MR. STEPHENSON (HHS): This is the open session of the Drug Testing Advisory
Board and we are asking everyone to sign-in on one of the sheets at the side
table. We have a number of hand-outs and hope that each of you have taken
copies.
We were fortunate enough to be included in a briefing for General McCaffrey
(ONDCP) a week ago. He was extremely interested in the details of the Federal
drug-free workplace program and our Federal workplace experience over the last
decade. We were able to capture some salient facts for him and he wants us to
give him a detailed briefing within the next couple of weeks.
Yesterday, there was a kick-off session for national "Recovery" month. This is a
treatment focused initiative in which we are also participating, because this
year it is focused on the links to businesses and to employers. We are working
with the Center for Substance Abuse Treatment, and within SAMHSA, to develop a
national "Prevention" month for next year.
We also have an interesting thing that is happening associated with treatment
and testing. One of the phenomena that many of us knew had been developing was
a resurgence of heroin, and officially it was announced at the end of last
month that admissions for treatment in the United States had now tipped the
scales in favor of those being admitted for heroin addiction as opposed to
cocaine addiction.
Due to the work of the board and many of the folks in the industry we have
effectively refocused and sharpened our awareness of the heroin problem and
generated a much more effective testing scheme and revised our Federal
guidelines in that regard, and we also have some very interesting promises in
our alternative matrixes and alternative technologies that may help in this
regard.
This is not a static program. Every time you design a system and you think you
have everything laid out and you know how you're going to combat the issues of
the future, reality slaps you in the face.
The last update is that we have a new Federal agency as of 1 August next year.
It is the Federalized Resources Support Services and Defender Services for the
District of Columbia. We are having to establish a drug-free workplace program,
set up issues for access for testing, and a variety of other things. I mention
that because this is one of the links where we have been going for sometime,
building our bridges into the criminal justice system, and from a number of the
other national social agendas that are out there to better network across the
different systems, and the criminal justice area is one of those that is going
to become a principal performer in an upcoming meeting that Dr. Bush will talk
a little bit more about, which we are gaining a lot of experience and
background knowledge from what's been going on in the criminal justice system
regarding testing.
DR. VOGL (HHS): Just an update on our efforts to revise the Federal custody and
control form. At the table, there are copies of the latest draft that we have
available, and we're working with a printer who has volunteered to develop the
proofs for this effort. There will be some slight changes. The copy that I
handed out is something that I put together with a cut-and-paste approach, and
obviously a printer can do a better job in highlighting specific areas of the
form.
We have also prepared a draft Federal Register notice to go along with the form.
We are hoping to get that published sometime in October. There will be a 60-day
public comment period, and after that, we will begin developing the final form
and getting it approved by OMB prior to the expiration of the current form.
The major changes are as follows: going to a six-part form (eliminating the
split specimen copy), locating the specimen bottle labels on the bottom of copy
1, the chain of custody section has changed in that only one collector
signature is required to document the receipt of the specimen, increased the
number of choices for the laboratory to report results to reflect the changes
that were made in our adulteration and dilution testing policy over the last
year, the split specimen result will be reported on copy 1 if the split
specimen is tested, and the MRO determination for both specimens will be
reported on copy 2.
In our Federal Register notice we are suggesting that the printer or user of the
form can print it by highlighting certain collector/donor data entry fields,
and they can use different colors for highlighting these fields, but they must
ensure that it will not prevent making a clear photocopy when copies need to be
made.
For the donor's social security number it could be a line, combs, or boxes where
again we would allow that sort of flexibility. Some users may elect to use
scanners for reading in the social security numbers, so they would have the
choice there. The location of the information at the top of the CCF is
flexible, although it does need to have the title "Federal Custody and Control
Form" at the top. The OMB number must appear in the right-hand corner, but it
can be vertical or horizontal. The name and address of the lab needs to be
there with the specimen ID number, the lab accession number, and any other
information that the user may wish to put on the form. There are third party
administrators that also provide forms and they may want to have some
information at the top. There is no restriction as to font size for that
information.
Step 1 is essentially the same as the current form. The major difference is that
we moved the collector address and information up from step 5 and it puts all
of the addresses and names in that top part of the form.
Step 2 is revised slightly, but the collector still marks if the temperature of
the specimen is within the range or, if not, to put a remark below. The
collector indicates whether it's a single or split specimen collection, if no
specimen is collected, to check the none provided box, and put a remark below,
and also if there is in fact an observed collection, to make it easy to show it
is clearly an observed collection.
Step 3 is the same. The collector seals the bottle, the donor initials the seal,
and the donor signs step 5 on copy 3, which is the MRO copy.
Step 4, the chain of custody section, is quite different from the current form.
The statement that the collector signs would cover the process from basically
receiving the specimen from the donor until preparing the specimen for transfer
to the lab and placing it in the tamper-evident leak-proof bag, and then would
simply sign this form, indicate the name of the transfer service, and put it
along with the specimen bottles in the tamper-evident leak-proof bag.
When the shipping container/package is received by the lab, the accessioning
person simply opens the bag or shipping container, gains access back to the
form and the bottles, checks the condition of the primary specimen bottle seal,
marks whether it is or is not intact, signs the CCF, and releases the specimen
to either temporary storage or to another individual. At that point, internal
chain-of-custody documents track the handling of the specimen bottles.
Step 5a is where the primary lab records the result on Bottle A. We have
included additional choices (i.e., adulterated, substituted, invalid result,
rejected for testing). We are trying to reflect what, in fact, has happened to
this specimen or how it is being reported, rather than using Test Not Performed
to accommodate all of these other possible ways to report the results. If the
testing lab happens to be different from the name of the lab at the top, they
put that information there, along with the certifying scientist’s signature,
printed name, and date.
If it is positive and the split is tested, Step 5b is used by Laboratory B to
indicate its name and address, the test result, and the signature and printed
name of the certifying scientist.
Copy 2 is the second lab copy. Everything is the same except the space where the
labels appeared on Copy 1. This area is replaced with Steps 6 and 7 for
the MRO to record the determination for the primary and split specimens,
respectively.
Copy 3 is the same as copy 2 with one exception. Step 5a from copy 1 is replaced
with step 5, which is completed by the donor, and the donor signs the statement
attesting to the validity of that specimen, and provides additional
information. It's the same as on the current CCF, and that information goes
through to the other copies.
We are hoping these changes make the form easier to use. It will be clearer to
those using it how to complete all the information, and we are moving forward
with getting the Federal Register notice published in October.
At this time, the new form will be available beginning August 1, 2000; however,
old forms could be used for a specified period of time. We do not want anyone
to discard thousands of copies of forms. It's just not a very cost-effective
approach. There would be a date, perhaps, January 2001, after which the old
forms could no longer be used.
DR. CAPLAN (Board Member): Is it possible to introduce the new form before the
old form expires?
DR. VOGL: Not until OMB approves its use.
DR. CAPLAN: I mean, you could submit it earlier. It's almost done now.
MR. STEPHENSON: Is there any advantage to do that?
DR. CAPLAN: I think it would be an advantage to get the new form out at the
earliest possible date. That would benefit the industry.
DR. VOGL: I would feel comfortable sharing the final form with interested
parties once it has been submitted to OMB, but clearly warning everyone that it
cannot be used until it is officially approved.
DR. CAPLAN: After it is officially approved, at that time or before July 31,
could you start using the form, or does one have to end before the other one
starts?
DR. VOGL: It depends how they approve that.
DR. CAPLAN: This form is a substantial improvement and I'm sure we would want to
use it as soon as possible.
MR. STEPHENSON: We can expedite the internal HHS reviews and send it over to OMB
at the earliest opportunity. If it would materially improve the performance by
the industry and improve the reporting based on comments from the public and
the Board, we will certainly act on that.
DR. SAMPLE (Board Member): I just want to support Yale's comments and how the
use of this form would improve the overall collection process, reduce the
number of possibilities for omissions during the collection process, and really
expedite and improve the quality of the drug testing. Anything we can do to
expedite the introduction of the new form would be appreciated by the
laboratories, by the collection sites, by all the users of that form.
DR. BUSH (HHS): And, I am sure, by the employers who have to interact with the
collection sites and the laboratories.
MR. STEPHENSON: We agree completely and will do what we can. Remember, we are in
a bureaucracy, and bureaucracies have rules and time lines of their own, but we
can try our very best to try to expedite it.
DR. BUSH: Thanks for that encouragement. It gives us the energy and the backing
to move it forward.
MR. STEPHENSON: Donna, why don't you take over and set the agenda for the rest
of the day.
DR. BUSH: Okay, let's switch gears. Back to our review of alternative matrices
and technologies for drug testing. Let us reflect back to our June Drug Testing
Advisory Board meeting. At that time, presentations were made on hair, oral
fluids, and sweat testing by their industry coordinators. They had had working
group meetings prior to that June meeting and shared the information with the
Board.
We had a lot of discussion and it was time to update our factors grid, i.e., the
grid that summarizes the factors required for reliable workplace drug testing.
Our newest summary has a green cover and it is dated September 9. The first
thing behind the cover is the updated grid that reflects the activities of the
Board following the presentations made by the industries and subsequent
discussion by the Board members and technical representatives from the groups.
MR. STEPHENSON: One of the things we committed ourselves to a couple of years
ago was to make a court-reporter-level quality transcript of the public
proceedings, and in turn to get those up on the Web as early as possible as an
electronic document. Have any of the members of the public or members of the
board actually gone to the Web site or downloaded that information and looked
at it? So it is a useful tool for you. We had actually used that internally as
a cross-reference as Walt Vogl has put a lot of this together, so this is the
way we keep ourselves honest and historically accurate as we go forward, and if
it serves you well, we will continue that process over the next months.
DR. BUSH: All of this information is up on the Web, and that does enable us from
our transcript capability to expedite the process of updating this manual.
Following the grid is an update on the oral fluids section. We have continued
to include the on-site section. There's been discussion at the board, but we
will talk about some working group activities later this afternoon. I don't
want to take that out of sequence, but we have updated the sweat patch section
and the hair section with the discussions and with the bullets and content from
the working group meetings that we have been provided as well as what has
happened at the Drug Testing Advisory Board.
We will take a look at our agenda. We had sweat testing as the first group up
for further submissions, discussions, questions, profound answers, and Jim
Meeker will be speaking with us.
MR. MEEKER (PharmChem): Let me boot up my computer. Neil Fortner was supposed to
be here, but he was unable to attend. It seems like the discussion at the sweat
testing meeting wasn't going through the grid. It was just looking at these
views on the sweat-testing technology.
Various issues were discussed. One of the items that was presented, which was
talked about here previously, we were looking at the stability of the drugs on
the patch itself. A couple of studies have been performed since the last DTAB
meeting and looking at the stability of cocaine and codeine on the patch
itself.
One study involved cocaine. Duplicate patches were worn by individuals in the
lower abdomen area. They were side by side. The patches were removed back in
November and December of 1995, and again in December 1996. One set of patches
was done by PharmChem in 1996. The other set was frozen and recently sent to
PharmChem for analysis. Originally, 18 patches were positive for cocaine at or
above the cutoff. Upon reanalysis in August 1999, this year, all 18 of these
patches were positive, above the LOD. The LOD is 1 nanogram/ml.
Another specimen involved codeine in much smaller amounts. They were done with
patches. The patches were collected during October 1995 to January 1996. One
set of patches was analyzed by PharmChem in January 1996, the other set was
frozen until recently. Originally, five patches were positive for codeine at or
above the cutoff, which was 10 nanograms/mL. Upon reanalysis in August 1999,
four of the five patches were confirmed above the LOD for codeine, and the LOD
was 1 nanogram/ml. The specimen that did not confirm originally had a codeine
concentration just above the cutoff.
A current study we're doing addressing the stability issue also is kind of a
combination of addressing stability and is also part of a proficiency test that
we're involved with for an outside lab. We recently spiked patches, pads with
basically the five drugs and their metabolites at various concentrations. These
drugs were spiked on the patches in the artificial sweat matrix base solution.
