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Department of Health and Human Services

Substance Abuse and Mental Health Services Administration

Drug Testing Advisory Board

Meeting

June 8, 1999

Mr. Stephenson (HHS): Good morning. This is the open session of the Drug Testing Advisory Board meeting and we would like to ask everyone to sign in if they haven't already done so we have a record of who is here. Thank you very much.

Dr. Vogl (HHS): A brief update from HHS, especially for the public attendees. The last time we mentioned that we are working on revising the Federal custody and control form. I placed several copies of the draft version over on the table with the other materials to be handed out today.

We have been working on this for the past several months. We have industry representatives assisting us in putting this form together and we are close to a version we will use in preparing a Federal Register notice and then publishing it in the Federal Register for public comment for either 60 or 90 days.

We hope to do that before the end of July. After we receive the public comments, we will get the working group back together, and anyone else who is interested can participate, and we will develop the final revised form by the early part of next year. This will then be submitted to OMB for approval.

The implementation would be early 2001. We have to allow several months for the laboratories and anyone else to continue using their existing supply of forms. There would be some date established beyond which the current form could no longer be used.

If you have any comments, mail or fax them to us, and we will consider them in working through this process.

Mr. Stephenson: We are all involved and interested in substance abuse and the workplace, that nexus, and the issues that we've always brought to the table in those kinds of discussions have been focused on accuracy, reliability, and interpretation of results for drug testing as it might be part of a comprehensive drug-free workplace program. On March 23rd to 25th, many of us were able to participate in a workplace focused track of a National Prevention Congress. It was one of nine different agenda areas. Out of that group there were 30 different sets of proposals that were put forth to a group of between 350 and 500 people, depending on which day of the meeting you were at. At the end of that meeting, there was a summary report and the part of the group that was still at the meeting, about 40 percent of the total number that had attended, voted on what they thought were the most important agenda items. The number one item identified that came out of the Prevention Congress was the establishment and promotion of comprehensive drug-free workplace programs. That doesn't mean that there were any things that were less important, but what it meant was it was almost a common sense approach that workplaces are at a nexus for a lot of our social agendas that are going on right now, and I think over the last decade we have demonstrated that a high quality program of drug testing can contribute significantly to many of these issues. It protects the public, it protects the individual being tested, and it protects private sector businesses who don't have government regulations to fall on, but must in fact rely on the quality of whatever program they institute themselves.

I thought I would share that with you because it's an important piece for us. It's also consistent with one of the four demand reduction goals for the national prevention strategy out of the Office of National Drug Control Policy. We see this as an important area for us to continue to work towards.

It's kind of ironic, but on the flip side of that same point, I have to tell you that we do not have a confirmation for the September meeting of the Drug Testing Advisory Board because we do not have the necessary funds to travel the members of the Board for that meeting. We are still working on that and we have not canceled it at this time, but we may have to reschedule or move it to the next fiscal year. The primary reason for this is the government plans 18 months ahead for any budget year and, in this particular year, we have spent a lot of time and converted many of what had been planned to be one-day drug testing meetings into two-day sessions to accommodate our agenda to address alternative drug testing matrices and technologies. Because of that, we have consumed all of the dollars that were available and we're still looking for more. Realize that this is going to be a little bit tougher for us than it has been before to get through to the end of this year for any more public meetings. We will certainly try to do that, and we will let the public know as soon as we have an answer.

Mr. Edgell (DOT): I have one thing that I would like to mention at this time, Part 40 has left our office and is in the Department for internal review. After that, we will assimilate the comments and continue the cycle to release it as an NPRM. My crystal ball is cloudy on when that might be, but it is a significant first step and we are on our way to first base with this.

ORAL FLUID TESTING

Dr. Bush (HHS): First on the agenda is oral fluid testing. I'll ask Dr. Sam Niedbala to make a brief presentation and then we'll take it from there.

Dr. Niedbala (STC): The way I'd like to do this is to start every meeting with the bottom line first. If we start with the bottom line first, our working group had its meeting in Pennsylvania in early May. At that meeting, we approached the topic of oral fluid or saliva testing for drugs of abuse by looking at principles first. This is an interesting fluid because there are a variety of ways that it's being used right now and in the future for potential workplace testing. There were some basic principles that had to be discussed and established before we could go further with, perhaps, the more technical details.

Let me review the bottom line conclusions, recommendations, observations that we had at that meeting.

Number one, and this was probably a point that could have been debated, but actually the group -- and I have to compliment everybody that attended - they were very cooperative, very positive in how they looked at the project. The number one issue was that products should reflect drug levels as nanogram per mL of drug in saliva. Therefore, in the future, the recommendation will be that every device normalizes reporting units to this standard. That was a key principle because in a few minutes as we look at one of our other table summaries you will see that there are different devices that collect it along different principles, but if every device calculates back to saliva in nanograms per mL then it becomes a way for us to normalize future products. That was probably the number one thing. If we could accomplish anything at this meeting, we wanted to get to that bullet point.

Number two was, at least at first cut, the list of analytes will mimic those tested in current urine programs and that there is additional data needed specifically for 6-acetylmorphine.

The third one is that the working group for on-site testing should include saliva-based on-site products in their discussions. This group is going to focus on the laboratory testing because it was too much to try and do both at the same time. The recommendation was that that group take on normalizing whether it's urine-based or saliva-based on-site testing in their working group and that this group would look solely at those devices that will be collected in the field and tested back in the laboratory.

The next bullet point was that all products should be FDA-cleared -- they should go through that scrutiny.

Lastly, we talked a great deal about tests to validate the sample and that human IgG was discussed as a possible marker for determining the sample adequacy.

These were the major points that we got through in terms of discussion items. We have another two-day meeting scheduled for mid-July in Pennsylvania, and we'll be at that time intending to go through each of the individual steps, and prior to the meeting we have committed to one another to circulate the information so we come prepared to summarize some of the other individual sessions.

Let me go through a little bit of the data behind things, focusing on the meeting. We listed at the meeting those devices that we knew to be commercially available or somewhere on the near-term horizon and we looked at the companies that offer them and the technology.

In simplistic terms, the way you should look at this is that for these three companies collect in the field and send the specimens back to the laboratory for analysis, and the confirmation also takes place in the laboratory. Whereas these two companies for on-site, perform the test and then it goes on for confirmation.

This is one of the reasons why we decided and recommended that we separate on-site from laboratory-based testing for oral fluids. There is just too much difference in the two in what they need to accomplish and the scope of what the group may be able to review. That was part of one of those conclusions.

Next was the analytes. Again, what we tried to do is go through the list of the most commonly performed tests and take a look at what it is we see as the cutoff for the screen and the confirmation based on the information to date. All of this is precluded on people bringing to future meetings scientific data to support things. In general terms, this is the way we concluded cutoffs to be for the moment, the analytes and metabolites that we would target, and then for confirmation testing also what we would be targeting.

As you can tell, for amphetamines the levels are fairly high in saliva 100 ng/mL screening and 75 ng/mL; THC (parent) with a screening cutoff of about 2 ng/mL and a confirmation level of 1 ng/mL; cocaine 10 ng/mL, confirmation 5 ng/mL; opiates 10 ng/mL, confirmation also 10 ng/mL. You will see free morphine, codeine, as the targets with 6-AM to be determined. That's some of the scientific data we have to come back to the table with. For PCP, we looked at a screening cutoff of 5 ng/mL, confirmation also at 5 ng/mL.

We did go through all of the sections in terms of the factors for reliable testing. Again, I'm trying to boil this down to the things that we had committed to one another or were at least able to take a look at.

When we got to MRO issues we started to look at topics for future meetings.

One of the issues was, was saliva different from urine in target analytes, and again the overall was that it appears to be about the same, 6-AM is questionable, and the clinical study data needs review, and this is something that was committed to.

Is there data to establish differences between abuse and exposure? Also, the list of possible explanations to be discussed/defined as interferences. We listed some of these: for cocaine, cocaine passive exposure; for THC, THC passive exposure, THC hemp oil, marinol; for opiates, passive smoke exposure, poppy seeds; amphetamines, to consider OTC the Vicks inhaler, D versus L, etc. -- just the common list that needs to be detailed for the Board, and we intend to do that at our future meeting as best as possible.

From the meeting itself, we concluded that there were no issues identified, as we looked through the factors, that would prevent future use of saliva as part of the comprehensive drug testing program for the workplace. We stopped at the end and specifically said, are there any killer issues that this group identifies when we look through the list, and there were none that we could see that could not be answered given some time and attention to gathering up the information. In addition, there were data that were promised by members of the working group to help facilitate this next meeting in July. This will include a review of GC/MS methods and performance characteristics to date, a review of potential interferences using saliva, discussions around data, also data and methods to assure specimen integrity -- this is a key one -- and then finally, further discussion of cutoffs for screening and confirmation based on what the companies will bring forward.

If you go through the factors, as we went through each one, we left it as P, I, or the blank, and a lot of the issues that were P's now became Blanks. It became that because as we discussed the factors we didn't think there was anything we could not overcome. You won't see information underneath each one of those bullet points as of yet because this working group has to fill in those blanks.

Dr. Bush: Let's take a look at the purple book which was updated from the one that you may recall from the last meeting, if you were here. Flip to the oral fluids section.

Mr. Stephenson: For the public attendees who haven't attended one of these before, each of you should have a copy of this. You will absolutely be lost without it. But this is an update that Dr. Vogl has done, taking it literally from the transcript of our last meeting, taking input from the various reports of working groups and putting it into this document.

Dr. Bush: In the oral fluids section, you see the issues that were inherent and the integral parts of the draft, the matrix defined in a brief manner, but nevertheless forming the cornerstone for the factors for accurate and reliable drug testing. We have formed a train of events from the very beginning of the development of this table, and have had submission of information and discussion amongst the Board and the technical working group input, and that's annotated then. Look at factor number B, the collector. You can see that under the first issue, training, there's information that was posted, how the matrix looked as of 8-20-1998. Then following our last Drug Testing Advisory Board we had additional information that led us to a change in the evaluation of those factors and where we were in the progress of their evaluation and how they fit into the table now. I'd like to turn it over to Dr. Caplan and Sam. How would you like to work this, since you were the gentlemen who were at the meeting?

Dr. Caplan (DTAB Member): This book doesn't have the May meeting in it?

Mr. Stephenson: Yes, it does.

Dr. Vogl: I put in whatever comments were submitted.

Dr. Caplan: I don't think it will take long because we're in between two meetings. As Sam indicated, we had a very good one-day meeting, but it was the first meeting of this group, and we did identify a lot of things and they're going to come back in the second meeting in July, and I really believe we can wrap it up then, so that whenever we meet next, whether September or October, we'll have most of the answers. I guess it's instructive to flip through the pages. Do you have notes from your meeting with you?

Dr. Niedbala: Yes. The overheads are actually here, so if we get to something that's a discussion item we can view it.

Dr. Caplan: I think we can go quickly page by page and see if you want to make a comment, if I remember a comment, if anybody in the audience or the Board wants to throw something new or additional in. I suspect for this group, I believe all the known manufacturers were at the meeting.

