DRUG TESTING ADVISORY BOARD
OPEN SESSION
March 8-9, 1999

 

March 8, 1999

Mr. Stephenson (HHS): Good afternoon. The issues before us today will cover a number of agenda items in a limited period of time. We ask that you sign in so we know officially who is here. We will offer an opportunity to any individual or group that has a need to make any public comments that are separate and distinct from the agenda of the afternoon. If there are any of you, please see the representative at the back of the room, and she will sign you up. Depending on the number of individuals who wish to make public comments, we will allow a limited amount of time for each and you will speak in the order in which you sign up. This afternoon, we're going to go discuss the Federal custody and control form working group meeting that deals with the way we are looking at identifying specimen collection, addressing briefly the on-site test report we placed on our website, discussing alternative specimens in terms of the basic process, and then performing a detailed analysis of hair testing. Our intentions are to update the matrix for hair testing. We will then provide an opportunity for individuals to respond to issues that are raised at the time. At this time I would ask Dr. Walter Vogl to give us a brief update on the Federal custody and control form working group meeting.

Dr. Vogl (HHS): I want to briefly update the attendees regarding a working group meeting that was held on January 20 and 21. We had approximately 30 to 35 participants. Several of the people here attended that meeting. We had most of the large laboratories represented, we had third-party administrators, collectors, MROs, and others who were interested in the workplace drug testing program. Basically the two-day meeting was a brainstorming session. We started by getting comments on the current form and then developed a list of consensus-type changes that a majority of the attendees wanted to see made on the form. We put copies of the first draft along with other information on the sign in table. The last pages are the preliminary agenda for the next meeting which is in two weeks. If you are interested in attending, let me know and I will add you to the list. The current form is a seven-part form and it's been used since 1991 or 1992. Originally it was a six-part form, but became a seven-part form when split specimen testing was implemented, primarily in the DOT programs. Every three years, we are required to have the form approved by OMB in order to continue using it. Since the current form expires June 2000, we are starting the process of revising the form. By August-September, we should have the final draft completed and then it will be published in the Federal Register for public comment. After the public comment period, the final draft will be forwarded for OMB approval.

I just want to highlight the changes on this first draft compared to the current form. We still have a one-inch space at the top which would be for the laboratory name and address, the specimen ID number, the laboratory accession number, and any other information the laboratory might want there. We would have the OMB number in the upper right-hand corner. As far as Step 1 is concerned, we're trying to put all of relevant information regarding the employer name, the MRO name, and collection site in the same area. It is either completed by the collector or employee representative, the laboratory preprints this information, or it is printed on-site. There is a space for the donor's social security number, the reasons for the test - trying to put those in a way such that in marking the box you are not going to mark two boxes at the same time, and the drugs to be tested. We also have a space reserved for some additional laboratory information. The laboratories were interested in getting a space that they could use for their own purposes - perhaps demographic information or other bar coding information. The next step, we rearranged how the specimen temperature was recorded and have two separate boxes to indicate whether it was a single specimen or a split specimen collection. We are still working on how to incorporate the direct observed collection into the form. The next step, the collector seals the bottle after receiving it from the donor, and the donor initials the bottle seals. Step 4 is similar to the current form. We are proposing to delete the split specimen copy because it serves no useful purpose. We believe, in the scheme of things, that the results for the split specimen could be easily recorded on a laboratory generated custody and control form. When the split is sent from Laboratory A to Laboratory B, Laboratory B can use the laboratory generated chain of custody form to record and report the result to the MRO. With regard to Step 5, this is a significant change. The collector certification statement would document all of the activities from collection, to labeling and sealing, and to preparing the specimen bottles for transfer to the laboratory using one signature rather than the collector having to sign the form three times. This statement and approach is being evaluated by our Department of Justice liaison. Assuming it is an acceptable approach, that allows us to simplify the chain of custody area. We would use a one-line approach, similar to what the laboratories use internally in documenting the transfer in handling of a specimen through the laboratories. We believe two lines would be sufficient when it's received by the laboratory. The laboratory accession person would sign the first line and in many cases, the purpose would indicate all of the actions that that individual will be dealing with regard to the specimen. Step 7 is completed by the laboratory reporting out the result. We recently issued a program document on the validity testing of specimens and are allowing laboratories to report additional information on specimens, such as, adulterated or substituted. Looking at the form, we believe it's important to have similar categories as to how the specimens are being reported out rather than to use the test not performed box to cover a variety of different results. It's more appropriate to mark the specific problem with this specimen or result, negative or positive, and then put in a remark indicating why it is an adulterated, substituted, or rejected. The remarks line is the entire width of the paper to allow enough space for the long remarks we require in some cases. There is still a line for the test laboratory if it's different from the one that's recorded at the top of the form. A certifying scientist would sign his/her name and date it. The labels are at the bottom of the form. We are trying to get the labels onto a standard size sheet of paper. We feel that from a cost saving standpoint, that would be very important and it is easier to deal with forms that are the size of a standard sheet of paper to allow using a standard printer. What happened to the package seal? We're working on that. There may be an opportunity to either eliminate the package seal or have a separate supply because it is not tied in any way to the specimen ID number. There is no reason you couldn't have separate package seals if you really want to continue using it. The MRO section would appear in that spot on the other five copies. Copy 2 goes to the MRO with the certifying scientist signature on it. Copy 1 is retained by the laboratory. That's where we are right now.

Mr. Stephenson: We are looking for your input. You are welcome to attend and participate in the next meeting. There will be a public comment period and we will need to get this thing moving. Walt, when did you say you hope to actually have this submitted to OMB?

Dr. Vogl: The approval package would be submitted to OMB in early Spring.

Mr. Stephenson: This is a major revision. This process builds on all the experience we have had with preparing a collection handbook and an MRO manual and it takes into consideration the flexibility for the laboratories to print their own forms

Dr. Vogl: Assuming it is approved by OMB next June, it would still take six to nine months for implementation. We must allow everyone who uses the form to use their existing copies of the forms. They generally have a few months' supply on hand and they would have to make software and printing modifications to ensure that they could begin using the new form on a certain date.

Mr. Stephenson: Next, the on-site test report update.

Dr. Bush (HHS): One of the handouts is titled, an Evaluation of Non-instrumented Drug Test Devices. There's a background and a summary of the device evaluation itself. This report reviews 15 devices. They are listed by name with the distributor, address, and phone number. The analytical data is presented in both a table and a graph format. Looking at the table, there is a perfect device (listed as PD) and then the other devices are encoded. We have blinded the identity of all of the information for display on our website as it appears in this document. If you want specific information on any one of these devices, please call the phone number listed. Each manufacturer knows which result pertains to their specific test kits. This study was performed for us under contract by Duo Research, and will be presented at the Society of Forensic Toxicologists. Shortly after the Society of Forensic Toxicologists meeting, if not concurrently, the complete study will be published in a peer reviewed scientific publication along with the identities of the devices studied. This is Part 2 of a study that was undertaken by the Administrative Office of the U.S. Courts a couple of years ago when 16 devices, that were on the market at that time, were evaluated. Since then, 15 more devices have been developed. I look forward to the peer reviewed scientific article with more detail.

Hair Testing

Note: The sections and elements (e.g., D-4, G-4b) in the following discussions refer to those in the Table of Factors Required for Reliable Workplace Drug Testing.

Dr. Selavka (Mass. State Police Crime Lab): The Hair Testing Working Group has met twice since the last DTAB meeting. In the information you have, the hair testing section has the input developed by the working group. I am not going to discuss A-1 through A-4 since they are blank and can be satisfied for hair testing. B-1 involves training collectors and B-2 is certification for collectors. Both of these are done by the hair testing industry. C-3 pertains to FDA clearance and any discussion is left to the Board and HHS. D-2 relates to multiple testing and the working group formed a consensus as to how much of a sample should be collected. D-3 relates to potential to split a sample and that can be accomplished if a sufficient amount of sample is collected. For D-4, stability of hair, drugs and metabolites are quite stable in hair. For E-6, the working group defined terms for tampering, adulteration, and an unsuitable sample. Transportation of the sample to the laboratory, E-7, is not an issue. Short and long term storage, G-2, does not appear to be a problem although there may be a slight degradation over a long period of time. G-3, can identify adulterated/substituted specimens, refers back to the same issues as discussed with E-6. Again, FDA clearance for the initial test kit is left up to the Board and HHS. G-4b, target analytes, were established for hair testing with the cutoffs given in G-4c. G-4d, the precision around the cutoffs can be established similar to urine testing. G-4e, a repeat initial test can be accomplished by either retesting the original sample or collecting another sample a few days later. G-5a, the working group recommends using GC or LC-MS/MS because the concentrations are somewhat lower. A detailed list of cutoffs were established for each drug class in G-5b. H-1, a certified laboratory program could be established. H-2, PT samples could be constructed to challenge the laboratories. H-3, a laboratory inspection program could be established. H-4, blind samples should be prepared using actual drug user hair samples. However, it appears that different types of hair may be needed to address the aspects of hair testing. I-1, certifying scientist review is possible. I-2, reporting results by specific drug is possible. I-3, results can be reported in a timely manner using a standard report form (I-4). With regard to interpreting results, J-1, the working group developed a comprehensive consensus statement. Alternative medical explanations, J-2, can exist as with urine. J-3, MRO training is possible. K-1, dose-time is similar to urine and involves a number of factors.

K-2, specimen contamination cannot be solved through a simple application of any single approach. With regard to color bias, the working group believes it is not the color that is the issue, but rather characteristics that affect bioavailability and incorporation.

COL Jacobs (DTAB member): With regard to future studies for hair testing, I think there is going to be some discussion of looking at other possible ways, and perhaps some of the studies we're either going to have to get the information back on or that we're going to discern will hopefully deduce some answers on that. If you live with a crack dealer, we won't go into why you do that, but does that necessarily mean that you can live with this individual for two or three months and you're going to test positive just from being there. Is that an excuse, do we want to accept that excuse, what kind of testing - what kind of levels are we going to reach? Again, we may have some information on that or we may look at trying to design some experiments that are going to give us some information on that.

Another issue I think we still need to look at is wash versus rinse. What do we mean by those two terms? What is a rinse? What is a wash? Can someone rinse it and then go to a different laboratory and use the wash and get more out? Do we digest the hair or not digest the hair? Are their mild methods? Harsh methods? And we send these samples out to various laboratories with these various vapor on the hair or soaked in drug or actually drug in the hair, are we going to get back the same answers? Because we want to at least make sure that we aren't giving someone a negative mark behind their name for something they didn't do, I think that they're going to have to come up with - and this is just me speaking here - other explanations for why they washed their hair with cocaine. But you don't want to accuse someone falsely. And we want to make sure that the rinse procedures work or wash procedures work, and we will be addressing some of those.

Dr. Vogl: On Page 21 with the cutoffs that you have listed or proposed, what is the LOD or LOQ for each drug class?

Dr. Selavka: For the most part, it is five times above the LOD, but it is different from class to class. THC, is probably close to five times higher. Cocaine is much higher than laboratories can detect. The value of 1.0 is way above what laboratories can do.

Dr. Sample (DTAB member): Can you explain the difference between the numbers on the top half of Page 21 and the bottom half, particularly with respect to THC and opiates?

Dr. Selavka: Page 21 contains information from a preliminary input mechanism that people had to detail last August and September. What follows below is the consensus formed by the HTWG. A group of people interested in developing some consensus across the industry and academia. I would say the top half is an initial list that has nothing to do with where we are now. I would ignore it.

Dr. Bush: That is a good point. I should have said this when we started out with each and every one of the pages in this handout. What you see at the top is what was provided by the industry representatives at the September DTAB in response to constructing the grid. This is the base level information that was provided by industry representatives for review and evaluation by the Drug Testing Advisory Board. Sometimes it is a restatement of what was known and as you see in cases here with the hair testing group, things have significantly changed.

COL Jacobs: Some of the cutoffs went up, some went down, and others we have added other metabolites to look at. That is fairly formalized now, but we are always open to input and changes. Please go ahead.

Voice: With respect to the cutoffs for the immunoassay, I'm confused about the reference to the uncharacterized marijuana analyte. It's referred to again down in the working group section that they haven't come to consensus on that. Are you saying we don't know what's being tested for at the laboratories in terms of the assay for THC?

Dr. Selavka: I believe the consensus of the group is that we do know the kits that are being used, whether they're home-brewed or commercial that are sensitive to those things in that drug class. But you don't know the specific contribution of any one of them until you test each one of them for cross reactivity, and I think across the board, that has not been done in laboratories. What we are doing now is we are saying let's set the set point on THC acid itself and remembering what the point of the screen was in the first sense is those things that screen positive should confirm positive because they contain those analytes of interest for that drug class. We have to work backwards and see what level of THC-acid in every laboratory is likely to give rise to a positive finding in hair that has THC-acid above the cutoff by GC/MS or LC/MS/MS. That's the point we have to backward engineer this cutoff and that has not been done yet with empirical data.

Mr. Meeker (PharmChem): How are these cutoffs set? For example, is there analytical data, GC/MS printouts that are available to look at? Sensitivity and interference available for other people to review, and seeing how you're setting these cutoffs on both the MS/MS and the GS/MS or the LC/MS data that's provided? Secondly, for opiates - where you have the disclaimer underneath - that any opiate analyte may be reported as a stand alone finding - what is the purpose of that? Because heroin can be smoked in the environment and you still have the problem with that as well.

Dr. Selavka: That's a good comment. Dr. Martha Harky raised that as we were leaving the meeting last time. As you mentioned, we may have to revisit the opiate only. Cutoff or reporting requirement, I think that's a good point. We will be revisiting that for the reason you brought up in your second question. The first question - there are data available to the public that underlie the setting of these cutoffs by LC and GC/MS methods. I don't think they have ever been published it, but most laboratories that validate their methods also do not publish their validation studies. If you're a laboratory and you want to generate such data and if you know how to do it, set up a validation experiment.

COL Jacobs: Those probably would be the types of things that when laboratories are inspected we would look at. If this continues and becomes part of the program, I think that those types of cutoffs and levels would be looked at and reviewed and from what I have seen, it looks quite comparable in most ways, to all other testing and all other types of chromatograms.

Dr. Selavka: If I could revisit the second one. If yours is the first one - if I was the original, the thinking is you wouldn't find 6-AM without morphine. But Martha's point and I guess yours also is that it could happen. We better put it into the protocol for the studies we do on environmental exposure.

COL Jacobs: The next working group meeting is March 29 and 30 in San Antonio. If anyone wants to attend, let us know. It has been a large group, but I don't think that's been a problem. There have been a few times where side issues get talked about, but we're getting to the end here and we're reaching agreements that I thought would be two or three years down the line. I believe we are getting somewhere.

Mr. Stephenson: One of those issues should be, at this point, based on the information that has been presented today, and we had an opportunity for discussion among the Board, are the Board members ready to examine and update the matrix in these particular areas? I think you have adequate information.

COL Jacobs: I would like to think the areas where this group has reached consensus that the Board could look at those things and say yes, this is reasonable, they've reached agreement, and this makes sense, or it doesn't and give it back to the group to readdress.

Mr. Stephenson: How do you want to go about that?

COL Jacobs: A-1, A-2, etc.

Dr. Bush: Do we need to go over each one?

Mr. Stephenson: If we update the matrix, what we can do is put it back up on the web with an update in this area for the rest of the world to see as we go through this. This is a process we said we were going to do, that we would have this done in open session, and that we would make the changes.

COL Jacobs: We're going to go over them one point at a time and decide. Just for those who don't know or haven't seen, the reason why we did not look at 1, 2, 3, and 4, that's on the collection site. Since they are all blank, that means we can satisfy the requirements, that the preparation of the collection site can be accomplished for hair testing, the security, the privacy, and the observed collection. Those things aren't a problem for hair testing and can be accomplished. So A is done.

Dr. Bush: Reflect back to the table as of August 20, 1998. Because those blocks that were blank for each individual specimen and technology in each individual aspect, we were evaluating at that time, our discussions amongst the industry and the Board members. The agreement was for each that we were comfortable, the Board was comfortable at that time, that a satisfactory resolution could be reached with existing information at the time. That's what all the blanks are. Then P was the letter that was put in the box if it was possible - if it was thought to be possible, but needed a little more information, more discussion, more evaluation on the part of the Board. I was insufficient information. It needed much more information than a P. And then N was a criteria where a given technology couldn't satisfy a requirement. Happily, there were no N's that were assigned in this grid. It is now a place to say, can a P be replaced by a blank, and can an I be replaced by a P or a blank.

COL Jacobs: I'm going to start with B again. B-1 and B-2 are training and certification, Page 1 and Page 2. I think that this working group has answered those things and I think it should move to a blank. They have training videos, they have pamphlets, they have graded examinations, and they have certification that is provided for the collector. I think that is what we asked, and it has been provided. Do I have any comments from anyone?

Dr. Sample (DTAB Member): Training and certification, is that vendor specific or global?

COL Jacobs: At this point, there's nothing other than vendor specific. Do you want to say that it has to be global and move to that? Because my feeling is now, I don't know.

Dr. Sample: Do all vendors provide that?

Dr. Vogl: Wait, this isn't for on-site testing, this is can a collector be properly trained to collect a hair specimen.

Dr. Sample: The information suggests that training and certification is available now, but that training and certification may not be applicable for every hair specimen that they collect, is what I thought I heard being said.

COL Jacobs: I'm saying the information can satisfy the requirement.

Dr. Bush: When you say, can satisfy the requirement that we as a group could craft statements and craft collection criteria and training requirements?

COL Jacobs: If we want to, I think there are places out there who have crafted their own for their own needs and have done that, and I think those are acceptable. It doesn't mean that all places are doing that now.

Ms. Bernstein (DOT): That would be the issue because you talk about a grading examination. Does that mean that each entity has their own graded examination?

COL Jacobs: Yes, they're separate. There has been no need to get together, to compare our exams, and to go out and say we now have one exam.

Ms. Bernstein: I want to go back to Dr. Bush’s issue - is this something or do we have to make this decision today? In terms of talking about each entity or vendor that performs this, they can have their own examination, and that we don't care what's in it, or just that it is possible, or is this something that still has to be done in the future on a global basis? Those are very different things, so I'm certain what decision is it that we want to reach today?

Mr. Stephenson: I could really throw a curve in this and say, do we want to have an ISO 9000 standard? What are your thoughts in terms of how to move from say a P to a blank in this area? Where do you think the burden should be in terms of process?

Dr. Caplan (DTAB member): From a process point of view, I think what we should be doing here is that working group gave a recommendation and on the basis that a program has been demonstrated to have been done indicates that a training program would be required and we could come up with a statement saying training would be required, but we don't define the training. We have the first level here as to look at whether or not this minimum objective has been met and if it has, change that status and move on. Later on you have to write the regulation -- like an adequate training program. Then we'd have to move across the various other grids, like what it currently says about urine. What do we say about the other things? The end result is there has to be an adequate training program. What we've demonstrated here is that the industry has already indicated they could do that, and, therefore, we know that is not a problem. We would move on without being specific as to what the program is.

Ms. Bernstein: I don't disagree with that, but my question is, in looking at the grid, does that satisfy the requirement or does it become possible, that is what my question is, because we're supposed to come up with a grid at the end of this.

COL Jacobs: Are we arguing over whether a blank means cans satisfy requirement?

Ms. Bernstein: Right.

Dr. Caplan: The blank obviously has an element of possibility. It's not finished; it can be done.

COL Jacobs: What's the difference between possible and can satisfy?

Mr. Stephenson: Level of information.

COL Jacobs: My understanding is possible, somebody probably can do that and can satisfy the requirement, somebody out there has done it and has a program in place. Not everyone is doing it, but they can satisfy the requirement.

Dr. Caplan: The other part of the process, the grid is not the final end of this, just moving us towards writing the regulations. Therefore, the writing of that regulation can be done because there are blanks. I don't know that we could decide on what the regulation is going to say on each thing at this stage. That's the next stage.

Mr. Stephenson: Let's take it one more step and say, using these first two elements of B-1 and B-2 on Pages 1 and 2. Could we suggest a process so that it doesn't take a week to do this - that we do it by exception - that if members of the Board have issues they want to address that they would raise them at that time? Otherwise, unless there is a strong negative sense that we would adopt the proposals for the working group and that that becomes the structure for each of these working groups as they come online. That would be made by a representative of the Drug Testing Advisory Board and not a member of the industry, this way we could move through this in an orderly process. Does that make sense?

COL Jacobs: I think what we're doing is going through it more quickly and we're going to state B-1, does anyone have any issues with it, but at the same time, we're going to have to say someone's going to have to propose, are we move the P to a blank or are we.

Mr. Stephenson: You're going to do that?

COL Jacobs: I propose on B-1 and 2, we remove the P and change it to a blank.

Dr. Bush: Any negative comments from the Board members? You need to speak up if you have a problem with it. Silence is going to be agreement with where we're moving.

COL Jacobs: C-3. I don't know if we want to look at this or not. This is FDA approval, insufficient information. I guess we could move all of these to a P here if we want to say it is possible. I don't know if we want to do that or not, and I suggest we leave it as it is and move on. D-2, multiple testing. We still have that as needs discussion, but I think that what we have accomplished at the meeting was work to the point where we agreed on the amount of hair in milligrams that should be collected to answer multiple testing - multiple testing being a second test of hair. If they ask for a retest, go back - you still have hair to do it or send that hair to the other laboratory. I think that has been answered and I propose we change it to a blank.

Mr. Crouch (DTAB member): Some of us saw this last night and some of us just got this, so to go through these step by step and think about them and digest them and be able to respond intelligently to them, I don't think as a Board member, I've had time. I don't feel prepared to do this, I will go with the flow if other people feel prepared, that's fine.

Dr. Caplan: I think as we go through them, some will be more obvious than others. If anybody has a problem, we can skip that one.

Mr. Crouch: There are six subparts to this question.

Dr. Caplan: My question had to do with why three months? I would like to hear some comments on why three months was agreed upon as opposed to one month or six months, other than the fact that people had been doing that commercially. Was there are any discussion about that?

Dr. Selavka: There was a lot of discussion. The laboratory I came from used to test the whole length. The question is what puts the three month requirement on here. We were thinking workplace environment, three months is an adequate time period for demonstrating or not demonstrating, freedom from repetitive uses and exposures. On the other end, there may be investigative questions where you want to use the whole hair or less than that length and so that is where laboratories have been working with many of their clients for many years. That was the period that employers wanted to query and so that is why it was selected. You could always do different time periods when the analytical question is very different.

Mr. Crouch: How do three and four interrelate, because if you have 75 milligrams of hair that's 12 inches long and you cut that into 3.9 mm segments, then you don't have much hair left.

Dr. Selavka: That was factored in as well. What we determined was the average aliquot that is used in testing. If you collect 75 milligrams regardless of the length of the hair, in our experience, you should have adequate aliquots for all the tests that are required. That is why I was getting back to the point before with the LC pre-concentration step, you won't have enough hair to do that if you were to try to pre-concentrate by using more mass of hair.

Dr. Bush: Carl, I think I missed part of that. 75 milligrams of my longest length, that's 6 to 8 inches, you would take 75 milligrams of this entire length, that is not very many hairs relative to my boss's hair here, and it's definitely not 6 to 8 inches long. So you would take 75 milligrams of my long hair and 75 milligrams of his hair, you would be missing a patch and I would be missing a much smaller patch of hair, is that right? And there would still be sufficient hair for re-analysis at a second laboratory from those swatches?

Dr. Selavka: The way we have written this up is very carefully crafted to allow for the collection of a minimum of 75 milligrams. If you use the collection procedures correctly, they will generally be providing more than that. I was after a gram of hair and I knew that was never going to fly, but we recognize there are differences. Again, if you want to test this, this is -- is based upon years of experience and lot of laboratories that do this thing. We crafted carefully. I really don't have data with me to show you how much 75 milligrams of hair is, but it doesn't look like much. But you've already segmented it to 3.9 cm segments by that point so it's going to be 75 milligrams, is the total mass. That is going to be then providing you with 3.9 centimeter segments.