The concentrations we spiked, including below cutoff concentrations, at the
cut-off, 25 percent above cutoff, and then various higher concentrations,
trying to mimic what we might normally see. We spiked a total of 25 patches in
quadruple, a total of 100 patches, four sets of 25. One of these sets is
currently being analyzed at PharmChem. A second set was sent to an outside lab
who is involved in doing drug analysis with a sweat patch as part of their
proficiency testing program. They had recently submitted the data back, and
we're evaluating the data, and the remaining two sets will be analyzed at
various intervals.
That is one thing that I wanted to bring up for the group here. We were going to
analyze these. I was thinking about analyzing these at 6-month and 1-year
intervals, but as the CV grid says, it should be a 60-day interval, if I'm not
mistaken. It was addressed on item G2 page 17 of the sweat-testing group, at
the very bottom.
DR. BUSH: If we want to take a minute here to review the information on page 17
of the sweat patch section. Do you want to open it to the Board, or open any
discussions about this?
DR. SAMPLE: I think in reviewing this, this doesn't really relate to testing at
60-day intervals. It related to the standard retest and storage-type time
frames that we currently have in place for traditional urine-based testing,
where they have up to 60 days to test the Bottle B initially, and then we have
to maintain under frozen storage for up to a year, a minimum of a year, and so
I think really what this is relating to is that you need to look at that in
that 60-day window, then also look 12-months out to assess stability.
MR. MEEKER: We have 30-day data already that was presented previously.
DR. SAMPLE: But only 30 days.
MR. MEEKER: Correct.
DR. SAMPLE: I think what we're looking for was to look at 60 days, and then also
look at 12 months.
MR. MEEKER: That is what we will do. By the next meeting we should have the
data. We currently are analyzing a batch now, then 60 days from now we will
analyze another batch, then after 12 months we'll analyze a third batch to get
stability data on that, so that will be available.
DR. SAMPLE: Is there an additional patch, then, that's less, since you set these
up in quadruple hits?
MR. MEEKER: We're doing an initial one. We already have 30-day data. We'll do a
60-day, then we'll do a 12-month.
DR. SAMPLE: So you do an initial, 30 day, 60 day, and 12-month?
MR. MEEKER: The 30-day data we already have previously.
DR. SAMPLE: So you have a fourth patch?
MR. MEEKER: Yes.
DR. CAPLAN: So you could do 60 days?
MR. MEEKER: We can do initial, 60 days, and 12 months, because the other, we
made four patches, but one of them was sent off with the PT.
DR. SAMPLE: So you've used all of your available patches?
MR. MEEKER: Yes.
DR. SAMPLE: Okay.
DR. MITCHELL (RTI): Jim, how are these being stored?
MR. MEEKER: They will be stored frozen.
MR. CROUCH (Board Member): How many cocaine samples were collected in '95, '96?
MR. MEEKER: 18.
DR. SAMPLE: You indicated they reconfirmed above the LOD, but then, looking at
the absolute numbers, did you see much degradation for the absolute numbers?
Were the absolute numbers relatively the same?
MR. MEEKER: The absolute numbers were variations. In some samples there was
little degradation, in some samples there was more, so there was really no
consistent pattern, other than to reconfirm.
DR. SAMPLE: What was the range of the percent differences before and after?
MR. MEEKER: I don't have that data with me but can provide it.
DR. MITCHELL: The 18 patches you're talking about, are these the ones that were
stored?
MR. MEEKER: No. These were actually the patch themselves. They were run as a
part of a project with the Nuclear Regulatory Commission, so they originally
just had the pad themselves, and the pads were submitted.
DR. MITCHELL: These are from donors, or individuals?
MR. MEEKER: These are from individuals given drugs. One of the other issues that
we discussed at the sweat testing group meeting was to look at designing
studies to determine the efficiency of the isopropyl wipe to remove potential
drugs from the skin.
Prior to applying the sweat patch to an individual, the area where the patch
would be applied was wiped with an isopropyl wipe. This was to remove any oil
compounds, to make sure the patch will adhere to the skin. We also looked at
the possibility of that isopropyl wipe removing potential drugs, dealing with
any drug contamination issues. We had performed a study in which we determined
the efficacy of the isopropyl wipe to remove externally applied drugs. This
design was ultimately a derivative of the sweat testing working group.
Basically, the study involved the application of drugs to the skin in a
methanol based solution. We applied the drugs to the skin with the methanol,
and it evaporated off with a hair air dryer.
The group felt that the use of the organic solvent solution was inappropriate,
because the solvent may alter or facilitate the drug transfer through the skin.
In determining the efficiency of the isopropyl wipes, I believe the initial
wipes, we determined we looked at 60 percent efficiency in removal of the drug
from the skin, but again, the fact that we used a methanol-based solvent, we
were not sure if we altered the potential to evaluate this data.
The group recommended the study group be redesigned to either apply drugs to the
skin in a solid powder dose form, some mechanism, or using a water sweat-based
form, by doing this better, to better mimic realistic conditions, and so a new
study is under current investigation to determine that.
Another area we're dealing with is again the argument we have dealing with
external contamination. The group discussed the issue regarding this and ways
to address this issue. One discussion involved whether the primary metabolite
should be required as a part of the analysis. It was felt that although the
present metabolite may be useful, the requirement that the metabolite be
present is inappropriate, and the present drugs had primary chemicals treated
in sweat.
Additionally, a review of data from various controlled-dose studies and actual
specimens revealed the metabolite is often not present above the LOD, and so I
think the use of metabolite, although it may offer some information, is not
appropriate.
A second discussion was whether or not the isopropyl wipe should be saved for
subsequent analysis to determine if the drug was present on the skin prior to
the patch being applied. The group felt that the requirement would be
inappropriate for several reasons. One, if a person recently used drugs within
the last 1 or 2 days the drugs would still be excreted in the sweat, and you
would expect the drugs would be found on the isopropyl wipe in that regard, and
secondly, if a person wanted to claim external contamination and was aware of
this, they could simply apply the drug on their own skin and beat the test. And
so, if we had this requirement, basically we're allowing a way that the person
could actually use the drug to adulterate the test, so the use of the isopropyl
wipe we felt was inappropriate as a mechanism of determining external
contamination.
The second-to-last item, PharmChem presented data in which we did a permeability
study in which we looked at cocaine and methamphetamine in water based
solutions. They were applied to the outside of patches. We ran these in
triplicate. Patches were placed on a glass plate. On the outside of the
patches, methamphetamine and cocaine in concentration amounts of 1 microgram
and 1 milligram were placed on the outside of these solutions. 100 microliters
of liquid was applied. The solutions were left on the patches overnight. The
patches were then subsequently removed and analyzed, and all patches with drugs
applied were negative, and so this study showed that patches were not permeable
to the methamphetamine and cocaine in a water based solution.
The group suggested that a second study should be performed on the patches that
had been worn by individuals for a week. This would address the integrity and
permeability of patches throughout the wear period, so this is subsequent, and
we were going to perform this as well.
DR. CAPLAN: What drugs did you use?
MR. MEEKER: This was cocaine and methamphetamine.
DR. CAPLAN: Applied in an aqueous solution?
MR. MEEKER: Yes.
DR. CAPLAN: How much? How did you set up the patch?
MR. MEEKER: The patches were applied, 100 microliters of the solution was
applied to the patch to get down to 1 milligram.
DR. CAPLAN: Applied to the top of a patch?
MR. MEEKER: Yes.
DR. CAPLAN: And the patch was worn --
MR. MEEKER: These patches were on a glass plate, and we just applied the 100
microliters of the respective solution to get 1 milligram, then 1 microgram.
These were in triplicate. The group recommended that we do a second study in
which an individual would wear the patch for a week, and then apply the drugs
to the outside of the patch. And I will supply this information to the DTAB.
DR. BUSH: There are a couple of questions here about that last study design that
you mentioned, where someone would wear the patch for a week and then have the
solution applied, 100 microliters, or small volume of a solution, and then
again you would use sufficient solution to get a 1 milligram or 1 microgram
concentration on the outside. Would that person still be wearing the patch when
you do that?
MR. MEEKER: I think in this regard we're going to have to make sure they're
wearing it, because if we take the patch off, you break the integrity of the
external seal over the patch, so somehow we're going to have to apply
it -- part of the design, that will be applied to the outside of the
patch, and they will wear the patch the rest of the day, then go ahead and
remove the patch. I can't see any other way. Once we take the patch off the arm
you destroy the integrity.
DR. BUSH: I'm sure you will take a look at how gravity, and a solution on
somebody with a patch who is wearing it maybe on a vertical surface –
MR. MEEKER: Yes. Eventually we will have to do that.
DR. BUSH: -- to make sure the drug stays there. That was part of the
discussion.
DR. ISENSCHMID (Board Member): Why would you limit that to such a low aqueous
volume?
MR. MEEKER: It's easier to handle when you're dealing with low volume, so if you
apply something like a milliliter over a patch, you've got a smaller area with
a chance of it going off the side of the patch, and that's one of the concerns
you have to have. Secondly, if we're looking at real-life situations, I really
can't envision where a milliliter of something with a solution is going to come
in contact with a patch, so even though we're trying to get high concentrates
to address this issue in a real-life scenario, I'm not sure where a person
would come in contact with a milliliter of a 1-gram-based solution.
And then finally, the last item that was not necessarily discussed but was
presented, was that we provided the board members -- we put together a
bunch of scientific articles, did a literature search and scientific
presentations dealing with issues of testing drugs in sweat, and also just
issues relative to articles and presentations of the sweat patch themselves.
Donna Bush had a copy of these articles that were presented and we are
continually updating the scientific articles. This is just a package here, if
anyone wants to take a look at some of them that were presented.
And so one of the interesting things in tracking these articles down, and doing
one of the articles -- I don't have the original article, but the first
article I came across that deals with testing for drugs in sweat was published
in 1911. I'm not sure how reliable that is by today's standards, but it's
interesting that it goes back that far.
That's all I have.
DR. BUSH: This is the stack of articles that Jim has provided to us. It is quite
a review. Jim assures us that he will continue with the review of the
literature and try to compose and construct the most comprehensive bibliography
so that we can all stay informed as well as keep track of court cases where
issues come up that may be necessary for us to consider and evaluate always.
It's very interesting, these issues always come up in cases. I need to say that
I'm very cognizant of copyright concerns. These are peer-reviewed scientific
articles that are from specific journals who have copyright protections on
their documents. In the context of our evaluation of these technologies I can
call these journals, but when I copy these, it is for our specific working use
with an evaluation of the data presented, and I don't photocopy things as
freely as I once did because of copyright protections, but I can and will
provide you with copies of these, should you wish.
MR. STEPHENSON: We can provide the bibliography itself.
MR. MEEKER: We have that together now, and I could supply you with a list of the
bibliography.
MR. STEPHENSON: If you could provide it to us electronically, then we can go
ahead and put that up on our Web site.
DR. BUSH: Thank you for your presentation, Jim, and I wonder if for consistency
and for our ease of assimilating this information and our completeness for the
process, I wonder if we should go to the sweat section of the grid and go back
page by page through this and let's address your presentation and where we are,
where it possibly applies in each section, and just go through this, the
page-turning exercise to assure where we are with you in this process.
MR. STEPHENSON: We're going to copyright Aaron Jacobs' comment of go to the p's
and turn the page, and if we don't say it quickly enough, then it's your job to
prompt us.
DR. BUSH: This is really important for us as we go through updating this grid
for every meeting. This is a lot of work, and we want to make sure it's done
right. I guess collection site, page 1 of the sweat patch section, collection
site, we have no issues.
Page 2. It appears we've addressed all the issues. We can turn that page.
Page 3, with the collector, we've changed it to yes, and we can turn the page.
MR. STEPHENSON: Have you found a page where you would like to make a
recommendation?