Dr. Niedbala: Yes.

Dr. Caplan: The number is small and all the parties were there. I'm not looking like there's something big missing that we haven't gotten yet. If that's the case, that's where we need people to speak up.

We are starting with A.1, and these are items about the collection site. Some of these things were already prior to this meeting blank, so they weren't in the old book. They weren't discussed in the meeting, but we can quickly go through them.

Dr. Vogl: I wanted to make it a complete section so I added all the factors that were always "Yes" or "blanks" from the beginning.

Dr. Caplan: That's exactly the point. Therefore, we didn't discuss some of those pages again. However, if there is anything new or new thoughts about them as we go through, because the next step and the next meeting is to add supporting information for the areas that we already said are okay. The fact we said they were generally okay by discussion will now by the group have to be followed up to say why that's the case. We can't just end up with a book like this that has all blanks and say it's okay. It's going to have to be filled in. To find out and identify the issues which were problematic or need attention, we want to identify them first.

We have to go back and fill in the whole book, because we need to say why it is okay. Are there any comments along those lines with regard to the collection site? It was never considered that there were any issues. This is A.1, 2, 3, and 4. There were never really any issues there. In fact, one of the stronger points about oral fluids testing and collection is that invariably it's going to be a witnessed collection since the individual has to be there and the collector has to be there physically with the donor, unlike urine. The site would be a lot easier to manage and the individuals that are being given the device to use will essentially have to be under direct observation. This whole issue about specimen substitution, adulteration, all those things, should be much more manageable to control. Do you have any other comment on A?

Dr. Niedbala: No.

Dr. Caplan: Anybody else have anything they'd like to add about that? (No response.)

The collector, B.1. This was, prior to the spring meeting, considered to be without any other issue, and certainly we'd have to fill in what the training should be and the fact that there are a number of different models. Therefore, the collection process, again by comparison, like urine, there won't be only one way to do it.

Regardless of what lab it would be, there will be device-specific collection issues perhaps. That would kind of follow how the alcohol program is today, so there is a model for that. And there didn't seem to be any concern there.

Dr. Niedbala: I think one key point that Yale made is that as we discuss things, whether it's proficiency testing or collection protocols and training issues, I think the DOT model for alcohol saliva offers us a starting point, and we intend on taking a lot of the strategy in our approach to each one of these.

Dr. Caplan: The next one was B.2, collector certification. Again, we already changed that one to yes. There are going to be some issues which are brought, when this is all done, are going to be across the board issues, meaning that if we don't certify certain people in one field we'll probably look at whether certification is needed in a variety of areas.

We agree that certification is possible. Whether certification is required or what level, that's going to be a policy type determination at a later date. From the technical working group, that's certainly possible.

Dr. Caplan: Again, if any of you are representatives of groups that are involved in collection, I know there are a number of movements going on with regard to urine collection and improved programs and certification of urine collectors and all that. This should follow a similar thing. Again, like the DOT alcohol model, there is obviously going to have to be some sort of collection training protocol. Whether it's a model program or whether it's a certification process or whether it's manufacturer-driven will be a policy thing. All of them are readily possible, and I suspect that we will as a group make a recommendation along those lines, but that's as far as you can go. Any other comments on the collector and the certification of collectors? (No response.)

Dr. Caplan: Collection devices, C.1 and 2, again, there was no problem. There may be something, but on the principle of the devices and things that may come there are at least three and maybe four different ways that the saliva can be collected. That is why Sam indicated when he started one of the big issues was are we going to revert this to a specific uniform entity, which we decided would be appropriate and recommended that, or do we have to look at different cutoffs, because a lot of these devices collect the saliva and dilute it automatically. Why don't you just summarize those again.

Dr. Vogl: I know the working group changed it to a yes. I didn't change it here because there were no comments provided in your summary that supported changing that to a blank.

Dr. Niedbala: The only comment I'd make is at that next meeting to make a consensus statement about each one of these, either a very specific one or a general overview kind of statement, to give a recommendation and even some guidance, if possible.

Mr. Stephenson: What you're really saying is we'll discuss it here, but we're not at this point putting forth the evidence or the information to have us consider it and then officially change it in the document, that you've already got the next working group meeting set up and that after that that's when you'll have it all packaged?

Dr. Niedbala: That's right.

Mr. Stephenson: Okay, that's fine.

Dr. Caplan: You were going to comment on how they collect the specimens.

Dr. Niedbala: This is a complex picture because there are different manufacturers who offer different modes of collection. Some claim whole saliva, others claim to collect something that also has some of the blood components in it. Because of the different technologies that are available, the important point here is that there are some basic pieces here that go along with each and every collector.

Obviously, you all have to put something in your mouth that's going to absorb something, and that each manufacturer will have to substantiate against the guidelines or the criteria that are being addressed by the group or recommended by the group to normalize their device against everybody else's. I think this will create the ability for different technologies to come to market, but yet have good stringent scientific criteria in order to present their products.

Dr. Caplan: Does anyone want to make any further comments on this?

Mr. Good (Avatar): I think Sam said earlier that the cutoffs were calculated back to whole saliva rather than looking at the cutoff based upon the sample collected and I think that was what you said here. It doesn't change that consideration on the cutoffs. We're still working back to saliva.

Dr. Caplan: Any other comments about the collection device?

Mr. Stephenson: We are discussing factors where you've got a few issues and we'll make these changes with the written materials at the next meeting; is that correct?

Dr. Caplan: Generally. I don't think there were any specific issues we want to change, to try to change the categories for now.

Mr. Stephenson: Right. These are just an opportunity to go through dialogue.

Dr. Caplan: The next was C.2, and I don't believe there was anything there.

Then C.3 was the FDA clearance. We could comment further on that one. You focused on it before. You might want to reiterate it now.

Dr. Niedbala: Yes. For all parts what I'm noticing, because I hadn't seen this before today, is that you had taken a lot of transcript language and put it in here. Whoever reads this, whether it's this part or any other part, you have to understand this was part of that dialogue of ten or so of us in the room. As you read these things, more questions may come up and I guess they can be directed back, which we're happy to clarify. But in this particular section the whole concept was that FDA should review these products, and that was one of the overall bullet points.

Dr. Caplan: If you want to consider that one, that is one that will probably get us from a B to a blank.

Dr. Vogl: You mean that oral fluids endorses or would want to have FDA clearance?

Dr. Caplan: Yes

Mr. Stephenson: The issue is we need to take that into consideration, as you already referenced here, that's going to become a policy call that we would look at a later time. Your recommendation is that it would be a blank because you think that this is something that is positive.

Dr. Caplan: Right, and that could be noted here on your next edition, that that is the recommendation.

Dr. Niedbala: Yes.

Mr. Crouch (Board member): I have a couple questions, Sam. We talked about this the other day. As I understand this, the test is tied to the collection device.

Dr. Niedbala: Yes.

Mr. Crouch: If someone took a collection device and used another, say, a non-STC/ RIA kit that did not have FDA approval –

Dr. Niedbala: Correct. As another way of looking at it, there are collection devices, some of those named, that have FDA clearances as a collection device, but not for any intended purpose. The analogous type of application would be something like HIV. The FDA has cleared devices along with test kits for HIV. Similarly now, they've done collection devices plus kits for saliva.

Mr. Crouch: Does it preclude someone from buying another device and using STC's immunoassay?

Dr. Niedbala: Yes, because the kits, as an example, all are calibrated for use with this one collection device. If someone were to take a kit and use it on a different collector with a different fluid, different technology principle, it could have entirely different performance characteristics with that other device. So a laboratory would have to be very careful about doing that, whether it's an STC kit or somebody else's kit, because there will be differences.

Mr. Crouch: Do you see a potential for someone -- and I guess it's already out there -- to make a generic collection kit and then it would be up to the laboratory to validate whether or not that kit works for them? Is that still acceptable under FDA?

Dr. Niedbala: Then you get into the whole home brew question for the laboratories, and that has its own set of criteria and issues. But the medical device manufacturer cannot knowingly have an FDA clearance for something and then sell the product for something else.

Dr. Caplan: Is your question whether or not it can go to multiple laboratories if the laboratory was linked, if the laboratory process was linked to it

Mr. Crouch: No. My question is are they two independent phenomena or two independent clearances, one device, one kit, or are they more likely tied together?

Dr. Niedbala: They're tied together.

Dr. Sample (Board member): Is that always or in some cases, because I thought I heard you say there are some devices that are cleared just as collection devices independent of the test methodology.

Dr. Niedbala: If there are cleared devices by FDA and somebody would use -- and again this is just my experience FDA. I don't know if there is anybody here in the room that can speak to this. But if there is a cleared device for no intended use for collection of saliva and then somebody uses it for a cleared purpose, then they would be in violation because the kit they're using has not been matched to it and it doesn't have the claim substantiated by FDA for safety and effectiveness.

Mr. Crouch: What about a 510k, where somebody comes along and shows equivalency with their device, equivalent results to the ones you're getting with your device in your kit? Are they then cleared only as a collection device or are they cleared as a collection device and a test?

Dr. Niedbala: It depends on what they would claim. It really comes down to that. If they had a different collection device and they used someone's kits that were also used with someone else's, then, sure, that could become another cleared application and intended purpose for that kit.

Mr. Stephenson: I'd like to go back to what Sam had originally said, that he is not purporting to be an official spokesperson for FDA. Our questions to him are only a reflection of his experience and his interpretation of what he thinks FDA would want to have. It's probably fairly accurate historically, but that doesn't predict where FDA may wish to go in the future.

Dr. Niedbala: And I'll quote FDA: At this time we will choose to regulate according to what we see to be appropriate. Having done about 40 or 45 of these submissions, that's where I come from in the experience.

Mr. Sample: In relating the drug concentrations back to nanograms per milliliter of saliva or oral fluid, that's really being tied as well to the testing methodology, is that correct? It's not really device driven. It's device plus the coupling with that test methodology.

Dr. Niedbala: That's correct. And I would envision for the first set of kits that are cleared right now by FDA that those manufacturers, myself included, have to go back and restate the package inserts to reflect that so that all users can look at the same sort of apples to apples comparisons.

Dr. Sample: I guess where I'm going with that question is that in the case of oral fluid you really are almost -- you almost have to be paired with test device and testing methodology because of this need to get back to nanogram per milliliter of original saliva regardless or irrespective of the collection device used.

Dr. Niedbala: Yes, I would think so.

Dr. Caplan: Maybe we're confusing on-site with the laboratory. The laboratory scenario, which we've decided to focus on here, we need to collect it, we need to send it to multiple laboratories. So it would be necessary that a device to collect the specimen and that device be FDA cleared to collect. Then it would have to be tested by multiple laboratories. What's not clear to me from what you've just said is whether or not each laboratory would have to clear a method for this to be cleared.

Dr. Niedbala: No, not each laboratory. The manufacturers would have to have a clearance for a particular use with a particular device.

Dr. Caplan: It's a use meaning a laboratory-based test, but a laboratory-based test doesn't have to be cleared to have a collection device?

