guidelines can play is that you can then use
those to develop clinical decisions support that can really work well. The last point
I would just make is one more lever to push, button to push, particularly related to severe
adverse drug events, is the liability point particularly in the United States, although
it sounds like this is an issue in other countries as well. Hospital leaders don’t like to
hear about the fact that hey we’re exposing ourselves to liability because we’re not
doing something to prevent these sorts of things. So if you’re like me where you’ll
use any tool in the toolbox to get what you want, you know, this is just another weapon
to add. Male Speaker:
Thank you. I just want to add that professional guidelines really [unintelligible] because
when you–the American society of professional, like American Society of Rheumatology, when
they update the gout treatment guideline to suggest there should be [unintelligible] testing
in Asians or in Thai. It was published and then you have a PDF downloadable all over
the world and our commission read it. So when they talk with the head of Rheumatologists
in Thailand, they concern about that recommendation, because it was published in your guideline.
Yes, so and also, the FDA recommendation here is also used in the other part of the world.
So if you have a recommendation update in the FDA or the professional guideline, I think
it has a worldwide effect. [laughter] Cynthia Sung:
Yeah, but I would say that we struggle with this, because, like for abacavir, it’s almost
absent. 5701 is almost absent, so it’s not cost effective at all in Asia. So, you know,
to just follow, you know — just follow what is coming out of the U.S. is not always the
right thing. And, we are struggling with allopurinol because of the limited alternative medications.
If you are 5801, there really aren’t a lot of other choices. So, I think we’re thinking
more along the lines of increase safety monitoring rather than changing the drug. Teri Manolio:
So I am a little bit curious, though, in terms of the 5701 that is not at all prevalent in
Singapore. Do you have abacavir hypersensitivity? Cynthia Sung:
Very little, but we also have very little HIV. Male Speaker:
Ok yeah, so you don’t use those — Cynthia Sung:
Because for anyone whose coming to the country to work, you have to take an HIV test, and
you don’t get your entry pass if your positive. [laughter] Male Speaker:
But we have abacavir testing in Thailand, and this is standard recommendation. And partly
it’s because professional guideline recommends to test before you use abacavir. Juan Lertora:
So we will conclude, then, this general discussion, and as Teri mentioned earlier, there will
be a group picture taken, a group photograph. Thank you very much, everyone. Teri Manolio:
Before you go — thank you very much, Juan. And before we go to break, we are supposed
to gather in that back corner there, and the more quickly we can do that and — effectively,
the easier we can get on to break, so please do that. Thanks. [end of transcript]

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