MR. MEEKER: Page 17. G17 was one we addressed, and we will have data on the
60-day stability study we're doing now.
DR. BUSH: This is good. We have your comments, and the notes.
MR. STEPHENSON: The next one.
MR. MEEKER: The next page that I have marked would be 29.
DR. BUSH: Wait a minute.
MR. STEPHENSON: You want to take 29?
MR. MEEKER: 29 and 30. In a previous meeting we mentioned we were in the process
of implementing PT samples and that's what I mentioned previously. We prepared
25 of these pads, submitted to an outside lab with requirements, here's how
these samples are to be tested.
I believe five of the samples were directed -- they were below cutoff
concentrations. They will go directly to GC/MS. The labs submitted the data
back to us. We required them to not only submit the results, but on the initial
performance we wanted them to submit all chain of custody and GC/MS data as
well. That way, we would review their GC/MS procedures and how they present the
data.
So that's currently being evaluated right now, that kind of addresses these
issues, and the ability to perform certification of PT samples. That's
currently what we're doing at an outside lab. It doesn't change anything here.
DR. BUSH: It's just a status update. Thank you.
MR. MEEKER: The only other section on the grid, that would be page 37 for the
MRO interpreted results. Again, this is where we provided scientific data,
bibliography, and performing additional studies to try and gather information
that would be better used by an MRO for evaluation of the results.
MR. STEPHENSON: In your parallel environment dealing with the corrections
industry, the folks in U.S. Probation and Parole Service, is there any medical
review performed, or have there been any interesting anecdotal cases come up in
which there has been an alternative medical explanation that would have fallen
outside of where you would have expected to see something, or a challenge to
try and explain the results you see? I don't want a case number or anything.
MR. MEEKER: I think the main issues that you see with the sweat test and excuses
or explanations for positives are really not a lot different than you see with
other matrices. I was with someone else who was using the drug, or past
exposure, or internal contamination are issues that we are trying to address.
One of the interesting things is, probation, they say, well -- I've heard
some arguments, well, I was in a room where people were smoking crack. First of
all, I don't think that is a reasonable explanation to have a positive, but the
second thing is, the Federal probation and parole, if you're around people
using drugs, you're in violation of your parole, so the issue of why you're in
a crack house first needs to be addressed.
MR. STEPHENSON: It is guilt by association, isn't it?
MR. MEEKER: Actually, it violates their probation in that regard, so the issues
I think are similar to those you see with other matrices, contamination, past
exposure.
DR. CAPLAN: Can you maybe update us -- and this is kind of a general
question which is unrelated to the grid, but questions about some court
controversies, and your input on them, that seemed to be occurring recently in
the area of sweat patch testing.
We don't have a lot of data. We don't know whether they're substantive or not,
but there has been some concern on some people's parts about it.
MR. MEEKER: One of the areas that -- there's another expert out there
saying that the patches are permeable to drugs, but they perform
studies -- there was the issue of the removal of drugs from the skin by
the isopropyl wipe. Those are the areas that seem to be being brought up.
It hasn't been brought up in court yet, but it's just, our expert's going to say
this in a case, and so the applicability to those arguments in court are what
we are basing the permeability issue. Again, I don't necessarily think that is
a problem.
The three studies we've done so far show it's not going to be a problem. I
reviewed some information from the other experts on their studies where they
show it's permeable, and their study design involved putting the patches in a
Petri dish and then applying drugs to the outside of these patches in two
separate solutions, one with a pH 8.5 buffer solution, and the other one was a
sweat-based pH 4.6 solution.
The abstract I reviewed showed that the pH, the sweat-based solution, there was
no evidence of the drug being present on the patch, on the pad itself, and the
pH 8.4, they said that that got through the patch, and I'm not sure whether
they applied 10 micrograms or 10 milligrams to the outside of the patch, and on
cocaine they said they found 1700 nanograms on one of the patches.
I don't have the complete data to verify, number 1, the reliability of that.
Obviously there's a problem with the study design as well, involving Petri
dishes being used, and from a common-sense point of view I'm not aware of any
likely scenario where someone was going to come in contact with 10 micrograms
or 10 milligrams of cocaine in a pH 8.5 buffered solution, and so it's
applicability to a real life scenario to me is somewhat minimal.
The article's issues of external contamination, there have been several articles
where people have looked at doing wipes, forehead wipes on individuals, and
what concentration of drugs they found on individuals, trying to differentiate
passive exposure versus active use.
If you read these articles they're somewhat contradictory in themselves, but one
of the articles talks about, if you found 15 nanograms on skin, then that would
be indicative of active use, versus an exposure, and again, those contradict
each other in different articles.
The interest of that, what I find in that article, number 1, that was on a
forehead wipe, and you do it on an 8-square-centimeter area. That's about 4-1/2
times the area that you use on the patch, and the patch cutoff concentration
for cocaine is 10 nanograms per mL.
You multiply that by 2-1/2 mL base solution, that's 25 nanograms total, and so
by their criteria 15 nanograms on 8 square centimeter area, and a patch that
would indicate that the patch would have come from active use.
The issues that are being brought up, I think the scientific literature is
actually more supportive of the use of the patch than this external
contamination.
DR. CAPLAN: In the original studies, this goes back, I guess, were there some
studies that were done by the original manufacturer on permeability?
MR. MEEKER: I'm trying to locate it. I haven't found whether these were done by
3M or Sudormed. I don't have the original permeability study. I tried to locate
those. I can't get a hold of them yet. If they're out there, I'm not sure where
they're at.
DR. CAPLAN: I guess that wasn't part of their FDA submission.
MR. MEEKER: In volume 1 and volume 2, I didn't find those studies in there. If
you guys have copies of those, whether they were performed somewhere else, I'm
not sure.
DR. CAPLAN: I guess it's 3M that makes the tape.
MR. MEEKER: Yes, 3M makes the outside of the adhesive.
DR. CAPLAN: They must have some information about the permeability.
MR. MEEKER: There's information about the patch only allows small molecules such
as water to go out and nothing to come in. The exact studies that were
performed I don't have. I will continue to see if I can locate them. --
MR. STEPHENSON: Do you anticipate the need for any further working group
meetings to further develop this, and if so, when?
MR. MEEKER: I would imagine there should be the need to have another meeting
somewhere down the line. I'm not sure when, and we could coordinate it. I guess
the next meeting is not going to be addressing this issue.
DR. BUSH: Well, our next meeting will be at the beginning of December, and we're
always open to a discussion of anything that you have.
MR. MEEKER: I definitely think it would be worthwhile to have another working
group meeting, I think as soon as we perform more studies and have more data. I
thought the last meeting was very useful. We had some data, and they came back
and said, we think you need to alter this type of study design, and so we think
that would work well.
MR. STEPHENSON: Well, the idea here is that if we can, we need a little lead
time in order to pull together a meeting and to help you, and so just give us a
couple of months heads-up on when you want to have the next meeting.
MR. MEEKER: Okay.
DR. BUSH: Any other questions while Jim is here and at the table with us? We're
okay? I'm not seeing any burning issues arising, so thank you, Jim, for your
presentation today.
MR. STEPHENSON: We seem to have a roomful of people and the agenda is not coming
together as cleanly as it should. We have presentations scheduled for oral
fluids, and that's supposed to happen at 10:30. We've already completed our
sweat testing presentation. Unfortunately, one of the members of that
presentation team has been very sick, so he isn't here, and we ran a little
shorter than we would have anticipated, too. What I'm going to suggest is that,
as we do each and every time we have one of these meetings, there's always an
opportunity for public comments and if any members of the public wish to
address us, we will make time available for those comments to be put forward,
or if there are any general questions the public has on the issues to date that
they would like to raise, we can do that for a few minutes. We will do this in
kind of a flexible format, because as soon as we do get our representative here
from the oral fluids group we will go ahead and do that presentation.
Are there any public comments that any members of the public would like to make
at this time? (No response.)
Are there any general questions? (No response.)
DR. BUSH: Let's take the item we had planned for 1:00 this afternoon, on-site
and laboratory-based urine drug testing, and where we were going with this in
terms of working groups, and we'll turn it over to Yale for a minute.
DR. CAPLAN: We want to tell you what the plan is. When this started several
years ago, there was an earlier on-site working group. The on-site folks had, I
guess, the biggest contingency, and at that time had a representative from a
trade union and they did handle some of the earlier presentations in the
meetings about 2 years ago. However, from the point of view of assessing the
scientific and technical data that process hasn't been quite as effective as
some of the other groups, and while we have now spent a fair amount of time
with the hair and oral fluids areas and the sweat patch today, we haven't had
the time or the mechanism to deal effectively yet with much of the on-site
testing. Donna and Bob have asked me and Bob Willette to co-chair a larger
group to look at, to get to assemble this data.
Since we were using urine, there are different types of issues, but they're not
the basic science issues, because we have the same specimen we have been using
before. Since the group is so relatively large, and also since, in the
inception of this, as oral-based fluids developed, we find that there is a
major on-site component to oral fluids. We have organized a large working group
meeting which will be totally open and this will be held on October 5 and
6.
The idea here is that since the group is relatively large, and we want all of
the ideas and the types of products and technologies that are out there
presented, we decided on a format that is different from the other working
groups. The other working groups were smaller because there were fewer
representatives for the area, and they met in a technical setting.
This meeting is going to be kind of a mix of our original meeting, some of the
component parts of the original 2, 3-day, or HHS SAMHSA, when we kicked this
off about 2-1/2 years ago meeting, and the type of working group, and so the
format is going to be to start off each of the two mornings with a series of
presentations from groups that are using, involved with, or somehow have some
experience and knowledge base in the area of on-site testing. Then in the
afternoons of each day we are inviting all manufacturers, all people that have
a product, to have a block of time -- and the time's going to be about 10
minutes. It will depend upon exactly how many people there are out there and
respond, and how many want to give a presentation -- to present their
products, but not from a product sales point of view, answering questions about
what the product measures, what the technology is behind it, what the studies
are that support it, what its indications are, and a series of things which are
indicated on the second page of the letter.
We are announcing this meeting, and we're looking for input from anybody that's
still, you know, at this meeting, either the public or the board, as to things
that should be included, and make sure we include everything, and Bob Willette,
who is the sort of co-chair in this thing -- I guess we were both drafted
at the same time into doing this -- who has a lot of personal experience
in operating some of these programs, and as you know has done several
independent studies on a lot of these devices himself and for other agencies,
including HHS, will take a focal point of assessing the technology there.
Bob will take a couple of minutes to tell you -- he has revised the grid
for this purpose, since the grid that we've been using is a little bit
different, and now includes several additional component parts that we need to
consider.
DR. WILLETTE (Duo Research): In the original factor grid, on-site testing, the
subtitle of urine was the single line in the grid, but it turns out on-site
testing is both instrumented and non-instrumented, and with the advent now of
oral fluid products both instrumented and non-instrumented, as well as
laboratory-based, which we're not dealing with directly. For the working group,
we will have a grid -- this is a draft of it, and we've actually taken the
one line and expanded it out to instrumented on-site saliva, instrumented
on-site urine.
Fortunately, we will have a lot of overlap of data and information and input
from the oral fluid working group as to the information on drugs in saliva, as
well as the urine side has borrowed a lot from the laboratory based urine
testing.
So it basically follows the grid that was in the original format, but it's just
broken out now into four subcategories of on-site testing, and so it's opened
it up to anybody that's interested in or developing or is currently marketing
or distributing an on-site product for either one of these fluids.
On-site sweat testing has been demonstrated but there's no current product on
the market, so we're not going to broaden out that far. It's going to be these
issues that are addressed at the working group, and we need input from people
that have data and information that they can provide at that working group
meeting.
DR. CAPLAN: If you got the letters that were handed out you will notice that
there is a large experience in a couple of areas like the information areas
that have used some of these devices extensively. There is the project with the
U.S. Postal Service that we will hear about, where there is a reasonable amount
of first-hand experience with these types of devices, and I guess of particular
note is the list of things which we want to get at which is on the second page
with the letter from the manufacturers, and I think it is real important that
we adhere to this sort of thing.