Dr. Walsh (Walsh Group): We went through the same issue. There are two different types of clearance here that are kind of getting mixed. Sam alluded to it. When Sudormed came up with the sweat patch it had been cleared by FDA as a medical supply and they tried to market it as a drug test, and the FDA, with encouragement of this office, formerly at NIDA, shut them down on that issue and forced them to go back around and to have it cleared under the Medical License Act. This leads me to my question, that I think Denny was getting at. Sam, do you see that the diagnostic manufacturers who are developing assays would have to specify the collection device in their application to FDA for clearance?

Dr. Niedbala: Yes.

Dr. Walsh: Then any on-site test would essentially be a package deal that would include specifying the collection devices that could be used with the kit and demonstrate data as part of their application process with FDA?

Dr. Niedbala: Yes, to separate out laboratory based testing at least from what's discussed so far is that they would have a certain screening kit that's used in the laboratory and that the collection devices matched to that. The precedent was set with the sweat patch and also has been set recently with those devices or those products that have been cleared already for saliva. I would anticipate that stays the same. On-site, to me making a saliva alcohol test, it's a single use collector with a single use device, and I think that's the way it comes prepackaged.

Mr. Crouch: How many cleared collection devices and/or processes are there right now?

Dr. Niedbala: As collectors alone?

Mr. Crouch: For drug testing.

Dr. Niedbala: For drug testing, I would imagine we would consider two. Avatar has a saliva collector, but that's for on-site. There's one right now.

Dr. Sample: If there was more than one and those oral fluid specimens could be going to a variety of laboratories, those laboratories then would need to have a different screening procedure for each device that they receive?

Dr. Niedbala: That's a potential issue. The laboratory I would imagine would normalize against that problem in their collection kits only using a certain device.

Dr. Caplan: It doesn't prevent the device from coming on the market, which just links to a variety of things in the laboratory. The ones now are linked to specific products because, I guess, there hasn't been a market just to collect and send to a laboratory. That's clarifying. I wasn't sure about that before we started this, but definitely the laboratory is doing the immunoassay test, if that's the one they're doing, that has been cleared by the FDA with the collecting device in the laboratory before they do the confirmation.

Dr. Niedbala: That's correct.

Dr. Caplan: I guess in that case they can't just take the fluid in the buffer and use another immunoassay.

Dr. Niedbala: Right.

Mr. Stephenson: I remind everyone this is a discussion and clarification that's internal to the Board and not necessarily encumbering the FDA for any potential use. I will tell you that I think the dialogue here and perhaps in the other segments where we deal with the other technologies and specimens should have the same kind of focus, with a sense of the experience of the participants that can be taken back through our transcript process and shared with FDA, because it may be a reflection of some things that will help position them to help clarify. Again, no one in the public should take this as a definitive statement of direction by anybody in the Federal government. But it is a very enlightening dialogue.

Mr. Crouch: Is the process proprietary or can the laboratory use a collection device and their own methodology? It just would not be an FDA-cleared process then.

Dr. Niedbala: On that particular issue, I don't know what the regulations state for the laboratories. I think that comes back to the home brew questions and all the quality control requirements that go along with doing that by a laboratory.

Dr. Isenschmid (Board member): Sam, you said you could not knowingly sell your collection product if a laboratory was not using the FDA-cleared protocol.

Dr. Niedbala: That's correct. FDA holds the manufacturers accountable for that and there are precedents where they've gone and, as was said earlier, asked companies to stop selling products because they did not have the proper clearances to do so. And I'm glad they're going to comment on everything I've said, good or bad.

Mr. Stephenson: Do you want to know what they've said?

Dr. Niedbala: Sure.

Dr. Caplan: Well, the key here, as Bob has said, as we go across this we have to decide what we want to recommend and what we want to ask FDA to do as well with us. The example, good or bad, is the urine, dilutions of urine, agents and other reagents in the laboratory, which this agency has had an agreement with FDA that said this was an appropriate practice and it's checked through the inspection process. So there are things that will have to come out of this that will be the recommendations, that we might want the product with initial FDA collection, but this program might be able to modify that by some arrangement either within the program or with the FDA. But the discussion is important to find out what's out there, how they work, and what each element is up against as they put their product or their process into the marketplace.

Anything else on the collection devices, which is C.3?

Dr. Caplan: C.4, which is impact of device on specimen, probably that's covered with the previous discussion.

Dr. Niedbala: Right.

Dr. Caplan: D.1, which is the specimen and the body site, that was already done.

Dr. Niedbala: We know what site it is.

Dr. Caplan: Do we know what it is?

Dr. Niedbala: No, that's the problem.

Dr. Caplan: No, that's the other. Anybody want to make any comments on the uniformity of the oral fluids specimen? We know it comes from multiple sources and it could be diluted with other things.

I'm still on D.1, which is the body site. We are collecting it from the mouth. I'm just asking if there are any comments and whether there's any problem. As the group, when the group met there did not seem to be any concern about whether or not the specimen was so substantially variable in the mouth that it couldn't be used.

Dr. Niedbala: I agree. We didn't spend a whole lot of time on this. In other sections, we talked about influences in the oral cavity, but not any issues directly of saliva or oral fluids alone, yes.

Dr. Mitchell (RTI): I do think the question came up here in our discussions whether or not two specimens or two samples taken from either side of the mouth would be the same, and I don't think there was a resolution to that at that point in time.

Dr. Niedbala: No. On that issue we had committed to bringing back to the next meeting before the working group to look at that question. Bilateral collection will be addressed at that time.

Dr. Caplan: D.2, multiple testing.

Mr. Liddy (Walsh Group): I wanted to, in terms of body or site, to discuss whether we're going to consider stimulated versus unstimulated saliva and condition, because at the working group meeting we were discussing about how some devices to collect you might want to give the donor a lozenge or a sour condition so there was stimulated saliva, and is that going to affect the concentration of the drug in the saliva. If there should be a policy about that, that's basically what I'm asking.

Dr. Niedbala: I know we touched on it. Ed Cone had some comments on it because a lot of his studies were done with stimulated saliva. But I don't remember what we concluded other than it should be on the agenda and we should make some sort of statement about it, or at least the manufacturers should supply data on whether stimulated versus unstimulated.

What we will do is walk a line on some of these where the manufacturer may say, I've collected unstimulated saliva and then I've gone on to test that and that's all I can claim. If you do something different than that, you're outside of what's been claimed and validated for those conditions. That would be probably the starting point, but we should also collect any data and put that on the agenda.

Mr. Stephenson: If you look at two areas, one area would be delta-9-THC, its presence in any subsequent test or collection of oral fluids; and something you put on your issues that you still needed to address, passive smoke from opiates. These are two issues that I would think are a little different. They're not external contaminations per se, but they're markers for difference between the presence in saliva from perhaps smoking or ingestion versus coming back out as a reflection of plasma levels or something like that. I think that's one of the areas that's unique for saliva that you might want to address, because there's always a temptation to draw correlations, i.e., potential for impairment measurement. I think those are two that you'd want to look at.

Dr. Caplan: Along those lines, there is going to be one major issue and that will probably come later in the pharmacologic end, is that in saliva we are measuring essentially parent THC which is adhering to the mouth, not having been metabolically absorbed and excreted. The question there, which parallels your question, is whether or not this process -- whether it can be used for direct impairment or not is a longer question, but whether or not that parallels in time a detection window equivalence. That is one fairly fundamental question that still needs some further elucidation. It has been shown that we're able to see that, but in this case we're not seeing THC which is absorbed and excreted. We're seeing a phenomenon of adhesion and then release over a similar period of time. One may ultimately want to argue that on its merits and we'll probably get to that. But the technique for detection is not metabolic. It's a little bit different.

D.2, I guess we're finished with D.2, multiple testing.

D.3, potential to split the specimen. That's what you mentioned earlier.

Dr. Niedbala: Bilateral collection.

Dr. Caplan: We're looking at bilateral collection and what those differences are.

Dr. Sample: I'm not sure it should be a blank at this point until we resolve some of those questions.

Dr. Caplan: Which ones?

Dr. Sample: On the split specimens.

Dr. Caplan: It was already a blank.

Dr. Sample: No, it was a P.

Dr. Caplan: It was created with a blank. It was changed to yes. I think the conclusion was that the specimens could be split. Now, whether the split of the specimen is of a uniform specimen once it's collected, the integrity of the composition of which is variable, or whether there are two separate collections might be the issue you're talking about now. But whether it could be split or not was the reason it went to the yes. I mean, you could collect what you're collecting, whether it is a specimen into the buffer, and then you could split that specimen into two component parts so you have an equal split of whatever you got. That's different than the bilateral collection, which is collecting it twice for two different sides of the mouth. This is why -- this process that we're going through of changing these things the best we can doesn't preclude the fact that when this is over we have to go back and look at all the blanks and say why and do this again across the board. So I don't think we need to be real concerned. We still have to justify the blank. The idea was is it possible.

Dr. Sample: I guess my concern is I don't want us to think that this issue was closed because it seems to me there's a lot of open issues still with respect to how one would deal with split specimens with oral fluids.

Mr. Stephenson: This is an example where I think internal consistency across the specimens is important to look at, too, because we're going to have to measure these at about the same point in time in terms of information to make a policy decision on them in terms of how we want to go about this. I think there are some science issues here that are unique to the collection device and maybe to all the related things with it, and I'm a little concerned if we have gone to a blank for saliva and yet for hair and on-site we've left it at a P, which is apparently, Barry, what you're kind of saying. It's possible that you're concerned that we've gone directly to a blank. Sam, would you have any problems?

Dr. Sample: Which implies that we've laid all the issues to rest and I don't think we have.

Mr. Stephenson: Could I suggest that we consider this one going back to a P in your area and that you will add this to your list of things to provide additional materials for after your July meeting.

Dr. Caplan: Okay, absolutely.

Mr. Stephenson: All right.

Dr. Caplan: All right. For the record, we'll make D.3 "P" again. D.4, specimen stability and storage. We still have data coming on that, right?

Dr. Niedbala: Yes, and that's going to be based on data that I took the responsibility to work on. I still believe each device is going to have to substantiate. If you tie that back to an FDA review process, stability, storage stability, is one of the things you have to answer.

Dr. Caplan: Section E, the collection procedure. E.1, donor ID, I don't think there's anything there. There was a lot on E.2, preparation of donor. Any other comment on that? There wasn't anything new that came out of the meeting on that?

Dr. Niedbala: No, not at all. Prepare donor for specimen, this one ties into a couple of other assumptions, which is what's the protocol with the waiting period or anything that's required before you actually collect the specimen, and to substantiate that there's no influence of food or soda or anything else that you might have done for a period of time before collecting a specimen. We said we would come back and discuss this one at length to be sure that the 10 minutes or 15 minutes, whatever the final recommendation is, has the scientific information behind it to substantiate that that waiting period is correct.

Mr. Crouch: Is this to ensure that there isn't something else in the mouth, or is this to ensure that the sample would be representative of possibly plasma or blood concentration?