Dr. Bush: That will be the submission for the analysis?

Dr. Selavka: Submission for the analysis in most cases.

Dr. Vogl: If you analyze each segment of the total 75 milligrams, doesn’t that give you different results because it's a different time frame?

COL Jacobs: If you segmented it and reviewed each segment.

Dr. Vogl: What you would have to do is chop it up into homogeneous small pieces and then you only take a portion of it to do one test?

Dr. Bush: No, you only take the 3.9 centimeters that are closest to the head, then you take the rest of this long hair and throw it away.

Dr. Selavka: You don't throw it away.

Dr. Vogl: When we say multiple tests -- in urine, you have the specimen and you can remove an aliquot, do the test, and come back the next day and it's the same specimen. How does this description satisfy multiple tests? How do you apportion the 75 milligrams so that each time you want to repeat something, if you have to, it's the same specimen?

Dr. Selavka: You've raised a good point. I think we add an element here that the portion tested is the 3.9 centimeter portion after it's been clipped. You say that in one pool, you do save the rest of the hair and the packet that it came with, you don't throw things away, but then if a re-test is done or an immunoassay comes up positive, your confirmation is done on the 3.9 centimeter segment. You sub-aliquot for each of these tests as you would with the urine. But you're taking the urine -- but you're taking the aliquot from the 3.9 centimeter segment not from the whole hair. I think we do need to add something to this to clarify.

Mr. Stephenson: If there is discussion like this that comes up an issue, my suggestion for the process would be maybe set this one aside for a second and then proceed and try to go through as many as we can and then we will come back to these or maybe use a mechanism of trying to address these things either by e-mail or a discussion in that way.

COL Jacobs: D-3 is the potential to split the specimen. I think that ties in with the previous one. I think we can do it and can quickly move to satisfy that requirement. I would like to tie it in to 2, and address both of them at the same time. When D-2 does get answered, then D-3 will have the same answer. Now, D-4, stability and storage evaluated. I think that carries enough here, if I recall correctly, to say that it can be stored. It is stable. We hit that requirement. There is enough hair collected and enough left over that when we check later, it is kept, it is stable, and it can be stored.

Mr. Crouch: Isn't this again contingent upon D-2? Because if you use all of the hair, then you're asking about the stability of the drug in the digest and not in the hair. So if you don't collect an ample sample or an adequate sample in D-2, then the only remaining portion is that that is already digested or been rinsed. So I think this relates back to D-2.

COL Jacobs: It does relate back. But my understanding from the group, there was that 75 milligrams, which was the amount - is more than enough to enough left for sample at a later time, either in that laboratory or a different laboratory.

Dr. Vogl: Of the 3.9 centimeters?

COL Jacobs: Of the 3.9 original, close to the scalp. Further comments, discussion?

Dr. Bush: Have you seen any data on that like from retests that have been at a later time? You know it's always one of those things, stability. We've had laboratories who have urine specimens in their possession. A year later when they're ready to throw things out, we might look at something where they are no longer under-regulatory control. Is there information?

COL Jacobs: There was lots of information. I can't say that I saw any chromatograms presented that says, here is this hair and here is the repeat. I didn't see that so I won't say that. But I think everybody there certainly said that they didn't have any that degraded more than 10 percent and that when they looked at them, either when it was asked for the re-test or at the time of discard when they looked at things, that it was stable and it was there. Does anybody here want to correct me on that?

Dr. Selavka: And I presented this data at a SOFT meeting a couple of years ago.

Mr. Crouch: If hair is 10 inches, it's about 25 centimeters. If you only take 4 centimeters, then your whole sample is about 12 milligrams total. If you take 75 milligrams of someone's hair that is 12 inches long and you cut off 4 centimeters of that, you're only going to recover about 10 to 12 milligrams total of hair to do all of these tests plus recovery or plus stability of the sample. There's something inherently wrong here.

Dr. Caplan: What's wrong is the 3.9 centimeters has to have 75 milligrams. You may get more.

COL Jacobs: Any other comments on this? Is it clear now what the 3.9 means?

Mr. Crouch: No, it is not. Are you saying on D-2, you're going to collect 75 milligrams and it will be represented in 3.9 centimeters or are you going to collect 75 milligrams total?

COL Jacobs: Just a minute, I see some heads nodding out here. Someone pop up because I'm not the one that's going to have to do this.

Dr. Kidwell (Navy): The intent was that in the 3.9 centimeter section it will be 75 milligrams. So the example earlier of Donna Bush's hair was probably incorrect or misleading. We're talking about a sample about the size of a pencil lead, the lead of a pencil when compressed.

Mr. Crouch: On someone with short hair, 75 milligrams is quite a bit of hair.

Dr. Kidwell: That's correct. And there was some discussion I think that we originally batted around 100 milligrams of hair and then we came out with 75 as a compromise. But you're correct, it is a lot of hair.

Mr. Stephenson: We can tie this one to the other one to clarify it.

COL Jacobs: We will put that aside.

Dr. Bush: We will have to tie D together.

COL Jacobs: We will tie D up in one bundle of hair. D-6, deter tampering/adulteration. I won't plead ignorance. I don't think we're quite done with this.

Ms. Bernstein: You're saying you're not done with that?

Dr. Bush: More discussion is needed so we will leave it as an I now.

COL Jacobs: B-7, transportation of specimen. Does anyone have any trouble with the transportation of the specimen. [NO RESPONSE.]

COL Jacobs: I would propose that we can satisfy the requirement for transportation of specimen and there is no problem with this. Is there any discussion? Are there any opposed? [NO RESPONSE.]

COL Jacobs: Done.

Dr. Bush: That changes from a P to a blank.

COL Jacobs: G-2, short and long-term storage. I don't know if it ties into D-3 or not. Does anyone have any problem with this?

Dr. Sample: I think if we are satisfied with the room temperature for the current analytes, but if any analytes are added down the road, it would have to be looked at individually.

COL Jacobs: I propose we move this to a blank. Does anyone have any comments? So let it be. G-3, can identify unadulterated substituted specimens. G-4, initial test, the FDA clearing. That is in the big FDA pile. It needs to be addressed. And do we want it?

Dr. Bush: We will deal with that later.

COL Jacobs: G-4B. We still have to discuss what we are looking at for THCA and where we want that cutoff to be based on what is the confirmation cutoff. G-4C. That fits in the same one as before when we talk about all of our cutoffs. I think that we do have numbers that we are close to agreeing on so if anybody doesn't like these numbers, please get with us, because what you see is probably pretty close to what we're going to propose. G-4D, performance around the cutoff. Does this look like a reasonable proposal that can satisfy the requirement by challenge samples at 75 percent and 125 percent of whatever cutoffs we have? Are there any comments? Is anyone opposed to saying that that can be met? Okay, we can take that one off.

Dr. Bush: So that becomes a blank?

Dr. Vogl: If you're going to change that one, I think you could change 4-C.

COL Jacobs: What we can say is we can reach precision around the cutoff. And let's say marijuana is one, that's fine. We can go from .75 to 1.25 but we may want to go back to marijuana and say we're going to make it 1.2, which we still can meet for on 4-D, but we will be changing 4-C and so until we know what 4-C is. We don't want to accept it, but we can do 4-D and then when we change it if there's a change to 4-C, we will still have to meet 4-D.

Dr. Vogl: Are you going to use spiked samples or real hair samples?

COL Jacobs: Spike samples. Anyone else?

Dr. Isenschmid (DTAB member): Is this what laboratories are currently doing?

Dr. Selavka: They spike, and there are two ways to spike into a blank solution or spike into an extract of a negative hair. Different laboratories do it differently. There are good and bad reasons to do it both ways.

Mr. Jones (DTAB member): How is that any different from external exposure in a donor, spiking versus the exposure?

Dr. Selavka: In laboratories, when you're trying to do your validation study, when you're using your immunoassay, you have to have something in which you have a known value of drug. The drug and metabolite usually both challenge your instrument with it and see if your response is equivalent to that which your standards have set up. You have controls first. Later on if you want to validate the method, you're going to have to use them as the quantitative standards in an environmental exposure situation. You would have hair itself in an experimental protocol and expose it to vapors and cocaine or powdered cocaine or heroin or whatever, and see whether you wash protocol can tell you whether that sample has been contaminated. It's a very different kind of experiment from the laboratory's point of view.

Dr. Sample: Doesn't this item relate to the assay itself and not to how controls are prepared? Shouldn't the discussion about controls themselves come under Section H and then we can talk about proper type of control? I think I hear what your saying is that the assays can reliably differentiate at the cutoff within plus or minus 25 percent. How you determine to make that control material is another matter that I think will come out under Section H and I would recommend taking this to a blank.

COL Jacobs: Does anyone have any opposition to taking it to a blank?

Dr. Mitchell (RTI): If I remember right, you were talking that there are different immunoassays that are used. Are all of those capable of meeting the plus or minus 25 percent criteria?

Dr. Selavka: We are told they are. The data will have to support it or refute it. But we think that's stringent enough criteria for immunoassay.

Dr. Bush: If we establish the requirement, then I assure you the kits will be manufactured and precision shall follow. They will be manufactured to be able to do it. It's happened in the past, and I'm thoroughly counting on it again in each matrix center that we look at.

COL Jacobs: This is the group that could do it. If they say they could do it, we could hold them to that. Okay, move to a blank and turn the page. G-4E, the ability to repeat the initial test. Unless this ties back into the 75 milligrams, and I'm not sure where we ended up on that. There is enough to repeat the initial test because we have an example, do we want to tie this into others.

Dr. Bush: Yes, tie it to D. It will be an easy evaluation next time if it is tied.

COL Jacobs: What is the issue with the 75 milligrams of hair? Denny, can you state that again so we have clear direction or would you like to attend the meeting?

Mr. Crouch: Yes and no. It wasn't clear to me the way it is written that what you're doing is trying to collect a sample such that the proximal 4 centimeters is 75 milligrams.

COL Jacobs: Then we will have that section rewritten, which should clarify about four of these areas.

Mr. Crouch: You may want to look at that because that is a lot of hair off a person who has short hair. If you look around this room, there aren't a lot of people who have 4 centimeters of hair. I don't know what the ratio is, but several people wouldn't qualify. So you would be taking a good hunk of hair.

COL Jacobs: I think you're right.

Dr. Selavka: There will always be some in the population whose head hair doesn't allow for this type of collection. That's why we have the other body source availability. Frankly, if there's no other body source availability, then another drug test would ensue.

Mr. Meeker (PharmChem): If you have another body source, doesn't that grow at a different rate? If you're trying to establish this 90-day window, then the rate of hair growth period from a different body source -' what I heard you say earlier, you're trying to establish 90 days of use. It just seems like with shorter hair, you're not going to do that.

Dr. Selavka: You're right it is different. What we wrote is - and we're now on page 4 which is at D-2. Hair collected from the ultimate body sites must on average be longer than 1 centimeter but will not be trimmed by the laboratory if the average length is greater than 3.9. That was based upon a long discussion about our lack of full understanding of cross-populations of the growth rate with all other body sites. Head hair, at its apex, has been very well characterized, but the other sites not as well. So this gives light to that fact that this may extend beyond 3 months. It may be less than 3 months, depending upon the collected sample.

Mr. Meeker: Item 2, you're allowing the 1 centimeter link for the hair on the top of the head. Now, you're talking about 3.9. There's a three-fold difference. Couldn't we say it has to be a minimum of 1 centimeter at least 75 milligrams of hair?

COL Jacobs: That is what we are trying to do.

Dr. Selavka: That is well stated, thank you.

COL Jacobs: G-5a, Page 19. We're done with this.

Dr. Bush: Do we just leave it as P and move on?

COL Jacobs: We'll leave that a P. It's possible we need to work on it. Does anyone have any comments on it or any further input on it, or what do you think we need to include on this?

Dr. Selavka: Larry Bowers has done a lot of work on the algorithms on this.

COL Jacobs: G-5b, Page 21. Here, we're going to have to talk a little bit further about those. Are we down to one we need to talk about?

Dr. Bush: It's already a blank, but there is still more needed discussion.

COL Jacobs: In other words we can satisfy the requirements, but we haven't decided what the requirements are?

Dr. Bush: Exactly, how to do to that, to establish the cutoffs. Okay, fine.

COL Jacobs: G-5c. The cutoffs reflect drug use. I think we need to define the fact that it's positive. We need to know what those cutoffs reflect in terms of drug use.

Dr. Bush: Which one are we on? Page 22?

COL Jacobs: This is the same issue we had before.

Dr. Vogl: It's precision around the cutoff.

Dr. Bush: This is just confirmatory.

COL Jacobs: Does anybody have any problem with saying t his can be met? The laboratory suggested it so they will meet it. I propose we move it to a blank. Does anyone have a comment? [NO RESPONSE.]

COL Jacobs: Page 23.

Dr. Bush: This may be where studies are developed for presentation next time.

COL Jacobs: QC/QA, Page 24, the certified laboratory programs.

Dr. Selavka: New York State has already established the investigation criteria for laboratories that do hair. They've already inspected at least one and I think two laboratories, now.

Dr. Bush: What's going on with Florida? We don't know any information on this, we have nothing.

Mr. Stephenson: We do need a review of the process and maybe some links to some folks who are doing it. I know we're doing the QC type of work in Florida on proficiency challenge, but I'm not sure whether they've encompassed this under certification of laboratories inside the state.

Dr. Selavka: I know Dick Jennings has been out to two of the laboratories to inspect them against New York state clinical laboratory standards.

COL Jacobs: We will have insufficient information, or is it possible?

Mr. Stephenson: Does it really matter if it's an I or a P?

COL Jacobs: I think it's possible, we just haven't satisfied it all. Does anybody have a problem changing this to a P? Okay, we'll move it up. Page 25, external PT samples. Has this been done? We've been taught there have been external PT samples sent out there, so not only is it possible, but it has been done. We can satisfy that requirement. Does anybody have any information or input on any of that?

Dr. Bush: I've never been told about how to do it or how the specimens are collected. I know that isolated things, that cadaver hair from Europe is collected and used. Places can get more information on this.

COL Jacobs: Public comments?

Ms. Murdoch (Bensinger Dupont & Associates): BDA is actually in the process of beginning marketing the proprietary program for hair analysis developed in connection with Stuart Bogema and we also have a laboratory inspection program that is underway for hair testing laboratories, forensic inspection program, and that's also being rolled out.

Mr. Crouch: Are these prevalidated?

Ms. Murdoch: I know there's a protocol for how they're evaluated and distributed, but I don't know the details so you will need to talk to Dr. Bogema. He was here before and of course, as soon as I was going to talk about this.

COL Jacobs: Julie, can we try and get some of that information. That's going to help us to change this to a blank. Can you somehow get with me or get with the group so we can look at it and say something is there?

Ms. Murdoch: Sure.

Dr. Mitchell (RTI): As the PT program currently exists, it's called a performance rather than proficiency. I can see how proficiency could fairly easily be done, but can we do performance testing in hair? I think there's still some questions in that aspect.

Dr. Selavka: Can you differentiate the two for the record?

Dr. Mitchell: Proficiency is can the people analytically get a correct answer. Proficiency, I mean proficiency performance, looks at the entire system through which the samples are tested. From what I have heard so far, I am not sure that we are currently, technically capable of doing that.

Dr. Selavka: Can you say which elements of the process are likely to be the ones where we have the biggest issue on the performance side so we can address them in our group?

Dr. Mitchell: I think the variability and the processing of the hair is probably going to be the greatest problem in trying to set up a performance testing system.

Dr. Selavka: Once collected, the rest are the preanalytical steps where we are likely to have the issue with performance?

Dr. Mitchell: While you have a problem, is that since the quantitative values will vary according to treatment? It's going to be very difficult to determine whether or not a laboratory has a quantitative difference due to its procedure of isolating the analyte from the hair, or due to mishandling the hair somewhere in the process? It's going to be very different or very difficult to distinguish between those two.

Dr. Kidwell: In the past, three types of samples were sent out, a powdered hair to just test the extraction ability, whole hair not to be washed, and the third was whole hair that went through the whole procedure. Whether that would be helpful now or not, I don't know.

Dr. Mitchell: I understand that, but we still have the same problem with analytical answers that are obtained and what they mean, if they differ from laboratory to laboratory.

Dr. Bush: My concern is whether we get reference laboratories and reference values for this. Where are we going to get the reference laboratories for this?

COL Jacobs: Are we ready to turn the page? We will leave this one alone. The next one is the laboratory inspection program and I think the way this is written, an inspection program can be established to inspect and evaluate all MSs in the laboratory. I think it is not only possible, but it can satisfy the requirement and I see no reason why we could not do that. Does anyone have any problem with taking on more inspections? Okay, we will move that to a blank and turn the page. Now, blind samples. This probably will relate to some of the other issues. It is probably possible, but we need a lot more information to tell you how.

Dr. Bush: We will leave that for now?

COL Jacobs: That's correct.

Dr. Bush: Let's leave it until we get additional information.

COL Jacobs: Page 29, certifying scientist review. The working group says yes. Are there any comments on the certifying scientist review? Are they reviewing anything that is much different from what we are already reviewing? Does anyone have any problems with moving that to a blank? Okay, let's do it and turn the page. Results reported by specific drug.

Dr. Bush: Do we want to link that back to the cutoffs and the analytes?

COL Jacobs: Are we on page 30?

Dr. Bush: Yes, Page 30.

COL Jacobs: Results reported by specific drug, the laboratory report can list results for each specific drug detected, they can and they do.

Dr. Vogl: Although we may change the cutoffs, whatever we decide, they can do it.

COL Jacobs: That seems like an easy one.

Dr. Bush: But that may change based upon how we change the cutoffs.

Dr. Selavka: I would say it better not change. We should tell people what we found.

Dr. Bush: Yes, but we are unclear as to analyte concentrations and are you going to revisit that?

Dr. Selavka: But as far as the specific drugs, we're saying the same thing.

COL Jacobs: Okay, we will change that to a blank. Page 31. I don't remember this being discussed at the group. It says yes. I don't see why they can't do it in a timely and confidential manner, in the same way that urine drug testing is done.

Dr. Bush: Agree, it shouldn't be any different.

COL Jacobs: Does anyone have a problem with moving this to a blank and turning the page? Page 32, the same situation exists, standard report form used. They can use a different form, but it can be standardized. Move it to a blank and turn the page. Interpreting results. No problem here? We're going to discuss this a little bit more so we'll leave it.

Ms. Bernstein: I would like to say one thing for the record. The fact was brought up that maybe marijuana is stronger these days and people feel that they are being wronged on the testing because of the passive inhalation issues. We have far more problems with drug testing than we do with passive inhalation, so we really have very great difficulty with the proposed method here.

COL Jacobs: Because?

Ms. Bernstein: Where it talks about in terms of the review policy, number 4, we would be opposed to donors offering alternative explanations in terms of inhalation, passive inhalation, and things of that sort. There are things that could undermine our whole program, so we are definitely be opposed to that.

Dr. Bush: 4-a on Page 34?

Ms. Bernstein: Why don't we say all of 4?

COL Jacobs: Do you want further studies done on higher levels of marijuana that are out there now?

Ms. Bernstein: No, we have not identified it as an issue in our program.

Dr. Bush: In the current program as it exists?

Ms. Bernstein: What Bob has said is in the normal course of things, that they're going to take after X number of years to revisit that issue, that is not being triggered by anything. We are seeing no problems or no need for any other alternative medical explanations within our federally regulated program from the DOT side. I cannot speak for HHS.

Dr. Bush: My understanding is that passive exposure has not been an issue that has been raised in DOT. It has certainly not been an issue raised in federal drug testing programs.

Dr. Caplan: She is saying that she can not accept a program for DOT which has hair testing that allows this type of explanation.

Dr. Bush: Element 4 on Page 34 outlines that passive exposure may contribute to a hair positive, may be responsible for a positive hair test. Then that is unacceptable as an alternative explanation.

Mr. Stephenson: My sense is you are asking for clarification and you want backup testing in this arena, is that correct? This is kind of what you're looking at, a fall-back position?

Ms. Bernstein: I don't think we're at a point to look at fall-back positions. I simply want to go on record that DOT does not feel the conditions exist currently, that passive inhalation is an alternative medical explanation. I'm not suggesting that we add an expense to our program in terms of fall-back decisions whatsoever.

Mr. Stephenson: You control for that with the studies we've done in marijuana, for instance, but we haven't done it for hair.

COL Jacobs: The bigger issue -- those studies were done for marijuana at a certain level that now that we have much higher levels, then personally speaking, I get calls occasionally from someone who wants to run the passive inhalation study. I tell them all that I know, and they say, but with higher levels, could you say that if that study was done again, could you say that they would all be negative or that one might be positive? The best I could say is, I don't know. Does someone want to help me here and say differently? I think we are saying here is an 'I don't know' and we need to find out with the current levels of THC if someone can test positive.

Ms. Bernstein: What I'm doing is a little different. I'm responding to the written piece of paper in front of me. And saying that officially from the DOT point of view, that we do not support offering a donor an opportunity to explain these circumstances in terms of - it says the program should be considered which would put employer funds for an additional test and we're not supporting that.

COL Jacobs: You don't want to give them an opportunity to say that you got an imprint.

Mr. Stephenson: You can use this as a place to make that statement.

Ms. Bernstein: That's exactly what I'm doing. This is a statement for the record.

COL Jacobs: Page 36.

Mr. Davis (RTI): Let me add one thing. While there may be, and obviously are, some higher levels of THC in marijuana, if you examine some of the data that has been generated, you may find that the average marijuana collection is not much higher as it is getting credit for these days. You may want to actually look at the data before you hang your hat on the position that the levels have increased dramatically.

COL Jacobs: I agree with that totally. I always try to determine how realistic the situation is because if they want to set up something that is totally unrealistic and then ask if the person is positive, I might say yes. But then they're going to have to address convincing someone that he sat in a phone booth for five hours.

Page 36, I think that relates to the previous section and we are going to discuss that at the same time. MRO training, Page 37. I do not see why they cannot be trained the same way that other MROs are trained.

Dr. Bush: Once we get that information from all the incompletes.

COL Jacobs: I'm thinking it might move up to a possible, but I don't see any reason moving it further. We'll get more information. I think we can satisfy it, but until we say specifically they need to know, which probably relates to the prior sections, those will all tie in and fall out at the same time. Page 38. I think we're still discussing this.

Dr. Selavka: I was wondering what the Board thinks. This is really near consensus, not comparisons of people to one another, but any person. We do think that's a fundamental difference between this and saliva testing and urine testing.

Ms. Bernstein: Can you define those response relationships?

Dr. Selavka: The response would be the extent of the positive you get in terms of quantification. So if you have 10 doses of a given amount of drug in one person, their hair will have a certain finding. If you have 20 doses by that person of the same magnitude in the time period represented by the same 3.9 centimeters of hair, for example, a second kind of use pattern would give you a bigger answer than the first kind of use pattern.

Dr. Sample: That's true of any biological sample, everything else being equal. If you correct for creatinine.

Dr. Selavka: Do we do it?

Mr. Crouch: The question is, is there dose response relationship in biological samples, the answer is yes, for almost all drugs. It may be variable in urine, but it's still there.

Dr. Vogl: We're just trying to determine if use has occurred. We don't care about dose time response for urine. I'm not sure why this factor is in here to be honest with you.

Ms. Bernstein: It sounds to me like it has something to do with marketing, would be my guess.

Mr. Stephenson: Do you mean the way it's phrased or just in general on the issue?

Ms. Bernstein: But my question is, is there anything in here that you're talking about? I understand you're talking about dose responses, or anything you're talking about having to do with impairment.