We really don't want to know why your product is great, or how pretty the box
is, or that sort of thing, but really why -- and all of that is nice, but
it can come later -- but why it works, and how it works, and how you got
it.
DR. WILLETTE: There's probably at least 40 branded products just for urine.
DR. CAPLAN: So there's a large number of products, and a lot of these things are
going to be fairly similar. Even though there might be 40 kits, there are not
40 manufacturers. There's a lot of interplay here, but we need to get at the
scientific aspects, and we are asking people to present what the source of
their material is and why it works, and how it works, and what drugs are
included, and there are some very focused questions in here that are real
important, like, how should the device be evaluated prior to use?
There are some very fundamental things we need to get at here. The fact that
it's been used out there is one thing, but whether or not in the regulated
programs we're going to be able to utilize these things and what instructions
will need to be given, and evaluation prior to use, is like one of the big
questions. There's a tendency for on-site devices to suggest that you can just
use them as-is, but in a high-level quality control program, how is the batch
evaluated, and is it evaluated on a daily basis?
These are things that are very important to hear, because if we ultimately
formulate this into a program, that's the kind of guidance that has to be in
the program.
I mean, let the buyer beware is good, but not for us. We've got to go beyond
that. So anybody that has these in the audience, certainly feel free to
distribute this letter to anyone you know that has such a product, or
information about the product that follows the scientific entities. We need to
get at that.
It's probably on-site timely in that the other areas which had, I guess, more
technical issues which are slowly being resolved, adding the comprehension of
on-site, at least after this one meeting, maybe we'll need another meeting, but
by early next year we expect the on-site information, all the information to
sort of be at the same place so we can begin some coordinated cross-evaluation
of all the data.
MR. STEPHENSON: To refresh some folks memories, and just by saying it, maybe I
will refresh my own, we had a good representation from On-site Testing
Technology early on. The ideas of comparatively examining and reporting on the
performance of individual products has gone through 2 years' worth of product
evaluations performed by Bob Willette, the first year under his Probation and
Parole Services request to help them assess which are the effective products
that they could recommend for purchase and use by the individual field offices.
The second year we used the same model and undertook a second batch of about 15.
The industry has been somewhat desensitized, being compared across product
lines, and I think we have seen some actual development and improvement in
individual products through that process, and that in itself is of value to our
entire group of users who would benefit from this, and I think some benefits
directly to the industry itself, so that is part of our intent.
This is going to be an ongoing process, but this is an area where there has been
demonstrated a lot of interest by the Congress. There's a lot of interest by
businesses. There's a lot of interest by criminal justice, so the technology
we're assessing and going to be reporting on will have several different lives
of its own after we're through with our own report.
DR. BUSH: If you take a look at the agenda, on the third page you will see that
we're taking an awful lot from the experience of others. We want them to share
with us. We don't need to reinvent any wheel that has already been evaluated.
We would like people to share, and people have been generous with their time to
do this.
When you take a look at this agenda, if you see a to-be-arranged, that means I
have people I have spoken to, yet I don't have necessarily a point person who
has agreed to make the presentation. Absent are presentations using on-site
oral fluid testing devices, so if you have any ideas, and maybe I could call
insurance companies, or try to get something, some kind of information from
them on experiences, if you see anything, even if you didn't necessarily want
to step up to the plate and help us out with a presentation, if you know of
someone I could contact, I would really appreciate it.
The meeting will be held in this hotel.
I think we've covered about all the bases on that on-site working group. Are
there any comments?
DR. SAMPLE: Are we starting off with a brand new grid with everything being I's,
or since we've gone from one column to four columns, are we transferring what
was listed here as on-site before to being the non-instrumented on-site on that
grid and moving everything else to I's, or what is our starting point?
DR. WILLETTE: Actually the draft is totally blank. That doesn't mean they're all
yeses. The working group, following the 2-day meeting, all of the data and
information that's assembled, will then sit down and fill in the boxes with
what we consider the appropriate responses to present to the board in December.
DR. BUSH: A good question, Barry, because what we were doing at the time we
included this as a section in our book was taking a look at the
non-instrument-based drug testing devices. That was the initial approach, yet
as this has grown in complexity and depth over the couple of years we've been
doing this, we will certainly take what we have here, but then we will need to
reevaluate it for urine, on-site laboratory based, and then for the saliva,
oral fluid testing, so it's going to start out new, but with a history book
that comes with it.
DR. CAPLAN: This meeting's going to be a little bit different. We would not
likely have time to go through the grid at that meeting, but shortly after that
meeting Bob and I and some others will try to assimilate that and make an
initial presentation at the next Board meeting in December.
MR. CROUCH (Board Member): Does anybody know the extent of oral fluid testing on
site?
DR. WILLETTE: There is only one product that has been approved and another
product or two in field trials.
MR. CROUCH: I think that would be a low priority when compared to the urine
based on-site testing and on-site testing for laboratory devices on site.
DR. WILLETTE: I think the program is very sensitive to breakthrough strategies
and alternate approaches, oral fluid testing in general, whether it's
laboratory based or on-site might be one of the technologies of the future.
MR. CROUCH: I just do not think there is very much, if any, testing of oral
fluids for these drugs that are regulated here right now in the workplace. The
only common testing I'm aware of is for alcohol.
DR. BUSH: That was our thought, too, Denny. That is why we are taking this time
to appeal to anybody who knows if it is being done.
MR. CROUCH: I am making that suggestion. After having done some research with
saliva and on-site testing, not together, but trying to get them together, I
think it is not a big issue right now.
DR. BUSH: Okay. Then the grid will incorporate it. People will know out there.
People who are developing products. This is what we need for workplace issues
and workplace drug testing, and so a point very well taken, Denny.
DR. CAPLAN: There was interest in this at the oral fluid meeting, and again, so
as not to confuse the issue, because it was felt that the on-site issues with
urine and oral fluid would be sufficiently similar, it was decided to take it
up here wherever it falls out, rather than try to include both on-site and
laboratory based oral fluid at the same time in the oral fluid meeting, and it
may well be that it will be an area where there is a low amount of information,
but that may not be true by the time we get through this process because there
are several imminent products, as I understand, coming along.
DR. SAMPLE: I was wondering if you were going to comment on the laboratory based
urine testing since that is somewhat tied up in this or was that coming later
in today's program?
DR. BUSH: Actually, no. We can deal with it right now. Let's talk about it now.
Dan Isenschmid is the board member who has the lead on taking a look at this
issue, and Colonel Mick Smith from the Armed Forces Institute of Technology has
volunteered to work with Dan on taking a look at the laboratory based urine
drug testing as we know it today. Dan, do you want to make some comments?
DR. ISENSCHMID (Board Member): As we indicated at the last Board meeting, we're
going to be looking at the current laboratory based urine drug testing program
that has been in effect for 12 years, and in the light of the on-site testing
issues, clearly the laboratory based urine drug testing program is going to be
looked at critically, and we are going to be looking at different issues that
have come up with time and issues that could be used to improve the existing
program.
On that basis, we recently sent out a survey to laboratories, to all certified
laboratories requesting information on various aspects of the urine drug
testing program as it currently exists, and Mike Baylor (RTI) has collected all
of that information. We have responses from about 53 of the 71 laboratories at
this point in time. The results of that data are going to be used in
conjunction with the discussion of the on-site testing to see how we can
appropriately intermix all of that information and utilize it to re-address
some of the issues in the urine drug testing arena.
Some of those things will include issues such as looking at creatinine
normalization. It will include discussions as to controls that are used in
urine drug testing versus controls that are used in on-site testing. What are
the ramifications of having some in the on-site testing, or none in the on-site
testing, versus what we have currently in the urine drug testing, and looking
at the equality across systems, so we will be using that kind of information
and trying to put together a cohesive look at the entire urine matrix,
regardless of the mechanism by which it is being tested.
MR. STEPHENSON: Do you have a time line in convening any kind of working group
meeting?
DR. ISENSCHMID: We are going to be looking at the urine drug testing in
conjunction with the on-site testing meeting. Certainly, that is going to go
together and then we will probably have further discussions about that
afterwards. I think we will have additional information from other laboratories
on the survey in time for the meeting in October and that can be utilized to
further discuss issues related to the on-site as well.
MR. STEPHENSON: Has there been any consideration of incorporating a small block
of time for some discussion at the DOT HHS laboratory directors meeting coming
up in December, where part of this might be looked at?
DR. ISENSCHMID: I am not familiar with that meeting because I do not have a
laboratory director's hat any more.
MR. STEPHENSON: It might be a time to try to put some of this on the table.
We've made a very serious commitment to examine laboratory based urine with the
same magnifying glass because there's going to be so much we're going to be
learning.
We are examining adulteration and dilution issues. We are looking at it in terms
of on-site applications and collection site issues. We are looking at a lot of
different areas where each of these exercises are reinforcing the other.
We are getting a lot more exploratory, and looking at alternative matrices, and
how they may complement existing laboratory based urine programs, or strengthen
areas where we are beginning to see a need for that, so this is a good time to
try to put some of that together. Let's focus on this as aggressively as we
have with the other areas.
DR. CAPLAN: I think there will be an opportunity. The meeting was just decided
on a week or two ago, and the format is being assembled, but certainly there is
going to be a similar survey of the laboratories. I do not think it has
already, but within a week or so for similar questions and some additional
questions. There will definitely be an opportunity to merge because there are
some of the same issues that are addressed there and then all the labs will be
assembled there. That probably will be the first good time to present what Mike
has assembled, and in conjunction with what answers DOT gets.
MR. STEPHENSON: At this time we're going to go into the oral fluid testing
presentation.
DR. NIEDBALA (STC): I am going to cover the oral fluid update from the working
group. I wanted to start with the conclusions from our particular working
group. We had met in July, just before the vacation holiday season, so the
things we are seeing today are a cleaned up version of what we discussed. We
tried to use a format where we put all the factors into a word document that we
just updated each section, so you'll see some dialogue, you'll also see some
data, you'll see some conclusions, and recommendations in a few of the
sections.
It's a bit dynamic right now because there are people who have owed data and
between the vacation and travel schedule of the last month or so there are
holes, so this is an interim report, but I think there are things that we can
go through that are substantial today.
A couple of things that I just want to point out right from the beginning, that
in this particular section, or in this particular meeting we reviewed all
sections of the factors and spent time discussing all of those.
To Dr. Caplan's point with the upcoming on-site group, we also tried to
incorporate some of our thinking around oral fluids, and what may also be
relevant when that group meets, what we really got was a sense, and I'm
speaking from my own point of view right now, you got a sense of things
starting to come together in terms of either things we need to look at further,
as well as some conclusion we can draw that will probably be true across all of
the fluids.
The second major point I think we spent time on was screening and confirmation
cutoffs, and initial recommendations have been made. This is one that clearly,
from the vendors perspective and those people who may be working against
product development or product research, there's still some dynamics occurring
here as people are conducting more and more trials, but we're putting up the
data that was brought forth to date.
One of the key issues that came up was 6-MAM was detectable in oral fluids, and
there was some work that we've done between poppy seeds, negatives, and true
heroin users with GC/MS confirmation to show that 6-MAM is present, so that
question was one that was floating around, and we answered that.
Then just as a general suggestion, the group felt that the term oral fluid
should be used throughout the document unless there's a specific reference to
saliva, and the reason why oral fluid versus saliva really got down to the
technical issues of what is oral fluid and what is saliva, not from any sort of
market or perception that's nonscientific, but rather what is the composition
of saliva versus the composition of oral fluid, and it was felt that oral fluid
really is the correct technical name that we should refer to in the future. In
the notes that I have handed out -- and I'm going to go through these
factors one by one, we tried to be as consistent as possible. Where we really
mean saliva, it's saliva for a purpose. Where we say oral fluid, it's oral
fluid, because we're talking about this from a general perspective.
