I’ve posted at least one other deposition of Dr. Prausnitz. Here he is testifying on behalf of the plaintiff in another Duragesic lawsuit. This one also resulted in a win for the plaintiff.
VIDEOGRAPHER: This is Tape No. 1 in the videotaped deposition of Mark Prausnitz in the matter of Lee Hendelson, et al. versus Johnson & Johnson Company, et al. Today's date is April 30, 2007. The time on the video record is 9:34 a.m.
Would counsel and all present please introduce yourselves.
MR. DEAN: Richard Dean for the defendants.
MR. HEBSON: I'm Tony Hebson for the plaintiff.
MR. ANGWIN: Ed Angwin for the plaintiff.
VIDEOGRAPHER: Will the court reporter please swear the witness.
MARK PRAUSNITZ, Ph.D., having been first duly sworn, was examined and testified as follows:
EXAMINATION
BY-MR.DEAN:
Q. Good morning, Mr. Prausnitz.
A. Good morning.
Q. Have you ever had your deposition taken before?
A. I have had my deposition taken once before.
Q. How long ago was that?
A. More than five years ago.
Q. What case was that in?
A. If you'll give me a moment, I can get the exact information, if you'd like.
(Defendants' Exhibit-B was marked for identification.)
Q (By Mr. Dean) Sure. And actually, you're looking at the document we've already marked as Prausnitz B, so you go right ahead and find it.
First of all, what page are you on, Doctor?
A. I am on page No. 4, and the year was 2000 and it was SpectRx versus Non-Invasive Monitoring Company, et al.
Q. You're on page 4 of your —
A. 4 of my curriculum vitae.
Q. Okay. Thank you.
A. It's the CV — it would not have the same page number, perhaps, as what you have.
Q. So it was the SpectRx case?
A. That's right.
Q. What kind of patent was involved in that case?
A. It was a patent related to drug delivery using ultrasound.
Q. Dr. Prausnitz, I'm going to be asking you some questions today, and it's important that the two of us communicate. So if I ask you a question that you don't understand, I'd like you to tell me that and I can either repeat it or rephrase it or if you just haven't heard it, the court reporter can read it back to you.
A. Uh-huh (affirmative).
Q. Is that all right?
A. That's fine.
Q. And all your responses have to be verbal. You can't shake your head yes or no. Even though we have a videographer here, the court reporter needs some verbal responses; okay?
A. I understand that.
Q. Dr. Prausnitz, what were you asked to do in this case?
A. I was asked to evaluate the effects of Fentanyl delivery from a patch that could have a defect in it.
Q. Who gave that you assignment?
A. Mr. Angwin did.
Q. Was that assignment given to you verbally or in writing?
A. If I recall correctly, there was an initial verbal conversation. There has been some written correspondence since that time. I don't recall the — exactly what was in the written communication and if it specified the assignment as I've said it.
Q. Did you bring that written correspondence with you today?
A. I did not.
Q. Why not?
A. I was told to bring the scientific documents that I would need for the day and I brought those. I — if it's helpful, I'd be happy to provide that letter in the future. I didn't realize it would be needed today.
Q. Is it just one letter we're talking about?
A. There was an initial letter of engagement. There were a few other letters when something was mailed to me, some additional documents for me to look at. Those were cover letters that didn't have substantial information in them.
Q. When was your conversation with Mr. Angwin — your first conversation where you got the assignment?
A. I don't recall the date of that, but it was in — I believe it was in late 2006.
Q. And as best you can recollect, can you tell me what Mr. Angwin told you during that meeting?
A. He told me that he was involved with a case where somebody had died and a Fentanyl patch was suspected as the cause of death and that he needed help to evaluate technical aspects associated with that.
Q. What else did he tell you?
A. We discussed some logistical matters, about the timing of thin s and how much time would be involved, and he mentioned that he would want an expert report and that it could lead to other things, such as today's deposition.
Q. Was it at that meeting he told you that your task was to evaluate the effects of Fentanyl from what you described as a defective patch? was that assignment given to you at your first meeting?
A. The assignment was to evaluate — effects might be a right word, consequences might be a right word — of Fentanyl delivery that could result from a patch under various circumstances.
Q. And what circumstances were those?
A. One circumstance of particular interest was the possibility that the drug formulation could leak from a patch and questions about the consequences of that.
MR. DEAN: Let's go off the record.
VIDEOGRAPHER: Off the video record at 9:42 a.m.
(Thereupon, there was an interruption in the proceedings.)
VIDEOGRAPHER: On the video record at 9:43 a.m.
Q. (By Mr. Dean) Beyond the circumstance that you just mentioned, were there any other circumstances that Mr. Angwin wanted you to evaluate?
A. My assignment was to broadly evaluate Fentanyl release from a patch. So in addition to that, I evaluated the normal performance of a patch, the expected performance of a properly operating patch, and that was important baseline information as well.
Q. Did Mr. Angwin give you any assumptions about how much Duragesic gel that he wanted you to assume might get out of the — out of the reservoir patch?
A. No.
Q. That — that those kind of parameters were just not discussed at all; correct.
A. There was some information that was provided to me that originated at Alza in some estimates that would have been made by them, and that information was available and I considered that in my analysis.
Q. Fair enough.
But my question was: Did Mr. Angwin ask you to make any assumptions about the amount of gel that might leak out of a Duragesic patch for purposes of the assignment he gave you?
A. He did not give me any specific numbers. I considered various scenarios which could include a little leakage or a lot of leakage.
Q. Have you had any discussions with any other attorneys about the nature of your assignment in this case?
A. I provided an expert report in a previous case related to this one, in Gingher, et al. in California.
Q. In this case, Mr. Hendelson's case, have you had any discussions with any plaintiffs' counsel other than Mr. Angwin?
A. Yes, I have.
Q. Who was that?
A. So —
Q. Mr. Hebson?
A. Yes.
Q. Any others?
A. There — there was — on various occasions, there have been I believe two other attorneys present during conversations.
Q. When did you first meet with Mr. Hebson?
A. Yesterday.
Q. Okay. And who were the two other attorneys you just referred to?
A. I — I will need some help with their names, so I don't — I don't recall their names.
Q. Are they with Mr. Angwin's firm?
A. They were from other firms.
Q. Did you meet with Clay Robins?
A. Not in association with this case, no.
Q. So in association — fair enough. In association with this case, you met with Mr. Angwin, Mr. Hebson and two other lawyers whose names you cannot remember; correct?
A. That's right.
Q. Have you ever had a similar assignment to the one you were given by Mr. Angwin?
A. I have. I had a similar assignment in the Gingher case.
Q. Okay. Other than that, have you had a similar assignment?
A. What do you mean by similar?
Q. Well, you told me your assignment in this case was to evaluate the effects of the Fentanyl that would get outside of a patch; correct?
A. Yes.
Q. Okay. And you told me that you engaged in that kind of assignment in the Gingher case.
And my question you to is: other than the Gingher case, have you ever engaged in carrying out that kind of an assignment?
A. Okay. So if “that kind of assignment” means to evaluate Fentanyl delivery, I have not been involved in any other assignment involving a legal case.
Q. Have you — have you had that kind of an assignment, and by that I mean the way you defined it, evaluating the effects of Fentanyl that would get outside of a patch, in any context outside of the legal context?
A. The way you phrased it, no, no. I've evaluated transdermal drug delivery in the context of my research in many different scenarios over the years, but in terms of a Fentanyl gel on the skin, I have not.
Q. And let's expand the question. You know what a reservoir patch is because you've written about it; correct?
A. I am familiar, yes.
Q. Have you ever evaluated the consequences of any type of medicine getting out of a reservoir patch and onto the skin, other than in Gingher and this case?
A. I have not evaluated that specific scenario before.
Q. Have you written any articles that — where — not — obviously you haven't evaluated it yourself. But have you written any articles where you might have cited somebody who did engage in an assignment like that?
A. In an assignment on Fentanyl leakage from a patch?
Q. Let's do that first. Fair enough. That was — that's good. You're paying attention to my instructions.
A. No, I haven't.
Q. Okay. Now let me broaden the question.
Have you ever written an article where you cited anyone — cited anyone's work who evaluated the contents — the consequences of the contents of any — any type of drug getting out of a reservoir pouch onto the skin?
A. I — I have not written about the consequences of leakage from a patch.
Q. Okay, Dr. Prausnitz, now that we understand what the assignment was, tell me — what was your methodology in fulfilling the assignment?
A. The information that I relied on was primarily of two types: One was information that was provided to me; that is, official court documents that were provided to me associated with the case, as well as an extensive literature review of peer-reviewed articles, conference presentations, and other scientific information.
Q. Okay. Now, did you — do you have the court documents that were provided to you? Did you bring those with you?
A. One that was of particular use and relevance was the deposition of Suneel Gupta, and so I have that here, as well as the exhibits associated with that.
Q. Why don't you pull out the documents that fall in at that category and we'll identify them quickly. You don't need to describe them yet. You just pull them out and we'll go through them and get them on the record.
A. So matters become perhaps complicated because of the Gingher case that preceded this one. And so there was a lot of background information that I already had from the Gingher case that informed — informed me, since I had that as background information.
Specifically in this case, the documents that were provided that were central were from the Gupta deposition.
Q. You wrote your report before you saw that deposition, didn't you?
A. I — yes, I did.
Q. And you haven't supplemented your report, have you?
A. I have not.
Q. Just so we're clear — the only — you told me that the documents you reviewed in this case are two types: official court documents and scientific articles.
Is it your testimony that the only official court document that you have reviewed specifically for this case, the deposition of Suneel Gupta?