Dr. Selavka: No.

COL Jacobs: Denny, did I understand you to say that you think this can be a blank there because there is, with any biological, this relationship, or do you think we need to discuss it further?

Mr. Stephenson: Is this a dose response or dose detection relationship? If you're talking about in terms of giving a pharmaceutic to someone and you're looking at a dose given and a response detected in terms of impairment, for instance, or in terms of pharmacokinetics, then that's different than what you're talking about here. Because you're talking about dose detection. In that sense you're saying there is a relationship between the number of doses given and the size of the quantification of the results. But that's not the same thing as dose response, is it? Or am I mistaken?

Dr. Selavka: I'm just reading the matrix. We didn't make the matrix, but it says related to the time and dose that drug use occurred. I don't know what the input of the Board was when they wrote this.

Voice: I think it was the intent of the original conception of this matrix that this particular element response referred to the analytical response and had nothing to do with the biological or pharmacological response that might have been induced as a result of the particular drug or drug metabolite.

Dr. Bush: Was this concept to aid in the evaluation of information presented by the donor to the MRO? For example, I took dronabinol two weeks ago and that's why my urine is positive today.

COL Jacobs: I understood it to mean that we could relate the number of doses for the number of times to the level of drug that we get when we test the sample, just a straight-out question of if you took it once you will get real level, if you took it twice you would get more, if you took it over a longer period of time, you'd get a higher level than a shorter period of time. Is that what the question means?

Dr. Vogl: If it does, we do not need this. It is not a part of our workplace program. We want to know only if it is present, that is, positive.

Dr. Caplan: I think the reason for the question was a comparative one, whether or not as you go across the matrix lines and we have something with urine, whether or not the others are greater or less than that. It has nothing to do with pharmacokinetics, only to do with whether or not if we take it. That's why I was asking the question, whether we take a 30 day or 90 day amount of hair, is that going to detect people similar to or greater than or worse than what we're currently doing with the random urine.

Dr. Bush: Let's consider it something like a detection window in an oral fluid. This is where we're going, the window of detection.

COL Jacobs: So we can move this to a blank? It is answered.

Dr. Vogl: If we change it to detection window, it would make more sense. In other words, if a person takes a dose of something, at what point, how long can you detect that dose? In hair, if they smoked a joint, your window might be that you would have to wait two days until that hair started growing enough or ten days. There would be a minimum time before sampling, plus you could detect it as long as it is in that hair when you take a sample.

Mr. Crouch: Implicit in this is you could take a hair concentration of the drug and determine what the dose was. That's what is implied in this statement.

Dr. Vogl: No.

COL Jacobs: If that is what is implied, I am not sure that I'd be willing to say that's true for all people. I mean, if we give everybody in this room the same amount, we are all going to have a different level. That may or may not make sense to how much we took.

Voice: It is time and dose, not just time.

Mr. Stephenson: Does this lead to minor editing to make sure it does what you want it to do?

COL Jacobs: Do we need to edit the question, edit the answer, or do we want to eliminate the element?

Dr. Vogl: In my opinion, it is not an issue.

Mr. Stephenson: Why don't we leave it in the discussion because you have different opinions, even on the Board.

COL Jacobs: Who wants to leave it as an element? Speak up.

Dr. Caplan: I think we should leave it as an element.

COL Jacobs: Can you tell us why we need to leave it as an element? Maybe that will give us the answer.

Dr. Caplan: The reason we need to leave it as an element, is in the end when you write the final regulation to decide whether or not these specimens can be used for these purposes, you've got to have them in a comparative sense. In other words, are we going to say you can use a sweat patch for the same thing you can use a urine for, and the same thing as hair? I don't know the answer to that until we come out and do this.

Dr. Bush: It is a detection window, establishing the detection window.

Dr. Caplan: Is the detection window adequate for this program?

COL Jacobs: You're saying this should relate to a study comparing all the different testing methods to say what a dose in one testing system relates to another?

Dr. Caplan: Not necessarily, but if you write new regulations, we have a urine regulation. If you're going to add other matrices in there, then are they going to detect to the same degree that we're now detecting in urine, or are they going to be better or are they going to be worse. I think you have to answer that question before you write a program.

Dr. Vogl: Charts have been presented for years relating to different detection windows for different types of specimens. We already know this.

Dr. Caplan: Then we have the answer.

Dr. Vogl: This is not an issue, it is an applicability of using a sweat patch for a certain situation, and we need to discuss applicability when writing a regulation. You may not want to use oral fluid for random test, but you may want to use it for post-accident testing.

Dr. Jones (University of Mississippi): If I might go back to the genesis of this table, I don't have in front of me all the sequential edits that have occurred from its original conception, but this was a series of questions to which we had no answer when we started. The questions and elements were being developed to address potentially all future alternative matrices so I would suggest that you may want to keep it there to allow you to address the issues that Dr. Caplan is addressing. As you approach regulations, as you approach the writing of regulations for these particular alternative matrices, but that was why it was there. It was a question particularly with hair and sweat and saliva that we originally put the I in. I believe that we didn't have any idea whether any of these relationships existed or not. Now you're getting data that say that they do exist and that's good.

COL Jacobs: Does the question itself change the language?

Mr. Stephenson: Why don't we leave it where it is, do a minor rewrite and then come back because you will be to able to clean this up real easy.

Dr. Selavka: We need to know what the question is.

COL Jacobs: I think the next issue is one of the larger ones that goes on for several pages. I think that means we have some more work to do with specimen contamination. And that gets us to the end.

Mr. Stephenson: At this time, are there are any compelling issues the public wishes to address to the Board? We would make some time available for that purpose. If not, we will pick this up again in the morning at 8 o'clock. First up is sweat testing, then we will go through the other alternative matrices and ask for input and any updates that the members of the industry, from those alternative technologies, might want to bring to the attention of the Board.

I want to commend the small working group for hair testing. If there's nothing else at this point in time, this session of the Drug Testing Advisory Board is adjourned until tomorrow morning at 8 o'clock.

 

MARCH 9, 1999

Mr. Stephenson: Good morning. This is a continuation of the Alternative Technologies and Specimens Working Group discussions. As you recall from yesterday's efforts, we were successful in doing an update to the grid matrix for accurate and reliable drug testing related to the specifics of hair testing. We had gone through and reviewed the efforts of the Small Working Group. We had gone through and reviewed the areas in which there were still some complications and areas that needed discussion and then we had proceeded to make changes to the actual grid with recommendations in areas that we still needed to work on. That was a major piece of work. It is unique also because we haven't had the luxury or the experience of having other working groups anywhere near as advanced as this activity was concerned for other industries, but there has been progress made in other areas despite limitations in how formally they have met or how large they are and there have been, in the last couple of Drug Testing Advisory Board Meetings, a focus on hair. We retained the focus because they are our lead Working Group in the process we're going through. But today we have chosen to start today looking at one of the other technologies, and I'm going to have Dr. Bush introduce you to that group and to the process.

Dr. Bush: As follow-up to what Bob was saying, in our September meeting, we had some formal presentations by the industry representatives from the Working Group. It was very good. It established the basis for the work at the top lines -- the first part of the work that is on every page of your blue hand-out book -- and the groups that were subsequent to that and submitted a formal report like we saw yesterday with hair that work has been included also in this blue book as indications of progress and answers to questions that were outstanding and some that still remain outstanding. I would like to reflect back to the sweat patch because we have not heard from sweat as an alternative technology since that September presentation. In the December meeting, we focused on hair and on-site urine testing. We have been requested to discuss sweat testing, review what was presented at that September meeting. It is included here for memory-jogging purposes. Neil Fortner is here as the industry representative, and I'm sure he will work through any remaining questions in a manner similar to what happened yesterday with Dr. Selavka and hair testing with his follow-through on the Working Group. We will continue in that manner with Neil Fortner today, and I think Dr. Caplan will be taking the lead on this review for today's session. I know that Melanie Mallory in the future will be working specifically and directly as a Board member liaison with sweat testing. We can begin, Dr. Caplan.

Dr. Caplan: I think Neil is going to give us a quick update.

Mr. Fortner (PharmChem): I am the industry representative for sweat testing. As Donna had said, there has not been any discussion since we met in September pursuant to responding to the issues and questions that were asked of the industry back then. There is, at this point in time, no active Working Group pursuant to resolution questions addressing the issues we presented back in September. We have had numerous conversations with HHS regarding that status and part of the view, as I understood it coming back, is that the Board had not completed their review -- questions and answers of that information. There wasn't a lot for the Working Group to actually do as we go through the checklist and I think Yale will do that. If you will notice that many of the issues had been addressed back in September, there are some still outstanding issues, and some of them are program oriented but, nonetheless, there has been some additional research presented at the recent Academy meetings and some of the SOFT meetings, but that research, as it pertains to the sweat patch, has not been presented to the Board. My conversations with HHS indicated that the Board has not yet had an opportunity to fully digest the existing material, let alone go into new areas. There is no active Working Group at this particular time, but that will change as issues come up.

Dr. Caplan: Let me first thank Walt for putting the information in this format because it was difficult until now to systematically go through this. Although we have looked at all of this information over a period of time, it was never in a systematic format that we could go through with and really move positively or negatively on each of the points. Since sweat is represented mostly by one product at this time, there is not a large comprehensive group to meet and so probably the simplest way to do this is going through the checklist piece by piece. I'm going to look over to Neil each time and say, do we have anything new here, and then to the Board, do we have anything new, and do the same thing we did yesterday to identify things which are no longer an issue and we assume can be moved forward with additional work. In other words, we're not going to answer the question, what is the training program, but as long as we're satisfied, for example, that a training program can be done based upon previous information, we will move that question along and again, try to identify areas of research or areas of very specific questions to go back to Neil and the small group he has to do that. Let's start with Page 1 under the sweat group. Again, some things that have already been cleared are not, to my understanding, in this list. The first question is that of collection training and I will read what is on here and then ask Neil if he has an additional comment or update since some of these things do go back a couple of years and see what the Board wants to do. The first one has to do with training programs and the notes indicate that things are similar to hair, with video tapes and manuals have been prepared and are available. Is there anything additional?

Mr. Fortner: The statement speaks for itself and is the current status of the training program?

Dr. Caplan: Maybe you could comment on the scope. You trained a number of people. How has that gone? Is the training done by company people? Has the training been extended to third party groups yet or not?

Mr. Fortner: The answer to all of that is yes. The training is conducted at several levels. There is the trainer program and there's also training by industry representatives. This program has been used most effectively at this point in the roll out to all 94 divisions of the Administrative Office of the U.S. Courts. Federal Probation and Pretrial has made extensive use of this video tape, teleconferencing, on-site training program, as well as other agencies throughout the country. I don't think I have a specific number at this point. Suffice it to say, I think there are somewhere between 3 to 500 individual program sessions to train collectors and this is includes how to apply the patch, how to remove the patch, how to look for signs of tampering, ensure integrity, proper completion of chain of custody documents.

Dr. Caplan: Any comments from the Board?

Mr. Lucas (Administrative Office of the U.S. Courts): We have approximately 2000 probation and pretrial officers who have been trained in the application of the sweat patch. In 1998, we used approximately 11,000 sweat patches in supervising federal offenders, probation violators. In supervisory cases, we have had extensive experience in using the sweat patch.

Dr. Caplan: Any comments from anybody on the Board? Is there any reason why this having been a P should not be a blank?

Mr. Stephenson: Just for the group again to review the process that we set up yesterday of looking at each of these items and then to updating the matrix, going from either an I to a P or a P to a blank, meaning that -- that's where we are. Could you just review that and re-state that as a criteria that we will use today for upgrading each of the components in a similar manner that we did the review yesterday?

Dr. Caplan: Remember that the first section of the grid gives a summary of all the elements of the grid and on the first page, there's a key where we have blank. We had already decided that this would satisfy the requirements prior to today. A "P" was an indication that it was very likely this was possible, but we wanted to hear from the industry as to the specifics and experience which we just did, or "I", there was insufficient information that again, we asked the industry to provide the information or had a need to obtain that information from research source that may not yet be available or an N, which would say no, it cannot satisfy the requirement that ultimately if it can't be moved off, might be a limiting factor in being able to utilize this material. Our goal is to move this group forward to have removed the N's and changed the I's to P's and the P's to blanks and move in that direction systematically. On the early part of the whole grid, Walt did not reproduce any item on the grid that already had a blank. We're going to skip over the front grid part where there are blanks, we don't have pages in the text. Where there is a letter, we do have a page and that is what we're going to discuss and that coding is re-entered on the top of each of the pages that we're talking about. On the first page under training, the center column on sweat, there's currently a P and the question, that is, that on the basis of what we know today from the experience of the manufacturer and experience of the U.S. courts, that it seems reasonable to move this due to the fact that it has been done. I think we want to remember, we mentioned it yesterday, is that at this point in time we're not trying to write the regulation, we're only talking about whether the information is there. At a later date, this will have to be gone over again in specifics of what this training program is or should be in the eyes of the government, and the program will have to be restated. We're not going to try to restate that today and some instances, some of the elements will be stated. Like cutoffs, once we decide on the cutoffs, they will likely be replaced directly into the document, but the training program -- there will have to be some elements of what it will include, et cetera, but we want to get through this process systematically to ultimately ensure that we have enough information for HHS to draft the document for public comment. I don't want anybody to think that once we get through one of these things and move into a blank, that it's necessarily all over. It just means that we've moved the process along, where someone else can use the information that exists and draft that into the legislation. The other thing that is, from a personal perspective, is that I think we're also trying to look at these things in conjunction with each other and not each one in an abstract so when one goes to write the ultimate document, the document will be for all matrices comprehensively and not necessarily one at a time or one matrix, although there may be specifics about certain matrices that have to be entered in there. For example, if they get to the cutoff section, there's likely to be a different set of cutoffs for each matrix. But when you get to the training, there may be a very similar thing as to the elements that are required in training. But that's at a later date. Does anybody have any questions about the process?

Mr. Stephenson: Thank you very much for refreshing our memory and I think it served us well to do this whenever we begin. It is important that we standardize this process to make sure that it is consistent across each of the specimens and the grid.

Dr. Caplan: Do we agree that there is no objection moving collector training on B-1, from P to blank? [NO RESPONSE]

Dr. Caplan: The next element is certification. The statement is that a formal certification program including a written examination has been in existence. There is a training manual. Again, I would ask the two of you who have experience with that to comment on the use of the manual, whether it's changed or whatever. Neil?

Mr. Fortner: We have not had any updates or changes to the collection manual since it was written. I think our last revision was in 1997 and also the written exam has remained the same as there have been no changes in that process.

Dr. Caplan: There's a note on here about how to look for adulteration and what do you do about -- and how do you ensure the patch is put on. Can you comment on that?

Mr. Fortner: To comment on that, you need to back up a little bit and just review some general criteria on the patch. The patch is a collection device that is tamper-evident. It incorporates technology using some material from 3M Corporation, Tekraderm, which once it adheres to the skin, infiltrates the upper layers and when you pull the patch off, some of those skin cells come with it. So it effectively has covered the adhesive, which means you can't reapply it. Also, if individuals attempt to inject solutions into the sweat patch itself, which is, for all practical purposes, medical grade blotter paper, we will see puncture wounds on it and you also see visible discoloring of the patch, and we've had instances where individuals have attempted to do that. The other property that you have with Tekraderm is it doesn't allow anything larger than water to pass back and forth with the attempt to adulterate it using something like bleach or other solutions. It has the unfortunate property of trapping that under the patch, and we've had several instances where secondary chemical burns result because it doesn't release the bleach.

Dr. Caplan: Have you looked at other adulterants? You mentioned bleach. Are there other things that react the same way?

Mr. Fortner: We've looked at adulterants in the sense that what you put on the patch and then how a dose of adulterant affect the ELISA screening assays and that was all part of the FDA 510K process. We were going into specific ones. We looked at the bleaches, we looked at some attempts from individuals to try to flush the patch by using a syringe with water and just pumping water back and forth across it in an attempt to pull the drugs off the patch. Drugs have a tendency to be adhered a little bit more physically stronger on the patch. We end up using a methanol acetate buffer to remove the drug from the patch, so depending upon the drug, certainly THC is very difficult to flush out of there. But it does address the question, is there certification and is there tamper evidence, and that's part of the training program which includes glossy photographs of the attempted adulteration, and once you physically see people remove the patch and try to reapply it.

Dr. Caplan: Mr. Lucas, did you want to comment from your point of view?

Mr. Lucas: No.

Dr. Caplan: It's working?

Mr. Lucas: It is working.

Dr. Caplan: With 11,000 patches, did you have any adverse experiences?

Mr. Lucas: No, except for the instance Neil talked about, we have not. We have had offenders try to remove the patch and put it back on and the officers have been trained to recognize the sign, so it has been very effective.

Dr. Caplan: Any other comments from anybody else relative to the collector certification? Again, is there any reason why we can't move the P to a blank for this question? Any other comments from the Board? [NO RESPONSE]

We will go from P to blank on that. Neil, you started to talk about the next question, which is FDA clearance, which is a general question for all of the things we're talking about. This was FDA cleared. Maybe you can give us a brief -- of what is in the 510K and what it meant to get the device FDA cleared, both from the collections point of view and from an analysis point of view, if that is pertinent.

Mr. Fortner: I think that it is. There are really two independent distinct issues. The sweat patch is a non-inclusive collection device that is manufactured and produced by Sudamed Corporation, in Santa Ana, California. They actually own the rights to that particular product. In 1990, they had submitted, or actually prior to 1990, they had submitted and received clearance from FDA as a collection device under the Medical Device Division. So that process in demonstrating that the use of Tekraderm with medical grade blotter paper would not cause adverse reaction as a hypoallergenic. And certainly Tekraderm has been in use for many, many years in clinical applications, securing IVs, catheters, wound dressing, for that matter. So that's the process. Under FDA, for the medical device and in the presentation that I presented to the Board, that presentation had copies of the letters from FDA. One was October 1990 as a medical device and then subsequent applications were in 1995 and 1996. And we'll probably get into those a little bit later, but those specific clearances in '95 and '96 were specific and unique for demonstrating to the FDA Scientific Advisory Board that the sweat patch could in fact detect the use of drugs. That's a much longer process that started in 1992 and took several years to complete and involved a wide variety of clinical trials, controlled dose studies for all of the classes that it was ultimately proved for, which are amphetamines, cocaine, opiates, marijuana, and PCP. The only exception was that, for obvious reasons, we were not able to get approval, or Sudamed was not able to get approval, to administer PCP to volunteers, not that there was any lack of participants, but there were some issues in there and so the PCP data is from a self-report. The other classes of drugs didn't have controlled studies, stability studies, which I'm sure we will see later throughout the questions.

Dr. Caplan: Again, are there any other comments? I think there are two parts. One is if there's a special device where means of collection and the other is the analytical technique. It's my understanding that only the device has FDA clearance and not any other part of it, or part of the process.

Mr. Fortner: The actual testing for detection of drugs went through an FDA 510K utilizing the sweat test.

Dr. Caplan: And what immunoassay?

Mr. Fortner: ELISA.

Dr. Caplan: I want to be clear. The FDA approved both the ELISA device and the technology?

Mr. Fortner: The device, ELISA technology, screening, and GC/MS confirmation.

Dr. Caplan: Can you comment on the potential for variations? We look at this as not the only product, but there may be other products ultimately and one of the questions about what the FDA clearance is what we might require to be cleared from the point of view of the ultimate document and that question, whether that includes a device separate from the method at least in my mind, so in this case you have cleared the device?

Mr. Fortner: In this particular case, you have a device that is separately cleared from the methods themselves.

Dr. Caplan: The question is, are the methods otherwise cleared or approved by the FDA? Are you free to use the device with some other immunoassay technique?

Mr. Fortner: I believe there are a variety of immunoassay techniques. RIA includes some of the more sensitive polarization assays -- are certainly capable of detecting the levels that you see in sweat. I'm not sure if I fully understand that question or issue.

Dr. Caplan: It's whether or not the device is approved using one technique or can it be used by other people with other techniques in accordance with what the FDA has approved?

Mr. Fortner: I believe that going through the FDA 510K process demonstrated equivalency and deduction. I believe you could use other technologies that were similar technologies to ELISA or immunoassay screening coupled with chromatographic confirmation.

Dr. Caplan: Without going back to the FDA for additional approval, that was the question.

Mr. Fortner: Yes, I believe those are comparable technologies involved.

Dr. Caplan: What I was trying to get at as we go across the grid, the fundamental question will be, what are we going to require for the assay process. We talked about that right now, we have in urine, an FDA approved assay. We talked about it with hair, and I just wanted to include that in the discussion here that whether or not we're looking at a process where the analytical technique would require FDA approval. Anybody else from the Board want to comment? Let's talk about the device first. Did the devices need FDA approval in our opinion, and do we have enough information to change this from an I to either a P or a blank?

Mr. Stephenson: One of the things to think about here is we cannot speak to FDA's role or their authority or the determination to provide oversight in these areas. We have some pending decisions that have not been rendered in this area independent of what we might say, FDA is a separate authority. They know that even better than we do, in our experience in working with them. What we need to do at this point is to address whether or not an individual device has been cleared, but not necessarily to address the need for that clearance. If we are successful in getting clearance and make the recommendation, that could carry weight back to the FDA, but it might not make the determination in our favor, eventually anyway. You have to decide how you feel about this and give your best guidance to us. I'm not convinced that what we say they should do, they will necessarily do.

Dr. Bush: They have made it clear that they are open to our discussions and will entertain any recommendations that the Board makes.

Dr. Sample: I think there are two separate questions here. One, do they need to be FDA cleared? Does the container or has the container been cleared by the FDA? I think in this case the answer is yes, then we can move this from an I to a blank, then perhaps halt the discussion to whether we're talking more generally about whether FDA clearance is required.

Dr. Caplan: We are moving the question from I to blank, leaving the further discussion up to method, because I think that will come up at the end. As to whether or not the test will have to be done by an FDA approved method, does everybody agree that we have enough information to go from I to blank on this? The next question is, the ability to do multiple testing. The sweat patch is currently screened for the five drugs and I think all the drugs which are in the mandatory guidelines have been included. This question has to do with whether or not the size of the patch and the materials are sufficient for doing at least two confirmation tests. But is there adequate material for doing a second follow up test?

Mr. Fortner: Yes. After the initial screening, there is sufficient sample to do at least two GC/MS confirmations. We have instances where we have done more than two and found that you can actually go back to the patch and get more drugs off the patch because the initial process doesn't pull everything off and the patch is retained in this container indefinitely until ultimate disposal.

Dr. Sample: What percentage is removed off of the patch with your first elution?

Mr. Fortner: Somewhere between 60 and 70 percent is eluted from the patch.

Dr. Sample: How much would you remove with a second elution?

Mr. Fortner: You will get 60 to 70 percent of what's left, typically looking at the levels. We've not had any issues going back to those cases. For instance, in some we've gone back to do a D/L isomerization differentiation and found that we can pull adequate drug off of that, certainly at the cutoffs to provide detection well above the cutoff levels and even limit of detections if you go to that level.

Dr. Isenschmid: I want to clarify what's on this paper. It says at least two confirmation tests. Are we talking about two particular analytes or up to five analytes twice?

Mr. Fortner: That pertains to two classes of drugs. Typically we don't see a lot of polypharmacy in the sweat patches. We see they're predominantly positive for one class of drugs, but you could do a cocaine and amphetamine off of the material.

Dr. Sample: I understand you do one elution and with that one eluate, you're doing all of the screening and confirmation off of the single eluate?

Mr. Fortner: Yes, off of the single eluate.

Dr. Caplan: A simple eluate off of the whole patch?

Mr. Fortner: That's correct.

Dr. Caplan: When you say there is sufficient specimen released to do at least two confirmation tests?

Mr. Fortner: To do two confirmations by just splitting the eluate.

