Cynthia Sung: Good morning, and thank you to Teri, Carolyn,
and Jennifer, and the rest of the group that organized this very interesting and stimulating
workshop.
So I will share with you the experience in Singapore from the Singapore Health Sciences
Authority.
Okay, just to get oriented, Singapore is a tropical country located just one degree north
of the Equator, and our nearby neighbors are Malaysia and Indonesia.
A little further afield is Thailand and quite a bit to the north and east is Taiwan and
even further north and east is Japan.
I’m sorry.
Okay, so it's a very small country, 26 miles wide and 17 miles north-south in this island,
and just for some perspective, it's only slightly larger than the area encircled by the Washington
Beltway.
So we have some advantages of being a very compact country.
Okay, so there are 5.5 million people in the country; about 70 percent are citizens and
permanent residents, and the ethnic composition of that group is three quarters Chinese ancestry,
13.3 percent Malays, and 9.1 percent Indians, and then a small percentage of others.
Oh, sorry.
So one thing I did want to mention is that it does not have a national health insurance
system.
There's mandatory deduction from wages to medical savings plans that you can use for
large hospital expenditures.
There's a system of polyclinics which are subsidized by the government, but most of
the primary care is taken care of through private GP clinics -- private GP practices.
So the population is very sensitive to cost of medical procedures.
So the Health Sciences Authority is a relatively new governmental organization.
It's only 14 years old.
And it consists of three major groups: the Health Products Regulation Group, which has
a function very similar to FDA; CDER; CBER; and CDRH.
And it's primarily organized by premarket and postmarket, not by clinical discipline,
and there are about 300 people who work in that part of the organization.
They also run the national blood bank.
And then they have an applied sciences group which does all the forensics and some of the
drug quality testing.
Okay, so I'm affiliated with the vigilance program.
And so HSA, like most drug regulatory authorities, collects cases of adverse drug reactions.
It's a voluntary system.
And if we organize it by system organ class, skin and appendages disorders is the largest
class, with about 50 percent coming in under that category.
And from about 2009 to 2012, about 80 to 100 cases of SJS/TEN were in that -- were received
by HSA per year, about 100 per year.
So in 2008, we launched a pharmacogenetics initiative.
I think I mentioned yesterday that the -- whoops, sorry, how do I go back?
That the chairman of the Health Sciences Authority was also Director of the Genome Institute,
and he urged us to move in that direction of trying to figure out how we could use the
advances in knowledge in genomics toward regulatory science.
And so really, we had first some simple objectives to build some in-house expertise in pharmacogenetics,
establish collaborative networks with healthcare professionals and research institutes, and
build some infrastructure to collect and store DNA samples and the associated phenotype data
or clinical data of patients experiencing ADRs, and also to collect drug-tolerant controls.
And the ultimate goal was to be able to update drug package inserts and make recommendations
to health care professionals based on local data.
So we started out first, setting up clinical sites at the two major hospitals: the National
University Hospital, and Singapore General Hospital in 2009.
And we worked with the dermatology departments, because we were mostly interested in the high
number of SJS-TEN cases.
And then we also were collaborating with neurology departments because we needed to collect the
drug-tolerant controls for the anti-epileptic drugs that seemed to comprise a large number
of the SJS/TEN cases.
And more recently, we've added two other sites: Changi General Hospital and also the National
Skin Center.
So altogether, we have four sites, and recently we also expanded and are now collecting DRESS
cases.
So we have now, after five years, 59 cases.
Antiepileptics is the largest category.
We have antibiotics.
We have seven allopurinol cases and then a smattering of other things, and in that other
things, we -- includes two cases of strontium ranelate.
So -- okay, so we collected 13 carbamazepine cases and 26 drug-matched controls.
These were patients who had been on carbamazepine for at least three months with no reaction.
And all 13 of our cases were 1502 positive, and whereas only three of 26 were HLA-positive
in our controls.
So we were able to validate the finding from the Taiwan group that this was a very significant
association in our local population.
In the 13 cases were three Malay -- people of Malay ancestry.
Okay, so while the collection was going on, we were also concerned about the cost of screening
all patients who would be going onto anti-epileptics, and trying to understand what would be the
economic burden of requiring that.
So we worked with Duke-NUS, the Health Systems Services Group, and they helped us to develop
a cost-effectiveness model.
Our population was newly diagnosed adult epilepsy patients, for whom carbamazepine or phenytoin
were considered appropriate treatment.
And we looked at three different strategies: just the status quo, which is give it when
you need it and deal with SJS-TEN as it occurs.
Genotype and then prescribe carbamazepine or phenytoin only to those who tested negative,
and then give valproate or some alternative for those who test positive.
And then the third one was to just to start avoiding carbamazepine altogether.
Actually, we'd been hearing from a lot of neurologists that that's what they were doing,
because they'd heard about the association, and then in that case just go to some other
alternative drugs.
So just to show you the prevalence of HLA-1502 in the different ethnic groups in Singapore,
it's present in about one in eight to 10 Chinese.
It's very common in Malays, one in five.
Much less common in Singapore Indians, and then from other global databases, we found
that it's probably about one in 500 in Caucasians and less than one in 1,000 in Japanese.
So it's certainly not a pan-Asian marker.
So we developed a decision-tree analysis, and we used a common metric, which is the
incremental cost-effectiveness ratio.
And a commonly accepted cost-effectiveness threshold is, if you have to spend $50,000
US or less to achieve one quality-adjusted life-year, then that's considered cost-effective.