Dr. Niedbala: No. The screening kits will claim certain interferents that have been tested and those interferents need to be substantiated against specimens collected from people who have taken or been dosed with all of those potential things, soda, orange juice, etcetera. This is -- at least the discussion is viewed more from the standpoint of the procedural aspects of collecting a specimen from a donor and how are you sure that the specimen -- or that the donor is now ready and that the specimen will be valid.

Dr. Caplan: The next two, E.3 and 4, there was nothing. E.5, specimen integrity and evaluation, there was a lot of discussion about that. You mentioned a few things, and the discussion focused more on, A, the fact that it's almost an essentially observed collection, so you're going to get what you're going to get. The question was whether or not there was a marker, IgG or amylase or other things, which could be used like creatinine for urine, to look at whether an adequate specimen has been collected.

Dr. Niedbala: There were some literature references handed out to the group and we're going to come back and look at additional data, because this IgG test has been performed on all the clinical specimens collected to date that we've done and we'll use that as an example of a starting point to evaluate if it's an adequate marker. I think the principle was everybody agreed that some marker to show sample adequacy is important in sample integrity.

Dr. Caplan: E.6, anything further on that with respect to deter tampering and adulteration? (No response.)

Dr. Caplan: There was discussion about the types of devices, how it gets the saliva out, whether the person cooperates or how much they have to cooperate. I believe that was it. There weren't any other issues associated with that. That's still not concluded.

Transportation, no problem there.

Section G, laboratory testing, G.1, criteria for accessioning. I don't think there's any issues there.

G.2, short and long-term storage. Any further comment there? (No response.)

There was something from the meeting on the stability of 6-AM. Any other? (No response.)

G.3, specimen identity. Does anyone have any further comment on that?

Dr. Niedbala: No. I think the one thing we did talk about was this, at least for a few minutes, since this was a very easy specimen to collect and observe, that any potential adulteration -- one part is that direct observation is very easy and should be identified without too much problem.

Dr. Caplan: G.4.a, initial testing. That's the issue of FDA cleared. Sam covered that earlier. G.4.b, initial test to detect HHS target analytes. There was a lot of discussion about that, and the THC issue that I mentioned earlier was the biggest question or concern. I guess, surprisingly, that the information is that there are more metabolites and less parent drugs than at least I thought we were going to hear about detected. Do you want to comment any further about the correlations on these?

Dr. Niedbala: You mean in terms of windows of detection or metabolites?

Dr. Caplan: I was thinking of windows, but it might be another question since I can't predict the next question that's coming.

Dr. Niedbala: We had committed to one another to summarize the windows of detection concerning urine and other fluids between now and July, and then we'll be able to present that as a data summary to the Board to follow up on that.

Dr. Caplan: G.4.c, use established testing levels. There was a lot of discussion about the cutoffs. The key thing was normalizing all products to a saliva concentration instead of the dilutions which many used today, and the suggested cutoffs at this time, as Sam showed you earlier, they're also on this sheet. I think a couple people had some more data. Is this the revised data?

Dr. Niedbala: Yes, it is.

Dr. Caplan: I know there was some data which actually was revised after the meeting based on experience which couldn't be directly recollected at that time, but that's up to date here. This is the best thought of all the people that are doing this, the laboratories that are doing this, at this time. They may need a little revision, but it's close.

Dr. Niedbala: Mike Peat had committed to coming back with that info.

Dr. Vogl: Isn't that for each collection device -- do you know or can you determine how much saliva is actually absorbed, plus or minus a certain amount?

Dr. Niedbala: That's where we had discussions early on, because some of the devices may collect -- for example - If somebody spit on a piece of filter paper and shipped it back to the laboratory, there's a finite amount of liquid that was absorbed into an area. It's the same thing with these other collectors. The caveat is, though, that several of them have a fluid in the tube that acts as a preservative when it's shipped back to the laboratory. So there's a dilution. But you can back-calculate that and therefore normalize. That created the opportunity then for us to normalize all of the devices.

Dr. Caplan: While that might not be known today, that was doable and would be required in any process to make it uniform. Today the saliva goes on a device. The exact amount collected is not measured. It may have been studied at one time, but it's not that precisely known, and then it's diluted and the results are done on the basis of diluted concentrations. We decided that that would have to be -- the amount of saliva collected by a particular absorbing device would have to be known and then the dilution back-calculated to saliva units, so that anybody that came home with other devices would have to meet that criteria in the future.

Dr. Vogl: I think we talked about this briefly the last time. Are these levels or concentrations near the limit of detection, or have you arbitrarily selected concentrations that are three or five times higher than your LOD or LOQ?

Dr. Niedbala: No. The data that we have talked about with people committing to coming back with confirmation was based on ROC analysis comparing urine and oral fluid specimens which all were confirmed with GC/MS. The cutoffs selected were done analytically, the same way that it was done for the sweat patch several years ago. FDA has suggested that be the way, and I think some of the more recent NCCLS documents on how to look at new methods for immunoassay, also tie into using ROC analysis. It's not simply based on looking at two or three standard deviations from the zero and saying that's the lowest we can detect, therefore, that is the cutoff. It really is based on the clinical specimens that have been examined, both negative and positive populations, and then predict a value against those.

Dr. Caplan: G.4.d, initial test acceptable performance around the cutoff. This was an area that needed further information. The laboratories that do it have some information, but it was not available at that time and would have to be obtained. So there was no change there. G.4.e, initial test, ability to repeat initial test. I don't have anything on that.

Dr. Caplan: Dr. Mitchell, I don't recall anything specifically discussed about that, so that's still pending.

Confirmatory test on G.5.A. Any comments on that? The comments were made by Mike Peat, who has most of the data on that. Again, the data is forthcoming to support that. It is routinely being done.

Dr. Sample: There is evidence that traditional GC/MS will detect parent THC at 1 ng/mL in 150 microliters of oral fluid?

Dr. Caplan: Traditional?

Dr. Sample: Yes.

Dr. Mitchell (RTI): Repeat your question?

Dr. Sample: I'm wondering if there's adequate sensitivity with the usual GC/MS instrumentation that's employed by many laboratories to detect one ng/mL in a 150 microliter specimen of oral fluid.

Dr. Mitchell: 150 microliters, where is that? Is that from the earlier table?

Dr. Sample: Yes, it said 150 to 500 microliters is the specimen size. I'm talking about bench top type.

Mr. Crouch: Bench top CI. I think it's going to be a challenge, but certainly some chemical ionization methods would work.

Dr. Caplan: I don't know what methods are being used. Mike was going to go into that. That was additional information. He does not use HP equipment, right?

Mr. Crouch: Right.

Dr. Mitchell: I think that was one of the issues we said we had to wait and see the data in order to evaluate it.

Dr. Caplan: It was possible. Whether it was possible with the 5700 HP's or not and which ones was really not discussed. It was definitely possible with other GC/MS instrumentation, not necessarily MS/MS. That's data that should be coming back at the next meeting.

Mr. Good: I wondered, Sam, if these include the dilution or if they're also worked back to saliva? Is the real sensitivity one-third of that stated, or would it in fact be 3 nanograms for a 3 to 1 dilution?

Dr. Niedbala: For the GC/MS, Carl, or for the screening assays?

Mr. Good: For the confirmatory assays.

Dr. Caplan: The confirmatory assay will have to be run on the diluted, whatever specimen is submitted. It's going to have to have sensitivity sufficient to do that.

Mr. Good: These levels are really three times higher than what you'd actually have to obtain in the laboratory? Or is the actual confirmatory level 3 nanograms of THC, or is it three-tenths of a nanogram?

Dr. Niedbala: The table, that first table I put up which had the confirmatory methods, that matched it as ng/mL saliva. That did have the levels in there. Yes, this first one. Both are stated as ng/mL in saliva.

Mr. Good: A GC/MS on the eluted sample would have to be three-tenths of a nanogram if you went back to one nanogram?

Dr. Caplan: Right. But if it's diluted, you could use a larger volume. If you were to use the same 150 microliters, you'd have to be more sensitive.

Dr. Niedbala: Yes.

Dr. Caplan: I lost track of where I was. We went back to G.5.a, confirmatory test. We talked about G.5.a, which is more data. We needed a lot more data about the methods. They are being performed by several laboratories, but we did not have data at the last meeting to review and that's a problem for the next meeting.

Cutoffs reflecting drug use, G.6. That's the window, and we do need -- we are in search of more data for that.

Dr. Niedbala: The other comment we had on that is that we are comparing it to urine testing with GC/MS as the gold standard in every case.

Dr. Jacobs (Board member): I think we need to look at all of the different testings here and look more at the cutoffs. I'm not sure how some of those cutoffs are relating to each other or to some of the relationships. The recent raise in opiate cutoff -- and now I see here that what we see, the opiate looks very low. Are we going to get into the same type of situation with the very low opiate cutoff we just changed in urine?

I'm not sure what the relationship here between the different saliva, sweat, hair, urine, the different cutoffs are, and what they mean and what they relate to. I think all of the different working groups are going to have to look at these questions.

Mr. Stephenson: I think that's a good preface to remind us as we go through each of these sections, to look at this, because ultimately we're going to run out of science to help inform us and we're going to have to sit down and make some decisions about where this program needs to go, and that kind of information has got to be present.

Dr. Sample: I have a general question. I see that on several of these things we're saying more data is needed or more data will be provided at the next meeting, but yet they've been changed to a "B" or a blank, and I'm wondering if more data is still needed wouldn't that mean that it's possible and not that it's been resolved?

Dr. Caplan: Yes. The problem with doing these assessments is when you have one group of this size, you have another group of that size, and everybody says this can be done -- which is why we're doing it multiple times.

Mr. Stephenson: This again is what we have said before, that you're going to come back with more information. I think for purposes of the clarification and standardization we will wait until the next time before using any of this for any judgment purposes. This is an interim document that's simply being looked at.

Dr. Caplan: Correct. I want to reiterate, the process of making something move along just means we have more information. In the end, we have to go back to every blank and re-approve why it's blank and fill that in with information. In order not to focus on doing that first and to focus on trying to do the things we seem to be missing, we are forcing more things in that direction for later evaluation to get to the -- "to spend the time on the bigger issues."

G.7, internal QC program. Any comments on that? John?

Dr. Mitchell: No.

Dr. Caplan: You were there. We've got to use you. There weren't any issues discussed.

H.1, certified laboratory program. Nothing to prevent doing this in the future, but a number of things would have to be done to achieve that sort of thing. Do you want to make further comments on that?

Dr. Mitchell: Currently there's not a certification program available for saliva, and neither is there an external PT program. Those issues -- we talked about them and what would have to be done. It certainly appears to be possible.

Dr. Caplan: The same thing on H.2, external PT specimens.

Dr. Niedbala: We had talked about the external PT and using the sort of analogy for the future, in other words, the idea being that there may be a specimen group created and that different collectors and test methods may all become a bank of data each comparing their methods against those specimens, and then that would have to be monitored to have this external PT program. Is that fair? Do you want to add to that? As one potential way of going about doing this.

Dr. Mitchell: Right, that was one of the questions. The question was whether or not it would be advisable to send the PT samples to the laboratory on the device or whether it should be submitted as a solution, a saliva solution which contained analytes. That's a decision that would have to be made after more information is gained, I think, for some time. I think it's possible.