The one thing we have which is still the same from our first meeting is talking
about the differences between the laboratory based systems and on-site systems,
and the laboratory based system consists of a collection, a laboratory
analysis, and a confirmation where the on-site systems may be a screen test and
then a confirmation in a laboratory based setting. We separated those out for
the moment, but as I said in my opening statements, the ideas for on-site
testing were included as much as possible in our discussions, and you will see
that throughout.
Now, the factors may not have changed, and Walt, this is something you could
look at afterwards and as we get to conclusions, and so we didn't try and spend
time on the letters as much, but what we tried to do is put the substance in
each of the sections and get our thoughts, and when we talk about the
collector, and especially things like training, we really tried to look at some
of the models that are out there.
I will jump ahead a little bit, but what we did for training purposes for
collectors is, we tried to look at the DOT training units versus urine
collection and the parts that are associated with each one of those. When we
had our discussions about that, we came to the conclusion in our discussions
that the manufacturers must provide or define training for specific devices.
That is unequivocal when you look at the commercial devices that are available,
and that training program has to be driven by the devices and the manufacturers
themselves.
The question for certification was discussed in terms of individual training,
much like you have to do for the DOT program for the STT's, and I know this has
obviously been debated for urine testing as well, and we spent some time on
that. However, when you looked at it, what it came back to was that the
individual device must be well supported, and that comes from the manufacturer
rather than the regulation of it.
To be consistent with what was handed out, these are the additional sections for
STT training versus the urine training, or urine collection, and what we tried
to do was match up wherever it looked familiar, so you can go back and look at
that and see how your thoughts mesh with it, but we used this as our structure
for discussion during the working group.
The next section we addressed was the collection container, and we talk about
that the devices should be drug free, that the specimens should not be
affected. This is actually pretty consistent with what we would expect for the
urine container as well in this particular case, and that the collection
container -- we tried to put a definition here to help -- is
referring to the device components required to get the valid specimen and
transport it to the laboratory for immediate testing, and the thoughts here
are, cover the laboratory base testing as well as the on-site in our
discussions.
Capability to secure the device was similar in that a piece of tape or some
qualified means must be available.
DR. SAMPLE: Sam, what is B?
DR. NIEDBALA: It was blank. The blank was what had previously been there, but as
we said, we wanted to make sure that we at least discussed every section, not
get hung up on a P or an I or a B, because those conclusions will come
downstream.
As a general statement, in the next section, which talked about FDA clearance,
it was the working group's opinion that all systems for laboratory based and
on-site should be cleared by the FDA as medical devices intended for drugs of
abuse testing, and that is an important distinction, rather than just a
collection device for oral fluid with no claims against it, so that the science
is well validated and understood for any particular collection or testing
device.
Section 4, impact of device on specimens, this is one where it was felt that the
manufacturers must substantiate the information specific to their particular
device, and that this substantiated all of the information necessary for
storage and stability, and that there was some minimum expectations that the
device should be capable of collecting specimens without affecting the drug or
metabolites and measured in the follow-on screening and confirmation testing
scenarios. Again, no surprise, but we're trying to put at least some verbiage
to each section, where before we didn't address the section at all.
Multiple testing. This is obviously a requirement for any proposed system, and
we talked about four of the five target substances and in addition there should
be sufficient volume to do follow-on testing for 6-MAM and amphetamines, so we
looked at least one device, which is the STT intercept device for collecting
oral fluids.
We looked at the screening volumes currently required for the testing of those
devices, and you can see that out of the approximately 1 mL collected there was
more than sufficient volume for screening and confirmation, and volume left
over to do repeat testing, and in an effort to put some data behind each one of
these points, this was given as example data.
The potential to split specimens. Before I cover the next tables, there's some
interesting questions that come up with oral fluids, and splitting specimens is
something that is so routine in urine testing that actually, when you stop and
think about it, for an oral fluid specimen it has some challenges. For
instance, if I collect from one side of the mouth versus the other, is there
any difference in the results that I may see? Is there enough volume that I can
split one specimen, or do I have to collect two specimens, as an example. All
of these things were discussed to some extent during our working group, and
then some data was attached just showing some testing with some specimens
for -- I believe it's cocaine that follows, with right and left specimens
to show the differences, and what we find is you can see some differences, but
those will generally be with specimens right around the cutoff. For the
majority of specimens collected, we did not see differences, and we'll get to
that in a second.
As an example, what we said is there are may be two ways we can think about
this. One is division of the primary specimen into two aliquots, and two was
simultaneous collection of two specimens. This issue in essence has to come
back, and I think be discussed a little bit further with some additional data,
some recommendations from manufacturers in how they might do it. There has to
be enough, obviously, to split the specimen to have follow-on testing if
required, and so there's no conclusion out of this as of yet, but just to
present what we've at least discussed so far.
The next two pages really cover some data. This is for subjects which were
tested for cocaine. These are right and left specimens that were screened by
immunoassay, and some examples given where both right and left collected
simultaneously were positive, at least some data to support the idea that it
didn't matter which side of the oral cavity the specimen was collected on, or
collected out of.
Some additional follow-on data for opiates was also presented at the meeting,
and there are a couple of specimens here that disagree, and in looking at the
data for these, they are specimens that are around the cutoff, which is what
you would expect from a screening test, but it gives some idea that in general
terms right or left collection was okay to do.
DR. SAMPLE: Sam, you attribute all of these disparate results between the left
and right side due to cutoff issues?
DR. NIEDBALA: Yes, and it revolves mostly around the screening test itself and
the position around the cutoff. That is where you start to see the big picture
in terms of how these tests might be used and their performance
characteristics.
You will see one of the items, which we didn't conclude but clearly had
discussions about, was precision around the cutoffs. Traditionally we used plus
or minus 25 percent, and there was discussion about plus or minus 50 percent as
an example, because when your cutoff is, say, 1.5 nanograms per mL, plus or
minus 50 percent or plus or minus 25 percent is analytically a very difficult
thing to do, and that's where we start to see some of the differences in
technical performance, and also the kind of cutoffs and the ranges we're
working within.
You will see we made a note at the end of this section regarding the on-site
group. That, in looking at -- now we got off on a right or a left issue,
but also on the issue of retains, that the on-site group must also discuss a
collection of an alternative specimen or additional specimen regarding oral
fluids, and we will assume that that particular group will address that to some
extent in October if at all possible when they meet.
Storage and stability. This is another one where it was felt that the
manufacturer should bear the burden of substantiating the information on the
storage and stability conditions, and under what conditions each drug is
stable, and for what period of time, so that any potential laboratory user
clearly understands the boundaries in which any device or system is capable of
working. A lot of this really ties back in essence, too, to what has to be done
for an FDA submission, and one of the reasons we felt that was a requirement,
because in looking at any device, assuming these are 510K devices, every
manufacturer would have to produce such information to really show equivalency
and efficacy and stability of their device.
As related to this section, also talking about stability, we tried to put in
some data at least looking at the stability of the drug in the eluent of one
device. Where this particular device is collected, remotely sent to the
laboratory, the laboratory processes the specimen, after the sample has been
extracted, where the sample has been taken and ready for analysis, what's the
stability of these particular drugs. We have put up some data to date showing
40 days at 4 degrees and 37, 21 days at 4 and 37 for THC and opiates, to give
you some idea that the drug is stable long enough for any analysis to be
performed.
The next slide to that is the detail data, which I don't know if it is really
worth going through right now. I would just say that anyone can ask me
questions afterward or e-mail or call.
What this is related to is the curves for each one of these immunoassays as
measured by percent displacement, so what we look at to judge the stability of
the curves is the percent displacement and how those numbers change over time,
so if you study this a little bit you'll see that that's the general idea, and
then if you have questions on specific numbers, I can answer that after the
fact or a little bit later, after I get some coffee.
DR. SAMPLE: Why are some of those gray?
DR. NIEDBALA: I think it's just somebody playing with Excel for the most part.
Oh, in this particular case it's specific points they made judgments against,
so those are ones that they've used these as benchmarks for making some sort of
conclusion, which was previously, how long it was stable, what changes were in
there, and that those are relevant ones, because it's the cutoff concentrations
that we're going to want to look at in terms of being the bread and butter in
this, rather than every point along the curve. That was the way this particular
experiment was approached.
DR. NIEDBALA: And if you summarized this, we tried to look at it one other way,
which was to take percent displacement, which is what is generally used, and
take a look at the cutoff all the way across 3X, the cutoff, 6X, 12X, 20X, and
then the cutoff, and look at the percent displacement. This is probably an
easier one to look at over time at each one of these temperature points.
DR. ISENSCHMID: Sam, what is percent displacement?
DR. NIEDBALA: Percent displacement is probably the new generation, the ELIZA way
of looking at B over B zero, so if a curve looks like this, and in this
particular case this is an inverse relationship between concentration and
signal, then this would be a small amount of drug gives you a high signal and a
larger amount of drug displaces and lowers that signal. The percent
displacement is, if this is, say, 100 percent, and this is 40 percent of the
zero signal, then that would be 60 percent displacement, or that's the ELIZA
way of looking at the B over B zero. If the Board would like to see any of this
data rehashed some other way, or explained differently, we're happy to do that.
Collection procedure. In the preparation, this was another one that I would say
was kind of a critical discussion, and it's time that some data be discussed in
terms of a waiting period before an oral fluid specimen could be collected.
We have had a discussion about this, because there have been some folks who have
said a mouth rinse before a specimen is collected, a waiting period may be one
way of doing it, or no waiting at all, and that there's no effect, but in the
case of trying to make something that can be generic across an industry that
may practice something, the waiting period was what was discussed at length by
the working group.
And what we tried to do is put up some evidence that a 5-minute waiting period
is probably a good period of time, based on some data from one of the
manufacturers, and in this particular case we took a THC study. Notice, the
percent displacement which is an important part to this, because that is a
standard way of looking at this, and we looked at an unadulterated curve all
the way through water, sugar water, orange juice, cranberry juice, toothpaste,
antiseptic wash, cough syrup, Coca-Cola.
This study was done over 15, 20 minutes, but at the 5-minute waiting point we
were showing data that concluded that a 5-minute waiting period was sufficient
time before collecting a specimen to say it would not be affected by these
particular substances if someone were to drink those before they went in to
give a specimen or rinse their mouth or do anything else with that, and so what
we concluded in this particular section was that a 5-minute waiting period
would be a good period of time to have as a minimum. I think that there's more
data that should be presented for each of the analytes. We only put up THC as
an example for the group, but I wanted to put some tooth into the idea and
propose a starting point for how this particular section, how this particular
factor may be addressed.
Often you will see these asterisks at the end. At least the way we did is
oftentimes they pointed out something that was a controversy, and something
that was important to let everybody know we at least talked about it or
something for the on-site group.
In this particular case we talked about the possibility of a donor opening his
mouth and someone looking in it before a specimen was collected, and it was
felt that that was really not going to work, and not a very good suggestion,
but it was discussed in case it comes up again, and that we did conclude back
that a waiting period was probably the most decent way to go about conducting
this portion of the process.
Specimen integrity. There are a couple of ways that this was looked at in terms
of specimen integrity. One was to know that you had a sufficient amount of
specimen, and the other is to make sure that the specimen is not substituted or
adulterated. We talked a lot about the way the process was being put together,
at least in our minds, where there was a waiting period. We had data to show
that had someone drank or ate or tasted or rinsed with certain things that it
didn't affect the test results. We also talked about the benefits of direct
observation, and this was a big one among the working group. The simple idea
that we can observe somebody makes a big difference in this whole process. We
felt that direct observation really gave it a lot of credibility, but that
there also should be the employment of specific biomarkers to help us assure
that the specimen was unadulterated and was adequate.
There is data to suggest that 0.5 micrograms per mL IgG is an easy way for
someone to determine that it is human IgG and that it was an adequate specimen
for at least one collection device.
MR. CROUCH: What is a normal IGG?