Dr. Caplan: Any other comments or questions? The question is whether or not the patch has sufficient volume to do the testing. Does anybody have any thoughts about that?

Dr. Bush: A question concerning retest?

Dr. Caplan: That's the next question. The split is the next question. They are linked. Maybe we ought to do them together before we decide on one because the question on the next page is the potential for split specimens. The way I understand it, there has been additional thought given to that, but that is not necessarily the way the patch operates.

Mr. Fortner: That is correct. There has not been a request to do split specimens in the formal sense of how you would define a split specimen under the program. Two independent samples, one tested and one not tested. I mean, it's certainly possible to do that if you wanted to either put two patches on or modify the existing patch to have two absorbent pads that would increase the physical size. That is not problematic. I really believe that D-2 is a separate question from D-3. D-2 says is there enough to do multiple tests and D-3 says split specimens. My interpretation would be under the formal program, you would have to apply two patches at this point to do split testing.

Dr. Caplan: Would you apply two patches or would you create a patch that is two component parts?

Mr. Fortner: If you wanted to do it tomorrow, you would apply two patches, but the manufacturing process to do a dual component is not that difficult. It would require a few months lead time.

Dr. Caplan: Would that require FDA evaluation?

Mr. Fortner: It just physically increases the size, and I wouldn't believe that that would require a resubmission.

Mr. Good (Avitar): I wondered, and perhaps this applies to multiple testing about different analytes, whether there has been any consideration given to accumulation of DNA or PCR testing to identify who the actual donor of the sample was.

Mr. Crouch: You have a schedule so the potential is there.

Mr. Fortner: If you wanted to retain the polyurethane covering, which in some cases we have agencies that send it to us so that we can inspect it to see if there has been an attempt at adulteration. There are epithelial cells on that product. It is not something we have gone through to investigate that, but certainly the potential exists.

Mr. Crouch: Neil, do you know how homogeneously the drug is distributed in the patch? If you cut a patch in half, would you have concentration on each half being the same?

Mr. Fortner: Given the physiology and the excretion of sweat, I would expect it to be fairly homogenous. You could cut it in half. We have no specific studies that demonstrate that. That is fairly straightforward to do if you so desired. Again, if you're going to do a split along those lines, it would be much better to have two patches as opposed to physically cutting it. Then you've got to worry about other issues of contamination and identification.

Dr. Caplan: The next question is whether or not the feeling is that there is no sufficient information that the patch collects an adequate specimen to do the testing which would change this from an I to a blank. Does anybody have any thoughts?

Dr. Sample: I have a question for perhaps not just for sweat, is the use of one eluate. Does that really entail a two aliquot type of methodology that we are used to in the more traditional screening techniques. And I think this question really cuts across multiple alternate technologies. If you were to develop a system that is exactly analogous to what is being currently performed in urine based screening, might then require a second elution from the sweat patch on the basis the sweat patch is the collection device just like a container is a collection device.

Dr. Bush: Alternatively, one could consider that initial eluate, the original specimen, then take an aliquot from that for screening, an aliquot from that for confirmation. You're right, that is absolutely a possibility, but I think we need to come to a decision as to what constitutes a specimen.

Mr. Stephenson: Do you want to hold that thought for this purpose here and look at that as one of those issues we will address across the specimens? Maybe I would ask for thoughts from the different small working groups.

Dr. Sample: That's essentially where I was going with that comment.

Dr. Bush: That applies to any oral fluid collection device where you would have a pad where you perform an initial extract which then becomes the volume from which aliquots may be taken, so point well taken.

Dr. Sample: That's why I raised the issue.

Dr. Caplan: Do you raise that issue such that it questions whether this is an I further, or do we want to deal with that as a separate issue?

Dr. Sample: In my mind, we need to answer that first question, the question I just raised first prior to moving these from an I to a P or to a blank.

Mr. Crouch: I think that's a different question than split specimen sample, but it's still multiple testing.

Dr. Caplan: Multiple testing could be construed as, is there adequate volume here. I think that's probably answered yes. Another question which may not be directly on this grid, is whether or not the specimen is subject to aliquoting. Again, we can hold this. Let's hold this question and leave it as an I in light of looking at this other issue. Have we thought about maybe just taking the patch and inserting it in the liquid and then the liquid itself elutes and then the liquid becomes the specimen?

Mr. Fortner: Into a disposable transfer vial. There's 2.5 milliliters of methanol acetate buffer and it goes on a horizontal shaker for 30 minutes and then we use what is analogous to a serum separator that goes inside the tube, presses the patch down to the bottom and the fluid goes up, and the patch stays in the bottom.

Dr. Caplan: It can be identified in the future? You didn't make a transfer?

Mr. Fortner: The patch stays inside that original container.

COL Jacobs: I think we can satisfy the requirement. I think we have some means here to say if you need two patches or three patches, we can satisfy the requirement. I don't know if we need to get into the details of how exactly someone is going to satisfy those requirements here. But I think Neil has laid out that it can satisfy them and if need be, it can be done.

Dr. Sample: Are you talking about from the multiple testing standpoint or the split specimen's standpoint?

COL Jacobs: Both.

Dr. Caplan: The recommendation was to leave this alone and add this other issue to it. Is there anybody who wants to change that?

COL Jacobs: I think they should both be blanks here. I think they have been answered, they can be answered. You can meet the requirement.

Dr. Caplan: Any other comments? We have one dissenting vote. I mean, we're happy to move on. Whichever way, we need to make a decision.

Ms. Mallory (DTAB member): I think it does meet the multiple testing. He stated himself that in the formal sense, it does not meet the split, but I do think it meets the multiple testing.

Dr. Sample: From my standpoint, I think just the opposite. I have a question about the multiple testing that I think we need to flush out in general for all of these alternate technologies.

Dr. Caplan: I'm going to make a suggestion that we move this from an I to a P and then continue to discuss it further so that it has moved up a notch. But since we don't have all the answers and we're not going to get them all today, let's leave this and we can come back to it when we go across the matrices with the question about whether what constitutes the original specimen. Does everybody agree to move it to a P? And this is D-2 and it's also D-3. Let's take D-2 first. D-2. Do we have agreement to move this to a P? We've answered some of the questions. We do have information but we are now less uncertain about one point.

COL Jacobs: Have we clearly defined what the questions still are so everybody knows how the next step will be taken?

Dr. Caplan: The question is whether the original specimen can be effectively aliquoted for multiple testing, not whether there's sufficient volume that the patch can collect a sufficient specimen. The question that remains is whether there is the ability to aliquot that so that you won't always be working with the same aliquot for all of your tests.

COL Jacobs: I don't understand. Let's say we have a bottle of urine or a bottle of fluid taken from a sweat patch. What's the difference between the two fluids and aliquoting for testing?

Dr. Sample: The difference is the laboratory has processed that specimen, if you will, in order to produce that aliquot, which is not the case with urine and a collection container coming straight from the collection site.

COL Jacobs: You're talking about a fluid and pouring some of the fluid. We have to deal with what we have here.

Dr. Caplan: I think the question is whether we go back to the original bottle for a second aliquot where that's possible.

Dr. Sample: And whether it's a requirement.

Dr. Caplan: That has not been necessarily demonstrated.

COL Jacobs: You want to go back to the original patch for the second aliquot as opposed to going back to the fluid produced to get the second aliquot?

Dr. Sample: No, I'm not saying that necessarily. I just think we need to answer the question whether or not there is a requirement to do that. As we're talking about the sweat patches, we're talking about salivas, we're talking about hair. Do we have to go back to that original specimen which is either the patch, the saliva swab, or the hair follicles and re-generate that eluate with that digest in order for it to be a second aliquot. I think that's the question we need to answer before we can adequately answer D-2 for all of these technologies.

Dr. Caplan: Do we want to make this a P?

COL Jacobs: That's a move in the right direction.

Dr. Caplan: We will continue with that question across the board, so we will change this I to a P.

Dr. Bush: I suggest that Board members take a look at the pros and cons and evidentiary requirements.

Dr. Caplan: Do you want to do the same thing with D-3, the split?

Dr. Isenschmid: I have one more question on the split, and that is, if you actually went to the two patch system, what would be the homogeneity between the two patches in terms of collecting them from different sights?

Mr. Fortner: That has been looked at. In fact, in the 510Ks, patches were applied to a variety of places on the body. Typically, it's placed on the upper arm, it can be worn on the back of the lower rib cage. All the studies from the clinical control dose where they were wearing many - I think the largest study put 17 patches on an individual - their controlled dose and you're looking at patches being taken every hour or every several hours and they showed no statistical differences in patches collected from various portions of the body.

Mr. Crouch: But isn't it true the distribution of the sweat glands is not even across the body? There should be some variation depending upon where it's split and what the density of sweat glands is in that particular are?

Mr. Fortner: That is correct, I did say that there were no differences in the levels when we went through and did statistical analysis. They weren't statistically different for the areas we were applying. If you look at the lower rib cage, the upper back and the arms, I think the upper arms are going to have similar sweat. Now if you look at the palm and the hands or the bottom of the feet, a completely different scenario. I would expect much higher levels in those areas just in the production of sweat.

Dr. Caplan: And the time frame for application was what?

Mr. Fortner: How long did they wear those? They have to wear them at least 24 hours and some of these studies went out a better part of a week.

Dr. Caplan: Anything else? Any other questions on the potential for split? Is there any reason not to change this to a blank? We will move this from an I to a blank. Page 6 is D-4, stability and storage. Do you want to comment on that?

Mr. Fortner: Sure, if you just go through and read the summary of this. Under the 510K, stability in patches was required to be demonstrated. We had both worn, and unworn. And the issue here is stability of the drug on the patch itself. We have multiple studies where you had both worn and unworn patches, drugs applied to it, subjected to a variety of storage conditions, including shipping them to other sites and shipping them back and then going through the process that was outlined in the 510K elution for this material and screening and testing to look for differences in stability. We haven't gone to it here, although I can tell you on retest samples, we found the drugs in the methanol acetate buffer are very stable, capped at minus 20 degrees or lower.

Dr. Caplan: That's eluted?

Mr. Fortner: Right, we went for as long as 28 days just looking at stability of the drug on the patch itself.

Dr. Sample: That was part of your initial filing, but have you done any subsequent studies for a period of time longer than 28 days?

Mr. Fortner: No, we haven't. Under the current program, we don't have anybody that holds a patch for 28 days before they send it in for testing.

Dr. Sample: But what about after you've received the patch?

Mr. Fortner: Pending processing, holding it? Well, we haven't done anything beyond the 28 days again, because our turnaround time is mandated by the client. We don't store them.

Dr. Sample: If you were to do a second eluate, as you mentioned, you had the capability of doing the second eluate. What's the longest after being stored that you could do that?

Mr. Fortner: Our experience right now is somewhere between six and eight months of doing the retest of the initial eluate. The original patch has already been eluate so it's like having the liquid sample. We haven't done more than 28 days of a spiked patch, non-eluted.

Dr. Sample: Earlier, didn't you say that you could do a second collection and recover drugs on the second elution?

Mr. Fortner: Yes.

Dr. Sample: What is the longest time interval between the first elution and the second elution that you've ever done and still have been able to detect evidence on the second elution?

Mr. Fortner: That's what I referred to as the retest in the six to eight month window where you've had to go back and re-elute to be able to do a D/L isomer.

Dr. Caplan: Any other questions?

Dr. Mitchell: Has the stability data for all of the analytes been conducted in the long term?

Mr. Fortner: Long-term meaning after they've been eluted?

Dr. Mitchell: No. On the patch itself?

Mr. Fortner: Yes, all of the patches had up to 28 days for all analytes.

Dr. Mitchell: We haven't had the data for say, a year, like the stability data we would have in urine or in hair, for example?

Dr. Sample: You indicated in a retest for D/L. You had gone six to eight months?

Mr. Fortner: Right.

Dr. Sample: Have you done other analytes other than D/L in a retest scenario in that six to eight month time frame where you've had to re-elute off the patch? Because that only occurred with the D/Ls, have you done it with all the analytes?

Mr. Fortner: The re-elution has typically only occurred with D/Ls. We have had retests by other laboratories that are in that time period for cocaine, but they do not involve re-elution.

Dr. Sample: That was from the original elution?

Mr. Fortner: Right.

Dr. Sample: So there really is no stability study on the patch itself, off of the patch, for longer than 28 days other than for D/L amphetamines?

Mr. Fortner: Correct.

Mr. Crouch: Don't you store the patch at room temperature?

Mr. Fortner: When we receive it, yes.

Mr. Crouch: So you have 28 days at room temperature.

Mr. Fortner: The stability studies are for 28 days.

Speaker: I think you're getting to your question of the re-elution of the patch. I don't think that is an appropriate scenario because depending upon the level you're dealing with, we're getting 60, 70 percent off the original extract and we had to go back and re-elute. We had 67 percent of what's left, then quantitatively, we may be below the cutoff so I don't necessarily think that is applicable in that situation. As far as stability, I'm getting kind of confused because when the patch comes in, we put it through the extraction process originally and it is stored in that liquid.

Mr. Crouch: What I'm trying to equate this to, and I think what other people are trying to equate this to, is urine stability, not more urine samples, are present in testing your stability is at room temperature for 28 days, but you really don't store these and you haven't taken those extra measures to see if the sample is optimal.

Mr. Fortner: The samples that are possible, the eluates go into long term frozen storage. The dry patches and cell stability study is what was submitted to demonstrate stability on the patch prior to elution. Now their deviation is one variation of the question. Stability of the drugs in the eluate. Is that your issue, were stability of the drugs not eluted off the patch that's in the container?

Dr. Caplan: Certainly the stability in the eluate would be parallel to keeping urine for a year and seeing whether you still could recover the drug.

Dr. Sample: No, I don't think so. I think stability on the patch.

Dr. Caplan: One question is whether or not after you've done the analysis on the eluate, whether you can re-construct that analysis within what time frame to reconfirm that if that were necessary akin to saving urine for a period of time for that purpose. The other question is how long it is stable in the patch and whether that is an important consideration or not. There are two stability questions and the net result is that you've got 28 days on the original patch, how long do you have on the eluate? Have you done that?

Mr. Fortner: Not for all analytes.

Dr. Caplan: It is a question we want further information on.

Mr. Jones (DTAB member): I think this goes back to the original question, D2. What is the specimen, what do we consider the specimen.

Dr. Baylor (RTI): Are you covering G-2 as well as D-4? G-2 is laboratory testing. It's the short- and long-term storage to ensure specimen integrity. That seems more likely eluate, extraction stability. This I believe is more in the shipping of the specimen.

Dr. Sample: It's just the time frame to the laboratories so we may be jumping ahead.

Dr. Baylor: It seems like we've integrated D-4 and G-2.

Dr. Caplan: Some of the questions do unfortunately.

Dr. Baylor: This would be more than a dry patch for 28 days.

Dr. Sample: If you were to separate out the storage essentially from the time of collection to the time of arrival at the laboratory, which is the way you should interpret D-4, that would be one question. Then we'd get into the stability on the patch and the stability of the eluates, perhaps as G-2.

Dr. Baylor: For urine, they're kind of the same. But for this, they are separate.

Dr. Caplan: Why don't you frame what you would like covered under D-4 and G-2 separately.

Dr. Sample: I think the question for G-2 is have you studied the stability of the drugs on the dry patch for greater than 28 days and have you studied the stability of eluates for all the drugs for say, 12 months, which is the standard of the traditional urine based screening?

 

Dr. Caplan: No matter how you look at it, that data is not available, whether it's G-2 or D-4.

Mr. Fortner: I'm not sure about D-4. My interpretation of D-4 was pursuant to stability, shipping, product. I mean, whether it's a sweat patch or an oral fluid or hair to the laboratory. And I think D-4 is separate from G-2.

Dr. Sample: That is what I was just saying. I think those two questions I just posed really relate to G-2 and not to D-4, and I really think there is enough information presented here to answer D-4. But all the discussions we had are going to come up.

Mr. Fortner: I didn't say that.

COL Jacobs: Are you saying D-4 should move to a blank?

Dr. Caplan: Yes, that's what we're coming down to. The D-4 should move to a blank.

COL Jacobs: Then let's move it to a blank and turn the page.

Dr. Caplan: All the discussion about D-4 applies to G-2. We might as well dispense with that right now. Do we agreed then that D-4 is a blank but G-2 is still a P?

Dr. Sample: I think G-2 is still a P.

COL Jacobs: Let's wait till we get to G-2.

Dr. Caplan: I don't want to do it twice -- an I to a blank on D-4. Page 8, collections, procedures, specimen integrity, evaluation. Do you want to comment on that, Neil?

Mr. Fortner: I think we already covered part of this in the collection procedures with respect to the training examination if the patch is adulterated and it was compromised in any form or fashion.

Dr. Caplan: Any other comments on that?

Mr. Lucas: Yes, I would like to say that six federal court judges reviewed the chain of custody procedures and upheld the test results of the sweat patch.

Dr. Caplan: Do we have enough information to move this? This can move from an I to a blank. Now, collection procedure to deter tampering/adulteration.

Mr. Fortner: I think we've already discussed all of this.

Dr. Caplan: Any other comments?

Mr. Schoening (DTC): The question is, the adhesive you use as manufactured by 3M. Can it be reapplied by a donor in an attempt to reapply the patch? He's taken it off his arm. He has Tekraderm. Can he go and put a coat of Tekraderm and have it reapplied and would it hold and would that be detectable?

Mr. Fortner: Could they get access to the specific product Tekraderm if you peeled the patch -- to put it on another piece of Tekraderm, it pulls the release liner which eliminates the unique identifier. There's a unique identifier incorporated in every patch. If they took this, peeled off the blotter paper and put it on, there would be no unique identifier on the patch anymore when they presented themselves, the patch wouldn't match because that identifier is recorded and the chain of custody is applied. We have had a report of people trying to take the patch off, taking a razor blade, cutting around the outside, trying to reapply it. In our experience, we've been able to detect that because it is physically different on the individual who wears the patch just because there are the products in sweat. There is some slight discoloration so we have to come and present themselves and patch is bright white as when it's initially applied. I think that is highly suspicious as well, and those things are incorporated as part of the integrity checks to look for potential substitution and adulteration. Also clearly because of the properties of the Tekraderm, if they come back in and the whole thing is held back on by band-aids, then there are some serious questions on the integrity.

Mr. Schoening: The question is, they've got a hold of some Tekraderm, could they put it back on?

Mr. Fortner: If they pulled the patch off, it releases the integrity.

Dr. Caplan: Any other questions or comments? Any recommendation?

Dr. Sample: Move it to a blank.

Dr. Caplan: Any objections?

Dr. Bush: This is E-6?

Dr. Caplan: Correct. Now, E-7, transportation. If the patch is damaged or lost in transit. Is there any other comment, a recommendation from P to blank? Okay, the lab testing, G-2. Have we sufficiently agreed this should stay as a P, that we need additional information on the stability of the dry patch for 28 days and the stability of the eluate for a longer period of time?

Dr. Sample: I think we need to decide what constitutes a specimen first before deciding whether or not we're talking about the patch itself or the eluate. Once we answer that question, then we can adequately determine what needs to be done for G-2.

Dr. Caplan: That may be a while before that occurs and if that occurs in time, when the stability studies are another year away.

Mr. Fortner: I think it's two separate issues. We can demonstrate stability of the drug on a drug patch with existing eluates by going back and doing a reanalysis. I think that's one thing to address in terms of additional information to the Board regarding those two areas of stability.

Dr. Sample: If you want to be proactive, you can go ahead and do both. One or the other is going to be needed, or maybe both.

Mr. Fortner: I think both will be needed. I'm not sure that it would address the ultimate question of what constitutes a specimen.

Dr. Caplan: It's only for a year of what would be previously analyzed would be akin to, say, to the urine specimen for possible reanalysis.

Mr. Lucas: Are we going to set any parameters on what we expect for results here? Are we going to see if the drug can be detected after a year?

Dr. Bush: Are you looking to get quantification so you can compare that sample? I would be looking for regular retest type of scenario. Can you detect that drug -- is that drug still present at a concentration greater than the cutoff.

COL Jacobs: So you're looking for detection?

Dr. Sample: Correct.

Dr. Caplan: So that stays a P. G-3, Page 12.

Mr. Fortner: I think we've covered this previously.

Dr. Caplan: Adulterated and substituted specimen while certainly substituted meaning the patch coming off. You made some comments about the detection of bleach and other things. Are there any other questions about that?

Ms. Murdoch: Is this at the laboratory? It appears that the question that refers to what test or processes can the laboratory institute to identify adulterated or substituted specimens like the tests that are currently being done for urine at the collector site, identifying this sort of thing and that question is not answered.

Mr. Fortner: Well, I believe the question is answered. Number one, the laboratory does have analytical tests to detect for adulterants, bleaches. The most common form that we have seen with respect to substitution, all the programs have the ability to send the entire device, the Tekraderm, in addition to everything through the laboratory for physical examination whether it be microscopic or otherwise to look for punctures, substitution criteria.

Dr. Caplan: Did you have something specific about that, Julie?

Ms. Murdoch: My question is getting back to the specimen size and what's a specimen. Are you trying now to identify common adulterants on the sweat patch? Do you elute and then test the elution for the adulterates and are you using part of your specimen for the adulteration testing? I was trying to compare it to laboratory testing for urine and I wasn't getting there.

Mr. Fortner: Currently we are not aware of any products that are using the adulteration process that are taken internally that would be subsequently excreted by the body. Even the products that we see in urine, they're externally deposited. If they are externally deposited on the patch, then you have to physically remove or adulterate the patch in order to perform that function. If bleach is added to it or some other compound, whether it be formaldehyde or liquid form of nitrites, and in that process in doing it, they've compromised the patch because they would have to physically expose the patch in order to perform that or they would have to do it via a syringe.

Dr. Sample: The question is assuming they somehow devise a way to externally adulterate the patch, if that cannot be detected with the tamper evidence that you currently have, do you routinely perform adulteration tests on that eluate or do you have the possibility of doing that, then I think that really would answer that question.

Mr. Fortner: We don't routinely perform unless the physical examination of the patch indicates it has a discolored appearance.

Dr. Sample: The question is, are there tests available to determine the presence of adulterates?

Mr. Fortner: Yes, you could perform them on that eluate.

Dr. Sample: I think that answers the question.

Dr. Caplan: Is there anything in addition to that or do we still need information? In other words, that's theoretically possible now? Should we go from I to a blank or an I to a P?

Dr. Sample: An I to a blank.

Dr. Caplan: Okay, an I to a blank. Now, G-4 initial test. We talked about FDA clearance as an initial test, that was my question from before. I'm not confused about it, but the question is, do we want to require it or is it desirable to have FDA clearance for the initial screening or additional testing procedure? Any comments on that?

 

Mr. Crouch: Has any manufacturer obtained FDA clearance for the testing of a sweat patch and how about any of the RIA kits.

Mr. Fortner: The only one we've ever gotten was DPC.

Mr. Crouch: Do you know if they have gotten an FDA clearance?

Mr. Fortner: We don't routinely use it.

Mr. Crouch: So there is at least one FDA cleared device to test for these five drug classes?

Mr. Fortner: From the manufacturer agent standpoint, yes. That's probably a compound question with respect to FDA clearance overall.

Dr. Caplan: That was the question. Is FDA clearance required for initial testing, as it is now for urine testing? And if we go through other specimens, is FDA clearance and initial testing going to be a requirement or not. It seems like that is something that we need to think about some more globally and we don't have an answer across the board.

Dr. Sample: Didn't we leave this as an "I" yesterday with respect to hair pending the determination as to whether or not FDA clearance is required? If so, I recommend that we leave it as an I for the time being for the same reason.

Mr. Fortner: This has the clearance behind it. I think that is different from whether there is a clearance.

Dr. Sample: The question is this test should be cleared.