Mr. Stephenson: One of the things that comes up at this point, I'd like to draw the attention for the public and again for the Board that as we look at the external PT program as a part of an initial certification review and ongoing proficiency challenge as part of our continuing certification, we've requested that RTI begin the process of looking at how to create those specimens and at what levels they should perform.

One of the things that we'll be talking about will be how they can participate during these group meetings, and we'll be coming back to help inform the Board. As we learn more about what happens in the individual small working groups, it will also help inform us about the things we need to be doing in parallel to develop the PT programs that will help for the initial certification and ongoing maintenance process. And that goes across all the specimens.

Dr. Caplan: The CAP analogy that's noted on there is the difference in procedure. In most of the PT that we've been involved in with urine, there is basically one specimen and everybody gets the same thing and does it the same way. But clinical laboratories that test for a particular analyte may test it by a number of different methods. Usually the point of care type methods have a number of nuances, often the data is grouped by method or process-specific. That would be new or something that we would have to consider, if that was the case. That's because of the need of the large groups that CAP serves to do 100,000 clinical tests, and do a PT for it. You run into a lot of method-specific things and a lot of other arguments. That's why we say the analogy here, it's the method-specific classification of processing. We certainly want to avoid that if we can, but that was discussed.

Laboratory inspection. Any other comment on that? That's certainly possible to do.

H.4, blind samples, any comment on that? There was discussion.

Dr. Mitchell: Certainly, if an external PT program appears to be possible, then this would also be possible.

Dr. Caplan: Right. It's just a matter of whether they use simulated specimens or collect real specimens. This is another thing that CAP has dealt with, and in a lot of the CAP surveys they are simulated specimens. The urine, many of the urine specimens that are made for CAP purposes are synthetic urine. We may have to look at that if there are other situations here where we can't use the direct fluid.

Reporting, there really wasn't anything there, nothing at all with reporting. The whole reporting, the I section, 1, 2, 3, 4, I guess there wasn't a lot of discussion around this. There didn't seem to be any need.

MRO, the J section. Again, we didn't spend any time at that meeting on this. Does anybody here have any comments on any of the MRO-related things? We have to know more about the window in the clinical studies.

Mr. Stephenson: I don't want to underplay this, but it's an important area. When we say we need more information, I think it becomes one of the critical elements that safeguards the entire process, is how we inform and educate those that we have charged as doing the final audit for our entire program, the medical review officer. So maybe at a time when we get a little further along we can actually set up a part of our Board meeting when we have this information, we think we have it, and actually offer it for discussion with a group of medical review officers as a part of this process and see where the comfort level is there.

Dr. Caplan: The miscellaneous issues. We already discussed the dose response, the dose-time-response situation. Is there anything further on that? That was one of Sam's first slides. And the same thing with specimen contamination. I think that's it. Anybody else want to make any comments on anything along the update of the saliva review process? Anybody that was at the meeting? John and Sam and myself and Charlie.

Mr. Meeker (PharmChem Laboratories): I have a question on the adulterant issue. Have you looked at the possibility of someone having something like adulterated candy where they could put something under their tongue and it would dissolve? I don't know if it's possible, but it would seem like if you put something in your mouth you get a very high concentration of some adulterant in the saliva. Have you looked at that possibility?

Dr. Niedbala: Again, this working group is going to look at all of this. We have tested a number of things that go from toothpaste through soda or orange juice. I don't know of an adulterant tablet. I'm sure we're creating a new industry as we speak. But we have not found something that -- as long as, if someone does that and then we properly collect the specimen, call it the 10 or 15-minute waiting period, then we've taken those specimens and tested negatives and spikes, we don't see differences from normal activities like that.

Dr. Caplan: And there would be consideration, as Sam mentioned earlier, in this process of some sort of monitoring period or perhaps mouth-rinsing period, and maybe we should all promote sodium hydroxide chew tabs on the Internet and take care of these people right up front.

SWEAT TESTING

Mr. Stephenson: At this time we're going to begin with our next segment, which is on sweat testing, and to predict that this will not take the remainder of the morning. We'll have some choices to think about a little bit later on. I would like to retain the integrity of each of the segments, so that we're not breaking up any presentation to go to lunch. But if we do break a little bit early, then we may go to lunch a little bit early and then come back, and then we'll begin hair testing and then come back. Neil Fortner is going to give the presentation on sweat testing.

Mr. Fortner (PharmChem Labs): I think we're just going to go through the list.

Mr. Stephenson: Is your intention to try to provide information for purposes of making changes in the grid, or are you just doing an update?

Mr. Fortner: No, we had the first working group of the sweat testing the middle of May, the same week that the oral fluids had theirs. From that meeting there were a number of discussions, issues, and a consensus from the group, and those are some of the issues we'd like to go through. Those were the outstanding issues which I had sent to Walt, and I see that Walt has incorporated the comments into the format so we could go through and review that, and hopefully we'll be able to get through that this morning without too much difficulty.

I think just for general review, we'll just go through the checklist.

B.1 at the March meeting was moved to a blank on collector training.

B.2, certification, was also moved to a blank at the March meeting.

C.1 was already a blank from previous meetings, as was C.2.

C.3, FDA clearance if required. At the last meeting we had discussions that the patches, sweat patch, is cleared both as a collection device and then we'll see in subsequent issues also cleared under a 510k format. So that had been moved at the last meeting.

Mr. Stephenson: Approved under a 510k?

Mr. Fortner: Maybe "approved" is the wrong word. "Cleared" is the appropriate term under the FDA. It is, both as a collection device and then subsequent applications for detection.

C.4 was already a blank.

D.1, specimen body site, was a blank.

The first issue of discussion then comes to D.2, multiple testing. In the May working group meeting we spent a fair amount of time discussing clarification and definition of what constitutes a specimen, because this was an issue that was raised in the March DTAB meeting. The conclusion that the group reached was that the patch itself functions as a collection device. If you think about how this operates, the biological sample is sweat which is deposited, evaporated in essence, and concentrated on the device. Then that device is placed into a suspension solution, which we've gone through before, which is a 75/25 methanol/methyl acetate buffer, and in essence resuspending the drugs and producing an eluate that can then be subjected to standard testing. It was the consensus of the group that, while sweat is the biological specimen, what is really being tested by the laboratory is the subsequent eluant from the patch, and the patch serves as a collection device.

Now, one of the issues that had come up before was multiple testing and availability or how much sample is there to test, and we spent some time discussing that. Without making any current changes to the existing protocol, we had the opportunity to tour the testing laboratory in our facility. One of the things that was noticed is the current technology that we use to subsequently separate the patch from the eluant is analogous to a urine separator device, and that doesn't completely remove all of the eluant from the patch. There's about a half mL that's left in the bottom underneath this tube.

We've used an early predicate device which was developed I believe for saliva by Starsted, called a Salivette, and it's a centrifuge tube that has a small hole in it. You could in essence place the patch and the eluate in that and centrifuge it, which would force all the fluid out of the patch, so we gain another half mL in testing.

Now, one of the things that was discussed, is there any reason why you could not increase the total elution sample volume to either 3.5 or 4 mL's, because the consensus of the group was still that the drugs be expressed ng/mL of eluant, and this would give you almost double what the current testing volume is to allow for subsequent retests going back and forth. That was one of the recommendations from the group, to move it to a 3 to 4 mL extraction.

Dr. Bush: That's going to concomitantly require a change in all your GC/MSs, your confirm methods, because you're going to have a more dilute specimen?

Mr. Fortner: Not necessarily. I'm not sure that we would reach that conclusion. We have more than enough sensitivity currently using the existing methods.

Dr. Bush: That's where I was going. That's fine. But that was considered? Because if you change one thing that early on in the nature of what you're testing and the concentration of the analytes therein, it trickles down through the process.

Mr. Fortner: You're looking at a cutoff for most of the drugs of 10 ng/mL, which you have an LOD of about 2 for most of those. I don't believe adding additional eluate is going to impinge on that.

Dr. Bush: No compromise, all right.

Mr. Meeker: We also discussed that the only other change that we could slightly modify would be to increase the volume injected in the GC/MS. Typically they inject 1 to 2 microliters. They could do it with 2-3 microliters.

Dr. Bush: Good point.

Mr. Fortner: To expand on that, with the exception of the THC, which is done by negative CI, these other ones are currently done on HP 5970 MSD's. The sensitivity on those is not a real big issue, or at least with the patch we have plenty of sensitivity.

Based on that, it was the recommendation of the group that this be moved to a blank. It was a P in the March meeting.

Dr. Jacobs: I think that's probably a good idea. I think the questions have been answered here and we probably should move it to a blank.

Dr. Bush: Wait a minute. We have to come to some closure on this. There's a move, then, to change the P on this issue to a blank. I heard Dr. Jacobs state that clearly. Do we have agreement by all members of the Board that this is an appropriate thing to do?

Dr. Sample: Are we saying then that the eluate is the specimen?

Dr. Jacobs: Yes.

Dr. Saker (Board member): How do we standardize, then, to compare data from different laboratories? We have to have a standard because if not one laboratory is going to get a certain amount for the volume and another laboratory a different volume.

Mr. Fortner: I think you need to restandardize the reconstitution. Currently it's at a certain amount. It's at 2.5. Moving it to 3 or 4 would then become the standardization. It's a standardization across the board, because if you reconstitute with more or less you will certainly change the concentration per milliliter.

Dr. Jacobs: I think that there may still be some questions that we need answered, but this particular question - is the volume size of the specimen sufficient to conduct several tests - I think that has been answered.

Dr. Sample: I would agree with that. The reason I was asking is the eluate, the specimen, really relates to the next question.

Dr. Jacobs: It's called a setup, huh?

Dr. Sample: Yes.

Dr. Bush: Do you want to, then, review and change, possibly change P to a blank before you talk about the next? Is that okay? Are they independent in your mind?

Dr. Sample: I think they're independent. We've defined now that the eluate is the specimen. There is sufficient volume to do multiple testing from that eluate. I would not have any problem with changing D.2 from a P to a blank.

Dr. Bush: I've heard that from a couple Board members. Any Board members not in favor of that change? Okay, we'll change the P to a blank.

Mr. Fortner: D.3, potential to split specimen. At the March meeting, we had moved this from a P to a blank. We had discussed that in the strictest sense of the word a split is two patches, not a split of the 4 mL's. I think the approach that we had gone through under a formal split would be a separate patch not tested by laboratory A, and that would just mean the application currently of two patches. Based on that, we had moved it from a P to a B.

Dr. Bush: Right.

Mr. Fortner: D.4, stability in storage. This was in the last meeting moved to a blank.

I don't believe that there were any outstanding issues in section E, collection procedure, E.1 through 5. Unless there are other issues on that, we can just move to E.6, which is deter tampering, adulteration. In the March meeting this was moved to a blank. In the working group meeting we had some other discussions on this. We have already spoken with 3M Corporation with respect to incorporating another technology into the Tegaderm adhesive that uses two different degrees of adhesive, so that when the patch is physically removed it's detectable and it will either show a void or a letter or something along those lines. 3M indicated to us that the next time they produce a lot, which is probably later this year, they would be able to incorporate that technology. It's analogous if you've seen envelopes that have "Confidential" or "Void" when you open them. That uses two adhesive properties to produce that "Void." Analogous to that is the other technology incorporated to deter tampering, adulteration.