DR. NIEDBALA: There is a range that is generally quoted in several literature
articles. This particular cutoff was the minimum that was found among the
populations tested for human IgG. I don't remember the specific range.
MR. CROUCH: Could someone rinse their mouth out and, therefore, dilute ten times
and still pass this standard, or is it two times?
DR. NIEDBALA: No. This also tied into some of the data that was presented for
the same device used for HIV, where the mouth was rinsed and people had then
collected the specimen and looked at IgG. I do not have that data here, but I
certainly can put that together if that is one that people feel that we should
do. It's a good question, though, Denny.
MR. GOOD (Avitar): I think that that relates to the waiting period, as well,
because the mouth is continually flushed with saliva. If you have a waiting
period, there is less probability that cleansing the mouth earlier would have a
significant effect on the sample because the saliva is continually replenished.
MR. CROUCH: Do you know the normal concentration of fluids in IgG?
MR. GOOD: No more than Sam does.
DR. NIEDBALA: Denny, I can answer that question for you. I just don't have it
with me.
We talked about deterring tampering and adulteration. This is where you started
to see, at least in our discussions, the whole idea of the algorithm for using
oral fluid as a collection and then testing medium. The idea of a minimum
waiting period, direct observation being the leading factors in the prevention
yesterday in the prevention, identification of anyone who may try and tamper or
adulterate a particular specimen.
In addition, it was felt that the tamper-resistant seals, tape, et cetera,
would provide the added measure that really would make this a valid specimen.
And we had left it at that.
Transport of the specimen. We tried to identify, were there any regulations,
anything preventing the transport of specimen. We could not identify any of
those. Dr. Mike Peat had pointed out that thousands of specimens are currently
being shipped within the United States, and on a worldwide basis, daily using
oral fluid, as we're discussing now, not obviously for workplace testing, but
for other analytes -- for HIV, for insurance risk assessment -- and
that there have not been any occurrences of any adverse events that the group
could report on to make the committee and the Board aware.
Moving to the laboratory testing section, this is a section where we are looking
at individual types of collectors. It came back to the opinion that the
manufacturers have to substantiate, with clear information, the ability of
their device to store specimens and keep specimens for short and long periods
of time.
At a minimum, and whenever we made a statement like that, we tried to put either
"min/max" or some qualifier, that these devices should be able to demonstrate
that it also does not affect any of the drugs that would be targeted or the
metabolites that may be of interest in any secondary testing, and that
confirmed positives obviously should be able to be stored for up to a year.
Again, we are not trying to change the model too much from what already exists,
just acknowledge the differences that may be, or information that needs to be,
supplied for oral fluids.
The next section was to identify adulterated/substituted specimens. This goes
back, again, to the five-minute waiting period, direct observation,
tamper-resistant seals -- a lot of the same things we've already
discussed. Whether it's chemical or immunological testing for adulterants, it
could be performed similar to that utilized in urine testing programs.
There is an industry that will be created out of every one of these matrices for
people to try and find a way around this. The point is the devices right now,
at least in our discussions, have all been designed around the idea of knowing
that you collected enough specimen, assuring that it is a human specimen,
direct observation, effect of how long you wait. You could see the building
blocks adding up for us to try and help with a technical case for how
procedurally we will assure that the specimens are valid and that they've been
correctly collected.
And so at the testing point is when we see that's, for the first time, linked to
what happened at the collection site. The initial test being FDA, again, the
statement that all of the screening tests that go along with a collector should
be FDA cleared. As far as the targets are concerned, Section B here, that the
levels of analyte are significantly lower than in urine -- this we already
know. However, the list is essentially the same, but does include the parent
compound in some cases, such as, THC and cocaine.
In addition, and this is how I started this morning, is that 6-MAM is
detectable, and we have some data at the end that will show you how we
determine that, at least on a pilot basis.
We put together a table and updated it, in terms of what we know now about the
immunoassay cutoffs. What we are looking at is the comparison between urine and
oral fluid. You can see the differences here in how we discuss things. Notice
the amphetamines/methamphetamine is high in comparison to some of the other
compounds. That is based on data from package inserts as well as clinical
trials that have been conducted by manufacturers to date.
Acceptable performance around the cutoff -- there is some data that have to
be filled in here. It was a point of discussion during our working group, where
we talked about specifically what should be the performance around the cutoff,
plus or minus 25 percent as traditional with urine testing, is really not going
to be possible. There is a plus or minus 50 percent.
I had actually put up on the board minus 50 percent plus 200 percent. Of course,
we are so ingrained right now with plus or minus 25 percent and all of the data
that has supported that over time. This one needs additional information, which
was promised, but between vacations and other things, it has not all been
assembled into the documents. We will come back to that.
The ability to repeat the initial test -- if you go back to D-2, we gave
some volumes that are used, at least for one device. You saw that there was
about a half a mL that was left over to actually do repeat testing -- more
than enough for the screening test. Then, for confirmation, what we talked
about, now moving from collection to screening for confirmation, is that MS
should be used for the identification and quantification of the drugs. However,
we really talked a little bit further about this and would like to recommend
that hybrid MS techniques also be allowed to be used. For example, GC/MS/MS,
LC/MS, et cetera, always using MS as the basis for gold standard
reporting.
As far as the cutoff levels for confirmations, we tried to put together a
similar table.
MR. CROUCH: Can we go back to that last one? It says confirmation
testing -- it is expected that MS will be used. It is a recommendation
that MS/MS will be used. Is that what that is saying?
DR. NIEDBALA: It is expected that MS will be used for confirmation of positive
specimens.
MR. CROUCH: Then it is recommended that MS/MS be used?
DR. NIEDBALA: Be allowed.
MR. CROUCH: I don't see the "allowed."
DR. NIEDBALA: That's what we're saying, that should be allowed. For purposes of
discussion and reporting back to the Board, looking at the cutoffs for
confirmation that are being recommended, you can see the differences now
between screening and confirmation for every one of the drugs. There was also
some discussions made, good rhetoric, around what does a cutoff mean. For
example, if you're looking at cocaine, and 10 is the cutoff for cocaine and
cocaine metabolites, could it be, say, 6 nanograms of BE and 5 nanograms of
cocaine, and now you are above 10 total of cocaine and cocaine metabolites. The
group felt that that was not acceptable, that this should be a cutoff of 10
nanograms of BE or 10 nanograms of cocaine in a particular specimen.
Again, if you tie this back to the screening, because there is some data that is
over here as the acceptable performance around the cutoffs and precision,
et cetera -- and I know Donna is going to tell you that.
MR. ANDERSON (Ansys Diagnostics): I had a question about PCP. I noticed the 5
cutoff for GC/MS and a 3 for the screen.
DR. NIEDBALA: For the moment, I think that has to be debated. The confirmation
cutoff score reported by Dr. Mike Peat at Lab One, and his experience using
GC/MS/MS, and the screening cutoffs really are from the manufacturer of
screening kits. So there is a disconnect there. I believe that they're both
going to be probably around 3, but the data was not there to support that for
both.
MR. ANDERSON: Is there any data, looking at positives from the field, on what
the difference in a cutoff makes in terms of positives? Have you seen that?
DR. NIEDBALA: Yes. That's not presented here. That has been part of FDA
submissions and package inserts that were previously looked at. Everything was
done on the basis of ROC analysis, to determine what was the correct cutoff for
populations. Populations were defined in two ways. One is from known drug
clinics, which is a bit dangerous if you're going to do ROC analysis. The other
is based on prevalence studies on about 10,000 subjects.
DR. SAMPLE: Do you have preliminary data at least with respect to performance of
the cutoff for the confirmation methods as you did for the screening --
DR. NIEDBALA: For the precision?
DR. SAMPLE: Yes.
DR. NIEDBALA: I don't. I know that that has been promised. And I do not have it
yet.
DR. SAMPLE: So you do not have any numbers that you can share?
DR. NIEDBALA: No.
Then we get to how cutoffs reflect drug use. This section, plus some of the MRO
reporting at the end of it, really becomes the very interesting points to
debate among the group. I thought that it was positive in the way the group
worked together and tried to flesh out the issues. I very much appreciate how
everybody interacted here.
What we first tried to do was look at what are some of the issues that we know
will be on the table and which ones that need to be evaluated. These are
obvious ones that need to be looked at -- poppy seed consumption, passive
inhalation, products that contain hemp, Vicks inhaler as examples. There are
data that exist for some or all of these to some extent. The issue becomes
individual devices. I think that you have to have the data supplied by each one
of the vendors to be able to address that.
We will look at one example of this in the poppy seed area as something that at
least we have some data to work off of now in terms of how we interpret and
discriminate poppy seed exposure from a true opiates users. And 6-MAM again,
just like we're trying to use it now in urine, offers a potential solution
there. I think additional data is going to now be added to this to address as
much as possible all of these. But as we know, there is a great deal of work
that has to go into making sure that each and every device would have
supporting data to address every one of those issues.
I'm going to drop back over to the certified laboratory program. John Mitchell
had given us feedback, and the group had discussed whether or not there were
any issues that were known that could prevent construction of a certified
program. This is a bit of the chicken and the egg in terms of how we talk about
it. We have to know what kind of program to put together, but we also have to
know what we are targeting for that program. Those things just don't exist.
The way we discussed it was, are there any kill issues that can be identified
right now, in what we have discussed either with the science of collection,
screening, confirmation, that would somehow prevent us from putting together a
certification program? John, I don't know if you want to add anything on that.
DR. MITCHELL (RTI): I was trying to remember.
DR. NIEDBALA: I have had six hours in the car so I remember just about
everything right now.
DR. MITCHELL: I think the main thing that we were talking about is that, on the
surface, there doesn't appear to be anything that would prevent the
construction of one. There are still some instructions in the PT area, and the
group did recommend establishment of a pilot program to try to identify those
issues which are identified if there are issues associated with being able to
monitor the program in the PT sample.
DR. NIEDBALA: I think that is a great segue to this section, which is exactly
what we were going to get to next. I think that has to be discussed by the
Board. But it was clear that some additional information is needed, and that
this is neither something that is going to come from the manufacturers or from
any of the group. This falls as the in-between project that somehow needs to be
addressed. And part of our job was to bring those up onto the table so we can
come back to the Board, to say this is one of the items that needs to be
addressed.
Laboratory inspection program is a similar sort of discussion. There were no
kill issues, as we called it, that can be identified, but still this has got to
be thought through entirely to make sure that none surface. It was felt that,
really, it should parallel what's done for urine right now.
Similarly, when we talk about blind specimens, there are commercial suppliers of
these materials, but we haven't given them the targets yet to even know what it
is they should go against. Once all the recommendations are accepted, debated,
and hopefully concluded, we can certainly expect that there will be commercial
suppliers of these materials. That will come with time.
Reporting. You won't see a whole lot of verbiage in this section. We expect this
to mimic the urine sections of the current guidelines. We do not see any reason
to change that. Nothing came up in any of our discussions that would suggest
that we need to somehow readdress the way it's already done to make it specific
in any great manner for the use with oral fluids.
The only point on the next couple of items are the standard reporting form, is
that it was felt that on the standard report form that we should be consistent
and include everything now as nanograms per mL of oral fluid. Remember, out of
our first group meeting, we concluded that all units should be normalized
against the same standard -- meaning nanograms per mL. We talked about
saliva at first. But, after further discussion of what saliva really means, we
want nanograms per mL of oral fluid, as well as any information on biomarkers.
DR. VOGL: When you say milliliters of oral fluid, that implies you know exactly
how much was collected by the device.
DR. NIEDBALA: That is correct. And if there is a range, then there should be a
range reported. If there is an exact amount, it should exact. But it should be
all the same units that are used.
Barry, what I mean by it is none of the devices are going to collect a precise
100 microliters, as an example. There is going to be some tolerance that they
all have. And as part of their insert, they should report what that tolerance
is in the collection volume. So that has to be reported. That has to be part of
the calculation in their reporting out their units.
DR. SAMPLE: Do you have a range of concentration?