Mr. Fortner: Yes. It says FDA cleared test. I interpret that to say, not should it be cleared, but is it cleared.

Dr. Caplan: If we compare it to the current guideline, which is where we started all of this, the initial test is a screening test by immunoassay for urine and that's because there's a requirement that it be an FDA cleared test, not the testing, not the collection.

Mr. Fortner: Agreed. And the response is that the ELISA assays as used for a screened patch are FDA cleared.

Dr. Bush: So I'm hearing that it's a fact that certain kits have been cleared for testing the patch. It's a fact that it is cleared?

Mr. Fortner: Yes. Why don't you ask the more global question, should they.

Dr. Bush: That's where I was going. The test kit should be cleared by the FDA as a diagnostic medical device. We were going to leave that as an I for everything, pending further discussion, further information, further findings by FDA. As I understand it, we leave it as it is and turn the page.

Dr. Caplan: Page 14, the initial test detects HHS target analytes. These are the ones you've noted were measured and found.

Mr. Fortner: I think the only clarification is, the screening test does pick up methamphetamine and amphetamine.

Dr. Caplan: Any comments or questions on whether or not the five regulated analyte classes can be detected by this method?

Mr. Fortner: No, I think I would also clarify, you do get cross reactivity of carboxy-THC as well, both urine and carboxy.

Dr. Caplan: We have satisfactorily answered this question, that the target analytes can be detected satisfactorily. So we'll move this from I to a blank. Okay, G-4 on Page 15, the cutoff question. Do you want to comment on that? The cutoff question is something that's going to have to be established independently for each matrix so the question then is what evidence do you have of these cutoffs being either appropriate and able to detect users for some period of time.

Mr. Fortner: I think it's important that it goes to the more general question in terms of what is the acceptable approaches for determining cutoff. I mean, across all the alternate matrices on the cutoffs established in the sweat testing, we went through and approached using empirical data and ROC analysis, there would be true positive, true negative and relying on studies, clinical and controlled-dose studies.

Dr. Caplan: When you say clinical, have you done studies where you collected patch and/or collected urine or hair?

Mr. Fortner: Hair wasn't any part of that study but we have some very large clinical studies, over 10,000 urines correlated with over 1,000 patches, because of different wear periods, three urines a week per person, correlating data that was in a controlled and locked-down prison in Michigan, as one of the bigger studies. And then federal probation has two pilot studies that they conducted looking at hair, urine, and patches in dosages as part of the clinical correlation studies that were conducted.

Dr. Caplan: Can you maybe summarize that? How frequently was the urine and how frequently was the patch.

Mr. Fortner: The typical wear period of the patch was one week. The urine was going through it on the average two to three times a week.

Dr. Caplan: Are you saying the correlation is perfect?

Mr. Fortner: I didn't say that.

Dr. Caplan: You have to start somewhere every time you had seven days.

Mr. Fortner: What we found was the patches detected, if I recall specifically, 33 percent for frequency of drug use relative to the urines that were collected during the same time that the patch was worn.

Dr. Caplan: Were you using multiple urines?

Mr. Fortner: Right.

Dr. Caplan: Are you saying any one of the three urines compared to the patch, or would it be considered positive, or would it have to be all three?

Mr. Fortner: No, I didn't say that. I said the patches detected 33 percent more positives than urine. We had instances where the urines were negative and the patches were positive, but relative to the windows of detection. The unique component of the patch is it retains the drug as it is excreted. You're really looking at just different snapshots of time.

Dr. Caplan: Does the 33 percent more mean you had 33 percent more patch positives to any one urine positive?

Mr. Fortner: Yes.

Dr. Caplan: What about the numbers?

Mr. Crouch: I just saw the word levels in here.

Dr. Caplan: They're not quite as high as concentrations. The general question of whether or not these numbers or any numbers were adequate or whether we want to address that now or leave that to some further across-the-board elucidation.

Dr. Vogl: Is it a concentration in the eluates? Or it should be nanograms?

Mr. Fortner: We express it as a nanograms per milliliter. It's 2.5 mL eluate.

Dr. Caplan: But the ultimate reporting should be probably per unit, per patch.

Dr. Vogl: But you're only getting 60 or 70 percent off of the patch.

Mr. Crouch: You don't correct for recovery in urine? If the recovery for carboxy-THC in one lab is 90 percent and it's 85 in another, then you have a slightly different answer.

Dr. Caplan: The question is whether you quantify the original material as milligram per patch.

Dr. Sample: I think it should be per square centimeter of patch. The larger patch you have, the more you're going to trap even if the eluate volume changes, the concentration cutoff, perhaps, would not be appropriate in that case. You really need to relate it to the size of the collection device.

COL Jacobs: I think we need to wait on all kinds of cutoffs for all testing methods because we don't really know how they relate or how we want them to relate to understand these numbers and they can get them and that is out of the elution. You were saying that in urine -- we know we only get 60 or 80 or whatever, that's when you add the internal standards. We're not adding the internal standard here with the patch. I think we are waiting until we get the fluid off. I think we have too many things to look at to make a decision on this now.

Dr. Bush: It goes back to your original concept of what is the original specimen, the eluate or the patch?

Dr. Caplan: There is data to show some comparison. We will need to do some further refinement for establishing what these ultimate criteria are.

Dr. Bush: Can I clarify something here? These cutoffs, were they established and carried through the FDA clearance process?

Mr. Fortner: Yes, they were established and reviewed by the Scientific Advisory Board of FDA. If the Board wants the filings, that's fine. They're about 1000 pages per drug.

Dr. Baylor: This is based on wearing a patch for seven days?

Mr. Fortner: Yes.

Dr. Caplan: Anything else? We need to get more information and deal with this comprehensively later. The FDA has a comparison performance as opposed to absolute numbers. I don't know that that would be of great assistance at this time anyway.

Mr. Fortner: It's available should the Board decide.

Dr. Caplan: We are on Page 16. We're beginning to talk about actual characteristics of the laboratory testing, the initial test, and the ability to perform around the cutoffs.

Mr. Fortner: This is additional data from our screening thresholds. These are the CVs for that data.

Dr. Sample: 25 percent above and 25 percent below?

Mr. Fortner: Yes.

Dr. Caplan: Any other questions or comments on that? We'll move this from an I to a blank unless anybody objects. G-4, Page 17. G-4e, the ability to repeat the initial test.

COL Jacobs: The same question, what's the initial test? Is it the fluid or is it the patch?

Mr. Fortner: Whether you define what is the specimen or not depends on whether you repeat the initial test, was how I responded to that question.

Dr. Caplan: In light of what we talked about before, we probably ought to defer this. Also it's going to depend upon how you define the specimen. Does anybody object to deferring this?

Dr. Bush: That's consistent.

Dr. Caplan: Confirmatory testing, G-5, Page 18, use MS for identification and quantification.

Mr. Fortner: It is not MS/MS at these levels. You don't need that. We do use chemical ionization on the THC analysis, but it is conventional MS.

Dr. Caplan: We're talking about MS on the eluate, which would be no different. Out of the concentration ranges, there's no sensitivity issue?

Mr. Fortner: No. There's a slight difference, concentration screening versus confirmation for THC. The other ones are straight across because we're looking for a different compound.

Dr. Caplan: Any other comments? We are looking at different drugs now. There are no problems with the parent THC?

Mr. Fortner: No, that is what we confirmed. Is there a recommendation?

COL Jacobs: Move it to a blank.

Dr. Caplan: Okay. 5-B.

Dr. Sample: There's already a blank.

Dr. Vogl: They are just giving us the numbers. It's a yes, you can do it for all of them.

 

Dr. Caplan: It's just a matter of ultimately defining what the number is.

Dr. Bush: And the marrying of the screen and the confirmed method for the analyte.

Dr. Caplan: This is for information and comparison. G-5c, Page 20, acceptable performance around the cutoff of the confirmatory test.

Mr. Fortner: The minus is a 40 percent number.

Dr. Caplan: Are there any issues or questions there? What do you want to do with this, move it to a blank?

Dr. Bush: Excuse me for backing up a minute here, but if we go back to Page 18, G-5a. With the notation that the GC/MS is done by CI, which is something that we do not use currently in the existing program, do we want to have discussion about criteria, acceptance criteria, in a way that we talked about MS/MS or anything like that?

Mr. Crouch: Just to refresh your memory, there was a laboratory that was certified that did CI on urine and that was fully acceptable and it was in the program for two or three years, and they voluntarily dropped out so I don't see it's any different here than it would have been in the urine testing that's still allowed in urine testing.

Dr. Caplan: Page 21, do cutoffs reflect drug use. I think we've answered that one a number of times. Does anyone have any other question about that?

COL Jacobs: I have a question about that. I understand that it does reflect drug use, but are we redefining here -- deterrent or a detection? I don't know what Neil's levels relate to. Are you trying to go as low as you can because of what these tests are used for? This isn't really a deterrent patch, this is an absolute detection program.

Mr. Fortner: I think it does have deterrent properties just from the fact that they're wearing it. There is a significant increase in drug use. I think that if you wanted to use a detection system, you have not gone through immunoassay, you would go to GC/MS and you could confirm it, which is not what this program does.

Dr. Caplan: We have to assign cutoffs.

Mr. Fortner: Detecting the same and in looking at acceptable ROC analysis for true positives as compared to the traditional error base.

Dr. Caplan: Any others? Okay, move it from I to blank unless there's objection. Page 22, certified lab program.

Mr. Fortner: I think it's possible to establish one, but there is not one established at this time.

Dr. Caplan: That is again the question, does anybody have a comment on any idiosyncracies that might exist?

Mr. Stephenson: Can we go back to Page 21, G-6. That the cutoffs haven't been identified, whatever they would be, reflect drug use. What we're saying is -- we're not saying in this sense, illicit use versus licit use. We're not talking about anything beyond the issue of actual consumption or use of the drug as opposed to environmental contamination or some other external element so what you're really saying here is that you can say, unequivocally, that when you have a test positive that does reflect drug use by the individual period.

Mr. Fortner: Yes, at some point. In past exposure studies for all drugs, PCP, methamphetamine, we did do eventually passive exposure of cocaine and marijuana.

Dr. Sample: You did test for external contamination?

Mr. Fortner: Yes. I mean, applying the drugs to the outside of the patch. I think there was some discussion on preparation on the site if there are drugs already existing on the individual's skin, could they be absorbed in. I think there may be some issues in there.

Dr. Caplan: Maybe Bob's question might more clearly reflect, is there a greater sensitivity of the patch to detecting passive inhalation?

Mr. Fortner: The passive exposure studies have been done and have demonstrated no detectable levels of drugs on the patch.

Dr. Caplan: I think you might have been asking, is it possible that one of the other technologies other than the urine that we're familiar with might be more sensitive to the passive exposure?

Mr. Fortner: I certainly think other technologies, whether they're more sensitive or susceptible, depends upon the analytical procedures that are used in those. But from what we've done, exposure, and direct application of the drug to the outside of the patch to simulate a worst case shows that those drugs are too large to pass through the Tekraderm properties for THC and cocaine. We had ones in the classical exposure with vapor and no detection.

Mr. Stephenson: I think the most important aspect of all of these exercises, in all of these areas, is answering that specific question. If you're not able to do it with an understanding of the human study subject's involvement of the role, then that's the problem. And so we haven't quite gotten to that level of detail yet and I needed to have that, and I think we need to bear that in mind for every one of our points of discussion with the other alternative technologies.

Dr. Caplan: We didn't do each one yet. G-6, we said was a blank. Now, H-1. What did we do with the other?

COL Jacobs: Yesterday we moved the other one to a P. We said it is possible.

Dr. Caplan: I think it is the same thing here.

COL Jacobs: I agree.

Dr. Caplan: Does anybody object to moving H-1 from I to P? All right. H-2, external PT program. That's going to be one of the critical areas.

Mr. Fortner: Not only is it certainly possible, we actually have one program in place right now. John Mitchell spoke yesterday about performance versus proficiency testing. The program right now just looks at the ability that the sample is indeed fortified to be positive, was it reported as positive by the laboratory. And that gets to the blind proficiency programs run under the Department of Transportation guidelines. There are both positive and negative patches sent in blind to the testing laboratory by an outside client.

Dr. Caplan: Do we know how they're prepared?

Mr. Fortner: They are worn patches. They spike them with methanol solutions of the drugs we're testing for and then send them in. They're not from known drug users. They're drug-free patches that have been either fortified or sent in as negatives.

Dr. Sample: It is not clean blotter paper?

Mr. Fortner: No, it is a worn patch, so it presents itself as a worn patch on their chain of custody with fictitious identifiers.

Dr. Caplan: They have someone negative wearing the patch?

Mr. Fortner: Yes, multiple people wear the patches and some they will send in without spiking them, some they will send in spiking different drugs.

Dr. Caplan: Any other PT comments? Does the client have someone else doing that?

Mr. Fortner: No, currently they don't.

Dr. Caplan: I was asking if there was any other experience in the audience.

Dr. Bush: I would like to ask a question just concerning that matrix itself. Whenever you take a look at that PT, a spike versus a worn, I want to revisit that. Are there concerns about that?

Mr. Fortner: I think you've eliminated the matrix issue because they are spiked, worn patches, so all the other components you would see in sweat are going to be on the patch since it is a worn patch.

Dr. Bush: That will take some of that matrix effect -- it is like a blank urine.

Dr. Sample: In my mind, it is like spiking a blank urine.

Dr. Bush: You have a big pool of negative blank urine and then adding the analytes of interest, and using that, then packaging it and then sending it. Okay, thank you.

Dr. Sample: The only difference is it is not a pool of blanks. Each blank is going to be different.

Ms. Murdoch: How do you know that the blanks are actually negative? Do they wear two patches and one is sent for verification to make sure in fact that it is a negative patch?

Mr. Fortner: I don't believe they do that.

Dr. Sample: But it certainly could be done.

Mr. Stephenson: I think the issue would be similar to yesterday. We have not moved beyond this issue even though there was a similar PT program in the hair environment, but the issue was reference labs. How are you going to establish this?

Dr. Sample: I think it was a different issue yesterday with respect to hair because it's difficult to incorporate the drug in the hair in vitro, whereas, you could easily incorporate the drug into this collection device in vitro. So I really see a difference between yesterday's discussion and this one.

Dr. Caplan: There's still the question of whether it can be done and whether it's been incorporated enough for a mass program.

Mr. Stephenson: It goes beyond one individual lab doing it with one client. That's another issue.

Dr. Sample: You still can.

Dr. Mitchell: I think there's one additional similarity between hair and that's going to be the quantitative aspect since we do not have 100 percent elution from the patch at any one time. There are some issues that are associated performance wise with this that aren't associated with matrices in which all of the material can be extracted. In this case, however, we're dealing with one laboratory and it probably would not rear its head until additional laboratories and may have somewhat different procedures. I mean that's the potential.

Mr. Crouch: I don't think we should get hung up on their recovery of the drug from the patch. That's going to depend on the method. If somebody modifies the method a little bit, it's going to increase the recovery. We did this back in the 50s. We adjusted our concentration for recovery. I think we stopped doing it in the 60s so I hope we don't go back to that sort of analytical approach.

Dr. Mitchell: Again, without absolute numbers in quantification, that is where quantification could be verifiable, it is going to make some aspects of performance testing a little more difficult.

Dr. Bush: We've had immunoassay manufacturers make our performance in the urine testing program a little more difficult too.

Dr. Mitchell: I understand that, I'm just stating what the potential problems are.

Dr. Caplan: It seems there's really a limited amount of information in this stage. It's another across-the-board thing to look at. The information is very limited. It can be done, but I don't think we know yet whether we can produce the patches uniformly and can you make 100 of these and they're all the same. I don't know that we know that.

Mr. Davis (RTI): It would appear to be simpler than the corresponding case in hair.

Dr. Caplan: Unless there was something in the patch that didn't allow distribution. Do you want to move it to a P? Certainly it's not a blank. An I to a P. Any objections? It's not an area where we're likely to get more information.

Mr. Stephenson: This sounds like an interesting segue, opportunity, an I to a P.

Mr. Stephenson: Because of the snow storm, we ought to be through in time to get you guys out the door and to your airport by 4 and that means our finish time has to stay, at a minimum, where it is to be through by 3 to 3:30. To that degree if we can look at what we have in front of us, how much more time do you think we're going to need with sweat and then we need to go through oral fluids. Let me just ask those representatives from the other entities, do we have a similar presentation to make for oral fluids?

Dr. Bush: Yes.

Mr. Stephenson: The other thing is on-site. That should pretty much cover this. Now this does not mean that we're not going to examine laboratory-based urine testing too, but the issue today is to try to bring back into perspective the other alternative specimens. We've spent so much time and concentrated focus on hair testing in the first couple of these sessions and now the rest of the industries are looking for their opportunity to get updated. That is where we're going right now. I'll turn it back over to you, Yale, to continue.

Dr. Caplan: The lab inspection program. The same issues as before. I guess there's no one that's expecting sweat patches at this time.

Mr. Fortner: That's right.

Dr. Caplan: Any comments?

Mr. Crouch: How many labs might be interested in certification?

Mr. Fortner: We have five laboratories in the U.S. right now that are involved in some form or fashion of referee testing that have approached us about doing sweat patch testing independently. And then a fairly large organization in western Australia that has run, for the last three and a half years, their own program.

Dr. Sample: I guess the question is, can it be established, and I think the answer to that would be yes. As we did similarly yesterday with the hair testing, yes, one could establish a laboratory inspection program.

Dr. Caplan: We can move that one to a blank. Any other comments? We will move it from an I to a blank. Is there any objection? Now, blind samples, H-4, Page 25. We made some references briefly earlier.

Mr. Fortner: The references I made earlier were centered around an external blind. We do have an internal blind program where we spike the patches ourselves so you're looking at samples analogous to what you have in the urine testing program.

Dr. Caplan: Discussion.

Dr. Sample: Would this be analogous to the external PT? We could move it to an I to a P? I think you have the same issues whether it's internal or external.

Mr. Fortner: I thought this was the internal. It's possible to submit negative/positives if they were donor specimens. You have to be prepared but -- like we would prepare our urine.

Dr. Caplan: You have to prepare someone by having them wear a patch?

Mr. Fortner: Yes, you see a matrix issue.

Dr. Sample: I think it would be a P. You still have to prepare them in the same manner.

Mr. Crouch: What don't we understand about it? Why isn't it possible?

Dr. Sample: Why did we leave external PTs as being a P then?

Mr. Crouch: I think there are a lot more issues with the external PT than there are with blind samples. They already have a blind program. Certainly it can be done. There is no performance testing protocol set up. I think it's a different issue.

Dr. Caplan: I think if it's a different issue. But Barry's point -- it is possible to move it to a P, but if it hasn't been done, we don't have the experience other than taking your word for it. The question is of the ability to do that and the documentation. The question as to whether it's uniformly made in those types of things, I think, is Barry's concern.

Mr. Fortner: Well, if we could specify or clarify what the issue is, that would be fine and we could respond to it.

Dr. Caplan: How are you assured that they are uniform and what the track record is.

Dr. Sample: Have you prepared those blind samples? How do you verify? Do you blind PTs?

Mr. Crouch: I think that's sort of a practical issue of how a program runs and I don't think we're asking these other people those sorts of questions. That's an inspection issue. The question says, can it be done. It's possible, and it's being done. So certainly it's possible.

Dr. Sample: But yesterday, didn't we also leave the same question as an I?

Mr. Crouch: I think we're talking about a different thing.

COL Jacobs: We did, but I think it's for other reasons. I think those reasons where we couldn't decide, if you turned to Page 27 in here, there's quite a write-up of, is it real positive hair or is it spiked hair. And there are a few different issues we're going to work with on that which may be different here.

Dr. Sample: I guess that's my question here, is it really different or is it the same issues?

Dr. Caplan: Any other thoughts or comments? Well, we've got two choices, three actually. I to a P, I to a blank. How do you feel?

COL Jacobs: I propose we move it to a blank. I think they've answered it.

 

Dr. Caplan: Does anybody disagree? Okay, we move this from an I to a blank. Now, certifying scientists review. I assume you're doing this?

Mr. Fortner: This is no different than our urine program with the exception we're not releasing necessarily to the MRO at this point, but that is in compliance with the program. There's a full review by certifying scientists, just like you have in the urine program.

Dr. Caplan: Are there any other comments? Change it from a P to a blank? Now, reporting, Page 27. There's a couple of places where it says, see lab report.

Mr. Fortner: In the September material, there was a copy of the laboratory report which lists our standard report list screening, various screening levels, confirmation levels, by drug, and then report by drug. It's fairly standardized.

Dr. Caplan: Any issue with I-2? Move it from a P to a blank? Now I-3, the turnaround time. To keep the confidentiality of the donor, the same thing. Okay, the standard report form. Any objection to moving it to a blank? Okay. Interpreting results, Page 30. Under MRO, the scientific information is available to allow an MRO to properly interpret a positive test result. I guess a number of these things have been presented before. We had commented and had discussion on whether that's all sufficient. Now, scientific data from the controlled dose studies was made reference to before in clinical trials cleared by the FDA and publications that have been reviewed. Is there anything else?

Mr. Fortner: The only thing we have not done was to generate what would be analogous to an MRO and we would incorporate that into part of the training.

Dr. Caplan: The question is do we have enough information for an MRO to make a judgment, and judgments are going to be similar judgments about positive or negative versus the passive exposure.

Ms. Murdoch: One question that occurred to me was whether or not you've done any studies to determine whether there's variability in drug uptake or excretion. Between classes we talked a lot about hair testing in terms of race or color or whatever. Is there a variation across gender? That was my question. That old expression, women perspire and men sweat. Is there any difference there in terms of quantity of drug that's excreted into the patch or any other class differentiation?

Mr. Fortner: A two-part response. The answer is no, we have not done gender-specific studies. If you look at the properties of the transdermal sweat collection device, you're looking at sensible versus insensible sweat. Primarily, the body's insensible sweat is the mechanism of regulating temperature control, is the primary mechanism that we see, depositing drugs onto the patch. A person need not be an Olympic level athlete with an exercise regime to produce sufficient signal in the patch. Most of the individuals in these studies were in restricted activity environments. In many respects, we certainly note that under those conditions and in the filings, that the patch needs to be worn for a minimum of 24 hours to generate sufficient drug for detection.

Dr. Caplan: Do we think any other studies are needed?

Dr. Bush: Were there any females included in those studies that were done?

Mr. Fortner: Yes, they were not excluded, but we didn't do an analysis breakdown specific to the results based on gender or any other classification.

Dr. Bush: Did you capture that information, what the sweat patch result was, and the identity of the person to that type of demographic?

Mr. Fortner: I know we captured information that was available on gender, and I believe there was some information from some of the studies with respect to other classifications.

Dr. Bush: I think it may be a good idea if you go back through your database and gather that information. You can forward it to me as the Executive Secretary of the Board, and let me see what it looks like. I can fax it to the Board members, whatever is provided in the future. And see what kind of demographics you can gather. This would go back to the FDA study?

Mr. Fortner: Yes, encompassing all of those studies, both controlled-dose and clinical studies.

Dr. Bush: It would be good if you could isolate that by dose, by drug, and the other demographics.

Mr. Fortner: I won't claim we have everything, but we do have a lot of that.

Dr. Bush: I understand.

Mr. Stephenson: One other thing here for the Administrative Office of the U.S. Courts. In your 11,000 patch analysis, did you capture demographics on the donors, the sweat patch donors?

Mr. Lucas: No, we did not.

COL Jacobs: Can you go back and get that? Is that still available? Could you relate the results back and get those answers?

Mr. Lucas: Yes, we could, by following the bar code numbers of the chain of custody forms.

COL Jacobs: It might be a lot of work though.

Mr. Lucas: It would be.