A. The opinions that I presented in my — in my expert report and that we will discuss today have been informed by additional court documents that I obtained through the Gingher case.
Q. Did you bring those with you today?
A. I did not. A number of them are cited, however, in my expert report.
Q. Well, as a matter of fact, the report of Gingher and the report in this case are pretty much the same, aren't they?
A. They're very similar, yes.
Q. Okay. Have you reviewed any documents specific to Adam Hendelson?
A. Can you — can you clarify what you mean by that specifically?
Q. Have you reviewed any medical records relating to Adam Hendelson?
A. I have not.
Q. You don't know — you don't know any medical information at all about Alan Hendelson; is that correct?
A. I have some information about him in terms of his — the Fentanyl level — the blood Fentanyl level that was reported for him at autopsy, his age at death, information of that sort.
Q. And have you reviewed any of Mr. Hendelson's medical records?
A. I have not reviewed the original source material, no.
Q. Do you have any notion as to how thick Mr. Hendelson's skin was in comparison to the average person?
A. I do not have that information; although, I'm not certain of its critical relevance.
MR. HEBSON: It's very important for lawyers to have thick skin, though, I can assure you.
Q. (By Mr. Dean) Did you review any articles in the course of carrying out your assignment in the Hendelson case that you have not reviewed previously for the Gingher case?
A. I regularly read the literature, and so I'm certain I have read things that are relevant, but nothing that changed my views in any substantial way.
Q. Is there any specific article that you can cite me to that you have read since you wrote the report in the Gingher case that in any way impacted or informed your views in the Hendelson case?
A. The only substantial item that I've read was the Gupta deposition.
Q. Did you consult with anyone about the methodology you were going to use in carrying out your assignment?
A. No.
Q. Did anyone provide scientific and medical articles to you in carrying out your assignment?
A. All of the articles that I read were either ones that I identified and my assistant helped me obtain them, in some cases, or were ones that were provided as part of court records, exhibits to the deposition, for example.
Q. Did you — were you provided with exhibits to the Gupta deposition?
A. Yes.
Q. Do you have additional views that you are going to express in this case as a result of reading the Gupta deposition?
A. My views have not substantially changed after reading that.
Q. Did you do any type of laboratory tests in carrying out your assignment?
A. I did not.
Q. Did you consider doing any laboratory tests?
A. Certainly there are additional experiments that could be done that would provide relevant information. So as any scientist, when one reads what others have done, one always thinks, well, I — I could have done this in addition, this would be advantageous. So those sorts of thoughts went through my mind, but there were no specific plans to carry out experiments.
Q. What — what went through your mind as far as what you might have done?
A. There's some interest to know about, as you brought up, gel leakage from a defective Duragesic patch. It would be valuable to have access to some of those defective patches, and even more, to have access to the specific patch in question in this case and to be able to do — to do certain tests on it. But those tests are quite difficult to do, especially with the — with the one patch that's available in this case.
Q. Have you examined the one patch that's available in this case?
A. I've seen photographs only.
Q. So I take it you have not put it down on a table and looked at it in person; correct?
A. I — I have not seen it in person. That is correct.
Q. When you looked at it in the photographs, did you see any defect?
A. The magnification and the quality of the image were not sufficient I would expect to see a defect.
Q. So you didn't see a defect, did you?
A. The photograph that I was supplied with was not of a sufficient magnification or quality in order to assess whether or not there was a defect, so I can't reach a personal conclusion on that.
(Defendants' Exhibit-A was marked for identification.)
Q. (By Mr. Dean) For the record, Exhibit A is the amended notice for taking of this deposition. And it asks you to bring certain documents with you, if you look at page 3, and directing your attention to paragraph 1, I assume that you didn't, from what you've already said, you didn't bring any of those documents with you?
A. Let me read it.
Q. Sure. Take your time.
A. I did not bring documents listed in item 1.
Q. And item 2 asks you to bring your complete file on the matter.
Can you read that?
A. Yeah, I am reading it.
Q. Okay.
A. I brought some of those items.
Q. And is what you brought with you what you've got sitting to your left?
A. This — this pile is what I brought with me, yes.
Q. Is that the entirety of what you brought with you today?
A. It is, yes.
(Defendants' Exhibit-B was marked for identification.)
Q (By Mr. Dean) Exhibit B is your report in this case; correct?
A. Yes, it is.
Q. Does this — does Exhibit B state all of your opinions in this case?
A. This exhibit provides the major conclusions that I have reached. There are, of course, additional thoughts that support these, but these are the major conclusions.
Q. So it — it does contain all of the major conclusions; correct?
A. It contains all of the major conclusions, yes.
Q. Does it contain all of the bases for those conclusions?
A. No, it doesn't. It — it includes the most important points that I considered to reach those conclusions, but I've — I've read extensive literature and did not cite everything that I've read.
Q. But again, it does contain the most important reasons to support those conclusions; correct?
A. Yes.
Q. How much time have you spent in this matter?
A. About 20 hours.
Q. Have you reviewed in the context of this case, the Hendelson case, have you reviewed the expert report of Dr. Gary Levy?
A. No.
Q. Do you know who Dr. Gary Levy is?
A. I don't know him.
Q. Have you reviewed internal Alza or Janssen documents?
A. I have reviewed some.
Q. So I take it you signed a confidentiality agreement; correct?
A. Yes.
Q. Okay. What Janssen or Alza documents have you reviewed? Let's speak generically; okay?
A. The — the documents that were of — of consequence that I spent real time looking at, there was a study in looking at variations in patch design, or I should say, perhaps, patch defects, involving a slit in the patch or a replacement of the rate control membrane with a non-rate control membrane and looking at the consequences of delivery. Another study —
Q. By the way, that was done by Walter Demo. Do you know Walter Demo?
A. I don't know him.
Q. Do you know his reputation?
A. NO, I don't.
Q. As you sit here today, you've never heard of Walter Demo; correct?
A. That's right. I've not read his literature outside of this context.
Q. What's the next article or group of articles that you can remember reading from documents from Alza or Janssen?
A. There was another study involving rabbits where a Fentanyl gel was applied to the skin and absorption was assessed in that context and compared to an attack patch.
And another study that looked at gel evaporation. This was a non-animal/non-human study just looking at evaporation in an oven and measuring those rates of evaporation.
Q. Anything else?
A. There — there were various other documents as well. I have read some things related to the manufacturing process for the Duragesic patch, that was some background information, but did not factor in a significant way into the report that I prepared. And there were — there were other documents that I looked at that likewise were not major contributors.
Q. Did somebody hand you those first three documents and tell you to review them?
A. I was provided with those documents among many others, so they were not highlighted for me.
Q. Have you ever reviewed the new drug application for Duragesic?
A. I have not.
Q. Have you ever reviewed adverse reaction reports for Duragesic?
A. Yes, that was another set of documents that I saw correspondence between, for example, Alza and the FDA about the manufacture defect, what would be done about it, what the consequences of it might be and so forth.
Q. Do you know what conclusion the FDA came to in that regard?
A. Ultimately, the — the patch continued to be sold because, my understanding is, the FDA was convinced that the manufacturing process was safe enough that it wouldn't happen again and that there was a complete recall of all of the defective patches and that a stern warning was added to the package insert after that.
Q. Do you know whether the FDA came to a conclusion about the health consequences of gel on the skin?
A. This is information provided in the Duragesic package insert, language that is always scrutinized and approved by the FDA. And the language says, “Duragesic patches are intended for transdermal use (on intact skin) only. Using damaged or cut Duragesic patches can lead to the rapid release of the contents of the Duragesic patch and absorption of a potentially fatal dose of Fentanyl.”
So it's my understanding that the FDA supports that language.
Q. Were you provided with an April 15, 2004, letter from the FDA to Alza and Janssen about the health —
A. I might have been.
Q. Is it there?
A. Probably it isn't. What I have here is — is primarily, if not exclusively, my — my literature information and not things that were provided from the court record. If you have it, I'd be happy to look at it and jog my memory.
Q. Do you know what level of recall the FDA assigned to the recall in 2004?
A. I don't know the level.
Q. Do you know whether the level — do you know what levels there are for an FDA recall?
A. I don't know the FDA terminology with regard to these levels.
Q. Do you know what the criteria are for the different levels?
A. I'm — I'm not familiar with the FDA regulations on recalls.
Q. Well, your assignment was to figure out the consequences of gel on the skin; correct?
A. There can be, of course, many consequences. The focus for me is the consequence, namely, of the degree to which Fentanyl would be absorbed into the body.
Q. Well, in carrying out that assignment, you'd certainly be interested in what position the FDA would have taken on the consequences of gel on the skin, would you not?
A. Yes, and I believe the FDA concluded that it was potentially fatal.
Q. But you don't have any notion as to how they — what level of recall they assigned it; correct?
A. I do recall reading some of the correspondence, as I'd mentioned, between the FDA and Alza and the positions that each took. I remember a series of significant questions that the FDA asked, expressing real concern about these consequences.
So although I — I cannot recite to you the level of the recall, I can tell you that I read materials provided by Alza to the FDA and, likewise, from the FDA to Alza.
Q. Would it surprise you to learn that the FDA concluded that there was not a significant health risk from gel on the skin?
MR. ANGWIN: objection. That's a mischaracterization of the updated position.
Q. (By Mr. Dean) Go ahead.
A. Could you repeat that?
Q. Would it surprise you to learn that the FDA has concluded that there is not a significant health risk associated with Duragesic gel on the skin?
MR. ANGWIN: Same objection.
THE WITNESS: It would surprise me if the FDA concluded that there was not a significant health risk, because I believe that there is a health risk.