So if we use an ethnicity-weighted approach to the Singapore population, it came out to
$30,000.
So, overall it was cost-effective.
But if you drill down a little bit deeper into the different ethnic groups, you see
that it is cost effective for Chinese and Malays, not so much for Indians.
So with the cost-effectiveness findings and the strong odds ratio in the case control
collection, we thought we needed to update the drug label.
But before doing that, we held a consultation session with clinicians.
And we told them that we wanted to go out with something very strong in the label, and
we got a lot of resistance.
And they said that "Well, you know, the test costs $300 US and it takes a week to get it
back, and that's just too much money, and we need to know the answer faster."
So we had a lot of discussion about how to deal with this issue.
And we came to the conclusion we needed to have a centralized testing facility so that
we could get economies of scale, and the through-put so that we could turn around the samples faster.
And the director of the National University Hospital Molecular Diagnostic Center offered
to screen various formats for this test and validate one, and become the centralized facility.
So she was able to get the cost down to under, like, about $170 US and turnaround time two
to four days.
We were happy with that, too, because at the time, the only place where you could get this
test was at the Bloodbank, which they do for, you know, tissue typing.
And so we felt a little uncomfortable saying, you know, “We're going to mandate a test,
but you've got to come to us."
So anyway, we -- just to quickly, then, go through -- this was what we came up with,
our final recommendation: The Ministry of Health came in and said, "this is now standard
of care."
HSA changed the package insert to highly recommend testing.
We stayed away from the mandated, but we did have some caveats.
It's not required in patients who've been taking carbamazepine for more than three months.
We said it shouldn't be prescribed before knowing the results.
That you should not use phenytoin either, if you're positive.
And then we had some other caveats that you should still maintain appropriate clinical
vigilance.
And we've had about 200 tests per quarter.
The rate's been pretty constant over the last year and so.
And since making testing standard of care we haven't had any cases, whereas before we
had on average 15 cases a year of carbamazepine SJS-TEN.
So just as my last slide, we learned through this it was really important to engage the
clinicians especially and that we needed to really focus on lowering costs and turnaround
time.
And that we needed the cost-effective analysis to help the Ministry of Health come in with
-- actually, they came in with a 75 percent subsidy for low-income patients, and that
really helped cushion the effect of our recommendation.
So these are the people involved.
Thank you.
Juan Lertora: Thank you very much.
[applause]
We have a couple of minutes for questions and discussion.
Elizabeth Phillips: I was just wondering about B*1502 and screening,
and the issue of if it's pretty clear in Southeast Asian populations, that if SJS-TEN does occur,
it's going to occur in a B75 serotype that's not 1502 in a screening type situation.
So I was wondering I guess, first question is if you've got any information about the
B75 serotypes other than B*1502, and whether it might be a cost-effective approach just
to actually identify B15.
Given that most of the B15 in Southeast Asian populations will be the B75 serotypes, and
just to encapsulate all the risk alleles, even though there's only a very small risk
I guess of having B15 -- B75 serotypes outside of B*1502, there still is a risk.
Cynthia Sung: Well, so we know that there's in the Malay
population, I think it's 1511 or 1513, I'm not quite -- I can't remember -- that's actually
quite high, so that -- and I don't think that that's associated with SJS, so we did need
to go to 1502, to four-digit resolution.
Does that -- I'm not an immunologist, so I don't know if that answers the question?
Elizabeth Phillips: Yeah, I mean, I'm just wondering if there's
a way of designing an assay like, you know, even an SSLP or molecular assay that sort
of defines the risk without actually sort of screening test.
I guess similar to what we did for 5701, where we actually defined sort of, you know, in
the unlikely setting that there were rare alleles that came up that were very similar
to 5701, that might be risk alleles, that you'd still be defining that area at risk.
And I'm not --
Cynthia Sung: I --
Elizabeth Phillips: -- sure if that's being done for 1502 or B75.
I know in other populations and, you know, Wen-Hung and Shuen-lu, you've had certainly
a number of patients who've had B*1521, which is another risk allele.
Male Speaker: In Taiwan, we must have hospitals do the easier
way.
We just took the B*1502 because there will be a ton.
It's quicker than to look at all the actual B genotype.
But some hospitals can provide all the actual B [unintelligible] instead of actual B*1502,
so if we -- some hospitals have more information about all the actual B genotype.
We find some patients with B75 alleles, such as B*1511, B*1558, then we will also recommend
should be careful.
And we recommend them to choose another antiepileptic drug.
Male Speaker: But it's not just -- not available for most
of the hospitals, about 10 percent.
Teri Manolio: Could you use your microphone?
Elizabeth Phillips: -- with deep sequencing techniques, now, some
of the alleles that were previously called B*1502, for instance on Sanger sequencing
actually will be re-called B*1521 anyway, so I just wonder if there's any data of how
much of -- I would assume we're encapsulating most of the risk population by screening for
B*1502?
But it's not the entire risk population, I guess is the issue, so you're not quite up
to the 100 percent negative predictive value, not including all of the B75 serotypes.
But it may be very population-specific I guess, so that's one consideration.
Juan Lertora: Thank you, Dr. Phillips.
That's a very relevant comment, but we need to go on, please, to the next presentation
on the Indonesia Experience.
And we have Dr. Rika Yuliwulandari, who is the head of the YARSI Research Institute at
YARSI University.
[end of transcript]