Mr. Stephenson: The issues related to this I think are important. And in cross-cutting in each one of these issues, I think we're going to be sensitive too. We need to look at gender bias and we need to look at other racial marker differences, and we need to address them cleanly and openly across the board in all of these topic areas. If you haven't done it, look at your data sets to see whether you can, and if you have the data, but you just haven't analyzed it. If you can do so, if it's going to take something to correct or to modify a database prospectively, let's talk about that. If there's some way we can help you, if there's something you need to label administrative support, let us know. We'll do what we can.

Mr. Fortner: Aaron, we may be able to assist you on that. We don't have the identity of the individuals tested but each carry a unique identifier. We can capture that so we can provide a list, I believe, sorted by prisoner or probationer ID, which would then facilitate your offices from identifying the demographics.

Mr. Lucas: We would have to go back to the original chain of custody form that is held in the district and they would be able to match up the demographics.

Dr. Bush: If we could supply you with some administrative support, could you do that?

Mr. Lucas: Sure.

Mr. Crouch: If you're going to capture this, you should decide what the data is going to tell - female certain percentage positive; males a certain percentage positive; blacks, a certain percentage positive; whites, a certain percentage positive. Unless you know what the dose is or have some other measure of whether they should be positive and what the positive rate should be, it's not going to tell you anything. It may create more questions than answers.

Dr. Bush: You're right, Denny. Say you're referring back to the information that Neil has from the FDA submissions, they were controlled dose studies.

Mr. Crouch: I referred to the data that Mr. Lucas might have. You need to have some measure about whether the person took the drug or other test such as urinalysis or hair.

Dr. Bush: My point is, Neil's is much more controlled since he has the controlled dose study, whereas this is mere observation.

Mr. Crouch: I'm trying to defend Mr. Lucas a little bit before we send him off to do 11,000 tests. We might have information on 11,000 prisoners, but it might not tell us anything.

Mr. Stephenson: I can tell you in a major analysis in the criminal justice analysis, of another technology in which there is no knowledge about the dosing levels or amounts or timing and yet it has become a definitive piece.

Mr. Crouch: The question is, what's definitive? You've got to have something to compare it to. If you don't have anything to compare it to, I wouldn't use the word scientifically.

Mr. Stephenson: I would use it in the sense of it's definitive in the use by the industry in examining the role and appropriateness across racial lines.

Mr. Crouch: What industry? If we're asking for scientific information and Mr. Lucas has something, that's great, but we should look at the database before we send him off to do this. Because if there isn't some other kind of measure, then it's not very usable.

Dr. Caplan: How about the environmental temperature, was that measured?

Mr. Fortner: Certainly in the more controlled studies. That information is available, the conditions and dosing and pre-dose, ascertaining status. Do they sweat a lot or sweat a little, that type of stuff.

Dr. Caplan: That would be a factor in setting the minimum amount of time.

Mr. Fortner: As we go back and pull that off those studies, we provide that information as well, sort of the conditions for the study.

Dr. Caplan: So adulteration constitutes staying at 65 degrees or less?

Mr. Fortner: Actually the application issue temperature-wise presents itself only if they come in from outside from a high temperature and the body doesn't have a chance to cool down a bit. If they're still in an active form of perspiration, then even the preparation of the site isn't going to adequately dry that and that will affect adhesion, which says the patch will be likely to fall off fairly soon. That's just a function of what the clinical trials show from the real world.

Dr. Caplan: One question is, if someone stayed in a low temperature, will that adversely affect the test?

Mr. Fortner: It could potentially, and if you have them living in a cooler environment, although, we're not really looking at active forms of perspiration.

Dr. Caplan: Could someone be negative in 24 hours because of the environment?

Mr. Fortner: Hypothetically, I think that's possible.

Dr. Caplan: Do you think that the normal body temperature regulation is sufficient in and of itself?

Mr. Fortner: I think that's been looked at. One of the large pilot programs was run in the middle of winter in Michigan, which is certainly on the cooler side.

Dr. Sample: I have two questions. First, is there a mechanism for determining whether or not an adequate amount of sweat is collected on the patch?

Mr. Fortner: We have looked at other markers to determine if the patch was actually worn and was it worn for an adequate amount of time. We've looked at other things such as salts.

Dr. Sample: Do you recommend that?

Mr. Fortner: No, we have looked at that to determine whether the patch was actually worn. We have not established if it has been worn for X amount of time based upon minimal acceptable levels, such as urine, creatinine.

Dr. Sample: That's what I'm driving at. Is there a way to assess that suitability?

Mr. Fortner: Yes, I think there is a way to assess it.

Dr. Sample: At this point, this is an open issue in terms of recommendations on how to do that?

Mr. Fortner: Yes.

Dr. Sample: My other question is, you indicated the patch would fall off easily under certain conditions?

Mr. Fortner: In that condition, if they come inside from a very warm environment and not adequately cooled down, the body is still in active perspiration. Even if you prep the area with an isopropyl alcohol patch, you may not get it sufficiently dry.

Dr. Sample: In that case, when it falls off, does it show as being voided or removed? Can the donor keep it off, dry themselves adequately, and put it back on and no one's the wiser except to the fact that he hasn't worn it for the last week or she hasn't worn it for the last week?

Mr. Fortner: Typically our experience is going to marked as a void fall-off because it would happen typically within 24 to 48 hours, so it's something that happens fairly soon after the patch has been applied as opposed to 7 days later.

Dr. Sample: But can you detect that it has fallen off?

Dr. Caplan: If it doesn't apply initially because of moisture, can it be applied later or is the glue shot?

Mr. Fortner: I don't believe we've tried to apply it later. I don't think I can tell you that I know the answer to that question.

Dr. Caplan: This is an issue we might want some more information on.

Dr. Bush: Neil, will you take note of that please and get some information on that?

Dr. Caplan: The scenario is you put it on, but if the person is kind of wet, he or she could take it off and put it back on before coming back.

Mr. Meeker (PharmChem): Typically with a patch, if it falls off, it tends to shrink up a little bit too and you're not going to get the good adhesion that you want on the arm. It has to be a very smooth adherence. When the patch comes off, it does start shrinking up.

Mr. Fortner: When you do apply the patch, when it is properly applied, the Tekraderm is fairly smooth off of that. When it comes off, the Tekraderm, by its very nature, does have a tendency to shrink and wrinkle, which is one of the telltale signs of a reapplication because it's no longer a smooth one. They tried to put it on. Secondly, there is a physically detectable change in the patch from a pristine white to an off yellow just from oils and other materials that are excreted by the body.

Dr. Sample: That could be duplicated, I would think, in an in vitro situation?

Mr. Fortner: Anything is possible.

Dr. Bush: Can we get back to the question of interpreting the results?

Dr. Caplan: Does it appear that there is sufficient information?

COL Jacobs: This also does say interpreted a positive result. I don't think the things we're coming up with are positive results.

Dr. Bush: Neil is aware there are a couple of things you need to take a look at with the patch - the reapplication and the fall-off scenario - because of too much sensible sweat over hydrating that area.

Dr. Sample: I think we need to move back to E-5 on Page 8, based on the discussion we just had and capture these questions that we have with respect to E-5, which is the specimen integrity evaluation and perhaps then move this back to an I or to a P until we get these questions answered.

Dr. Caplan: Let's go back to E-5 where we changed it from I to a P before, or an I to a blank and we should put a P down.

Dr. Sample: Can we leave it at an I or a P?

Dr. Caplan: What's the recommendation?

Dr. Sample: I would say an I.

Dr. Caplan: The recommendation is we go back to E-5 and reinstate it as an I.

Mr. Jones: Would that fit better under E-6, Page 9?

Dr. Caplan: It sounds like the early days of the inspection program.

Dr. Sample: Personally, I'm not too hung up on which bucket it's put into, I just want to be sure we capture it as still being an open issue somehow and not leave this as a blank with questions. If we have questions of this nature, I think we need to downgrade it from blank status.

Dr. Caplan: Do you want to call that E-6 and leave E-5 alone and change E-6 back to an?

Dr. Sample: The questions that we have specifically then would be in the event where it fell off on its own prematurely and then was reapplied at a later time. Is it possible to detect that? And a corollary to that, is there a way to assess adequately the volume of specimen, if you will, for lack of any other way to put it, by use of some marker, and if you could provide data on that?

Mr. Stephenson: Moving right along.

Dr. Caplan: Back on J-1, is there any other issues for the MRO interpreting results? The issue we had before, there was the variability of the drug uptake across genders and the need for gender-specific so it appears it stays as an I also. Does anybody disagree?

Dr. Bush: Neil, you will provide all the information you can based on the clinical trial, the clinical trial dosing studies you used?

Mr. Fortner: Right.

Dr. Bush: Also the peer reviewed scientific articles, any peer presentations you've made? I did not make it to the academy meeting. Did you make a presentation there on anything relevant to this topic?

Mr. Fortner: No, we did not. There were presentations by Ed Cone and some of his students.

Dr. Caplan: Do any of these bear specifically or did they add to what's already been submitted?

Mr. Fortner: Actually it takes it to another level because it looks at conditions of more rampant detection of drugs in sweat using forced stimulation, I guess would be the closest thing, heat-activated stimulation of the sweat glands on the palm of the hand. And that demonstrates that you need to wear it for maybe 20 minutes and obtain five times the amount of drugs that you would get out of the existing patch on the arm compared to five days. It has some other application, perhaps more pursuant to the some of the workplace testing, but when I talked to HHS, we said we need to get through the existing stuff before we go to the next level of information.

Dr. Caplan: One of the other things, after we go through this, we are limited to one product here and we have to probably end up looking at guidelines which would look at other products as well. I'll point out again, as we did a couple of times, we're going through this matrix. How ever many times you do it, it is only bringing the information level that is going to have to be looked at as comprehensively. Again, across the matrices -- at the same time before you write regulations about this and that then therefore other approaches would have to be in these guidelines.

Dr. Bush: I will need to get copies of those abstracts and then go back to the presentations that were made at the academy meeting to see how relevant they are. It sounds like they're relevant, and I will bring it to the Board's attention when I get them.

Dr. Caplan: Alternative medical explanations, Page 31. I think we've discussed all those issues. The question is, is there adequate information. Any comments? It is an I. Do we have enough information or do we still need information?

Ms. Murdoch: Shouldn't that stay an I?

Dr. Caplan: That's the question. In the earlier discussion, Neil, it was stated that there is no evidence of any external contamination exposure or whatever, to the patch being worn on the individual if there is drug positive, it's from use.

Mr. Stephenson: But the alternative medical explanation, isn't that the issue? And wouldn't it have to be tied to J-1, if you don't have the underlying architecture for that result, yet how can you go and look at the other side of that same point if you're using the same identical data and looking for medical explanations as an alternative to drug use?

COL Jacobs: On J-1, where we're looking to see a gender study?

Dr. Caplan: Yes.

COL Jacobs: Now the alternate medical explanation is from either male or female and that's why it's positive. Did I miss something here?

Dr. Bush: No, what about Tylenol #3 ingestion?

COL Jacobs: We're relating the two here. Do we want to relate the two or separate the two?

Mr. Stephenson: If you can honestly answer, you're neither male nor female, we would give you a pass.

Dr. Vogl: If you have a prescription medication, that's the reason for the positive that allows the MRO to make an interpretation. That's the alternative medical explanation. I'm not sure what the problem is on this one.

Ms. Murdoch: Yesterday, when we were talking about hair with the very similar elements, we decided that the two were correlated and needed to stay together and should be addressed together and so both of those stayed aside. Seems to me the same thing is true here.

COL Jacobs: I think yesterday the reason why we left them both as I's was that we could not rule and had not done a study on passive inhalation and that was interpreting the results, was it due to passive inhalation, and that was the alternate explanation, was passive inhalation or exposure.

Dr. Sample: On that basis, have we ruled out if somebody had a fair amount of dermal content prior to removal of the patch? Is the site preparation adequate to remove all of that dermal contamination? If that is not answered yet, I would say it would need to stay as an I, similarly to the issue with passive exposure.

Dr. Niedbala: In the package insert for all the screening devices, there's a whole series of interference that were tested, both spiked onto the patch, then outside the patch. So as you're looking at interpretive issues, there's clear information on the cross reactivity of the antibodies used as well as some of -- these are in vitro studies, granted they're not in vivo studies, but at least they're some basis to make decisions on potential interference that may or may not be present.

Dr. Caplan: In the interest of moving along, let's keep this as an I.

Dr. Sample: My question is, do we have adequate information to address the issue.

Dr. Caplan: I think it's borderline.

Dr. Sample: Do we need to specifically request what we want to see?

Mr. Fortner: The procedures at the area is cleaning it with isopropyl. I would submit that we don't have all the information. Does it remove all the drug?

Dr. Sample: That is something that you can get for us.

Mr. Fortner: I'm sure there's a drug-dependent concentration depending upon how much drug you're rolling around in. We will work on that one.

Dr. Sample: At least provide what you have this point.

Mr. Fortner: Right

Dr. Caplan: Page 32, MRO training. There is training available now. I'm sure it is relatively easy to do.

Mr. Shults (AAMRO): I was very interested in what the Board had to say about the MRO's role in all of this. To me it's very conceivable looking at it that it is quite possible that we have the MRO playing a similar role here because of the similarity of the data and ask myself what does a medical review officer do and basically they're answering the question, is this legal or illegal use in one degree or another that involves an understanding of the underlying signs, the underlying collection process, the underlying analytical processes and the ways in which these laboratory results can be interpreted. Now there is some variables we have here today that still exist, despite the fact that it's well-accepted, that are very similar to the issues we're talking about in sweat. But because of the similarity in terms of the notice response and window of detection time, I think the process here -- to me it seems like this would warrant an evaluation as a P in terms of both the MRO's interpretive value, is this legal or illegal usage, from a prescription or not a prescription, has the testing been adulterated. But it would involve I think when you get into a formalized program, training of the MRO's and the underlying mechanism because today even though we have certified and highly competent MRO's, if you ask them to interpret a sweat patch, they would balk at it, they would balk because they don't understand the basic underling principals of what this data is. But presented the way we present the urine data, I don't see any bar right now to their being trained and doing an effective job as they do for urinalysis data, basically on the fact that there is such a correlation between the detection times and what we know as comparing sweat patch data to urine data. It's very similar to what we're talking about with on-site testing as well. So again, although it's perfectly okay to leave it as an I, I think because of what we know, that this could also be legitimately characterized as a P in all of those areas, both the role and the ability to train and certify the physicians.

Dr. Caplan: I guess you had no specific experience other than the training you mentioned earlier?

Mr. Fortner: That's right.

Dr. Caplan: Shall we move it from an I to a P? Is there any objection? It says is, so it is not available. Okay, Page 33. We had this discussion yesterday, what we really mean by, related by dose. We don't mean pharmacokinetics, we mean detection capability and detection window. Maybe you can comment further. You mentioned earlier about the 33 percent, but what you didn't do is say it is 33 percent better or equivalent for all analytes or just cocaine.

Mr. Fortner: We certainly saw the highest detection level relative to urine for cocaine. I think that that's influenced by the fact that also happens to be one of the most prevalent drugs of choice in those particular populations. For instance, we saw very little, if I remember, one methamphetamine. In that part of the country, that is not unusual. If you go west, it's a completely different scenario. I think that in the initial response, I had interpreted the question differently. When you talk about detection, then I believe the answer is yes. I was thinking as a classical dose response and you cannot detect multiple doses because it retains the drug on the patch.

Dr. Caplan: Let's just clarify. We are talking not about pharmacokinetics. Does everybody agree with that? We are talking about detection windows. So maybe the question wasn't phrased as clearly as it should have been, but it is detection window and you did previously say no. Are you saying that all drugs have a similar or equal tendency on the patch compared to urine?

Mr. Fortner: Yes, particularly across the board, we see a higher incidence and it's probably because the window, the differences in the window of detection, patch versus urine.

Dr. Caplan: Do we know enough about how long the patch would need to be worn?

Mr. Fortner: Yes, I believe we note that off the clinical dosing studies that show subsequent to dose with the exception of PCP when the drug first appears when it peaks in the sweat and then its retention in the patch from there.

Dr. Bush: Neil, I'm remembering back when much of this data was presented at the FDA clearance hearings, and I believe there were presentations concerning just this.

Mr. Fortner: Yes, in the FDA summaries there are tables and graphs showing detection windows, when it first appeared, how long it was there, when it no longer peaked. So you're looking at detection relative to a window.

 

Dr. Bush: I think that would be a lot of very good information for the Board to have for a variety of reasons.

Mr. Fortner: It is certainly a part of those filings. We can either send you the entire thing or send you sections of the summaries.

Dr. Bush: Now, Neil, in front of all of these witnesses, I'm going to ask you to send me the filing.

Mr. Fortner: We will send you one copy.

Dr. Bush: No, refresh my memory. It's going to be 1,000 pages for each drug?

Mr. Fortner: Per drug.

Dr. Bush: I'm getting voted down by my staff who knows they will have to deal with this, but I want to be sure about the completeness of this information. I don't want to have to go through this again.

Dr. Caplan: Is there a way to summarize this?

Mr. Fortner: Let me tell you that there are two volumes. Volume 1 is a half-inch thick. It contains the study design and the summary. Volume 2 contains summary tables of all the analytical data that went into the generation of the conclusions so perhaps we could start with Volume 1, which is the smaller of the two sets.

Dr. Caplan: I think that makes sense. We're not testing the voracity of the number.

Mr. Fortner: There is a more condensed version that looks at study design results, conclusions in Volume 1 and all the tables that went into that are contained in Volume 2. We could certainly provide Volume 1 which is maybe 80 pages per drug.

Mr. Meeker: I just have a clarification.

Dr. Caplan: So many of these things do overlap.

Dr. Bush: The short version for each drug is a half-inch summary?

Mr. Fortner: I think it's 60 to 80 pages for each drug.

Dr. Bush: That would be great. I will send it out to everybody and we will see where we need to go from there.

Dr. Caplan: It sounds like that makes this I into a P. We'll look at more stuff, but it looks possible. Does everybody agree that we can change the I to a P? Any objections? Okay. The last question on sweat is specimen contamination. We talked about that in a number of things before. What do we want to do with that?

Dr. Sample: I think this is slightly different.

Dr. Caplan: Can you elaborate on the wrinkle?

Dr. Sample: Is it possible, based on environmental factors at the time of application, perhaps on the part of the collector, the collection site, et cetera, or at the time of removal to contaminate the patch and the answer to that I think I heard from the audience.

Mr. Meeker: It would be both.

Mr. Fortner: I would have said yes, provided there are drugs in the environment because the pad is exposed once you remove the Tekraderm. Without the Tekraderm the pad is exposed to the environment. If you have sufficient drugs in vapor or aerosol form, that could be deposited on the patch, then you could classify that as a potential for external contamination.

Dr. Caplan: But it would have to airborne?

Dr. Sample: Or dirty gloves.

Mr. Fortner: The standard procedures uses disposable gloves and disposable tweezers in the published literature off of the cocaine vapor studies. There was one incident that was attributed to contamination of the patch in the handling process and removal.

Dr. Sample: In theory that would be true for any specimen-type including traditional urine based. If the collection site is dirty, if the collector's hands are dirty, if the collection container is dirty, you're going to have contamination. In my mind, this really is not an issue specifically related to sweat, if we're talking that type of external contamination, because if you have a bad collection, you're going to have a bad collection regardless of the specimen.

Mr. Stephenson: This issue also addresses what it is you're detecting and you had also raised the issue earlier about markers, looking if a patch is applied, is it worn for X period of time and then third, what are you looking for in terms of a marker to make sure that you're dealing with the metabolic process rather than just an external drug that somehow gets onto that patch. Do you detect or do you process for any metabolic products?

Mr. Fortner: Yes, I don't remember the page that it's on, but all of the drugs look for a parent drug and metabolite.

 

Mr. Stephenson: Do you do ratios?

Dr. Sample: For urine, you're looking for a parent. In the case of codeine, you're looking for a parent in the case of amphetamine, you're not looking for parahydroxilated amphetamine metabolites as part of that analytical procedure so that the issues are the same for many of the drugs, for many of the specimen types, because there are no metabolites that we are looking for as part of the analytical process.

Mr. Stephenson: What we're doing right now is cross-cutting issues, which warrants a generalized update to the sensitivity?

Mr. Crouch: I think we need to be more global on this and I'll try to micro-manage each step of this. Given a reasonable environment, these specimens can be void of external contamination. Anything is possible and anything can occur and there may a possibility of contamination of a urine sample. I think we need to step back and say globally, if you followed the right protocols, what is the possibility of this happening, and it's slim. It's certainly no worse than urine.

Dr. Sample: On that basis, I would take it to a blank.

Dr. Caplan: We have information about it which is all the question asked for is, do we know about it. There's nothing special that makes this less susceptible or more susceptible to contamination so we will switch this from an I to a blank unless there's any objection. Now I've reached a blue page. Does anybody else want to make any general comments about providing information or ask any questions about the sweat testing?

Mr. Edgell (DOT): I have an issue on something that Neil said that we might be missing on or miscellaneous issues. In workplace testing, the refusal to test is always an issue. An individual comes to the test site unable to provide the requisite amount of urine or breath, perhaps even hair or saliva, but with this patch, you're going to attach the patch and the individual will leave the test site and return sometime later -- and the ability to determine whether it fell off because they perspired too much, sweated too much, or did they take it off and then claim that it fell off. I mean refusal to test is something that employers certainly have to deal with, medical review officers get involved with to some extent.

Mr. Fortner: This is not a new issue under the sweat testing. Did they pull it off in the population where the product is being used. Family courts and probation drug rehab. It is to their best interest for the patch to fall off because they've already figured how to beat the urine test.

Mr. Edgell: The same would apply to workplace testing.

Mr. Fortner: That could apply. We've been working -- pursuing with 3M some other indicators that are tamper-evident, meaning if they physically peeled it off, it has adhered and there's a physical removal. We've been looking at one product that produced a void type of lettering across the Tekraderm. If it doesn't adhere -- active sweating and you don't get it dry -- probably it doesn't adhere so the adhesive haven't picked off and it falls off, the void aspects are still intact. We don't have that yet. We're in the early stages of working at it, but because of some issues -- but that's other information that we will be provided as those details are worked out and we will perhaps address some of the issues raised by the Board.

Dr. Caplan: It is kind of like a shy bladder issue. You might have to deal with it.

Mr. Edgell: You certainly have to deal with it.

Dr. Caplan: I don't know that we can answer that.

Mr. Edgell: In the shy bladder, there's someone between the individual and the physician looking for the physical condition or some pre-documented psychological condition as to why the urine is not picked up.

Mr. Stephenson: In this situation, the answer is no sweat.

Mr. McClain: I work in an oil refinery and sometimes the areas I'm exposed to are 120 degrees and I might sweat 4 or 5 pounds in a day. How is that going to affect this patch?

Mr. Fortner: We have used the patch in conditions across the country that approach that. In Nevada and Texas, in particular, there are some rather warm areas in the middle of summer. We've also used it in clinical trials on people who sweat a lot, but they sweat because they're long-distance runners -- and what we have found is that in that production where it's not unusual for them to lose 4 or 5 pounds, you can see some scenarios where the sweat is produced at a rate fast enough that if it doesn't keep up with the evaporation or vaporization and say, get a little bit of moisture onto the pad. Now as they stop exercising, then it catches up and evaporates. We haven't seen that fill up and swell up and explode or burst, based on excess fluid reduction.

Dr. Caplan: Does that condition increase the likelihood of detection if they lose their fluids so fast?

Mr. Fortner: If you were to take it off while there was still a lot of fluid in there, that could potentially dilute some of that. I think it increases the likelihood of detection because it forces more sweat, which in turn, pulls the drugs out.

Dr. Sample: I think part of the question is, it would increase the likelihood of detachment.

