Department of Health and Human Services

Substance Abuse and Mental Health Services Administration

Drug Testing Advisory Board

Meeting

September 9, 1999

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.