Q (By Mr. Dean) And as you sit here today, you don't have any recollection of seeing an April 15, 2004, letter from the FDA, do you?
A. I saw various letters. I may have seen the letter with the date you mentioned, but simply reciting the date is not sufficient to jog my memory.
Q. You didn't cite that letter in your report, did you?
A. I did not cite that letter.
Q. Are you consulting on any other legal cases involving transdermal patches, other than Duragesic cases?
A. No.
Q. How many other Duragesic cases are you consulting on?
A. There are additional cases that Mr. Angwin's firm is handling, and although I've not provided specific testimony for those, it may be that I will in the future.
Q. How many are there?
A. I'm aware of three cases, including this one.
Q. So we have Hendelson and three others you're consulting —
A. And two others.
Q. Okay. And you consulted with Mr. Robins in the Gingher case; correct?
A. That would be a fourth case, yes.
Q. Are there any others — is that the whole universe of cases that you either have or are currently consulting on regarding Duragesic?
A. Yes.
Q. Are you currently consulting on any other legal cases involving the pharmaceutical industry?
A. NO, there no — there are no cases that I'm currently involved with.
Q. Do you know the chemical contents of the gel in the Duragesic — in the reservoir portion of the Duragesic patch?
A. Yes, I'm familiar with those contents based on the package insert.
Q. Do you know what percentage they are present in the pouch?
A. I can check those numbers. Again, I would get them from the package insert.
Q. Do you think those numbers are in the package insert?
A. There is information provided about the content of Fentanyl, as well as the content of alcohol and water.
Q. Can I see the document you're looking at, please? The package insert doesn't tell you how much ethanol is contained within the reservoir pouch, does it?
A. Can I have the document back, please?
Q. Let me see if I can find mine.
A. It states each system contains .1 milliliters of alcohol USP per 10 square centimeters.
So based on knowing the size of the patch, one knows the amount of alcohol that's present.
Q. Are you in the “How Supplied” section? Is that where you're at?
A. No. “Description.” It's at the very beginning, just after the warning.
Q. Okay.
MR. ANGWIN: I'm not sure you're looking at the same document.
THE WITNESS: I think we are. It's formatted differently. This is an Internet printout.
MR. DEAN: I think the substance is the same.
Q (By Mr. Dean) Do you know how much water is contained within the Fentanyl patch?
A. I don't believe this document provides that information.
Q. And are there other content — what's your understanding as to what other contents are within the — within the gel component of the patch?
A. My understanding is that the composition is primarily water and alcohol. There is clearly Fentanyl, in addition. There is also a gelation agent which in typical formulations would be a minor component.
Q. So you don't know how much — what percent of the contents would be taken up by the gelation agent; right?
A. I don't know the exact formulation.
Q. But is it your testimony from the package insert that you do know how much Fentanyl is in the contents of the patch?
A. Yes, the package insert says in the table at the beginning the Fentanyl content.
Q. And is it your testimony the package insert also tells you how much ethanol is in each patch?
A. Yes, it does.
Q. So the two ingredients you can't tell, as far as the — how much they are found in the contents, is the water and the — what you call the gelation agent?
A. Those concentrations are not provided in this document.
Q. Is — in regard to the assignments you were given, is the amount of water contained in the contents of the patch relevant?
A. The — the — the presence of water in the patch is relevant and influences its performance.
Q. How is it relevant in regard to the assignment that you were given in this case?
A. It will affect the solubility of the Fentanyl. It will affect the physical properties of the gel. It will affect the evaporation rate.
Q. How — how will it affect the evaporation rate?
A. If there is more water present in the formulation, the evaporation will be slower.
Q. Will ethanol evaporate more rapidly than water?
A. Yes.
Q. How much more rapidly?
A. I don't — I don't have numbers for that, but it would be more rapid.
Q. Do you — recognizing that you can't give it to me with mathematical precision, can you give me general parameters of how much more? And if you can't, that's fine.
A. It — it — it will be significantly faster.
Q. I want to skip back, and I apologize. This is my fault.
I'd asked you before about whether you knew anything about Adam Hendelson's medical history. Specific follow-up: You do not have any knowledge regarding whether or not he had any abnormalities in his skin, do you?
A. I don't have any knowledge of that.
Q. Do you understand how the Duragesic patch works?
A. Yes.
Q. Is the Fentanyl in the patch in solution or suspension?
A. The Fentanyl is dissolved in the gel and diffuses from the gel to the skin.
Q. Is it your testimony that all of the Fentanyl in the patch is in solution, then? Is that your testimony?
A. The Fentanyl that is being delivered to the skin is in solution. It's possible that there could also be some Fentanyl at, for example, earlier times in the Fentanyl patch usage, that would not be in solution.
Q. Do you know whether there is — this is a very simple question.
Is there Fentanyl in the patch in suspension? Do you know that?
A. Is — is some portion of the Fentanyl that's in the patch not in solution and, that is, in suspension? Is that your question?
Q. Yes.
A. I — I don't know if there is Fentanyl in suspension.
Q. Okay. Now, how in the — in the Duragesic patch, tell us how the Fentanyl is delivered.
A. In a normally functioning Duragesic patch, the Fentanyl will diffuse across the rate control membrane through the adhesive and into the skin.
Q. And where is the adhesive?
A. I'm sorry. Say it again.
Q. Where is this adhesive?
A. Where is the adhesive?
Q. Right.
A. The adhesive is between the rate control membrane and the surface of the skin.
Q. Is there any Fentanyl in the adhesive that's being delivered from the adhesive?
A. Yes.
Q. Okay. How much?
A. This depends on time. Initially, during storage when there is no skin for Fentanyl to exit into, there is some Fentanyl buildup in that adhesive. Once the patch is applied, then that Fentanyl concentration is going to change, it will drop, as Fentanyl starts leaving the patch and going into the skin.
Q. What — what — so you — you understand that in the — that in the adhesive on the Fentanyl patch, there is — strike that.
You understand in the adhesive on the Duragesic patch that there is Fentanyl embedded into the adhesive; is that your testimony?
A. There is Fentanyl present in the adhesive.
Q. And what is the purpose of that?
A. Part of the reason that there is Fentanyl present in the adhesive is inherent to the design. It would be difficult to keep the Fentanyl out of the adhesive during storage. There is, in addition, an advantage to having Fentanyl in that adhesive, because it has already crossed the rate control membrane and therefore, when one puts the patch on, there is initially a greater delivery of Fentanyl.
Q. And if that Fentanyl wasn't in that adhesive, there would be a slower delivery of Fentanyl to the bloodstream; is that correct?
A. If the Fentanyl were in the reservoir on the other side of the rate control membrane, then the delivery would be slower. Because it is on the other side of the rate control membrane in the adhesive, it is faster.
Q. And, of course, the only place where the Fentanyl in the adhesive is building up in the skin is directly underneath the patch; is that correct?
A. In a properly functioning patch, the Fentanyl that is not being constrained by the rate control membrane would be in the adhesive.
Q. Directly underneath the patch?
A. The — when you say directly under, I'm not sure what you're getting at. The patch has a reservoir region, and there is a lip around it and so there is adhesive in the lip as well and there could be Fentanyl in that portion, which is not immediately under the reservoir.
Q. Fair enough.
I'm not trying to trick you here. I'm just trying to phrase the questions as best I can.
Would you agree, then, with your addition, that the Fentanyl that is attached to the adhesive that you've talked about would be in the skin directly underneath the entire patch?
A. Certainly the — the large majority of the adhesive would be directly under the patch and the Fentanyl would be in that adhesive.
Q. What is flux?
A. Flux refers to the amount of a drug that goes, in the case of our discussion, across the skin, as a function of time and area of skin.
Q. What about concentration?
A. Concentration is the amount of drug per volume that is contained in the drug.
Q. Again, I was very inartistic.
What about concentration in terms of the issue of flux? Isn't concentration important there, too, Doctor?
A. Absolutely. The flux will increase as concentration — concentration in contact with the skin increases.
Q. And so it's not as simple as area and amount. You have to look at the concentration, correct, to determine flux?
A. If you want to determine flux, you need to know the concentration of the drug.
Q. And if the concentration, for whatever reason, is decreasing, flux would decrease as well; correct?
A. If that's the only thing changing, yes.
Q. And you agree that if water is left on the skin, it will evaporate; correct?
A. Water, over time, will evaporate off the skin.
Q. And ethanol on the skin will evaporate; correct?
A. Yes.
Q. Fundamental scientific principle; right?
A. Liquids will evaporate, yes, this is a fundamental principle.
Q. And ethanol will evaporate more quickly. I think we already said that; is that correct?
A. I agree with that.
Q. Do you have any financial interest in any company that is developing transdermal products?
A. Yes.
Q. What is that?
A. In the context of my financial holdings, I have mutual funds and those mutual funds have, of course, many companies that will include companies with those interests.
Q. And, again, that was a poor question because that wasn't what I was after. Let me rephrase the question so I can get what I'm after.
Are you consulting with any companies that are developing transdermal products in which you have a financial interest in the company?
A. By “financial interest,” do you mean —
Q. I don't mean a stock —
A. — shares in the company or receiving compensation from that?
Q. Either.
A. Either. Then the answer is yes, I do.
Q. And what companies are those?
A. So those relationships are listed in my CV, if you'd like to look at that.
Q. Okay. And where are they, Doctor?
A. “Consultantships and Advisory Board Appointments.” It's towards the beginning.
Q. Right. I don't want to go through the entire list, or at least I don't think I do. Are — in any of those that are listed there, do you have an interest in the company other than what you get paid for consulting?