Dr. Vogl: Is there a change?

Mr. Fortner: I think it was already a blank. We had changed it. I was just providing additional information.

E.7, transportation, was already a blank from the last meeting.

G.1, laboratory testing criteria for accessioning, was a blank.

G.2, short term and long term storage. In the March meeting this was a P. There was a question raised at the last meeting, can we demonstrate stability of the drug? At the end of this handout section, we went and retrieved samples that were more than a year old, so eligible for discard, and we went back and did re-analysis of those. Those summaries, the data are contained in those tables. We had already gone through and shown stability of the patch or the drugs on the patch under dry conditions, so this is one to look at under methanolic acetate buffer. The study did show that the specimens originally confirmed positive reconfirmed after one year of storage. There are some differences in the actual levels in one or two, and I think in one we didn't get a qualifying ion issue off of that, but the drug was certainly there. One of the things that we noticed in there is there is some conversion or it looks to be conversion of cocaine to benzoylecgonine in which the levels, even though these are in a methanol acetate buffer, decrease from the cocaine and saw a corresponding increase in benzoylecgonine, but not in all cases.

Dr. Sample: The methamphetamine from March 5th that doubled or nearly doubled, that's a pretty good stability.

Mr. Fortner: The other thing that is important in looking at this, remember this is a primary methanol acetate buffer solution. They're not in Teflon caps. They're in plastic caps. What we suspect is we got some evaporation even though they're frozen or in a freezer. We're suspecting -- we didn't have any way to normalize against anything else. What we suspect is some evaporation of the eluate. It's not across the board. It's only in that particular case.

Dr. Sample: You're suggesting that all the others showed degradation of methamphetamine, but this specimen perhaps was not as tightly capped?

Mr. Fortner: It was a single point calibration. It's not a multi-point calibration in a curve. What we're really focusing on right now is it a positive negative at 10 nanograms. So there could be certainly linearity issues in some of these as well. But the focus was do we have a positive now, do we have a positive a year plus later.

Dr. Mitchell: The big concern should be with the opiates and the 6-AM. Considering that you have -- your solution is methanol acetate - I'd be worried about the conversion of morphine to 6-AM.

Mr. Fortner: Acetylation.

Dr. Mitchell: Yes, that would be my one concern. I do see that the 6-AM's do appear to go up.

Mr. Stephenson: You've explained how that may have been, and that looks rather consistent across most of your retesting, most of it. But have you figured out how you will correct that.

Mr. Fortner: In terms of normalization?

Mr. Stephenson: Or secured storage.

Mr. Fortner: I think what you'd have to look at is a better storage system that would cap these bottles tighter, possibly Teflon-lined. Right now it's a plastic cap on it. It's fine on the urine side. We use plastics because they freeze. But we've got predominant methanol in here. It's not going to freeze at any temperature. I think a better capping system would eliminate or reduce that evaporation potential.

Mr. Stephenson: What an interesting phenomenon, though. Would you have ever predicted this was one of the things you would have seen? This is what this kind of real experimentation produces, real world results rather than something that you prophecy.

Mr. Fortner: I don't think we would have ever predicted some of these phenomena.

Dr. Bush: It appears from a review of the data that you have reconfirmation of the results from the initial test.

Mr. Fortner: Yes, looking at stability. If you were to apply it at a limit of detection or re-test, I think you would have agreement in terms of positive and at some time later positive.

Dr. Welch (Board member): This is re-testing the extract, right, not re-testing of the second patch?

Mr. Fortner: It's re-testing of the extract. Currently there are not dual patches worn.

The group reviewed this data at the working group meeting and based off of this reconfirmation, it was the consensus of the group to move this from a P to a B.

Dr. Bush: Right. Would the Board like any further discussion or would like to entertain discussion, further discussion of changing this from a P to a blank?

Dr. Welch: If we're going to call a split specimen two patches, I think we need some information about what happens to that second patch if it's stored for a year or a certain amount of time.

Mr. Fortner: The original 510k filings had 30-day stability at room temperature under a variety of conditions. Certainly under the DOT guidelines with respect to split you could redo that and extend it to 60 days.

Dr. Bush: I'm just looking to see where that might fit in a little better, because what we're talking about here is short and long term storage.

Dr. Sample: What we're saying is for the purposes of the A, the specimen is the eluate, but for purposes of the B the specimen is the patch.

Dr. Vogl: Yes, a split specimen.

Dr. Bush: That's what it would appear to be, because nothing would happen in laboratory A to the B patch. That would stay in situ, stored in whatever mechanism, under whatever conditions, and then upon request for re-test would be taken out and subject to any extraction and analytical procedures at that time.

So we'd have to look at patch storage over time. But that would be under -- that would fall back under D.3 actually, even a subset of that, potential to split specimens. Certainly the fact is you can split the specimen by wearing two patches, but then it's what happens to that second patch.

Dr. Vogl: You could just qualify it. It involves both the B patch or the eluate from A, both under this category. We just have to state what we are talking about, i.e., the long term storage of the eluate.

Mr. Fortner: It would be more appropriate, since we already talked about it in E.3, it's possible to split, now you're talking about short and long term storage.

Dr. Vogl: And that applies to both.

Dr. Bush: That would be at this point, then, documented for.

Mr. Fortner: What we're looking at is some additional data for patch B.

Dr. Vogl: For patch B.

Mr. Fortner: For 60 days.

Mr. Stephenson: For stabilizing or normalizing the eluate itself for long term storage, and that probably is a container issue.

Mr. Fortner: I think that that's a container issue. While it's possible to look at some of the other components in sweat for normalization, that would be very difficult. It evaporates. It's just going to concentrate it into more.

Mr. Stephenson: Volume is volume.

Mr. Fortner: I think a different storage container to minimize evaporation loss, and then some data on 60 day storage of patch B.

Mr. Stephenson: Do you have your next meeting scheduled?

Mr. Fortner: Right now we're looking at the middle of August.

Mr. Stephenson: Well, if you started something now you would have the data by then.

Mr. Fortner: We would have the data by then.

Mr. Stephenson: Why don't you think about that and leave it where it is for now, and then come back with it at that time. The march will not go on without you.

Dr. Vogl: Let me ask, your 510k submission and everything, the summaries you gave us, it talks about the dry patch and the storage of it, the stability of it for 20 days, 30 days.

Mr. Fortner: Right, right.

Dr. Vogl: Do we feel we need a longer time period for stability of the dry patch?

Mr. Crouch: Where did the 60 days come from?

Dr. Vogl: I don't know. That's why I'm asking. Here all the previous discussions were 28 days. If it's the split, it has to be tested within a couple of weeks.

Dr. Sample: No. They have that 60-day window.

Dr. Baylor (RTI): It's 30 days to request, 60 days or destroy it.

Dr. Sample: Right, 60 days to destroy it. Then in theory they need stability up to 60 days.

Dr. Vogl: That's fine.

Mr. Stephenson: Then you've still got the ability to do that study and to come up with the data by the time you have the working group meeting.

Dr. Sample: It has to be tested in 30.

Dr. Vogl: The donor has to request the re-test within 72 hours.

Dr. Sample: Right, of being notified by the medical review officer.

Dr. Vogl: Right. Let's assume that all happens within two weeks. If it's not requested, they have to keep the bottle at least for 60 days.

Dr. Sample: Yes, there is an inconsistency there in terms of the timing. But nevertheless, the current policy is that we have to keep the specimen for 60 days. And I guess if we were notified between 30 and 60 days we'd still have to honor that request.

Mr. Stephenson: Yes, it's a protection issue for the donor.

Mr. Fortner: Requests come in much longer than 60 days.

Dr. Vogl: HHS policy on splits would be to keep the split for a year. That's our policy, for positives. Theoretically -- it depends on regulations or implementation of our program, to include sweat -- it could be, if we all agree, to keep the dry patch for a year.

Dr. Sample: Then stability would have to be up to a year.

Dr. Vogl: You can't get that by the September date.

Mr. Fortner: No, that's a little tough.

Mr. Stephenson: But that's a good question. You ought to come up with a proposal on how to do the prospective study and try to do a fix on your container issues so that you've got both of those addressed the next time you come back to the large group.

Mr. Fortner: All right, we'll leave that as a P for now.

Dr. Bush: For now, based on the discussions.

Mr. Fortner: G.3, can identify adulterated/substituted specimens. That was moved to a B at the March meeting.

G.4,a, initial test, FDA cleared test. The working group -- in part, one of the things that we did was reviewed the 510k's and actually provided copies for those members that asked for them. I think we had sent some of those.

Dr. Bush: Yes, you did.

Mr. Fortner: Based on that, whether this becomes an issue addressed on an overall basis, it was the consensus of the group, because these are FDA 510k's, that we should move it to a blank.

Dr. Vogl: I'm not sure. It would be for the sweat patch, but not necessarily for some other device to collect sweat. If we write general regulations -- your device is cleared, but –

Mr. Fortner: Well, it's cleared as a device and the applications, the test, the screening analyzer or the screening test, which is what this talks about, the initial testing, are FDA cleared. Now, whether the group ultimately decides this has to be adapted or applied across the board is a different issue. But the consensus of the working group is they are FDA cleared and move it to a blank.

Dr. Bush: And they're cleared in tandem, in a similar manner to what Sam Niedbala was talking about this morning, the collection device with the testing methodology that follows that?

Mr. Fortner: No. That's not an absolute requirement. They're not linked. The device is not linked to a specific application. You could use another device. You could use RIA or something else with the same type of sensitivity. Now, we happened to use an STC ELISA-based product, but that particular product is FDA cleared.

Dr. Vogl: The clearance is for the sweat patch and the data just happen to be based on using the ELISA equipment?

Mr. Fortner: No. It says FDA, initial test, FDA cleared test. I mean, this says, has the immunoassay been submitted, the 510k, for this particular application, and the answer is yes.

Dr. Jacobs: I suggest if there isn't any more comment that we move it to a blank.

Dr. Bush: I'm trying to frame my thoughts, because FDA is currently in a decision making process concerning test devices and collection devices and subsequent tests that are performed on specimens contained in those devices. At this time, I think it would be a prudent measure to just leave this for the time being.

Your points are well taken. They're included in here as part of the record. But I think we'll just wait until the next Board meeting, and at that time maybe FDA -- some decisions may be made in writing from the FDA concerning their policies. I just want to be consistent in our conveying of knowledge and information back and forth between this Board and other federal agencies who are addressing similar testing issues.

Dr. Baylor: If consistency is the desire, then wouldn't urine have to be moved back to an I also?

Dr. Bush: We'll get there, won't we, Mike?

Mr. Stephenson: We're going through these one at a time and this is one of the issues that we talked about at the beginning of the day, was this an element we'll want to have dialogue on and provide information on to help inform that potential FDA linkage.