DR. NIEDBALA: There is going to be some variation in materials used to collect.
This is not a simple fluid in all of them. This is a very general statement on
my part, but all of them will have some sort of process or some, in essence,
expression of the fluid off of the pad or swab or whatever it might be.
DR. SAMPLE: Wasn't there some discussion at the last meeting about doing it per
device as opposed to -- or am I confusing different methods?
MR. CROUCH: There was a discussion. And we decided not to do that.
DR. SAMPLE: Thank you for refreshing my memory.
DR. NIEDBALA: That, I thought we had concluded, was really a dangerous way for
us to go about it, and that we wanted to keep a standardized unit for
everybody.
MRO issues, I am trying to think how to extract out of this the summary of all
of it. This is where we really started to talk about the idea of the accurate
review of oral fluid based testing rather than saliva alone. And there are some
basics for interpretation of positive and negative.
We also felt that there were many similarities now as more data is coming
available between urine and oral fluid. I think we have a mind set that we can
work off of. We have to now apply it just to the nuances that will come with
the oral cavity and the oral fluid that would be collected. If we work through
a few of these, we see that from the group's discussions, that the cutoff
suggested really represent the recent drug use. We also felt that, similar to
urine, a negative oral fluid represents a true negative or levels of drug in
the sample below the suggested screening and confirmation cutoffs.
These may seem like very obvious things, but we tried to point out, so to speak,
both the pros and cons of each one of these points as you look at oral fluid.
We also looked at some of the data from the scientific literature, from various
studies, from manufacturers, looking at the detection of these drugs in oral
fluid, and that multiple sources of information are available to support the
MRO's conclusions as to true drug abuse and/or aware that a drug may have been
come from poppy seeds.
I think an important metabolic portion to this is that oral fluid -- the
presence of drugs in oral fluids may come from two directions. One is the
distribution of drugs into the oral cavity from the bloodstream, from the
circulatory system. The other is that it may be inhaled or delivered directly
into the oral cavity.
Both of those routes of administration result in the same thing -- that
there really is an abuse of a substance and that any one of those constitute
what we would call the abuse and the detection thereof. We know that for some
drugs -- as an example, cocaine and THC -- are sequestered also for
various periods within the oral cavity and may give us some of the observed
concentrations that we see that are building up over time, whereas, others may
be metabolized very quickly. The overall conclusion out of all of that rhetoric
was that a positive specimen, nonetheless, represents either a combination or a
single dose of a drug distributed or sequestered from a variety of routes of
administration and does reflect recent drug use.
The other issues that may come up in the future, and that interpretation of a
positive oral fluid may include, is exposure to environmental sources of drugs,
food products containing drugs and, of course, transfer or exchange of body
fluids. We are looking for volunteers. This was the kissing question. We are
looking for someone to volunteer for that study.
These are things that we are bringing up. It is our job in this group to
recognize these things and to put them on the table for discussion.
If we look at a few of those things, we see that there is limited data,
suggesting environmental and some food sources do cause positive oral fluid
results. At least one study with smoked marijuana showed that individuals
passively exposed did not have positive oral fluid test results. In
addition -- and we will look specifically at a couple of tables in a
moment -- ingested poppy seeds for opiates and hemp oil tested for THC did
not produce a positive oral fluid result. All of these things are building up
the database to answer each issue one at a time.
The last one, the kissing question, transfer exchange between body fluids may be
possible. However, the concentrations we would expect should be minor, and that
the prescribed waiting period to collection, we expect to minimize this
particular issue. You see now how the whole algorithm starts to tie out and
we're trying to conclude that now, of how do you interpret a positive result. I
think that this addresses a lot of the major concerns.
DR. CAPLAN: Is it the feeling that you need substantial study there? Can you
comment on how much additional study is needed on the fundamental question of
the differentiation between the potential passive inhalation or exposure and
the active drug users?
DR. NIEDBALA: I know that through the end of the year there are about five
studies that are all queued up on our part, all addressing different aspects of
this, from passive exposure to further prevalence studies to look at
populations, to hospital emergency collections to gather certain specimens.
There are a variety of things that are all in motion here. I expect that we
will bring back more and more data on each of these issues.
DR. WEST (NRC): Is the waiting period you're referring to five minutes?
DR. NIEDBALA: Yes. We are trying to be consistent now from the initial
scientific evidence and our conclusions then as to how you would perform this
type of analysis, question and analysis, all the way to here, where we are
reporting out the rationale for positive or negative specimens.
When we get to alternative medical explanations, we really don't expect a
difference here -- was our opening statement. You produce between a liter
and a liter and a half of oral fluid per day. However, there are individuals
who may have a dry mouth due to medical reasons. We felt, at least in our
discussions, that such drugs or medical reasons should be obvious and should be
reported when the subject is filling out their forms, ask certain questions,
and that those things should come up at that point in time.
As far as MRO testing, it was felt that for oral fluid we will have similar
content and scope as for urine. We do not see anything outside of the norm in
this particular area, and it should be consistent with what's currently done.
The last part of this is the results related to time, dose, and response. Now,
what we did is start to put together a statement here. You will see this
statement goes on for several pages. I think what we tried to do is address the
idea of, one, looking at the mechanisms of how drugs make it into the oral
cavity, along with literature and data to support what we see. There are some
recent articles, as near as the last couple of months, that have come out, all
looking at summaries from European studies as well as that which exist in the
U.S. already. If you look at diffusion of drugs from the blood into the mouth,
direct deposition of drug into the oral cavity through the nose or the mouth,
or smoked, you can start to conclude, we believe, certain aspects.
What we did here is we went back and looked at, theoretically, what should
happen based on the pK of the drug, all the way through the supporting data
that exists in the literature. I think that, in this particular case, rather
than everybody trying to read this and comment, this may be another one where
everybody can read it, come back with comments, ask some questions, to further
substantiate it. But it was written in part by the group.
I want to thank Ed Cone for actually finishing it, getting it back to us.
Everybody commented. And this is the product we have right now.
MR. STEPHENSON: Could you send that to us by E-mail?
DR. NIEDBALA: Yes.
DR. VOGL: Do you have a bibliography of the references?
DR. NIEDBALA: Yes.
DR. VOGL: Earlier we said we were going to put the bibliography for sweat
testing on our Web site. It would be great to do the same for oral fluid.
MR. STEPHENSON: Cognizant of the copyright issue, the bibliography with the
citations would be a good start. We could put that up on the Web site.
DR. NIEDBALA: Yes, that is usually part of it. And we handed that out at the
working group. I know, for myself, I have an ongoing, updated list of all the
references coming out. And then we just have that tabulated and handed out to
everybody. You will see this go on for several more pages. Obviously, there was
a lot of time and thought spent on this.
DR. SAMPLE: I just want to make sure that I understand the last sentence that
begins with: However, those studies that employ highly sensitive analytical
methods frequently reported detection times as long as four hours or more, not
unlike detection times reported for urine testing. Is that saying that typical
detection time is on the order of four hours for oral fluids?
DR. NIEDBALA: No, that is not what that means. It does mean that at times that
has been reported. For example, for THC we have seen as long as 24 hours. There
may be new data that people are looking at now. That also has been as short as
that many hours. Those are the kind of things that we are trying to build with
the database.
DR. SAMPLE: The references that address this would be most helpful.
DR. NIEDBALA: I will get that to everybody. I have a couple more things to just
conclude, but let me just be consistent here.
Specimen contamination -- we didn't address this in our discussion, because
we felt that that was already talked about above in the other sections. We did
not put any verbiage here on this particular section. Certainly we will have to
put something there eventually.
Let me walk you through just a couple of overheads here regarding opiates and
6-MAM. The question that came up by the time we had our first working group
session was about 6-MAM and whether it was detectable in oral fluids. In this
particular case, there were patients collected from a clinic, an abuse clinic,
and these specimens were analyzed by GC/MS/MS. We looked for the presence of
codeine, morphine, 6-MAM, and heroin. We looked at ratios for both codeine,
morphine, and 6-MAM and morphine. But in absolute concentrations, you can get
an idea from this that 6-MAM is definitely present among the abuse population.
We have no idea of dose in this particular case. These are random specimens.
These are self-reported by people coming into a clinic, not unlike things we
typically see for urine studies that are done.
As you look across, I was really surprised, talking toxicologically, I was very
surprised at the concentration of 6-MAM that we saw in these specimens.
The question became how to use this information. As a first conclusion, we've
shown, by MS, that the presence of 6-MAM can be concluded.
The second question was whether or not poppy seeds, if they were used or taken,
would 6-MAM be present. We had several volunteers who consumed 40 grams of
poppy seeds and then collected an oral fluid and urine specimen from 0.25 hours
to 24 hours, and looked at the concentration -- this is only reporting for
oral fluids -- codeine, morphine, and 6-MAM.
What we found when we collected their specimens over this time period, we did
find, at least with this particular subject, that we could see morphine in the
oral cavity. What we actually suspect with this is that this was probably poppy
seeds left over in someone's teeth and in the oral cavity itself. What was very
interesting was that 6-MAM was never found.
Then we took, as a next experiment, poppy seeds themselves, the same ones that
were given to people, and we put them into the buffer that is part of this
particular device, stored them for up to 24 hours at room temperature. And
these are individual seeds. Then you get up here, and you get to about 40
seeds. That's 20 milligrams. Then we just continued in milligrams, showing that
this is a lot of seeds.
What you see is that once you get out far enough, we started to see the presence
of morphine climb dramatically, but we never saw 6-MAM come up at all. And
metabolically, we would expect that this is the case, but here is some data now
to show you that this indeed is what occurs.
I just wanted to conclude with that and give you some flavor for how we're
trying to address each one of these issues and how the data is progressing. I
also want to apologize for being late.
DR. SAMPLE: Can we go back to page 6. Also, the one immediately following that,
showing the amphetamine oral fluids. As I understand that, looking at the
delta-9 THC DOA eluate, you're showing the percent displacement for a standard
curve essentially.
DR. NIEDBALA: Yes.
DR. SAMPLE: And you're saying that the cutoff then is 0.35 nanograms per mL?
DR. NIEDBALA: This is of the acid, yes, in this particular study, which is the
equivalent of a 1.5 nanogram per mL of the parent.
DR. SAMPLE: You are using that value to set your cutoff for the specimens or
controls or whatever you analyze in the lower part of the table, where you have
the zero, 4.2, 8.4? For example, at time zero, you are using 33.4 as the
determinant.
DR. NIEDBALA: Right. It's analogous to this table on the following page, where
you look at 3x, 6x, 8x.
DR. SAMPLE: My question, in looking at this, is it looks like values -- if
it's 0.35 you are using relative to 4.2, a tenfold difference does not
produce -- 10 times above the cutoff does not produce a positive response?
Or if that 0.35 really relates to a 1.5 for the same analyte that you're
looking at below, it would be a 3x difference before you see a positive
response?
DR. NIEDBALA: Let me make sure I understand what number you're looking at.
DR. SAMPLE: Well, what you're saying is -- let's just look at the t-zero
column.
DR. NIEDBALA: Yes.
DR. SAMPLE: You are using 33.4 percent displacement as the determination of
whether a positive result occurs, or presumptive positive.
DR. NIEDBALA: Right.
DR. SAMPLE: If you go down to the table that's labeled "Concentration of delta-9
THC," 4.2 corresponds to 3 times the cutoff?
DR. NIEDBALA: Right.
DR. SAMPLE: As I understand this row, it looks like all of those 3 times the
cutoff analyses were negative except for one, the 37 degree at the time equals
one week? Because they are all less than the corresponding cutoff.
DR. NIEDBALA: Yes.
DR. SAMPLE: In fact, if you look at the row labeled "8.4 nanograms per mL," you
actually have one 6x value, 6 times the cutoff value, that is also negative.
DR. NIEDBALA: Yes.
DR. SAMPLE: Is that the correct interpretation of this data?