A. An interest other than pay. Associated with some of those relationships are stock options.
Q. Are any of these companies competitors of Alza?
A. They're competitors in the context that they're, in some cases, in the field of transdermal drug delivery, but they are not competitors in the context that there is a specific product that they have that would directly compete.
Q. You've got Alza down there from 1996 to 1999; correct?
A. Yes.
Q. Were you a consultant to Alza?
A. I would characterize the relationship that way. I — I visited Alza a few times in that time period to give a seminar and have a scientific interaction with them.
Q. What were you consulting on?
A. There was general discussion on drug delivery with a specific interest in the topic of microneedles or a technology that has spun off from Alza called Macroflux.
Q. Were you ever an intern at Alza?
A. I worked there for under a year after I graduated from college.
Q. Who did you work for?
A. My direct supervisor was Rick Gyory, G-Y-O-R-Y.
Q. What did you do?
A. I did laboratory research to look at the use of electricity to help drug delivery across the skin.
Q. Was your work limited to electricity issues, for want of a better phrase?
A. The scope of my work was exclusively using electricity for this kind of drug delivery, for transdermal drug delivery.
Q. At any time when you were — during that internship, did you do any work on Duragesic?
A. No.
Q. Did you have any access to Duragesic documents?
A. No.
Q. During this work, did you meet Suneel Gupta?
A. Not that I recall.
Q. Do you ever recall meeting Suneel Gupta?
A. No.
Q. During this work, did you meet Robert Gail?
A. Yes.
Q. What was your interaction with Mr. Gail during the time you were an intern?
A. I believe he was in the same building and I would see him maybe at lunch or in the halls, but there wasn't a formal interaction with him.
Q. So you knew who he was, but you didn't work with him? Is that fair?
A. That's fair.
Q. Did you — during the internship, did you have any interactions with any of the — any of the pharmacokineticists besides suneel Gupta?
A. No, no — and again, passing, hello in the hall kind of interaction, but no significant ones.
Q. Based upon your time spent there as an intern and the time you spent consulting, is it your view that Alza is a good, responsible pharmaceutical company?
A. In my experiences with Alza, I — I never saw anything that made me question the company.
Q. Indeed, at some time since this time frame we're talking about, you've actually asked Mr. Gail to make presentations to one of your classes; is that right?
A. Mr. Gail has made presentations in my classes in the past. He has not made presentations since this case has — I've become involved with this case. That is not because of any good or bad or any interaction. It's just that I haven't taught the class since that time.
Q. Right, right. But you, I take it, you were teaching the class, you affirmatively reached out to Mr. Gail to in some way participate in a couple of those classes; correct?
A. I asked him to give a guest lecture.
Q. And he did that?
A. And he did.
Q. Have you asked anyone else from Alza to give lectures in any of your classes?
A. No.
Q. Do you know how — how it was that — well, strike that.
I assume your first assignment was, in the Duragesic world, was for Mr. Robins; is that correct?
A. That's right.
Q. Do you know how it was that Mr. Robins came to your doorstep?
A. I think he was referred by an agency that identifies experts, but I'm not certain of that.
Q. Do you know what agency that was?
A. I don't.
Q. Do you hold any patents on medical devices?
A. Yes.
Q. Are those in your resume?
A. There is a list of the patents in my resume, yes.
Q. And could you direct me to that?
A. It is toward the end, it's on my page 22. It's after all of the papers and conference proceedings, just before research grants.
Q. So number one relates to silicone hair spray; correct?
A. That's right.
Q. No. 2 does as well; correct?
A. Right.
Q. What's No. 3 relate to?
A. I'm not certain I have the same printout as you. I printed my resume just recently, and so is this —
Q. Wait, wait. Which one — are you on the actual exhibit?
A. No, I'm using my —
Q. Let's get to the actual exhibit, so we're both —
A. Okay.
Q. So we don't have that problem. I think you have the exhibits there?
A. Oh, it's in this. Fine. This one here, Exhibit B.
MR. HEBSON: Isn't that your resume?
THE WITNESS: Yes, it's in here. That's right. Right. So on page 28 of Exhibit B.
Q. (By Mr. Dean) Yes. So we've already done 1 and 2.
What's No. 3 about?
A. That has to do with using electricity for transdermal delivery.
Q. And in the Duragesic patch, there's no electricity used in the delivery of the drug, is there?
A. That's correct.
Q. Maybe we can short circuit this. Do all of these relate to — is the term electroporation?
A. Electroporation. They do not all relate to electroporation.
Q. Why don't you tell me the ones that don't and we'll talk about those.
A. So 3 and 4 do and the rest of them do not relate to electroporation.
Q. Microneedle is something different from electroporation; right?
A. That's right.
Q. So 5, 6 and 7 and 8 all relate to microneedle penetration; correct?
A. That's right. Or microneedle, not just penetration, but microneedles broadly for drug delivery.
Q. Very good. Tell me about No. 9. What does it relate to?
A. No. 9 relates to the use of ultrasound for drug delivery.
Q. And ultrasound is not used to deliver drug in the Duragesic patch, is it?
A. That's correct.
Q. No. 10, there's a microneedle application; right?
A. Yes.
Q. As is No. 11; correct?
A. Yes, as is all — all of the ones that remain.
Q. Are any of these patents that are listed here being commercially marketed, the product being commercially marketed?
A. There are no products based on these patents. There are products under development.
MR. HEBSON: when you get to a good stopping place, let's stop for a minute.
MR. DEAN: I was going to ask. I'm fine, but I realize other people may not be. Let's go off the record.
VIDEOGRAPHER: off the video record at 10:47 a.m.
(Thereupon, there was an interruption in the proceedings.)
VIDEOGRAPHER: This marks the beginning of Tape No. 2. We're on the record at 10:54 a.m.
(Defendants' Exhibit-C was marked for identification.)
Q. (By Mr. Dean) Doctor, I think the notebook's marked Exhibit C; is that correct?
A. Yes.
Q. Okay. I've got some questions for you about the notebook.
First of all, I'd like to you turn to tab 3 of Exhibit C. What I want to do is go through these articles and establish which of the articles relate to in vitro testing as opposed to in vivo testing; okay?
A. Okay.
Q. And we may have a few other questions about these, but that's going to be my primary focus right now.
Tab 3 relates to in vivo testing of some type of Fentanyl patch other than the Duragesic patch; correct?
A. Tab 3 is a research article that is in vivo in humans, and it is — its context is to evaluate the Duragesic patch and I would have to check here if the Duragesic patch was actually used or not.
Q. Well, you cite this article, don't you, in your paper?
A. I do, and if you'd like me to refresh my memory, I'd be happy to take a moment.
Q. You can't tell me — you can't tell me whether the Duragesic patch was the patch being tested? You don't know that off the top of your head, I take it?
A. Certainly they made their own modified patches in order to answer the question that they sought to answer.
Q. Who made their modified patches?
A. Alza I don't believe did. I can find out who did.
Q. Whose patch is being tested here, Doctor?
A. If you'll give me a moment.
Q. Sure.
A. So the patch that was used was made by a different company.
Q. Cygnus; correct?
A. Yes.
Q. You don't know the formulation of the contents within that patch, do you? As far as by that I mean the strengths of the components.
A. The strength meaning, say, the concentration —
Q. Yes.
A. — of the various components? The detailed formulation I don't believe is given.
Q. Article — I'm sorry, tab 4 is basically a review article, is it not?
A. It is an article that provides — oftentimes “review article” means that there's just a summary of existing information. There's new information here. New theoretical analysis provided.
Q. What I was trying get at, this does not deal with laboratory testing in vivo or in vitro as far as the specific focus of the article. Would you agree with that?
A. The focus of this article is theoretical analysis.
Q. Mathematical analysis?
A. Mathematical analysis.
Q. Now, turn to tab No. 7, and would you agree that this relates — article relates to in vitro testing?
A. Yes.
Q. And look at article No. 8. Would you agree that that article relates to in vitro testing?
A. Yes.
Q. Look at article No. 10. Would you agree that article relates to in vitro testing?
A. Yes.
Q. Look at article No. 11. Would you agree that article relates to in vitro testing?
A. Yes.
Q. Look at article NO. 12.
A. Yes.
Q. Would you agree this article deals with in vivo testing of something called tritiated Fentanyl, T-R-I-T-I-A-T-E-D?
A. This article deals with the in vivo delivery in humans of Fentanyl and there is a tritiated label that has been added to facilitate the assay.
Q. And this article was written in 1987; correct?
A. It was published in '87.
Q. Right. And that was three years before the Duragesic patch was marketed; correct?
A. I would have to check the date. I don't know that.
Q. Let's just leave it this, this article does not purport to deal with the gel from a Duragesic patch, does it?
A. That's true.
Q. Article No. 13 is in vivo; correct?
A. In vivo, yes.
Q. And article 14 is in vitro; correct?
A. In vitro, yes.
Q. And what is article 15? Is that in vitro or in vivo?
A. 15. It includes both in vitro and in vivo.
Q. But it is not — has nothing to do with Fentanyl, does it?
A. This study does not include an evaluation of Fentanyl, but lessons from the study are relevant to the discussion.
Q. So having gone through this list, Doctor, how many articles do you cite where there is in vivo testing of a Duragesic patch?
A. On articles that are cited in my expert report —
Q. The ones we've just been through —
A. We've just been through.
Q. — how many of those articles relate to in vivo testing of a Duragesic patch or the contents of the reservoir of the patch?