Dr. Baylor: I just didn't see urine on the agenda.

Dr. Bush: It's on the agenda. Okay. For now we'll just leave it as it is, discussion well noted, and we'll turn the page.

Mr. Fortner: G.4.B, detect HHS analytes. At the March meeting that was moved to a B.

G.4.C, use HHS established testing levels. This was an I at the last meeting. In the working group meeting that we had we reviewed how the cutoff levels which are listed on this page up above were established and they were done through ROC approach, using controlled dose with the exception of PCP. And this was part of what was submitted to and reviewed, cleared through the FDA process.

Although they represent different levels than they are in the urine, I think you'll have that with all the different alternate matrix, and the consensus on this is we've moved it to a B.

Dr. Jacobs: I think we may be a little preliminary here in accepting these cutoffs, and that ties into all the other cutoffs of all the other specimens we're collecting. By making a blank I think we are saying HHS is accepting these cutoff levels. I think they can do these. I think they're good numbers. I'm just unsure how they relate to what we want them to relate to or what they actually mean at this point.

Dr. Bush: Part of our responsibility in the total picture of the program is to take a look at interpretation of results that come from each and every one of these tasks, and I think that's part of the hesitancy here to accept these numbers without a sufficient amount of information on interpretation. We may be able to get a lot of that, Neil, from information that was provided in your submissions that you shared with us, the submissions to the FDA. But I'm not in the position -- I have not had time to go through it with that kind of detail to look at interpretation issues in these cutoffs, because it's very important for us to know what these results mean. We're the ones that get the calls from the medical review officers. We need to train the medical review officers to make sure that employees are given the benefit of the interpretation of the results based on the cutoffs we choose. Is that fair?

Dr. Jacobs: Yes. Do you have more data -- I think I know the answer. Do you have more data comparing these levels of your sweat patch to urine collected at any time during this, or blood samples, hair samples? Any relationship to anything else other than these standards?

Mr. Fortner: No hair in these studies. The one large clinical study, which was in the Michigan Department of Corrections, had, I don't remember the exact number, 10,000 urines and a thousand or so patches. That is information and data that's in the FDA file that you have. You only have volume 1.

Mr. Stephenson: Are you participating in any of the marijuana studies that's going on at the Addiction Research Center?

Mr. Fortner: Yes.

Mr. Stephenson: There will be at least one specimen group?

Mr. Fortner: There's marijuana and actually I think some of the work that's also being done, there's some methamphetamine and similar cocaine work being done. And they're using patches as well as every other conceivable.

Mr. Stephenson: But the point is that there will be some comparison issues between blood and I think saliva and sweat.

Mr. Fortner: From my understanding, Dr. Heustis is collecting just about everything it's possible to humanly collect.

Dr. Jacobs: Neil, could you also accept -- I see amphetamines, cocaines, and opiates all have the same cutoffs. That's something we're not used to seeing in urine. Is there some reason you have to same cutoff for all those, or just address it any way you can.

Mr. Fortner: Only in the sense that when we went through and did the analysis, or actually some of the other agencies did the analysis under ROC, those were the high confidence levels. If you look at the one paper by John Fade and Vina Spieler on methamphetamine, it actually suggests we should be doing screening at 5 nanograms. But you get a higher confidence level at 10.

Dr. Sample: Neil, would these cutoffs have been changed on the basis that you've changed the volume of the eluate from 3.5 to 4 mills?

Mr. Fortner: No. The calibrators are made up in a comparable volume.

Dr. Jacobs: You're still high enough above the level of detection that these are no problem?

Mr. Fortner: Yes.

Dr. Sample: But in the notes it's expressed as ng/mL using 2.5 mL eluate. If you change the volume of eluate --

Mr. Fortner: Do you drop them down?

Dr. Sample: Yes, for comparability, so that the decision point is the same.

Mr. Fortner: You could go to that approach.

Dr. Sample: Well, that changes the set point.

Mr. Fortner: Yes, it does.

Dr. Sample: If you're using the larger volume to do the elution and you don't change the cutoff, you've now changed your set point relative to those ROC curves.

Mr. Fortner: Depending on what you diluted it to, if you diluted it to 4 mL's you could do a proportional change on the cutoff.

Mr. Stephenson: That's where the devil is in the details, right, and that's exactly what this is about.

Mr. Fortner: The sensitivity of these assays, the levels are significantly above the background, and I don't think there's any problem with running plus or minus 25 percent controls even at these levels.

Dr. Caplan: If you're going to continue to change those -- and I think you said the committee agreed or your group agreed with reporting it this way.

Mr. Fortner: Yes.

Dr. Caplan: Wouldn't it be better to report them as nanograms per patch?

Mr. Fortner: Or per total volume. It's a calculation. You could do that. It's a conversion back to total drug per patch.

Dr. Caplan: As we go forward, to keep changing these things it won't be clear. If we're able to standardize or normalize and say it's some minimum nanograms per patch regardless of the volume of the eluate, that's what you adjust. But the rule or the guideline would follow a set number which would be not changeable.

Mr. Fortner: I think currently you'd be looking at 25 nanograms per patch at that level.

Dr. Caplan: That's okay.

Mr. Fortner: That would almost say you could vary the reconstitution as long as it was per patch. But I think the discussion was you want to keep that the same.

Dr. Vogl: Didn't you say the last time they're only extracting or removing 60 to 70 percent that's on the patch the first time?

Dr. Jacobs: I think just previously we tried to move with the saliva group to a nanogram per milliliter, and now we're moving in the other direction back to the device. Whichever way it is, I think we should be consistent.

Mr. Meeker: I think this was a big discussion that we had in the group, whether it should be nanograms per patch or nanograms per mL. We kind of went back and forth as well. The reason we decided on nanograms per mL at the end is because we are talking about someone with a retest of the elution solvent. To be consistent between the laboratories, we'd want to have it reported ng/mL.

Mr. Crouch: All the retest laboratory has to know is what the dilution volume was and they can report it as nanograms per patch, too.

Mr. Meeker: No argument there.

Mr. Stephenson: I think that's a good point and I think it's one thing we're going to need to talk about across different specimens and matrices, to look at which way we want to standardize that. Where science can inform us, that's fine. But I think Yale has already said this before, that we need, at the end of the day we're going to need to make a judgment call on this. The more information we have on this, the better internal construction we'll make across these different specimens. Why don't we go ahead and move on.

Mr. Fortner: Where were we? Where did we leave off on 4.G.c, use HHS assessment level?

Dr. Bush: My thought was that we are not sure of the interpretation of these levels at this time and where they fit into the scheme of things with what we're used to seeing. We're clear that you can accurately and reliably achieve these levels, these cutoffs are reasonable and well thought out and well shown in your FDA submissions.

Right now what you are hearing is a little bit of thought on the part of the Drug Testing Advisory Board on how do we proceed with establishing the cutoffs. You're going to have to give us -- this puts the onus back on us for further discussion and evaluation of what we feel about these cutoffs relative to others. Do we have enough information to say, these are HHS-embraced and endorsed cutoffs? We may need some more information on that.

Mr. Stephenson: I'd link those two together, what's on page 22 and what's on page 24, and you need to be internally consistent across the two of them and look to see what the alternatives would be.

Mr. Fortner: On to page 21, G.4.c is an I.

Dr. Bush: Yes, for now.

Mr. Fortner: G.4.d was a blank at the last meeting.

G.4.e, ability to repeat initial test. I'm not sure, Bob, on your comment on linking this to page 22.

Mr. Stephenson: 22 and 24 both. We want to go forward and look at the issues across all of those.

Mr. Fortner: Well, I read it as the procedure allows initial test to be repeated, whether it's 2 mL's or 4 mL's or 5 mL's. We're talking 20 microliters or so for an initial test. So I think that G.4.e, it's the consensus of the group could be moved to a B. There's certainly more than enough specimen to do initial testing several times.

Dr. Bush: Do we have discussion on this? Any members of the Board, do we have discussion on this?

Dr. Sample: Let's vote.

Dr. Bush: Ready to vote. Ready to vote on this, G.4.e for a change from an I to a blank? All in favor? (A show of hands.)

Mr. Fortner: G.5.a, confirmatory test uses MS for identification and quantitation. In the March meeting this was moved to a B.

G.5.b is already a blank, as is G.5.c.

Dr. Sample: I think it's the same question for the confirmatory cutoff as it is for the screening cutoffs.

Dr. Bush: I know.

Mr. Fortner: You're back to G.5.b, Barry?

Dr. Sample: Yes.

Dr. Jacobs: I think probably we've moved these to a blank because we said they were capable of calibrating the procedure around a cutoff, but I think that the bigger question here may be what is HHS' testing cutoff concentration for these.

Dr. Sample: Right.

Dr. Jacobs: Until those cutoffs are established, perhaps this shouldn't be a blank.

Mr. Fortner: Does this move everybody back to an I or an P?

Dr. Bush: Yes, it looks that way.

Dr. Jacobs: It looks that way.

Mr. Crouch: I think we got lost here, because the last presentation and this presentation is suggesting that here's some cutoffs and this can be done, and what we're arguing is that, well, we're not sure those are right, but that's incumbent upon us to figure that out and not upon these guys to present more data unless we ask them for it. I'm not sure we should change these back, because it's really HHS' or the Board or whomever's privy to set what this cutoff is going to be. There are some suggested. We don't have to accept them, but I think they're doing their job in presenting some that they think will work based on the literature and based on their experience.

Dr. Jacobs: Would we leave it a blank if we just add after "HHS testing," "cutoff concentration when established by HHS"?

Mr. Fortner: That would apply to G.4.c as well.

Mr. Crouch: I agree.

Dr. Sample: We just need to be consistent here.

Dr. Bush: So where are we, G.4.c?

Mr. Davis (RTI): Neil, you indicate that the analyte for confirmatory testing is delta-9-THC.

Mr. Fortner: Yes.

Mr. Davis: And G.4.b, you indicate 11 or delta-9-THC, being the acid?

Mr. Fortner: No, that's not correct. I mean, what we see is the parent.

Mr. Davis: Okay.

Mr. Fortner: Clearly the immunoassays will have some cross-reactivity with the parent metabolite, but everything we've looked for is the parent drug. So that would be a correction typo on 19. We'll change that. On 19 that will be delta-9, consistent then with 24.

Now, G.4.c. Clearing my mind again, we're going to say when HHS establishes, or the same wording, G.4.c and G.5.b?

Mr. Crouch: That's my suggestion, with a note that HHS and/or the Board needs to verify that these are reasonable cutoffs.

Mr. Stephenson: Yes, this is part of your issues that you're looking across these different areas. Is that wording you'd like to see in this area?

Dr. Caplan: We're going to be looking at them all again.

Mr. Stephenson: Yes, exactly. Across each of these we would say the same kind of thing at this point, and that would be some wording which would be consistent with HHS cutoffs when determined by the Board, when established.

Dr. Bush: When established.

Dr. Caplan: That's one issue. The other issue is how they're established. I mean, whether they're established as per dilution or per unit. It has to be uniform, but that's a separate question, using the cutoffs.