DR. NIEDBALA: I think you are right. There is something in the protocol, the
thing that I have to go back and check in this because I do not have that with
me, is whether or not the standard curves from above also matched those numbers
below.
DR. SAMPLE: Well, you have no way to apply that.
DR. NIEDBALA: Yes, I know.
DR. SAMPLE: When you look at what the positive displacement greater than value
is.
DR. NIEDBALA: Right.
DR. SAMPLE: If we move to the amphetamine table, which is at the very bottom of
your overhead up there, it looks like that 3x cutoff is consistently less than
the cutoff and would not be interpreted as a positive, presumptive positive,
result?
DR. NIEDBALA: Yes, I agree with you. In the case of the screening assay, the way
this is addressed is that there is a gray zone around the cutoff. And above the
cutoff is generally where these particular assays start to flatten out, in
terms of the standard curves that are used. So positives such as this are
captured as presumptive.
DR. SAMPLE: But that would not be captured as a presumptive positive at the 3x
cutoff because it's less than --
DR. NIEDBALA: Actually, it would be. Because any particular gray zone that is
built around, based on the precision of any particular assay, the gray zones go
above and below. And so you're reporting the capture --
DR. SAMPLE: What you are saying is anything in the gray zone goes to
confirmation?
DR. NIEDBALA: Correct.
DR. WELCH (Board Member): Meaning there is no cutoff?
DR. NIEDBALA: No, there is a cutoff, because there has to be a gate keeping
value that is put on any particular task.
DR. WELCH: There a relationship between the cutoff and the gray zone? Is it
cutoff, plus or minus?
DR. NIEDBALA: The gray zone simply reflects the precision of any particular
result.
DR. SAMPLE: Well, in the case of the amphetamine, times zero-four degrees, would
that 63 percent displacement go to confirmation?
DR. NIEDBALA: I don't remember the precision of this particular assay. Most of
them are around 10 percent or less. If you took the 10 percent around the
cutoff, then you would say yes.
DR. SAMPLE: Okay. Go to four degrees, t equals seven days, 10 percent of the 68
would be 6.8.
DR. NIEDBALA: 6.8, yes.
DR. SAMPLE: My question is would a 60 percent displacement for a 3x, three
times, over the cutoff go to confirmation?
DR. NIEDBALA: No.
DR. SAMPLE: It would not?
DR. NIEDBALA: No. Not in that algorithm.
DR. CAPLAN: If I could follow up. The standard values you have on the left of
the column in the upper group and lower group do not really agree?
DR. NIEDBALA: No.
DR. SAMPLE: But that's explained. That is why I said this 4.2 really was a 3
times cutoff if you read the asterisk.
DR. CAPLAN: Why don't they agree?
DR. SAMPLE: As I understand it, why they don't agree is because this is THC. One
is a THC assay and the other one is THC parent.
DR. NIEDBALA: Yes. I agree with Barry. This is one of the issues around how do
you set standards around the cutoff for performance so you ensure run-to-run
accuracy of any device.
DR. SAMPLE: How do you determine a cutoff? A cutoff is an absolute number. It's
not a gray zone, plus or minus.
DR. NIEDBALA: But every analytical procedure has some variation around it.
DR. SAMPLE: Absolutely.
DR. NIEDBALA: Right.
DR. SAMPLE: But if you extend what is done in traditional urine based testing,
we do not say we get a response, say for amphetamines at 1,000 nanograms per
mL, and we know that the average CV at 1,000 nanograms per mL is 5
percent -- say as a real precision -- and then say, well, if we get a
response that is within 5 percent of that 1,000 it's going to go to
confirmation. It's an absolute.
DR. NIEDBALA: Whether you believe it or not, you actually do that. Because how
are your calibrators or controls made up? What's the tolerance of those?
DR. JACOBS: It is like changing your cutoff to 1,050 instead of 1,000.
DR. NIEDBALA: You adjust, but you have a tolerance within all the materials you
use. Whether administratively or not, you recognize it. You do it.
DR. SAMPLE: To a certain extent, I agree with what you're saying. But you're
really doing a double adjustment. Because the calibrators in an oral fluid
would have that same variation.
DR. NIEDBALA: Sure. And these are the kinds of analytical things we need to nail
down.
DR. SAMPLE: I am suggesting is this is a markedly different approach for
determining the cutoff response than what I have heard with any other specimen
type.
DR. NIEDBALA: Okay.
DR. ISENSCHMID: From a practical standpoint, if you have something that's 50
percent below the cutoff, that's always negative, but you have something that's
three times the cutoff, and it could be negative, maybe these cutoffs are too
low.
DR. NIEDBALA: That's a possibility. Again, you have to go back and take a look
at the clinical data and what you found. Remember, we always use GC/MS as the
defining for true positive and true negative in the specimens that were tested.
DR. SAMPLE: Would this be problematic for PT's and evaluation of PT results?
DR. NIEDBALA: Yes. I think that's why we need to have a project to research this
and see. You're going to see the same thing with the on-site devices. I'll
speak a little out of context, but you look at the precision being plus or
minus 20 percent.
MR. STEPHENSON: This is an area that may be very rich for discussion in a
working group setting or a working PT study, or maybe one of the general issues
we're going to have to address that crosscuts a lot of these after we get the
data in. Chances are your first shot at it will be in your PT study, where you
could look at it across all the different alternative matrices. This may be one
of those generic areas we need to examine carefully.
MR. CROUCH: On page 3, it says FDA clearance should be required for any of these
systems. How many current systems have clearance that you're aware of?
DR. NIEDBALA: For collection and screening, one that I know of. This is for
laboratory based testing.
MR. CROUCH: Which device is that?
DR. NIEDBALA: That was the Epitope device that has been renamed Intercept.
MR. CROUCH: I have seen considerable differences, depending on the concentration
that you detect, based on the collection device and based on whether it's
stimulated or non-stimulated saliva. I think that is an issue in setting this
program up. It is also a very big issue in interpreting what is in the
literature at this point in time. If you do not read the articles carefully,
you really don't know if it's stimulated or non-stimulated or partially
stimulated or what it is. Those concentrations can vary considerably, depending
upon how the specimen is collected. That's my experience.
I would like you to comment on that, about the literature that is currently
available to interpret results.
MR. GOOD: Our work has focused primarily on non-stimulated, non-washed saliva.
We do not use a wash solution. Initially, we were interested in that, but have
gone away from it. I think, like any biological fluid, including urine,
depending on the individual metabolism, you can have the values certainly vary
up and down, depending upon the individual. I think there is a lot of
literature on a reduction in the amount of material in the saliva based on
stimulation. I agree with you, it's difficult to interpret at times from
individual scholarly papers as to whether or not it was stimulated or it was
not. There is certainly an opportunity for more controlled studies to look at
these things in a more definitive way.
DR. NIEDBALA: In our discussions we talk about this in the context of
non-stimulated.
MR. STEPHENSON: Are there any questions by members of the Board on the proposed
changes that have been put in here, with the "B" standing for "blank"? (No
response.)
So you're not concerned about updating the matrix in terms of filling in the
blank, but simply adding the text at this time -- and that is the purpose
by which this offering is made?
DR. NIEDBALA: Yes.
MR. STEPHENSON: All right, that's fine.
DR. CAPLAN: Sam, we left the discussion of whether there would be another
meeting until now. What is your opinion?
DR. NIEDBALA: My thought right now is we would meet after the on-site meeting.
We want to get as many people as we can. We are probably looking at the
November time frame by the time we got schedules together. We have October 5th
and 6th for the on-site one now, and we'll see how many things we can then put
side by side that all match up.
MR. STEPHENSON: I have an update from the Department of Transportation.
They think that the Part 40 is moving along well, in a upward clearance process.
To directly quote Mary Bernstein, but don't expect it to be published in the
next 10 minutes.
That being said, I would offer an opportunity for any public comments, again, at
this time.
MR. ANDERSON: I had some general questions about saliva. You mentioned some
volume requirements for confirmation specimens, 450 microliters, sufficient to
do all five. Are those procedures pretty much widely spread in the industry or
is that R&D type of procedures at this point?
DR. NIEDBALA: Actually, the procedures right now are for non-regulated testing
being used for trial on specimens. This is instrumentation that is typically
available from Marion, HP, Finnegan, from a practical perspective, techniques
like GC/MS/MS, the instrumentations come down dramatically in terms of price. I
really believe this is within the reach of the laboratories to do and not be
overly burdensome in terms of cost requirements.
MR. ANDERSON: A standard GC/MS, a five-year old model, might have trouble
getting these kind of sensitivities, but the GC/MS/MS has no trouble?
DR. NIEDBALA: The standard GC/MS can do the work. There is no doubt about that.
The question becomes workload. This is not a scientific statement but a
practical one. The MS/MS, I believe, provides a cleaner specimen that allows
you to do robust testing. This is an opinion. Standard MS instruments can work,
but I think will require more maintenance. You have to hold the hand of the
instrument, so to speak, closely.
MR. ANDERSON: Is it fair to say that it's kind of premature to send samples off
to get results at this point? Are there places that would do this testing
commercially?
DR. NIEDBALA: Sure. If you know Mike Peat, his laboratory is set up to do this.
You can certainly contact him to get some specimens. There is an issue in terms
of cost and timing, et cetera.
MR. ANDERSON: Another question regarding shipping regulations of oral fluids. Do
you anticipate that drugs of abuse specimens would be shipped under the same
clinical specimen or biohazard kind of regulations that HIV saliva samples are?
Is there some regulations in terms of -- I'm wondering how these things
will be transported?
DR. NIEDBALA: Now they're transported standard FedEx or Airborne packs, similar
to what you might be doing with a urine specimen.
Anybody here on the working group is welcome to jump in. But there is nothing
that came up that said this is an unusual or a hazmat issue that is outside the
standard practices now used.
MR. ANDERSON: Any indication from these kind of shipping studies if the parent
THC and the parent cocaine are different in stability than you're seeing in
urine for the metabolites?
DR. NIEDBALA: Well, this is device-specific and the manufacturer has to be able
to substantiate the stability of either one of those. The target right now in
oral fluids, based on the metabolism of the drug, is the parent. The acid, I
couldn't speak to. The parent is, without a doubt, stable. Parent drug is
hydrophobic and so anybody has to account for that to make sure that it's
recovered off of the collection device.
MR. ANDERSON: A final question about the collection of an adequate volume of
overall fluids. As you pointed out, some prescriptions as well as some abused
drugs probably tend to cause dry mouth. Is it typical that if you have a
three-minute collection period that pretty much, even for the dry-mouth people,
you can get an adequate sample in three to 10 minutes?
DR. NIEDBALA: I do not know of anyone who has conducted studies with people
taking specific drugs. As you said, I know there are specific ones that will
cause dry mouth. I think it was Dr. Peat who had quoted some statistics
on -- and I don't have the slides here -- it was about 10,662
approximately. And out of that, he had about 0.05 percent that had an
inadequate specimen compared to a similar base of urine specimens. Which was
about o.7 percent.
DR. CAPLAN: Inadequate or unacceptable specimens?
DR. NIEDBALA: It was extremely small for that size of the population.
MR. STEPHENSON: But that is not an evasion of testing or a specimen collection.
That is just an inability to provide it. It is not the same thing.
DR. NIEDBALA: Correct.
MR. STEPHENSON: It is not a shy bladder issue. It is an inability to produce the
volume of specimen. I don't think you could treat it the same way.
DR. NIEDBALA: Yes. It's analogous to what happens with urine when someone cannot
deliver. The laboratory never knows about those people. How many people cannot
provide a urine specimen. I don't know, out of the thousands who try, what the
percentage of failure is for that.
MR. CROUCH: How do you determine that the 0.05 percent couldn't provide a
sample? Was that based upon IgG?
DR. NIEDBALA: It was based upon IgG.
MR. STEPHENSON: I want to thank everyone for participating. At this time, we
will adjourn the open session of the Drug Testing Advisory Board meeting.
The meeting was adjourned at 11:45 a.m.