A. Many of them, using your word, “relate” to the Duragesic patch, but none of them use the Duragesic patch itself.
Q. My question is: HOW many articles here relate to in vivo testing of a Duragesic patch? Let's start there.
A. Again, your word “relate.” I think all of them relate to that.
Q. How many of them study that, Doctor? How many of them report on that?
A. Again, it's a question of — of the words you are using. There is one that specifically in the introduction says that the study was inspired by and — and seeks to evaluate performance of a Duragesic patch, even though they did not use that patch in the study.
Q. Which article is that? Are you citing me to No. 3? Is that what you just intended to refer to?
A. Let me check.
Q. Sure.
A. No. 3, yes.
Q. No. 3 is not an article where there's in vivo testing of a Duragesic patch, is there?
A. In that study, a Duragesic patch was not applied to humans for testing.
Q. Which of these studies are in vivo studies of a Duragesic patch?
A. None of these studies have applied a Duragesic patch in vivo and made measurements.
Q. Which of these studies — strike that.
Have any of these studies done in vivo testing of the contents of the Duragesic patch on skin?
A. These studies have not measured the contents of a Duragesic patch on the skin.
Q. Do you yourself typically do in vivo and in vitro studies with drugs?
A. We study transdermal drug delivery — let me — let me clarify that. We study transdermal delivery of a variety of compounds in vitro and in vivo and some of those compounds are active drugs, other ones are model compounds.
Q. Isn't it commonly accepted wisdom that studies derived in vitro do not necessarily predict findings in vivo, as far as drug delivery's concerned?
A. In vitro experiments give relevant information to in vivo but there are difference between in vitro and in vivo.
Q. And indeed, some of the articles that you cited which we have here in Exhibit C, some of the authors have cautioned against using the in vitro data to necessarily mean that those findings would apply in vivo; correct?
A. I would agree that one must always be cautious to apply in vitro results in vivo, but that is to say one has to understand the relationship between the in vivo and in vitro environments and apply the in vitro lessons correctly, and they can be applied if one applies them correctly.
Q. Excuse me. I think you've got the patent there as Exhibit D.
A. Exhibit D, yes.
Q. What patent is that?
A. The title is “Transdermal Delivery of Analgesics.”
Q. What is — what compound is being used here?
A. I — I would have to look at this patent to become familiar with it. NOW, I can — I can answer some simple questions, perhaps.
Q. Well, let's do that, then, Doctor.
You see Figure 1 down at the bottom of that page?
A. Yes.
Q. The Y axis is labeled “Cumulative Fentanyl (UG/CM2); correct?
A. That's correct.
Q. And that stands for micrograms penetration per centimeter?
A. Per centimeter squared, yes.
Q. Thank you. And the x axis is for time; correct?
A. Yes.
Q. And they're tracking two different substances in Figure 1; correct?
A. Yes.
Q. And I want you to look at the bottom line —
A. Actually — that's not correct. In both cases they're tracking Fentanyl but delivered under two different scenarios.
Q. Fair enough. And under the first — under the scenario that generates the bottom line, that shows that after 25 hours, there were approximately 10 units on the Y axis; correct?
A. That's correct.
Q. Okay. And would you agree that that yields a result of .4 micrograms per centimeter squared per hour?
A. I brought my calculator —
Q. Sure.
A. — so I can do the math.
Q. Excellent.
A. Approximately .4 micrograms per centimeter squared per hour is the average delivery rate.
Q. And do you know what the average delivery rate of a Duragesic patch is in terms of micrograms per centimeter squared per hour?
A. Of course it depends on which Duragesic patch you mean, but in terms of the 75-microgram per hour patch, it's 75 micrograms per hour but one must of course divide that by the area of 30. So 75 divided by 30 is 2.5 micrograms per centimeter squared per hour.
Q. And what does the top line yield in terms of that calculation, the top line being the one in Figure 1 on Exhibit D?
A. The top line, after 24 hours there is approximately 40 micrograms per centimeter squared that has been delivered.
Q. Right.
A. And 40 divided by 25 hours would give 1.7 micrograms per centimeter squared per hour.
Q. Now, do you understand what these two substances are that are being measured here?
A. I'm sorry. Two substances —
Q. Yeah, they're tracking two things.
A. They're both Fentanyl.
Q. Right. But it's different concentrations or different formulations?
A. So what — I mean, what is being measured, the Y axis, is — is the same thing. It is Fentanyl that is being assayed, but the conditions for delivery are different.
Q. And what are those conditions?
A. In one case, the Fentanyl is being provided at a certain concentration, 5 percent, and this formulation additive is not present. In the second case, Fentanyl is provided at a higher concentration, 7.5 percent, and in addition there is a formulation additive, octyl salicylate. Should I spell that?
Q. Sure.
A. O-C-T-Y-L S-A-L-I-C-Y-T-A-T-E.
Q. And is that a, in layman's terms, a penetration enhancer?
A. Yes.
Q. Is it more powerful than ethanol?
A. That comparison is not being made.
Q. I know it's not being made in this document. Generally, is it a more potent penetration enhancer than ethanol, if you know?
A. Different enhancers enhance to different degrees depending on the drug being delivered. So now I assume you're asking the context of Fentanyl it a more potent chemical enhancer.
Q. Yes, let's do that.
A. And I don't know that.
Q. And do you understand from the patent how these — first of all, were they applied to human skin or some other type of skin? Do you know?
A. In Figure 1, the Fentanyl delivery has been across human epidermis. So that would mean in vitro human skin.
Q. What about Figure 2? I'm sorry. I'm sorry. Figure 1 — are both lines, are both formulations — what I'm after is are both formulations that are being tracked in Figure 1, were they applied to human skin?
A. My understanding of the text is that in both cases, the data in Figure 1 are human skin. There's also some discussion of work with snake skin. But my understanding is that the data shown are human skin data.
Q. In relation to Figure 1 —
A. Figure 1.
Q. — is human skin; correct?
A. That is m understanding, yes.
Q. What is the difference — I take it that the difference in the formulation is that one has the penetration enhancer and the other does not; correct?
A. There are two differences. One is the penetration enhancer but the another difference is that Fentanyl is being provided at a higher concentration when the penetration enhancer is used.
Q. Right. Okay. Fair enough.
So the differences are right there in the figure itself; correct?
The two differences you just —
A. The differences that I just described are in that figure. Being a patent, which sometimes doesn't go into as much detail as a full research article, the — the methods are not described in — in their full detail.
Q. And do you understand what actually — strike that.
Do you understand how these formulations were applied to the skin?
A. In the description given here, it — it doesn't explain that other than to say that it was a transdermal spray. Now, my reading of the literature more broadly would give me some additional understanding, but in any case, it was a spray that was applied to the skin.
Q. Do you think this is a relevant — I know you cited it in your work. Do you think this is relevant to your assignment in this case?
A. Yes.
Q. Okay. Do you think it's the most relevant citation, supporting citation, you've given in your paper?
A. Each article is relevant to a different component of what I have to say. So I wouldn't pick any one as the most relevant because there are a number of points.
Q. Which of your articles that you cite is there a compound containing Fentanyl that's actually applied to the skin?
A. In which —
Q. I'm sorry.
A. Yeah, I didn't get that.
Q. Let me start over.
I want you to set aside the references in the articles that involve patches, patches being applied to various people and things being studied.
Are there any articles that you cite where some type of Fentanyl is actually applied to the skin other than through the use of a patch, other than this patent?
A. Yes.
Q. Which ones?
A. If you're — are you including in vitro work? Because a patch is typically not used in the in vitro work, so there are a number of articles in that category.
Q. Well, let's stick with in vivo first —
A. Okay.
Q. — because you just told me this was applied to humans, correct, exhibit D?
A. Exhibit D is applied in vitro to human skin.
Q. Right. Okay.
A. So not to humans, but to human skin.
Q. Okay. Well, which other articles that you cite was there an application of a compound containing Fentanyl directly to human skin?
A. We can go through. It is — many of the articles do that. And, again, we can go through, if you'd like to.
Q. Let's do that.
A. Okay.
Q. No. 3 is not such an article because it relates to the use of a patch; correct?
A. No. 3 uses a patch applied to the skin, yes.
Q. Okay. Remember my question. I'm interested in articles —
A. That don't use a patch.
Q. — that don't use a patch where there is some type of compound containing Fentanyl that's put on the skin. You with me?
A. Yes.
Q. I think you are. Okay. So let's go through and tell me which ones fall in that category.
Well, No. 3 does not. We've agreed on that; correct?
A. No. 3 uses a patch, that's correct.
Q. And we already agreed that No. 4 is a theoretical mathematical article; correct?
A. That's correct.
Q. All right. Now, does No. 7 qualify in that regard?
A. Yes, there is no patch involved here. Fentanyl is applied as a solution.
Q. Okay. Do you know what the drug penetration level was that was yielded by this study? Is it reported by the authors?
A. There is a — let me correct a statement I made before. Patches were also used. They looked with the patch as well as aqueous solution, and they report a permeability value from which you can calculate the amount of drug delivery.
Q. But you can't calculate it from this article because they don't give you all the information you need to calculate it, do they?
A. Well, I can check my notes. I'm sorry. Ask your question again.
Q. Can you calculate a drug penetration level from the information the authors provide in article No. 7?
A. Let me back up for a moment. There are many things one can measure in an experiment. Some of them are very specific to the conditions that you have used and other ones are more generally translatable and therefore, are more useful because if someone doesn't use exactly your conditions, they can still learn from your results and, through appropriate analysis, apply them.
The information that is most applicable is something called the permeability, that is something that can translate between experiments, and that's what they've reported. So that is, in fact, the most valuable information. If they had only, for example, reported a flux, I would have difficulty translating that into what has happened in another scenario such as the Duragesic patch. So I think they have reported the appropriate information for interpreting Duragesic.