Mr. Stephenson: We will craft some words on that.

Dr. Sample: Okay. Is G.4.c back to a blank or are we leaving it as an I or a P?

Mr. Fortner: Or is G.5.b now?

Dr. Vogl: No, it stayed blank. It's just we need to agree. HHS needs to know what they are.

Dr. Sample: G.4.c is now a blank.

Dr. Jacobs: A star.

Dr. Sample: A star, a new category, a star.

Mr. Stephenson: The idea is this is a learning process for everyone and we become more informed with each of these individual sets of reports. We're finding a new area for consistency across them. That begins to shift us into this area of policy discussions later on. We're going to have to go there anyway. We're just talking about it, but it's a very serious issue and it's one that has a lot of impact.

Mr. Fortner: I think Yale said, even when you get them all to B's, there's still another process, going back, reviewing, and establishing policy.

Mr. Stephenson: Yes, and there may be more of a need for information then and dialogue, depending on that issue of what it is that you are standardizing against, how you standardize.

Dr. Caplan: That's another part of the process. It's not for the working groups to worry about right now.

Mr. Fortner: We've satisfied both of those questions.

Moving on to G.5.c, page 25. This asks for performance around the cutoff, and in the March meeting this had been moved to a blank.

G.6., in the March meeting this had been moved to a blank.

G.7 has been a blank for the last few meetings.

Section H, the QC and QA certified laboratory program. I think we've been working on a program. We have one agency outside the U.S. in development, but at this point I think the certified laboratory program has not been established. We'll leave it as a P.

H.2, external PT samples. This is part of a certified laboratory program. I think that we have discussed a number of ways to do it. It is possible. The recommendation was to leave it as a P at this point.

Dr. Mitchell: There's a couple of things. The cutoff question that we had earlier as to whether it should be on per mL of fluid or per patch will make a difference as to whether the program is going to be a qualitative or a quantitative program. If it's on the patch, it can be quantitative. If it's on a per mL, it would end up being a quantitative program approach. The reason for that is the recovery is not 100 percent from the patch. Therefore, if you put it on a per mL basis and the laboratories will not have to spike the calibrator's controls onto the patch, they can just spike it directly into the fluid and utilize that as their calibrator's controls. I think PharmChem is spiking the patches, so it doesn't matter to them.

Mr. Fortner: You would treat the standard control the same way you would treat a big sample.

Mr. Crouch: We don't adjust any matrix for recovery. That's incumbent upon the laboratory.

Mr. Fortner: I think what John is saying is if you're recovering from a patch and your standard or your controls are not spiked onto a patch and it's subsequently recovered, you can have a bias in that certain degree.

Mr. Crouch: To me, that's the laboratory's problem. You just set up methods that work based on the analysis of the specimen, and the specimen is the patch.

Mr. Fortner: I think there's a consensus on that.

Mr. Stephenson: I think this is an issue that John was wise to wait in the sense that we're going to have to also address it later on and which direction we're going to go in terms of PT.

Dr. Bush: When you prepare your PT material now, blinds or opens, do you spike the patch?

Mr. Fortner: Yes. The interesting thing, it needs to be a patch that's either worn or has been exposed to a synthetic sweat, if you will. It's like spiking a dry sponge. It won't absorb material.

Dr. Bush: John, just for the record, help me understand that a little bit. If we're looking at the result reporting as a per mL in terms of the units or per patch, per mL will be the quantitative program?

Dr. Mitchell: Qualitative per mL.

Dr. Bush: Per mL would be the qualitative.

Dr. Mitchell: It has the potential of being qualitative because of the differences in the elution from the patches, and the variation between laboratories is going to be much greater.

Dr. Vogl: Couldn't you spike the patch with the internal standard before you elute?

Mr. Fortner: You'd have a lot of positives with your screen.

Mr. Stephenson: This is exactly the kind of thing where this is part of the dialogue between RTI and their presence and participation in these working groups, and it might be one of the things you'd want to schedule as part of the discussion for your next small working group. If RTI can structure questions, that might be something at some point to put together.

 

Dr. Bush: Based on everything that was just said, I'm reflecting back to oral fluids discussions from this morning and I'm not sure. I can't make the leap between qualitative versus quantitative.

Mr. Crouch: Well, this morning what they said was based on saliva or oral fluids collected, and to be consistent I think it needs to be the patch, because once the patch is eluted or once the drug is eluted from the patch then the concentration becomes sort of arbitrary. If the patch is the specimen, then the concentration or the amount needs to relate back to the patch and then people can use whatever elution volume they want to use. It doesn't matter.

Dr. Caplan: You're using an elution volume because it's convenient and you get a certain recovery, which you study, I assume.

Mr. Fortner: Yes.

Dr. Caplan: You could either calibrate, so to speak.

Mr. Fortner: I don't think you'd want to use less.

Dr. Caplan: But you could use more. I'm saying you could get -- what's your recovery? I don't know, 70?

Mr. Fortner: About 60 to 70 percent.

Dr. Caplan: But you could get that out if you did a double elution, for example.

Mr. Fortner: Yes.

Dr. Caplan: You could also with a fixed volume probably get within 5 percent, recoverable percent elution.

Mr. Fortner: Yes, I would think so.

Dr. Caplan: Those are the kind of things, that go back to the saliva. Unfortunately, the specimen here doesn't have integrity and it only has integrity if you take it all off or you know the relative amount that comes off on a regular basis. But it would have to be equated back to that amount on the patch for consistency somehow.

Mr. Fortner: You express it per device.

Dr. Caplan: Exactly, per device.

Dr. Sample: When we were talking about oral fluids, we changed H.1, certified laboratory program, to a blank because there's nothing to prevent future construction of programs to quote what's on here. On that basis, I would say the same would apply to sweat.

Why would we leave sweat as a P?

Mr. Fortner: Because I had always interpreted this as a P is possible. If you want to do that you can move everything to a B and say we'll just bring the data.

Dr. Sample: I'm looking for consistency again in terms of how we're evaluating each of these alternative specimens.

Mr. Stephenson: You keep that in the front of your mind for every one of these as we go along to challenge.

Dr. Sample: A big flashing board up there, so we can remember what we decided on the previous ones?

Mr. Stephenson: That's why we've got a transcript.

Dr. Bush: That's exactly why we have the transcripts, and that's exactly why I have to go back over this where we're looking at per mL of saliva as the specimen and per patch here. I just wanted -- I wasn't real clear on that.

Dr. Sample: John, what's your opinion again in terms of having a certified laboratory program for sweat? Do you recommend a blank for that or a P?

Mr. Stephenson: It doesn't matter at this point.

Mr. Davis: As long as it's consistent.

Dr. Sample: Right.

Mr. Davis: It's up to the Board whether it would be called blank or a P. It is possible, but it isn't in existence now.

Dr. Sample: But blank means can satisfy requirement, is the definition of a blank.

Mr. Davis: I guess my recommendation would be P.

Dr. Sample: Then oral fluid is also a P.

Dr. Bush: Where are we here?

Dr. Caplan: A blank means it's there and it's sort of been established. A P means it can be done, but it has not necessarily been established. Those kinds of things are P's. It may be hovering in between. We know we can do it, there's no inhibition, but it hasn't been done, so there's not a model out there.

Mr. Fortner: That's how I had always interpreted the difference between a P and a blank. It's ultimately for the Board to decide how they apply these.

Dr. Caplan: As far as the subgroups are concerned, P's or blanks are all you need to get to.

Mr. Stephenson: The purpose of this dialogue is to help inform you for the issues that you need to focus on for your next working group meeting, and I think for purposes here you've gotten that kind of feedback.

Mr. Fortner: Yes.

Mr. Stephenson: Laboratory inspection programs, the next one.

Dr. Bush: H.3.

Mr. Fortner: I'm going to have to play the devil's advocate and now say, if H.1 was a P, following that line of thought, should H.3 be P's?

Mr. Stephenson: Yes, because it's the same issue in terms of consistency.

Mr. Davis: It's possible, but it doesn't yet exist.

Mr. Stephenson: And you'd want to have further dialogue, too, before there was an inspection program established for your program, and you don't necessarily have that from us.

Mr. Fortner: I believe that would be appropriate.

Dr. Bush: So do we.

Mr. Stephenson: I agree and a P is fine. Again, the purpose of discussion for this group, at this time, is to help in an interchange between members of the Board and the small working group such that you can focus on issues that you need to get to a point. I think without us trying to do a horse race with every individual column having an I or a P or a blank in it, the purpose of this discussion for two of these presentations today has primarily been to get us to a point where there's a good understanding between the Board and the small industry-based working group that you can continue your work to get information that will help us ultimately make the kind of decisions that we've got to make about the program, how to write a proposed rule, how to get it out for discussion, and what are some of the underlying principles that we need to deal with. We're getting there.

Dr. Jacobs: We've been having a conversation here about what the meaning of P and B is, and P says possible and B says can satisfy requirement. Maybe B has become requirement satisfied and so maybe we've kind of changed the definition here of what a B is. Somebody say something here. Is that what the feeling is? That if it's a B it has met the requirement, it's done, rather than can satisfy the requirement?

Dr. Sample: I agree, it sounds like it's changed. Originally I thought B meant that not only is it possible, but we have sufficient information to say that it can satisfy the requirement, not that it necessarily exists yet.

Dr. Jacobs: Do we want to change that definition or do we want to leave it the way it is here?

Dr. Bush: When this grid was first developed back in 1997, I remember very clearly Dr. Skip Jones, who was key in helping us develop this grid, telling me clearly we would come to this point, and we made it today, where we're confused a little bit with the definitions that seemed so clear to us back then. Now we've come so far that we're having trouble seeing exactly in the context of that very sketchy, yet clear, grid. We're there. We're now getting into much more detail than that first grid set us up to get.

Mr. Stephenson: I think the bottom line for us here today is that we're looking across specimens. We're looking at -- strike this as a philosophical discussion about where we go. You start out with a concept, we're looking across the specimens to try to create one rewrite of a proposed rule that will incorporate all of the alternative specimens and technologies. To do that, we need certain information, certain constructs that will help us at each stage that have been defined as elements within this grid. For purposes of clarification, whether it's a P or a blank, for purposes of the internal working groups or the small working groups, it's probably not going to make a lot of difference as to where we ultimately get, because ultimately you're going to have to go back and measure across these different specimens, maybe in September or October when we have a lot of this work done. The areas that are important are looking at those areas where we had I's, or if we ever created an N and say you can't do it and that becomes a true barrier to going beyond where we are. I don't think that's where we are right now.

Dr. Sample: I thought that even P's meant that we needed more information back from the working groups, and I thought that a blank meant that we were satisfied and we don't need any further information from the working group. I feel like we've taken a step backward and muddied that by saying, well, P could mean that we don't need more information, but a P could also mean that we do need more information.

Mr. Stephenson: If we all had our philosophical and scientific hats on and we had it all in front of us right now across all these specimens and could answer each one of these elements and maintain it in our minds across all of them and then start the framing discussions for a rule, yes. But we're learning and we've got to re-inform ourselves. I think for purposes to get Neil of