 

Mr. Fortner: Our experience is no, once the patch is adhered on the skin barring that scenario, we talked when they weren't cooled down, it is a fairly aggressive adhesive and excess sweat production in our experience does not cause it to fall off. As Denny pointed out, it is not a high area density of sweat glands.

Mr. Stephenson: Not to try to stifle this very interesting exchange of information going on here, but we do have a couple more alternative specimen groups to go with? And we need to go ahead and move on in the interest of fairness and completion. Could we shift gears now if there aren't any final questions that the Board members are compelled to want to ask? If not, just write them down. You can get them to Donna. We will write them down and make them available to the industry groups for response.

Oral Fluids

Dr. Niedbala (STC): There are definitely places where we can clarify based on what's now available information-wise. There was a workshop given at the SOFT meeting in October on the subject and I know Donna and Walt were there. Certainly there are the overheads that were used at that particular meeting that I would offer as a follow-on.

Dr. Caplan: Why don't you just try to give an overview or summary of where you think things are and then we'll go through the checklist line by line.

Dr. Niedbala: The other thing I would like to say --I represent one person who's working with a particular system for collecting and then testing oral fluids. I know those other companies that represent collection devices and potential testing regimens. I'll try to answer from the viewpoint of experience I have, as well as things I know from the rest of the industry. I don't know who else is in the audience today, except for Carl Good who represents Avitar, a company with another collection device as well. But certainly I will try and couch everything that I say in light of a broad basis of knowledge in terms of things I wanted to say. Everybody's been very kind to me in saying oral fluids as much as possible, but you can also say, spit and saliva as well.

Mr. Stephenson: Just for one clarifying point. Have there been any attempts or process for structuring a small working group that would represent -- have you had any actual formation meetings or explored what you're going to do in that area?

Dr. Niedbala: There are a number of people that I've already volunteered to be on the working group and I think it is a good cross section of people who perform testing, people who have collection and screening devices. We are poised and waiting for direction from the Board in terms of the things we need to address.

Dr. Caplan: I think on that point, certainly it's going to be desirable, after we've gone through this checklist today, for each industry group that we started out with. I mean, for those of who might not recall, in the beginning, there was an industry chairperson that took charge of each of these areas. In some cases that has led to working groups that have already met, like in hair, and in other cases, groups have not formed. But certainly I think we would hope that in the next couple of months, certainly between now and a month or so before the next Board meeting if possible, that the group meets and refines the data in general amongst yourselves as well as the things that are directed from here. You said there's some other industry people with regard to oral products. Did you want to say anything in general by background information that would be helpful to us before we go throughout the list?

Mr. Good (Avitar): What I would like to say is our focus is primarily on rapid testing, rather than laboratory testing for oral fluids. There are some different concerns and certainly other areas with regards to samples and confirmatory testing. The fluid we're talking about really goes both to laboratory testing as well as rapid testing. And Avitar entered this through the use of a collector that is very low on the absorption of metabolites and we're looking at a direct sample procedure. I would like to provide comments as appropriate.

Mr. Stephenson: For purposes of historic overview, Yale has indicated at earlier meetings that he would be willing to be the Drug Testing Advisory Board member to participate with the oral folks. Is that still correct, Yale?

Dr. Caplan: I'm in a default position, meaning if anybody else wants to do it, they're more than welcome.

Mr. Stephenson: That being said -- as each of these groups has presented, we've identified a member of the Drug Testing Board who has acted as the liaison -- and we've also indicated if there's a need for administrative or for special assistance in convening a group or getting people together that might not have the ability to do so otherwise. We have provided some assistance in the hair testing group. We would make equivalent assistance available for the other technologies too.

Dr. Caplan: I would be glad to do that, but it's your lead when you're ready to jump in. Is there anybody else that wants to make a background comment or any information that would be useful? We will start the checklist and I guess go to 12 o'clock and take lunch, and continue after lunch. I suppose we have - it seems like -- that we have the least information, at least gathered on this form, about saliva compared to the others and so therefore, we're going to need a greater amount of input and I guess the procedure we used before was basically to identify the question and if you want to do it, that's fine. I'm first asking you to comment on it and if Carl, you want to immediately comment on each question, that's fine. Then we'll open it up for the Board and go right down the line. And it would be better if you sat at a mike if you're willing to do that. Page 3, with regard to the collection device.

Dr. Niedbala: In terms of basic requirements, if you look at it from a general perspective, there are several technologies used to collect saliva and each one of those have qualified themselves in terms of the fluid that they actually collect into the device and qualify the container as well. As Carl had pointed out, his company has the technology that they believe enhances part of the collection of the drug and then recovery of the device, while others use something as simple as cellulose to collect the material and then send it back to the lab. Would it be useful to write this then from the perspective of a broad requirement or a broad statement about the collection containers?

Dr. Caplan: Again to reiterate, everything has to be applicable to devising the guideline that would deal with multiple products that which we know exist today. And things that make up - obviously we didn't do that in urine, there are things we missed and issues that weren't in the guidelines that have come up, like adulteration later on, but to that degree we can have a global policy that encompasses or allows you an evaluation of a variety of devices.

Mr. Good: Our device, as appropriately stated here, has been through FDA review for HIV testing. Ours is different, where the epitope device is a sampler that goes into a tube for transport. Our focus is entirely, at least for the rapid testing, on immediate use of the device that doesn't dilute the sample. You use the oral fluid itself to actually run the test and there are some tricks in doing that. I think the epitope device, as far as official review, is certainly further along than we are and we expect to do the same procedures.

Dr. Caplan: Don't you define the term rapid testing as opposed to the alternative? I'm not sure I totally understand the difference.

Mr. Good: The focus is to use a rapid test device in which you place the sample. Most of them are chromatographic, based upon clinical or other materials within a 5 to 10-minute period to give you a screening answer.

Dr. Caplan: There is no different specimen structure?

Mr. Good: Other than the epitope device -- puts the collected saliva into an extraction transport buffer, because you have to transport it back to the laboratory for the initial screening test, as I understand it. Ours is a focus on obtaining the sample and testing them rapidly and then you still have the issues of the sample.

Dr. Sample: Do we need to add another column on this matrix for on-site oral fluid?

Dr. Bush: That was not my impression.

Dr. Niedbala: The conversations and all presentations up until now have involved around collecting the specimen just like doing it remotely and sending it back to the laboratory.

Dr. Sample: That is not what I am hearing here. That's why I asked that question - are we now talking about a sixth modality, on-site oral fluid?

Dr. Niedbala: Shouldn't that be in the on-site sample? Or maybe we add this into the on-site urine.

Dr. Bush: This was not our initial impression that was given us by the industry when we formed these groups in early 1997. We had no group come to us -- or no companies come to us that were essentially an on-site saliva testing device. And so we have proceeded in this manner, taking a look at what industries did come forward and it was the traditional specimen collection outside of the laboratory setting and then forwarding that specimen to a laboratory. I think for the purposes of this discussion here, and to at least bring this up to this industry who has participated since the April 1997 meeting, to bring them up to current discussion ability with the Board. I think we ought to focus back on that. Unfortunately, to the exclusion of a newly presented device, essentially an on-site saliva test, we have not entertained that. I don't know that we're in a position at this moment to entertain new devices.

Mr. Good: I would be willing to be on both working groups.

Dr. Sample: I think there's certainly some things that cross over into both the collection device, the collection protocols. Some of the issues related to specimen collection, specimen integrity, would be the same for oral fluid regardless of where the test occurs. When you move to the on-site testing component, the rapid testing component that really perhaps more appropriately belongs in the on-site arena, and so maybe Carl needs to work with both groups, as he offered.

Dr. Niedbala: In the original presentation, Carl's company had a second device, which I guess you're not focusing on now, which was for remote collection. You also had an on-site rapid test and so the context which was originally presented is all the devices were for remote collection that should come back to the lab. That's the original context. It's up to the Board to decide those that need to be expanded or changed.

Dr. Caplan: At this time, I think we should go through the checklist and the grid with regard to external collection and then when we get back to on-site, if it's appropriate. Because there are going to be many things that are common and a few that are not, and the same relationship that on-site has to urine. Other specimens may be natural corollaries but it would be difficult to get through this appropriately if we don't limit it this way. Having said all that, we still do not have complete information about the collection container and more needs to be provided. Any other suggestions? We're on Page 3. Sections 1 and 2, as in the other sections, did not appear.

Dr. Bush: I have a Page 1 and 2.

Dr. Caplan: Why don't we go back and do 1 and 2. Well, let's finish number 3 from whence we started. Is there any other information needed on Page 3 on C-1? We're going to provide additional information about the types of devices and what other information did we want? Was there something else? We need to know about the specimen, security integrity, transportation, labels.

Dr. Isenschmid: For these types of devices, we're also concerned about their equivalency once they get into the laboratory. It may be information we need to know about those devices.

Mr. Stephenson: If I can just interrupt briefly. It is snowing rather hard. My sense is we're going to be very challenged to go through the rest of the afternoon and have people willing to stay here in the presence of the kind of snow and so on that might be still forthcoming. If that's the case, if we could look at an expediting method that will help the Board provide the feedback to the industry and in turn, use it interactively with the folks from the industry to prompt questions that you would really like to have the Board focus on that you already know are vexing or that you want to look at. Maybe this would be a better way for us to try to look at this. That doesn't mean to short-change your time in the batter's box, but you may lose folks who just walk out and leave.

Dr. Niedbala: I'm fine with that because actually when you compare to the information you have available from the other fluids, there's laboratories that are up and running and have experiences and that's a lot of what's been honed in on or focused in. This is the one alternative where there really isn't a good commercial model already in progress except for a few analytes. If I can answer what I can answer, but by all means, I agree with Yale's comment originally -- this is going to have a lot of those incompletes, get us more information and frame it appropriately.

Dr. Caplan: I think my anticipation at this point would be to '- that we're probably not going to get to on-site, which we dealt with the last time. I mean, maybe there are some issues. I don't think we'll get through the whole thing, but I would like to get through the entire grid on saliva, which we have never done. I guess it will take another hour or so and then if there's a little bit of time to get some updates on the outside stuff without going through the whole grid, we would probably accomplish a pretty good amount.

Mr. Stephenson: Who is here representing the on-site industry working group?

Dr. Vogl: David Evans, but he's not here.

Mr. Stephenson: So we're not compelled to address that issue at this time.

Dr. Sample: But if there were people here interested in on-site, this would be a good opportunity for those people to get together and perhaps start moving towards forming a working group or figuring out a mechanism for getting the interested parties together.

Dr. Bush: David Evans had formed a group and they had met several times and submitted written information to us as well as other technical information.

Mr. Stephenson: I guess the on-site is not an issue for today, so we can take whatever meeting time we choose to have together as a focal point for the oral fluids. And I'm not trying to short-change you, but I'm really concerned that this is going to be a problem for us.

Dr. Caplan: Hearing no objections, let's go back to Page 1, the training issue.

Dr. Niedbala: It's anticipated the training model for oral fluids would be similar to that used for DOT right now, whether it's a video program or individual training sessions that oral fluid can be done that way.

Dr. Caplan: At this point in time, as far as you know, no one in your industry has already done a program?

Dr. Niedbala: Not for drug testing. There is a certain amount for insurance testing, but as a program -- and there is for HIV. And the HIV consists of a video and an exam which the collectors take.

Dr. Caplan: That one I guess stays as a P.

Dr. Sample: T he question is, can you document appropriate training has been given to the collector? I think the answer to that is yes, one could do that. It's possible.

Dr. Caplan: What's the recommendation?

Dr. Vogl: You can do it.

Dr. Caplan: Okay. Do you want to change that to a blank? Okay. Page 2, the certification program -- can be established.

Dr. Niedbala: Yes, the modeling is either insurance or DOT testing. There is saliva alcohol that is done now and there's a certification of collectors that is done.

Dr. Caplan: So that's a P-2 blank. Any objections? Okay, we did 3 already.

Dr. Niedbala: That's an I.

Dr. Caplan: Now, Page 4, FDA clearance issue.

Dr. Niedbala: We're a big proponent that FDA needs to clear these devices. We have already done them for sweat that was the model which FDA suffered through with us. And so four out of the five HHS drugs are now cleared for the one system that I can talk a lot about. PCP has actually been -- we have a letter which is an investigational device exemption which allows us to do PCP field studies because there will never be an IRB that will allow us to do doing studies. All of those things are in motion and I think FDA helped us in a sense to be disciplined about the type of information that's been presented and to keep potential users very aware of both the benefits and potential limitations.

Dr. Caplan: Other comments? So which kits have been cleared?

Dr. Niedbala: Amphetamine, opiates, cocaine, THC have been cleared as 510K clearances, as in vitro diagnostic test products, the same as urine. The only thing is, and this is the difference, is that device, screening device, is always linked to the collecting device so that the qualifications for the screening kit are controlled and that is not just any saliva or oral fluid. It is only one specific device that is used with these specific kits. It's the same as the sweat patch, in our particular case.

Dr. Sample: The sweat patch I thought was a little different. The sweat patch wasn't strictly tied to the assay, but in this case, it is specifically tied to the assay.

Dr. Niedbala: It is the case though with the sweat patch as well. In other words, those initial 510Ks were also tied to a screening kit.

Dr. Bush: I think what Barry's point is, is that the kit was cleared for something else on its own and then when looked at as the device for drugs of abuse testing that it was linked.

Dr. Niedbala: I'm sorry, I didn't understand. And it's the same exact thing. There was a clearance for saliva or oral fluid collecting device that had no diagnostic claims and then when the claims where drug testing occurred, it had to be linked to a screening kit.

Mr. Crouch: Sam, you can collect saliva and it looks like urine and all you need is a tube. So if you have an inert polypropylene tube, does that need to be FDA cleared?

Dr. Niedbala: The screening kits. Because as you know, there are matrix differences and different collection devices will collect and then deliver the specimen to the laboratory in different formats. I would argue that the laboratory, or in this case, the device manufacturer, has to control that or the whole system will go out of whack. This is the danger in some of this. I think that all of these systems for saliva testing has to be qualified in and of themselves.

Dr. Caplan: Any other comments?

Dr. Sample: I think we should move it to P.

Dr. Caplan: How about the other devices?

 

Dr. Niedbala: Laboratory based - there is no other collection device right now that has been FDA cleared. There are a number of devices out there, but there is no other device right now that has an FDA clearance for drug testing.

Mr. Good: You can get the Class I medical device clearance -- and a sister company of ours has done that using our collection materials which is also used in wound dressings and other medical devices. I think as we talked about earlier in the sweat patch area, there's sort of a Class I collection device outlinked to a test that this sort of seems like would apply to - and then you have the system, which is a collection device and a test which, as Sam said, are linked.

Dr. Caplan: It's really two questions. One, is are the devices FDA approved, and they are mostly.

Dr. Niedbala: There are some that are cleared as collection devices in and of themselves, but there's only one right now that is approved for use with drug testing kits, drug screening kits.

Dr. Sample: The FDA approval is of the collection device for this question.

Dr. Caplan: Do you want to change that to a P with the understanding that there's an another underlying thing here that in the ultimate regulation, it needs to be required and that's different from whether it is approved today or not?

Dr. Sample: Maybe it's blank if you're talking about collection device. There are a number of FDA approved collection devices.

Dr. Niedbala: And this is where it will get tricky because the FDA's policy to date has been that if you're going to use it for a particular purpose, it has to be both a collection device and a test kit linked together.

Dr. Caplan: I think in the interest of time, let's make it a P. We don't have to clarify this today. Okay, the impact of the device on the specimen, next page. If the device alters or affects the specimen or drug or metabolite '

Dr. Niedbala: The only point here was each device should have to qualify itself and its individual characteristics and in the context of the system itself will have to present sufficient scientific data to say that it works and the user is completely aware of its benefits and potential limitations.

Dr. Caplan: Any other comments? Okay, let's move to Page 6, multiple testing. Is the volume sufficient to conduct several tests and screening confirmation, if necessary?

Dr. Niedbala: If you use the epitope device, it collects between 1 and 1.3 mL, the volume needed for screening. And a secondary test for at least four of the drugs leaves about a half a mL for confirmation. After re-test there's about a half mL left over for GC/MS, so there's a screening that if you wanted to repeat the screening there is some extra, and then there's about a half mL left over.

Dr. Sample: The typical volume for a GS/MS confirmations of oral fluid, what volume is required?

Dr. Niedbala: Somewhere between 100 and 500 micro liters.

Dr. Sample: One drug could wipe out all of your specimen?

Dr. Niedbala: Yes, and it would need to be set up in some sort of hierarchy as to how you would address it.

Dr. Caplan: Is there adequate specimen?

Dr. Sample: I'm not convinced there's an adequate specimen for multiple testing.

Mr. Crouch: The difficulty is you don't necessarily get 2 or 3 milliliters by having someone spit into a tube. I don't want to get too myopic about what they're doing here.

Dr. Caplan: That's an I now. Do we leave it as an I?

Dr. Sample: Did we address minimum volume in the hair group when they came up with the 75 milligrams? Should there be a similar type discussion by the oral fluid working group to determine what minimum volume should be?

Dr. Caplan: We can move it from an I to a P? We need the information about how the volumes are utilized. Page 7, D-3, the potential to split specimens.

Dr. Niedbala: One of the questions when this was originally written is, if I collected a specimen from the right side and left side of the mouth as an example of one that's a lollipop, what happens? And there's been clinical studies that have been now where we've collected both sides as one example and have shown that their equivalent for both sides of the mouth so you take that to the potential of splitting the specimens. It says there's now data to support that two specimens would be OK to collect where one could be used for screening and initial confirmation.

Dr. Caplan: We have to collect two specimens separately?

Dr. Niedbala: That's one solution, simultaneously, and that's one solution to it, but we'll have to examine it for each of the devices that may be used. For just saliva itself, there is the possibility that we could meet the criteria and perform this.

Dr. Sample: So it's a blank?

Dr. Caplan: We don't have all the information.

Dr. Sample: We moved sweat to a blank and we have more information here.

Mr. Crouch: I don't think what we did with hair has anything to do with this.

Dr. Caplan: Everything is theoretically possible.

Mr. Crouch: I can tell you on saliva, it's very easy to do it. You can collect the liquid or collect two devices at the same time, then you have essentially, a split specimen.

Dr. Caplan: Is everybody satisfied to make this a blank? Again, we'll need more input on the ways that that might be achieved. Page 8, stability and storage.

Dr. Niedbala: I think this is another one of those where there's information that says that there's knowledge about the storage conditions and stability of drugs in saliva, but it would also be caveated that each collection device must also generate its own data.

Mr. Good: I would like to add for rapid test, it's less of an issue than it would be for a sampling and shipping test except for a confirmatory sample.

Dr. Caplan: We still need information. Should we leave this as an I? Collection procedures, Page 9.

Dr. Niedbala: This is basically a rip-off of the urine procedure with the oral fluids inserted, at least in my mind's flow. It needs to have more people on the Board look at it and really evaluate it.

Dr. Vogl: You can do it? You should be able to develop an appropriate collection procedure criteria for each device that you might use.

Dr. Caplan: Any other comments or discussion on this? Are you suggesting you want to change this category or not?

Dr. Niedbala: It is not incomplete.

Dr. Vogl: I think you can do it.

Mr. Crouch: Are there differences in the type of saliva based upon the different devices? And you would know this much better than I, depending upon whether it's cellulose or a pad or just spitting, the composition that is collected by the device.

Dr. Niedbala: From the patent literature and from some empirical data, I would absolutely say yes. And that's part of the reason why each device has a protocol or criteria that are established as a part of evaluating any of these products in the future where the scientifically and clinically show their own performance characteristics.

Mr. Crouch: And those are related to the saliva they collect or to the device?

Dr. Niedbala: I think it's related to the type of material the pad is made out of. That is one of the subjects of Avitar's patents. It's also subject to the fluid that it's stored in or transported back to the lab in this case, and then the third one which is more theoretical. But actually, different companies with different devices claim absorption of saliva and others claim absorption of components that actually are through osmotic pressure absorbed into the device so basically taking things out of the bloodstream almost and into the device itself in the mouth. Those are three extremes you get.

Dr. Caplan: What about contamination?

Dr. Niedbala: In other words, you drink a soda, as an example, and then you collect the device.

Dr. Caplan: Or smoke marijuana.

Dr. Niedbala: Let me break it down. Adulteration, at least for the studies I've done, with one of the devices we have looked at things like if I drank a Coke, if I had orange juice, if I had cranberry juice, if I used mouthwash, if I'd have used any of those things, how long must I wait before I collect a specimen? And that's how it's addressed. So in the protocols, and I think it is in this as well, there is I think a 10 or 15 minute waiting period before you would collect the test. That's also consistent with what we found in alcohol in the DOT testing which has an on-site alcohol test in the market right now. So those things are being addressed, at least with one of the device, but I think the burden will be on each device to prove out those aspects. The second part is, if I took an abused substance and it was in the mouth -- I would simply answer, is that a bad thing? Because if you would detect marijuana right after you smoke it, it's still marijuana. And it's definitely going to be above the cutoff.

Dr. Caplan: But you wouldn't be able to differentiate marijuana that might be residual?

Dr. Niedbala: We have done some studies, and I have talked about this earlier where we have had subjects who - we've actually done this in Europe where it's legal to smoke marijuana where people have been in rooms where there's been those who have actively smoked and those who are passively exposed and collected both urine and oral fluid specimens, screen tested by the screening assays and also tested by GC/MS to look at things like that. Also, hemp oil, as an example, with marijuana is one we have recently done where people have ingested it as a substance and then looked at urine and looked at saliva to see its effects. A number of those things were also being addressed, but the bottom line is they do have to be addressed for all the devices, I think, in the future to answer the question for potential users.

Dr. Caplan: It sounds like we need to have some more information on these lines. I haven't seen those studies. That's not something we got before, right?

Dr. Bush: No.

Dr. Caplan: This needs to stay an I then, I think. I mean, passive inhalation is one thing. External contamination still needs to be addressed before we can decide. This again goes back to the definition that any of these programs -- that if we ever came in contact in any way with the drug, then you could do a lot of things. But if that question gets refined as it seems to, in most of these instances, that we need to try to best answer those questions. Okay, this one stays an I and we need updated information from you unless you have any on current devices. And whatever studies were done to support the 10 minute, or whatever period of time, for normal use as well as the potential for contamination of the drug itself from external contamination.

Mr. Good: I agree with Sam. The studies have to be done. We were focusing on a wash-up procedure. So one would use water, let's say, that would clear them out before testing as well as waiting. In addition, one of the advantages of a rapid test is if there is any issue with the subject, that you then could default to a urine test or some other acceptable method if they would challenge it and say, well, I was in a room where I got passive marijuana. One might have an algorithm like is used in HIV testing which could have defaults if there is an issue to another type of test.

Dr. Caplan: To the degree that that's possible, some of the things you mentioned may not be possible by the collector. Okay, E-5 is sort of the same thing, along the same lines. Specimen integrity evaluation.

Dr. Niedbala: In the literature are several articles that would refer to the amount of IgG present in a competent specimen and so we've used that as a way that when it arrives at the lab, we can use one, it's human, and two, that a sufficient amount of specimen was collected so that's been the approach. I think in any case the device has to establish its own method of proving that the specimen has been competently collected and delivered to the lab.

Dr. Sample: The question you're trying to answer is, is it oral fluid?

Mr. Good: Again, one of the advantages of this type of testing is you can observe the sample acquisition without embarrassment. So it would be more difficult, I think, to adulterate the sample.

Dr. Sample: It is possible to test for adulterants. Has that been done at all?

Dr. Niedbala: Such as?

Dr. Sample: I don't know. They might have a lozenge or something containing -- something that's in their mouth that would be unobserved by the collector.

Dr. Caplan: Is this nitrite lozenge?