Q. Did they give you information from which you could — from which a reader could conclude what the level of Fentanyl penetration was in this case?
A. I — I — I have to — I can spend a little time to read through this if you want to ask me that. But the information is often embedded in various places. As I had mentioned, what I think is most valuable is permeability and that's what facilitated my analysis.
Q. And what they studied was permeability and they didn't report results on drug penetration, did they?
A. Well, permeability is a measure of drug penetration.
Q. Is it synonomous? Is that what you're saying?
A. Well, drug penetration isn't a technical term, so you'll have to define that technically.
Q. Did they report how much — what levels of Fentanyl were being absorbed in this test?
A. So yes, in fact, they did. Figure 1 tells you the amount of Fentanyl that is being delivered as a function of time.
Q. Okay.
A. And other figures as well.
Q. All right. Is that the same — are those the same grids that we saw in Figure 1 of the patent?
A. The same grid — this is different group, different data.
Q. No. I mean all — the x axis is the time grid?
A. So on the X axis in both cases, it is time, and on the Y axis in both cases, it is the amount of Fentanyl that's been delivered. The units are different, but it is the amount that is being delivered.
Q. Have you done any analysis to determine whether those are high or low levels that are being reported in this article?
A. High or low relative to what?
Q. The expected level of drug delivery from a Duragesic patch.
A. I haven't made that quantitative comparison.
Q. Well, let's continue this. Article 8 has nothing to do with measuring Fentanyl on skin, does it? Let me strike that.
Article 8 doesn't report results of applying a mixture containing Fentanyl on skin, does it?
A. It does not.
Q. And going back to 7, if I understand it right, that was some type of in vitro testing with human skin which would be similar to what happened in what was being reported in the patent, Exhibit D?
A. It is related. Both of them used in vitro skin and measured Fentanyl delivery.
Q. Okay.
A. But the preparation of that Fentanyl and the formulation was quite different.
Q. Sure. Understood.
All right. So does article 10 relate to putting some type of Fentanyl in some kind of a mixture on skin?
A. This has a liquid solution of Fentanyl applied to the skin.
Q. Can you tell what the amount of drug delivered was in article 10?
A. The data that are reported are in the form of permeabilities. So that — that gives information on the rate of Fentanyl delivery across the skin.
Q. Is that rate reported here?
A. The — the rate of delivery in the form of a permeability — that is, centimeters per hour — is given in a number of the tables.
Q. Article 11, does it fit the category of putting some kind of Fentanyl compound on the skin?
A. A Fentanyl formulation was applied to the skin and transdermal delivery was measured.
Q. And Exhibit 12 does the same thing, I think, does it not?
A. No. 12 similarly puts a Fentanyl formulation on the skin, but this study differs in that it's in vivo in humans.
Q. And in this study, it was not the contents of a Duragesic patch that was put on the skin, but some other formulation; correct?
A. That's correct.
Q. And it was also covered — that formulation was covered by some type of aluminum wrap; correct?
A. In that study, the formulation was applied to skin and it was allowed to fully evaporate to dryness. Quote directly, Allowed to evaporate to dryness in air. After that there was a covering put on.
Q. And what type of covering was that?
A. An aluminum patch backed by adhesive tape.
Q. And what was the purpose of that?
A. It doesn't state the purpose here, but I would expect the purpose is generally to protect the site so that there couldn't be any other influences on the absorption process.
Q. So are you telling me the author doesn't state what the purpose was? Is that fair?
A. Let me read it to double check. I don't believe they state a reason for placing that covering on.
Q. Would that covering — are you familiar with aluminum patch — aluminum coverings like this that is being described here?
A. I don't know the particular brand that they used.
Q. I wasn't asking that.
A. I don't know that.
Q. I was asking generically. Are you familiar with what's being described?
A. Yes.
Q. And would one of the effects of applying such a product be to limit any further evaporation of drug that might have penetrated the skin?
A. There should be essentially no evaporation of drug. There would be evaporation of the solvent, ethanol and water — well, in this case, water, but drug would not evaporate off the skin, in this case or in Duragesic's case.
Q. You have your report there, which is Exhibit B.
A. Exhibit B.
Q. Turn to page 2.
A. Yes.
Q. At the top of page 2 you say, “For comparison, lethal Fentanyl concentrations have been found to range from 3.0 to 28 nanograms per milliliter with an average value of 8.3.”
Is that supposed to be nanograms — did you switch?
A. Yeah, that appears to be a typo.
Q. I think it does. I want to make sure —
A. Yes, yes. That is — that — there's an error and let me —
Q. So that — that comes from —
A. Let me just verify the nature of the error. It should be nanograms per mil. So the units in the 8.3 are in error.
Q. So it should read 8.3ng; right?
A. “N” as in nanogram, yes.
Q. Right. Okay.
MR. HEBSON: Do you want him to change that on the exhibit?
MR. DEAN: No.
MR. HEBSON: Okay.
Q. (By Mr. Dean) Now, does that — do you take that to mean that there are some people walking around with levels of Fentanyl at 5 and 6 and 7 nanograms? Is that how you interpret that sentence?
A. I'm sorry. Are there people walking around who have 5 and 6 and 7 nanograms per mil in their blood?
Q. Yes.
A. This is not my area of expertise, but I would — I would imagine there are such people.
Q. Well, let's — let's talk about your — fair enough. Let's talk about your area of expertise for a minute.
You are a chemical engineer; correct?
A. My — my degrees are in that field, yes.
Q. You are not a — you are not a medical doctor?
A. I'm not a medical doctor.
Q. You hold no degrees in medicine; correct?
A. That's correct.
Q. You are not a pharmacologist?
A. I — I do not hold degrees in that area either.
Q. And you are not a pharmacokineticist; correct?
A. Again, I don't hold degrees in that area; although, I have done considerable research on the pharmacokinetics of drug transport across the skin.
Q. But there are people out there who have degrees in pharmacokinetics and you are not one of them; correct?
A. That's correct.
Q. Do you have any expertise on the impact of a given level of any drug on humans?
A. I — I don't have expertise on the, say, pharmacological or medical consequences of drug levels in the human body.
Q. Have you ever participated in any — in any way, I'm asking very broadly, in — in a clinical study?
A. If you define clinical study as one where drug is being administered to people and one is looking at those effects, yes.
Q. And in what context did you do that?
A. I've done that in the context of transdermal delivery of insulin, Lidocaine. I think maybe those are the only two.
Q. And was your role in formulating the design — formulating the design of the study or how did you — how did you touch the — or interact with the study?
A. I was the principal investigator, the lead investigator in those cases. I helped design the studies as well as interpret the data.
Q. Were humans being studied?
A. Yes, in human subjects.
Q. Okay. So you were the lead investigator on two different projects; is that right?
A. That's correct.
Q. Okay. And one was a Lidocaine product?
A. It was Lidocaine delivery. It was not a product.
Q. And did you work with a — in conjunction with a physician in that — on that project?
A. Yes.
Q. And who was that?
A. That was Allen Hord, A-L-L-E-N, H-O-R-D.
Q. And how long ago did this project take place?
A. This was a number of years ago. More than five, maybe even ten.
Q. And on the insulin project, how long ago did it take place?
A. That is ongoing. It's current.
Q. I presume there is a physician involved in that project?
A. There is as well, yes.
Q. And who is that?
A. His name is Eric Felner, F-E-L-N-E-R.
Q. And what — what company is developing that product?
A. That study is not being done in conjunction with a company. That is academic research.
Q. Was the Lidocaine one being developed for commercial use?
A. Again, there was no company involved.
Q. How many human subjects were there in these studies?
A. In the Lidocaine study, five to ten; in the insulin study, also around five. Although, in the insulin study, repeated experiments on each subject.
Q. Did you have to get FDA approval to do these studies?
A. These did not require FDA approval but did require approval from an institutional review board and they have been approved by both Georgia Tech's and Emory's institutional review boards.
Q. And have any of those studies been published?
A. They have not been published. We are still preparing publication on the insulin study.
Let — let me add, again, depending on how you have defined a clinical trial, we have done other studies in human subjects that have not involved drugs, but are evaluating the more general performance of drug delivery devices and their interaction with the body in the absence of a drug, and we have published work in that area.
Q. Would that be in the field of electroporation?
A. No. That would be in the field of microneedles for transdermal delivery.
Q. Would it be fair to say that most of the articles you have written that are in Exhibit B are either in the field of electroporation or microneedles?
A. Most of them. So it — it's probably in the neighborhood of half are on those two topics.
Q. And just for the record, what is electroporation?
A. Electroporation involves the use of a short, high-voltage electrical pulse that causes rearrangements in the microscopic structure of cells and tissues.
Q. You have not written any articles about the Duragesic patch, have you?
A. No.
Q. I think we covered this before. If we have, I apologize. I want to make sure.
You've not written any articles about drug absorption from drug on the skin from a reservoir patch of any type of a product; is that correct?
A. Drug absorption from — from something that has leaked from a reservoir patch? Is that the question?
Q. Yes, yes, yes.
A. That is correct. I have not written on that topic, but I've written extensively on drug absorption across the skin from a variety of formulations.
Q. I want to go back and ask you, we talked about the patch, the picture of the patch in this case that you had looked at.
Would you have any expertise to bring to bear in examining that patch if you have it in front of you?
A. I — I could bring expertise, yes.
Q. Tell me what that expertise would be.
A. My expertise is especially in the area of how drugs move, how they are transported within a device, such as a patch, and into the skin. So by examining the patch, I might be able to determine if there is anything unusual or abnormal about the patch that could alter that transport process.
Q. And how would you go about doing that if you had the patch?
A. Given that haven't seen it and I don't — I don't know the details of its condition, I would first want to examine it visually, with the aid of a microscope. My expectation is that that would provide limited information.
The next level of analysis would involve manipulation of the patch, and that gives me significant concern because as soon as I manipulate the patch to uncover something, remove something, expose something, in the process, I could cause some other change by my interference with the patch. And so I would — I would be hesitant to do that.
Q. Well, besides looking at it, what would you attempt to do with it?
If you were to manipulate it, what would your purpose be? what methodology would you be using?
A. One thing that might be interesting to know is the Fentanyl content in the patch and its distribution within the patch. So if you could take it apart and remove residual gel material, remove the rate control membrane, take it apart into pieces, and then with appropriate methods determine the amount of Fentanyl in the various pieces. That would be informative.
Q. What else might you do with it, if you had it and if you had permission to do what you wanted to do?
I'm just interested in what methodology you would bring to bear here. That's all I'm after here.
A. It would also be of interest to look at drug release from that patch, to apply it presumably in an in vitro scenario and look at the release. The fact that I understand that there is an additional overlay material that has been applied and has bunched up around it, that's an additional complication. Presumably one would need to remove that to expose the patch appropriately.
MR. DEAN: I tell you what, why don't we take our lunch break ten minutes early and maybe we can beat the crowd downstairs. You want to do that?
MR. ANGWIN: That's great.
MR. HEBSON: Fine.
VIDEOGRAPHER: off the video record at 11:50 a.m.
(Thereupon, there was an interruption in the proceedings.)
VIDEOGRAPHER: This marks the beginning of Tape No. 3. We're on the video record at 12:40 p.m.
Q. (By Mr. Dean) Doctor, I want to get some housekeeping out of the way with your documents there and mark what is not otherwise already marked. So I'm going to come around there.
The stack of documents that you're looking at are the documents that you brought with you to the deposition this morning; correct?
A. That's right.
Q. And we can agree that the first document is a printout of prescribing information for the Duragesic patch?
A. Right.
Q. Is there a date on here someplace so we can identify which one you have?
A. I don't see a date, but it — it is almost certainly one that's — that was printed off the web in the last few months.
Q. Okay. So we can agree it was a relatively recent package insert you printed off the web; correct?
A. Right.
Q. Well, let's go ahead and mark it as E, I guess. I was going to try and avoid that.
(Defendants' Exhibit-E was marked for identification.)
Q. (By Mr. Dean) Okay. The next thing you have is the deposition transcript of Suneel Gupta; correct?
A. Yes.
Q. And you have — let's see here — I have quickly found Exhibits 2, 3, 4 and 5 and 6.
Did you get Exhibit 1 or do you remember —
A. I don't — if you can tell me what Exhibit 1 was, I can tell you if I've seen it.
Q. Maybe we can.
MR. HEBSON: I'm betting on the deposition notice.
MR. DEAN: well, you would be wrong. It was his curriculum vitae.
MR. HEBSON: Okay.
THE WITNESS: Oh, and I did get that. I did.
Q. (By Mr. Dean) Is that in here, do you think?
A. I don't think it's here.
Q. And I just noticed — how far did we go here?
A. 6.
Q. 6. I just noticed that there is an Exhibit 7, a one-page e-mail with a Bates stamp No. 067952. Did you get that?
MR. HEBSON: Here it is.
THE WITNESS: No. That's 6.
Q. (By Mr. Dean) 6?
A. I was wondering if it got mixed in here.
MR. HEBSON: 6 was the one we didn't — we left a number out, 1 and 6. It was 2, 3, 4, 5 and 7 and there's 6.
Q. (By Mr. Dean) No. I'm looking just to find out what — 7 is a document from a Bill Randolph with a Bates stamp No. 067952.
My only question is: Have you seen it?
A. I don't know. It might — it might have gotten out of order. It doesn't seem to be in — there's nothing labeled “7” in this pile.
MR. HEBSON: Oh, I'm sorry. I misspoke then.
Q. (By Mr. Dean) Okay —
MR. HEBSON: Can I see that?
Q. (By Mr. Dean) — then the next document that you brought with you is a study, an evaporation study, bearing the Bates stamp No. GIN00959 through 00964; correct?
A. Yes.
Q. Okay. And the next document here is entitled “Transdermal and Topical Drug Delivery,” by Adrian C. Williams.
What is that?
A. That's a book.
Q. It's a book?
A. It is a book and this is a section of that book.
Q. Okay. Can we mark that as Exhibit F, please.
(Defendants' Exhibit-F was marked for identification.)
Q (By Mr. Dean) Just for the record, could you identify that again, Exhibit F?
A. Exhibit F is a book entitled “Transdermal and Topical Drug Delivery.”
Q. Is it a chapter from that book?
A. Let me check how much of it I copied here. Yes, it's chapter 4 from that book.
Q. Okay. Did you use that in formulating your opinions in this case? I don't think I've seen it referenced in your report.
A. That's right. I don't believe I referenced it. That was — as a book, it gives general — general — you know, fundamental information that's useful, so I did use it.
Q. Okay.
MR. DEAN: Can we mark this next document as Exhibit G.
(Defendants' Exhibit-G was marked for identification.)
Q. (By Mr. Dean) For the record, Doctor, could you identify what Exhibit G is?
A. This is a letter to the editor from a journal and the title is “comparison of Fentanyl Concentrations in unembalmed and Embalmed Liver Samples.”
Q. You didn't cite it in your report, did you?
A. I didn't. This is — this is something that was relevant but was not really used in my analysis.
Q. Okay. You've got the article by Roy that we've already marked. We've got the patent. We've got the -486 patent. Then you also have the -226 patent; right?
A. Yes.
Q. Let's mark that as Exhibit H.
(Defendants' Exhibit-H was marked for identification.)
Q. (By Mr. Dean) For the record, could you identify what Exhibit H is?
A. It's a united States Patent No. 6,818,226 B 2. And it's called, “Dermal Penetration Enhancers and Drug Delivery Systems Involving Same.”
Q. Okay. And the next article here is the one that we've already identified, the “system Functionality” article.
And the next article is by Suneer Roy and Gordon Flynn that I think is in the book that we've already looked at, is it not?
A. I believe it is.
Q. I believe it's at tab 10 or 11, why don't you check and make sure it's in there. No, actually —
A. It appears to be a different one.
Q. It does appear to be a different one.
A. It is not 10 or 11.
Q. Lets mark it, then.
MR. DEAN: Mark that as I.
(Defendants' Exhibit-I was marked for identification.)
Q. (By Mr. Dean) For the record, could you identify it, please.
A. It's entitled, “Transdermal Delivery of Narcotic Analgesics, Comparative Permeabilities of Narcotic Analgesic through Human cadaver Skin.” It's a research article.
Q. Was there some reason you didn't cite that article?
A. My guess is that the information was similar to what was in the other ones by this research group.
MR. DEAN: Mark that as J, please.
(Defendants' Exhibit-J was marked for identification.)
Q. (By Mr. Dean) For the record, could you identify Exhibit J?
A. “Physical chemical Determinants of Skin Absorption.” It's a book chapter.
Q. Did you cite it in your report?
A. I don't believe so.
Q. The next group of documents is grouped together by a paper clip. Is that — is that a grouping we should maintain the way it is?
A. It would be useful for me in my internal records to keep that grouping, but it's —
Q. We'll keep it that way, then. That's fine.
(Defendants' Exhibit-K was marked for identification.)
Q. (By Mr. Dean) Could you identify, for the record, what Exhibit K is?
A. Would you like me to go through each — each of the components that are in there?
Q. Yes — yes, I would.
A. Okay. Well, the first page is some of my —
Q. Before we do this, why don't we have the court reporter mark it K1, K2, all the way through so we're clear what we've done; okay?
A. That's fine.
(Thereupon, there was an interruption in the proceedings.)
(Defendants' Exhibit-K was marked for identification.)
Q (By Mr. Dean) Back on the record. Could you just go through, I realize there are a number of separate pages there, but you had them lumped together as one document, so please tell us what's in Exhibit K.
A. K1 is handwritten notes that I have that summarizes the observations that I extracted from the articles.
K2 is collection of abstracts from two different articles, and these are both abstracts for which I have the complete articles and they are elsewhere in the record.
Q. Okay. The next one, K — we have two things labeled K2?
MR. DEAN: well, we shouldn't have that.
(Thereupon, there was an interruption in the proceedings.)
Q. (By Mr. Dean) Let's go back here. Can you tell us what K3 is, Doctor?
A. K3 is a research article that we also discussed before, by Larson, et al.
Q. So that is a duplicate?
A. That is a duplicate.
Q. What's K4?
A. K4 is the abstract from an article by Roy and Flynn that likewise exists in full form elsewhere.
Q. That we just marked, I think. Okay. What's K5?
A. K5 is another article, abstract only, but the full article exists elsewhere.
Q. K6?
A. K6 is another abstract from an article that we have in full form elsewhere.
And the last one is an abstract from an article that I don't believe we have in full form here today.
Q. Okay. K7 is not an article that you cited; correct?
A. That's right.
MR. DEAN: Mark that as L, please.
(Defendants' Exhibit-L was marked for identification.)
Q. (By Mr. Dean) Could you describe for the record what Exhibit L is?
A. Exhibit L is a printout from the Internet. It's entitled “Patient Information, Duragesic.”
Q. Do these go together?
A. I have grouped them together, yes.
MR. DEAN: M.
(Defendants' Exhibit-M was marked for identification.)