Dr. Niedbala: There's information on the screening kits as to what could interfere. In other words, limitations on both ends of the extreme and then the laboratories that are performing oral fluid testing now do an IgG test at least with the one device that's doing drug testing, and that has tended to work well because usually if somebody is adulterating or - in the studies we've done if somebody adulterates - then it knocks the screening test out of whack, it usually produces a positive because in this particular technology, a low amount of signal, generated signal to positive to almost everything that you can think of to adulterate, causes a positive and so the person in essence sets themselves for failure if they try to do that. But the burden will be on the committee then to kind of frame that up for the Board.

Dr. Caplan: So IgG is a possibility, but not a requirement? Is it a requirement that some people test? Is that what're saying?

Dr. Niedbala: There are some labs setting it up as a requirement but not all. It is one possibility. I think it is one of these that for good laboratory practices, I don't know if it can be suggested, but I'm not sure it needs to be mandated.

Dr. Caplan: Where do we stand then? Move the I to P? Is there any objection from moving from I to P? Okay. Again, if you provide a little more information about what the markers are. We may want to reconsider it. Okay, Page 13, collection procedures deter tampering/adulteration.

Dr. Niedbala: At this point in time, what's being considered for some of the devices are the same as the urine cups with evident tape being applied. You could do that since it is being shipped back to the laboratory. There are some things that need to be considered in terms of tamper evidence. It's been asked, as an example, for one of the devices that comes with the fluid in it, already in the device, it's a preservative shipping fluid. How can you ensure that that fluid has never been tampered or touched and so I feel those kinds of questions will have to be answered and I think it will be device-specific.

Dr. Caplan: Any other questions or comments? Again, we don't have the whole story here. Should we leave it as an I? Okay, transportation of specimen. We need to protect the specimen from damage or loss.

Dr. Niedbala: It's really analogous to urine.

Dr. Caplan: Is there a current experience with a packaging device that can do this?

Dr. Niedbala: Yes. I mean the database, there's over 10,000 specimens a day now that are tested for one or more drugs of abuse, a limited number. Specific markets, but a lot of the paperwork chain of custody and shipping. There are examples right now.

Dr. Sample: To me it's fairly straightforward. There should be a means to package it and seal it and transport it in a manner that meets current guidelines so I would recommend changing it to a blank and moving on.

Dr. Caplan: Any other comments? Okay. We'll change that to blank and move on. The next are is G-2, lab testing, short and long-term storage.

Dr. Niedbala: Within the 510K cleared devices that already exist, there is a body of data that exists. It was not put in here, since originally some of those applications were still pending, but that could be supplied back to the Board now.

Mr. Crouch: Again, isn't it sort of device-dependent whether these criteria have been met or some validation has been performed?

Dr. Niedbala: I agree, there are examples. My point was to show equivalency to the urine testing that occurs now.

Dr. Caplan: Anything further? You have more information. We'll leave that at P.

Dr. Niedbala: The next one was answered in light of some of the IgG comments that were made a few pages back in terms of adulterated or substituted specimens. Now substituted is not going to be answered by an IgG. Certainly adulterated may be done.

Dr. Caplan: If it were substituted for another saliva.

Dr. Niedbala: It would still be a valid specimen. In that case, it doesn't answer the question.

Dr. Sample: Do you do an oral cavity examination prior to doing the collection to make sure that they don't have a small balloon of somebody else's spit?

Dr. Niedbala: I suppose we could be creating a new industry. We have not seen that as of yet, so I think there has to be some thought put into that.

Dr. Bush: Have you ever heard of anything, any adulterant device or go back to insurance testing or roadside saliva type testing that is done for other purposes? On the Internet and in high times, have you ever heard or seen anything?

Dr. Niedbala: If a person is properly taken through the procedure where they wait a certain period of time, then there's nothing that is shown up to interfere where someone has stolen away a sack of something and been able to hang and wait that long and then deliver the specimen. There have been occasions -- any insurance salesman in the room? There have been a couple of occasions where an insurance salesman tried to use somebody else's saliva so that they could get a valid specimen accepted. And that has occurred, but that is part of the training that would have to come along with this.

Dr. Caplan: Are the collection devices as you see them generally administered by the collecting party or are some of them much like providing a urine specimen today? They just go do it themselves?

Dr. Niedbala: Within the workplace, no, it would require some other technologies to assure that that is the right person. As you know, house arrest is an example where some of those things are used and the right technology is available. That is not something that is appropriate for here or available right now.

Mr. Good: Our collectors use for some DNA testing -- so a lot of these samples you end up with a sample that is adequate for PCR analysis. If you save the sample, you could actually do a PCR analysis.

Dr. Caplan: In all cases, all saliva is sufficient for a PCR analysis?

Mr. Good: I can't say that at this time.

Dr. Niedbala: I know for several of the devices that there is that application being used, but I haven't seen a large body of data to say that's absolutely a good way to go about it. It will probably come up as one of the suggestions, but we need to have the same scientific regimen as other markers would get so that where the burden comes back onto the device manufactured to do it.

Dr. Bush: Also for PCR analysis right away, always evaluating the cost to the employers who implement these programs, that would be a very steep cost.

Mr. Good: I think it would only be used in an exceptional situation but I believe it would be a possibility. I agree with Sam, you have to back it up with good data on a large study.

Dr. Caplan: Do we have enough information here?

Dr. Sample: Let's make it a P.

Dr. Caplan: Okay.

Dr. Niedbala: You're just going to see a bunch of yeses here, in the sense that yes, it's possible.

Dr. Caplan: Did you mention that it was FDA cleared?

 

Dr. Niedbala: Four out of five -- the screening tests, with a collection device as the system cleared.

Mr. Crouch: But there's only one manufacturer of the new assay products that do saliva, right?

Dr. Niedbala: At this time, yes.

Dr. Caplan: Do we need anything else here?

Dr. Sample: Isn't this consistent with what we did earlier today?

Dr. Niedbala: Are they I's because whether or not the FDA approval '

Dr. Caplan: Right. Are we going to put that in the guidelines as a requirement?

Dr. Sample: Then we don't have all the kits being cleared at this point or all the analytes being cleared.

Dr. Caplan: The next is the target analytes.

Dr. Niedbala: It's the same compounds in all cases except for THC, there is a certain amount of carboxylic acid. And the testing levels on Page 19.

Dr. Caplan: You're saying the drugs you actually have experience in detecting are what?

Dr. Niedbala: Amphetamine, methamphetamine, opiates, meaning heroin and morphine, a few data points on PCP now, cocaine, THC.

Dr. Caplan: THC, but not carboxy-THC?

Dr. Niedbala: No, we've looked for both. That's why I need to bring back the data. But we can show that the parent is there in a concentration between three and four times the amount of carboxylic acid and the cutoffs being as low as they are, you really need to look to the parent to be efficient.

Dr. Caplan: That's data we need to get? That's still an I. The next question is still going to be an I also until we know whether the initial test levels are good.

Dr. Niedbala: There's a pretty respectable body of data wherefore many of the analytes, now controlled dose studies, controlled population studies, meaning known abusers were pooled into a study -- and then also some fairly large prevalence type studies where we've tested say, 10,000 oil fluid specimens in a random population look for hit rate, to look for false positive, false negative rates and then confirm those. I owe that back to the Board as a part of this.

Dr. Caplan: For G-4c, we need more information, so we'll leave that as an I. Now, G-4d.

Dr. Niedbala: This is going to be a subject of some discussion among the Board and toxicologists in general, because to go plus or minus 25 percent at some of the cutoffs that are being discussed, is going to be a pretty hefty requirement. It's one of those that we were certainly do sensitivity studies based on the analytical information available. I just wanted to bring that up that we will have to look at this.

Dr. Sample: So it's detection not deterrence really is the way these assays are structured currently? It's a detection-based program rather than a deterrent-based program is where the cutoffs are currently set, to borrow Mike's terminology?

Dr. Niedbala: I'm not sure what the difference is between the two. I may have missed that earlier. We talk about it later I guess. The cutoffs suggested are based on clinical data, clinical sensitivity and specificity, not simply analytical sensitivity. There is -- because in some cases, the kits can go much lower in the limit of detection and the limit of quantitation but the clinical data that has been generated doesn't support that. It doesn't support the need to go lower and also comparison to data against urine because these are matching specimens in most cases. We look at the current cutoffs for urine and then we do ROC analysis, the same as the sweat patch has been done to determination what is the right cutoff.

Dr. Caplan: These aren't clinical studies that are dosed?

Dr. Niedbala: Some are dosed, some are looser in the sense that we have history of demographics and drug use habits. But we don't have them in a clinic where they have been given a dose for the FDA's purposes. There have been two questions they've asked of us for kits for both the sweat the saliva. What's the minimum dose you can tell you can detect if a person takes the drug? And the second is, in street usage, what do you see? Those are really two separate things that generally come out in the package insert information assuming you can do a controlled-dose study. That doesn't mean you will be able to tie your people down, but you'll at least be able to make the statement that at a certain drug given, were you able to see it.

Dr. Sample: I guess going back to 4-C -- the cutoffs were based on ROC comparisons to urine screen?

Dr. Niedbala: Right, and always using the GC/MS.

Dr. Caplan: The other issue, or corollary to that, is I think whether or not, while you might correlate the urine on a political study whether or not the detection window is broad enough for the same application as urine and in that case, the initial test level or how low you can go, may be a factor in the detection window. Do you have any data? We certainly need to see that data.

Dr. Niedbala: That's been done a couple of different ways.

Dr. Caplan: That may come up again. I think, therefore, we said 4-C, 4-D are still I's.

Dr. Sample: The cutoffs you're suggesting are based per milliliter of slide? Is that true with all devices?

Dr. Niedbala: It should be per milliliter near as I can tell right now. In other words, it is a liquid that is delivered to the laboratory bench for testing so we can put it on a per mL basis. There has been some discussion of per device, nanograms per device. I think that comes a little squirrel-er. So per mL within that particular device, that is part of the justification.

Dr. Sample: But it's not per mL of saliva?

Dr. Niedbala: We may have some pretty long debates about this one. If you say nanograms per device, you would probably now have some basis to work off of across all devices.

Dr. Caplan: I think ultimately you have to add per mL of saliva in the device. You will have to dilute it however it is and that's factored in, but the sensitivity has to go back to saliva or wherever the original specimen is.

Mr. Crouch: On an absorptive collection device, how do you determine what the volume of collection is?

Dr. Niedbala: Do you mean the amount collected?

Mr. Crouch: Right.

Dr. Niedbala: There are several ways to do it. There's one company that doesn't have a clearance for drugs of abuse test that does have a collection device that has a sample adequacy. In other words, when enough has gone into the specimen, a little window, you see a line in that window to say you've collected enough. Another device uses IgGs to say, I've collected enough, because the IgG is above a certain cutoff in other devices and we'll use, Avitar as an example. They simply are giving you back just fluid and so it is just straight saliva and then to use just a cup that you collect saliva in is just a straight mixture of all the components of saliva.

Mr. Crouch: If you use an absorbent -- and you collect 1 milliliter or collect 1.2, that's 20 percent difference, and how it would affect the cutoff or screening or any contribution then quantification, it seems there needs to be some way of quantifying how much saliva the device is collecting.

Mr. Good: I think that is technically possible. If you have a situation where you can collect without a human, the device itself can give you that calibration and in some of the rapid tests, when the material moves through the test device itself, it is self-stopping so when it gets enough sample, it is just saturated and no more will go into the device. There are ways to address that issue with the saliva sample.

Dr. Sample: I think a related issue, is if you have this absorbent material, how are you assured that you are then returning all of the drugs out of that device at the same concentration that they went into the device?

Dr. Niedbala: Right. Recovery is a separate issue. I got a moment to think about this and I can envision a couple of scenarios here where you can normalize based on the average amount you collect and then you could always have all the devices reported out in a similar fashion.

Dr. Caplan: You will have to give us more information on that. Move to G-4E, the ability to repeat the initial test. There's nothing written there. Is that the volume of collection question as to whether the volume is sufficient for your procedures?

Mr. Good: This may have a different effect as far as rapid testing as well because you could do an immediate repeat or you could collect a sample for transport back for GC/MS and so there is a difference here between the sampling systems and to the laboratory and the rapid test.

Dr. Caplan: I'm sure there is, but this is for initial test. The sample test and confirmation test, is there data to support the adequate specimens?

Dr. Niedbala: No, in the beginning, we had the other page where it said we needed to go back and show by device the principal and the amount that's collected and calculate that out so all the drugs could be confirmed so that is owed in a different section.

Dr. Caplan: That stays as an I. Now, G-5A, confirmatory test.

Dr. Niedbala: From the time this was written, all the drugs have been shown to be detectable at the required levels to support the clinical performance of the device, GC/MS. Although I still hold out that MS/MS may also be helpful and should be an option for the laboratories, if they would like to use it and specifically -- I think about THC.

Dr. Caplan: But those concentrations are for the target values you showed in earlier analysis and not on the sensitivity for longer detention?

Dr. Niedbala: No, they're based upon the ROC.

Dr. Caplan: I think we know that to a greater degrees as well and this one will stay as P. The next question is cutoff levels. And here, capable of calibrating the procedure, there is no notation here, but it would have to be demonstrated whether or not you could calibrate around the cutoff. There's no change there. Now, 5-C, the same thing. G-6, the cutoffs reflect drug use. We talked about that before. The certified lab program. I guess there obviously is no certification program.

Dr. Niedbala: There are no laboratories performing on this panel, so I think it is more, do you perceive it as being possible.

Mr. Crouch: What hurdles did you see?

Mr. Good: I think it is different because of the different methods of the test. There would be a certification of, in our case, more like a rapid test for the performance testing organization at the more local site and then there would be an issue for confirmatory testing and so it's two different levels and I don't know, Sam, on the collection itself. I would assume one would have some certification for the collector to move on through to a training process and understand how to collect the sample and the issues there. Both would have, I think, an issue of maybe certification at the test acquisition site and certification of any laboratory procedures that are performed.

Dr. Niedbala: I'm looking at this more from a laboratory's perspective. I don't see an issue. There are several laboratories doing this for insurance testing that are also drug testing laboratories. They are state-inspected currently by multiple states. They have their procedures in place, they have them documented and validated, I don't know of any major issue that would prevent us from doing this in the future.

Dr. Sample: We could change this I to a P, as we have for the others.

Dr. Caplan: Okay, Page 27, external PT.

Dr. Niedbala: Neil had talked earlier about people having to wear the sweat patch, and those sweat patches are spiked, and then used as controls for PT specimens, we haven't seen necessity to do that. In many cases, there's a fluid that comes along with these devices which can easily be formatted into specimens that can be used for proficiency testing in the future. In addition to that, we now know of various places where you can actually get true control, positive controls, but there are no companies I know of now setting up a program to do a proficiency testing program.

Dr. Caplan: You're saying true positive controls are available?

Dr. Niedbala: You can simulate it but you can also access different clinics and places where the drug users get the specimens.

 

Dr. Sample: Is protein bonding an issue at all?

Dr. Niedbala: Sure, in terms of affecting recovery.

Dr. Sample: In the preparation of these materials, a spike versus authentic.

Dr. Niedbala: The equivalency between a real specimen collected, and I'll talk only about one device because that's the one that I can validate against. There's not a difference between spike and real specimens because of the formulation of the diluents that are used so that the recoveries are equivalent, at least with that once device.

Dr. Sample: But in theory, that could be an issue for other devices and other techniques?

Dr. Niedbala: Absolutely.

Dr. Sample: That would be something to bear in mind.

Dr. Caplan: We still need more information here. Should we leave it I? Now, the lab inspection program. That's probably similar to what we talked about before. Is there any problem making this a blank? Okay, we'll change from I to blank. Page 29, the blind samples. Is it possible to submit negative/positive samples as if they were donor specimens?

Dr. Niedbala: The laboratories we're dealing with all do this so to me, it is possible.

Dr. Caplan: You find this within the laboratories?

Dr. Niedbala: In other words, yes, they have a QC department that would prepare a specimen and it is inserted.

Dr. Caplan: Questions or comments about that?

Dr. Sample: We made this a blank in sweat; in hair, we left it as it is. I think if there are issues with respect to what we just discussed with respect to specific collection devices, or the procedures relating to recovery, then I would either leave this as an I or make it a P until you get more data.

Dr. Caplan: Do you have a recommendation?

Dr. Sample: P is fine with me.

Mr. Crouch: We're actually doing this sort of testing and we fortified the saliva and we don't have any problems. That doesn't mean there couldn't be problems with different collection devices. That would be a front-end problem with the device, and not whether or not you could implement the program inside the laboratory. In my mind, I don't think there's any doubt that you could do it.

Dr. Sample: This isn't just internal blind, it's also external blind.

Dr. Caplan: Let's move the I to a P. We still need some information on the device specific. Okay, moving to I-1, certifying scientist review. That's no problem, so we go from P to blank. Now, onto the reporting the results by specific drug. Again, the labs have some examples of the formats used and how these are reported.

Dr. Niedbala: Right.

Dr. Caplan: Again, it's specific drugs. The differences between the specimens are going to be one or the other, or both. Now, Page 31 goes from P to blank. Now, on reporting, there's no anticipation that it will take longer. Are there any problems moving the P to a blank? Now, I-4, Page 33. Is there any problem there? We can go from P to blank. Now, interpreting results.

Dr. Niedbala: In the spirit of trying to understand the entire picture of the clinical studies and control studies that we have done also include, as I said, things like hemp oil, poppy seeds, all designed to give a complete picture of what are the advantages of this fluid in comparison to urine as the gold standard right now for testing. There is, at least for the Board, there is additional information that we can supply now that wasn't previously available on some of those subjects in addition to just showing which drugs you detect in the classic sense.

Dr. Caplan: We expect more information. We should leave this as an I. Okay, now, MRO, the alternative medical explanations.

Dr. Sample: That's the same thing.

Dr. Caplan: The MRO training.

Mr. Shults: I think all of those three issues are linked.

Dr. Caplan: Generally these are possible, so we should move the I to P. And then we're into miscellaneous issues, the time window. Now, you're indicating to me this is qualitative?

Dr. Niedbala: That was the original thought back then, but there's a lot more information now in both single and multiple dose situations. For most of the drugs, there are now time courses available and so there's a lot of new information that has to be supplied back. Some of it is also based upon whether you agree or not with this approach on sort of prevalent studies. We've done them out in the field on large bodies to compare urine versus fluid so I will have to supply that data.

Dr. Caplan: I think there's one critical across-the-board question, is how long you test which drugs and we have to answer that. Let's leave that I. And specimen contamination, again, that's the same information we talked about, that we need more information, so we'll leave that an I. Okay, that concludes the general checklist. Does anybody else want to make any statements or provide any other information regarding oral fluids?

Mr. Good: I would make a quick one. We did talk about this a little earlier but the way this is worded, it talks about metabolic process versus external exposure. And I think as Sam said earlier, you could have residual material in the mouth from smoking a drug that had not technically gone through a metabolic process, but did indicate use of the drug. And I wondered if the wording on this might exclude that type of situation.

Dr. Caplan: Certainly, we're going to need to look at it both ways. Again, as a general statement, I want to make a general statement about all of this, what we're doing, the process, because there have been a few questions from time to time and I think on behalf of the Board and at least myself, how we're trying to do this. This may hopefully be enhanced to what we did up until now, last meeting, and through today is go through this grid in a vertical guide, going up and down, having given some assignment of this arbitrary nature. These shouldn't be looked at as mutually exclusive or like a Board where as soon as you get all the things to blanks, something happens. This is a tool for the Board to collect information as a part of the process after the information is sort of collected vertically. And then we're going to wait for input from the current working group to the new working groups hopefully within the next couple of months, we're going to have took at this horizontally. In other words, we can't take each of these things totally in absentia. So to me, there are three stages, one we did the initial presentations to get general information, we created a grid which you're looking at vertically and now we're going to -' when that's done we're going to have to look at this grid horizontally. How does each of these concepts go across the various specimens so that we can come to the final ideas? What can be crafted or drafted as a regulation? And we don't know the answer whether we will encompass all specimen types or whether they have to be subrogated. So I want to point out that particularly because there has been emphasis more on some specimens than others is that this process, the fact that we have come to a blank, doesn't mean when we go across the horizontally, we won't ask for more information or something might become apparent. I don't think ' I mean, Skip drafted this draft pretty much when we started this and none of us are going to say that every issue that we can think of is in the grid, so there's going to be secondary pieces. So I wanted to at least, from the point of view of the Board, make people aware of what the process is and that is going to be a comprehensive process, going in different directions until we come up with a final answer. And we may very well come back to the beginning, including urine, lab-based urine will be affected by this. We haven't talked about that. When we go across this type horizontally, we're going to have to look at the lab-based urine as well and whether there are potential changes or needs of that program at the same time. Certainly adulteration is going to be an issue which will have to better addressed with more comprehensive regulations than we had the first time. So with that, we're finished with the oral fluids and whatever else you want to do today.

Mr. Stephenson: If I could get a sense from the members of the Board. At this point you feel comfortable in coming to a close and concluding the day, or are there any other compelling issues that individual members of the Board would like to address to the Board?

COL Jacobs: I don't think it's an issue I want to address, but I think we need to be thinking about this FDA issue in our minds so that we have something to bring next time we meet. And the other thing we need to about -- what is a specimen? Is it a collection device or is it the fluid or is the fluid the specimen? And just keep thinking about that so we can be a little further along next time we meet.

Dr. Sample: I would also add that I would encourage those that are interested in on-site testing to try and start coming together so that we can take that group to the same level that we're now at with the other three groups.

Dr. Vogl: In the on-site section, I do have all of the comments that were made at the December meeting. We can make sure that the on-site coordinator and then the rest of that working group, get that information. It would appear as if, based on the comments, there would not be many changes made to whether it's an I, P or a yes. I think they can take that information and start working on developing a response to answer those comments and issues that were identified the last time.

Mr. Stephenson: Any other comment from members of the Board?

Dr. Caplan: I would encourage all the groups to have a meeting within the next 60 days.

Mr. Stephenson: We will help facilitate it, whatever it takes. Are there any members of the public who would like to address a brief comment?

Mr. Thistle (Psychemedics): I just think, to echo Yale's comments, we were talking about a work in progress here for all of these matrices. As much as this is reported, I think there needs to be some caveat at the end that issues that we discuss here don't necessarily equate to problems, and lack of problems don't necessarily equate to the fact that there are no issues with testing across-the-board. Again, we haven't hit all of these matrices yet. There are things yet to come, but inasmuch as this is reported, either verbatim or close to verbatim, I think there should be some caveat that knowing how things are taken out of context, that we are discussing issues to learn more about these matrices and it should be just that.

Mr. Stephenson: These are issues that go beyond simply learning about them for purposes of information. It is for purposes of being able to make clear and accurate regulation that would affect the public sector programs in which the federal government has an oversight responsibility. Although your caveat is well taken, and I think we can craft, if not a disclaimer, it is an issue of focus so that it doesn't cause commercial product damage in areas where there are already ongoing activities. In most of these areas, there are. But the issue is in terms of applying it within the federal regulated environment. This has to be done with due diligence; it has to be done well. I would take us one step beyond that and add to what Aaron said -- that I would also like the members of the Board and others that are interested in this process to begin to look and review what you have learned about, not only the area of interest to you specifically from an industry point of view, but across the alternative specimens and technologies, such that we begin in this horizontal stage of the process to look at how one test may in fact become complementary, whether it's by drug class, whether it's by testing, circumstance, or other kinds of application. Because I think that truly, that is where we're going to find some good uses for current extent and so forth, but we have to be very careful how we craft it and to make sure that we have done it with the best knowledge that we have across all of the specimens.

Are there any other comments any other members of the group wish to make?

If there are no other constructive comments or needs to address the group, I hereby close this meeting of the Drug Testing Advisory Board.

Note: Adjourned at 2:50 due to snow storm.