Q. (By Mr. Dean) what about Exhibit M?
A. Exhibit M has two components. The first component is an Internet web page printout from a company called Acrux and it provides some data on their Fentanyl delivery system, as well as on Duragesic. And the second item is the abstract from the research article by Sebel, et al., and we have that article separately.
Q. Okay.
(Defendants' Exhibit-N was marked for identification.)
Q. (By Mr. Dean) could you identify Exhibit N?
A. Exhibit N is an Internet printout from the US FDA and it concerns the 2004 safety alert for Duragesic.
Q. And how did you get it?
A. I printed it off the Internet.
Q. Okay.
(Defendants' Exhibit-O was marked for identification.)
Q. (By Mr. Dean) Could you identify Exhibit O, please.
A. Exhibit O is printed off of the Internet. It's some comments about the Duragesic patch and the recall and issues related to that.
Q. And where did you obtain it?
A. I obtained it off the Internet.
Q. From what site?
A. This is a — a law firm website.
Q. And how — how did you wind up at that website?
A. If I recall correctly, I did an Internet search. This was probably in the earlier days, as you can see it's dated in May '06, and so I was just becoming familiar with the issues in this case.
(Defendants' Exhibit-P was marked for identification.)
Q (By Mr. Dean) For the record, what is Exhibit P?
A. Exhibit P is a collection of abstracts, three abstracts, as well as the last page is a listing of five article titles.
Q. Now, are they grouped together for any reason?
A. Yes, they are. They all relate to the role of hair follicles in transdermal drug delivery.
Q. Did you cite any of these articles in your report?
A. I don't believe so, no.
Q. That brings us down to material I think we've already identified as being previously marked; is that fair?
A. I — I can check that.
Q. There's one I'm not sure we have.
A. I don't think that's —
Q. Good for you.
A. — in that lift.
Q. Okay.
MR. DEAN: Q.
(Defendants' Exhibit-Q was marked for identification.)
Q. (By Mr. Dean) what's Exhibit Q?
A. Exhibit Q is a research article that — the title of which starts, “Intra-and Interindividual variabilities in Pharmacokinetics…”
Q. Did you cite it in your paper, your report?
A. I don't believe so.
Q. Okay.
(Defendants' Exhibit-R was marked for identification.)
Q. (By Mr. Dean) what's Exhibit R?
A. Exhibit R is a journal article. It's entitled, “clinical Pharmacokinetics of Transdermal opioids.”
Q. Did you cite it in your report?
A. NO.
MR. DEAN: S.
(Defendants' Exhibit-S was marked for identification.)
Q. (By Mr. Dean) what's Exhibit S?
A. This is a research article, the title of which starts the “Pharmacokinetics of Transdermal Fentanyl …”
Q. Did you cite it in your report?
A. No.
MR. DEAN: For the sake of completeness, let's do T.
(Defendants' Exhibit-T was marked for identification.)
Q. (By Mr. Dean) what's Exhibit T, Doctor?
A. Exhibit T is a printout from the Internet. It's entitled, “Urgent Expanded Product Recall,” and deals with the Duragesic recall.
Q. Okay. NOW, the — I want to ask you the question I asked you about four minutes ago.
The stack that we're left with here, could you review it and make sure that these documents we've already previously marked and we don't need to mark again, and I think that's the case. I'm going to pull the package insert out because we've already marked one of those.
A. My only question is if all three of these are —
Q. That's fair.
A. — in fact, in the collection.
Q. I think this one is not. Could you check? It's the last two exhibits.
A. It's right here. This one is modulation. So that one is included. And this one is that one.
Q. Is delivery.
A. So this one might not be there.
Q. I think this one is not.
MR. DEAN: We're up to U, I think.
(Defendants' Exhibit-U was marked for identification.)
Q. (By Mr. Dean) Can you identify Exhibit U, please.
A. This is a scientific poster from a conference presentation entitled, “Pharmacokinetic characterization of a Novel…,” and it continues on.
Q. Okay. Now we've now been through the documents you brought with you and we've identified them, but I — do I understand correctly that there are other scientific articles that you have back in your office that you looked at and reviewed as you were carrying out your assignment in this case?
A. There — there may be a few other scientific articles, but most of what I don't have with me today is materials that were given to me associated with this and the Gingher case.
Q. And —
A. And so that includes, for example, Alza, Johnson & Johnson, Janssen reports.
Q. Well, I'm going to take your deposition again, so nest next time I want you to bring the remainder with you; okay?
A. Okay.
Q. We'll issue another notice. This is your fair warning. I'd like to see what else you have reviewed regarding the assignment that you were given; okay?
A. That s fine. I'll go through my files.
Q. And you certainly can look at your report to answer this next question.
On page 6 of your report you make certain comments about the rabbit study.
A. I'm on page 6.
Q. And in the final two paragraphs you talk about the rabbit study; correct?
A. That's right.
Q. In any of the studies that you cited in your report, was actual gel from a Duragesic patch placed on animal or human skin?
A. Only in that rabbit study.
Q. Okay. Fair enough. Okay.
And I take it that that would include the articles you've seen but not cited in your paper? I don't want there to be any ambiguity in my question.
A. I'm not aware of published research showing Duragesic gel outside of a patch applied to the skin.
Q. Now, I think you mentioned before that you had seen a report from some — I don't know exactly how you characterized it, but I responded by asking you about Walter Nemo. This was a report where the rate control membrane was removed from the patch.
Do you remember that study?
A. Yes.
Q. You — you don't reference that study in your report in this case, do you?
A. No.
Q. Do you recall what was being studied in that particular study?
A. I do. I won't recall details, but I do recall the subject.
Q. In general terms —
A. Yes.
Q. — what was that study about?
A. My understanding of the study is that it — it preceded the concerns about the — the defective and recalled Duragesic patch and was anticipating possible — possible other defects in a patch and it considered two scenarios: One was the possibility that there could be a slit in the rate control membrane which would compromise it, and the second scenario is where the rate control membrane would be absent.
Now, the — the slit was relatively straightforward, a slit was simply put in the membrane. It did not have a large effect, which was useful information to have but did not have direct bearing on this scenario.
In the case of removal of the rate control membrane, the rate control membrane was not simply removed, it was replaced with a different membrane which was asserted not to have rate control properties. But there was no information given about what that membrane was.
What would be of greater relevance to this case would be direct application of gel to the skin as opposed to this scenario where the gel remained within the housing of the patch and had some other — some other membrane that I — I don't know much about. So that's why it wasn't cited here. It only had — it was related but was not the critical evidence, I thought.
Q. But is it your understanding that the rate control membrane was removed from that group of — in that third group of people?
A. Right. In one arm of the study, the rate control membrane was replaced with a different membrane.
Q. With — in other words, there was something between the top of the patch and the skin but presumably it wasn't a rate control membrane. Is that what you're saying?
A. There was a — there was a membrane between the gel and the skin —
Q. Right.
A. — and it was asserted to not be rate controlling.
Q. And you don't remember what the impact on the delivery of drug was in regard to that group?
A. Replacing the membrane — replacing the rate control membrane with this alternative membrane increased the rate of delivery.
Q. Do you remember by how much?
A. I don't remember the exact number. It was less than a twofold increase.
Q. Now, in that scenario that — all the gel is contained within a — within a pouch; correct?
A. In that case, the gel was still contained, yes, within the patch.
Q. So it was — the contents were not subject to evaporation; correct?
A. That's my understanding.
Q. And you would agree — I think you've already agreed, that if Duragesic gets out on the skin, you are going to have evaporation of water and ethanol; correct?
A. Yes.
Q. But you haven't done any studies to calculate the rate of that evaporation, have you?
A. I have not.
Q. Do you have any criticisms of the evaporation study that we've marked — we can find the exhibit number, but —
A. The study Alza constructed —
Q. Right. Correct.
A. — by placing Fentanyl gel in an oven and measuring the rate of evaporation is a function of the —
Q. Correct.
A. — the area of which it spread.
Q. Correct.
A. Yes.
Q. Do you have any criticisms of anything regarding that study, the methodology, the way it was carried out, the results, or do you accept the rate of evaporation that was generated by that test?
A. I have no reason to — to doubt that the rate of evaporation, under the conditions used in the study, was measured correctly. I assume they were good scientists. I don't know that.
But I think your question is: Is that rate of evaporation measured in that study the same as the rate of evaporation that would occur on somebody's body?
And there, I — I don't think they would be the same. They are going to be related, but there are some important differences.
Q. Well, for example, and you can — you're the one with a Ph.D, not me. But in the Alza study, there was — they had a control as to how much, the amount and the thickness, and they knew exactly how much they were dealing with; correct?
A. Yes. They put it on in a very controlled way.
Q. And if you assume, for the sake of argument, that gel escapes from a Duragesic patch, do you, first of all, have any way of knowing how much gel is going to escape?
A. One could do studies, but I'm — I'm not aware of that being characterized carefully.
Q. Fair enough. You, yourself, have not done any studies on that issue, have you, as to how much gel might escape from a patch?
A. No.
Q. And I take it from your answer that you're not aware of other people who have done such a study; correct?
A. I saw, as part of an exhibit that I received as part of these proceedings, there was some correspondence among Alza or J&J personnel that it appeared to be speculated about what could be released, but I don't believe it was based on a study, at least it wasn't described.
Q. And in addition to not knowing how much might come out of a patch, it would be total speculation, then, in an individual case to know what kind of area it covered, would it not?
A. I wouldn't say it's total speculation, but we — we don't know the area over which it spread.
Q. And I think in your — I can find it here in a minute, maybe, but in one of your hypotheticals you postulated an area that would be covered by Duragesic.
Do you remember that?
A. Yes, I do, although let me get to it so that we can discuss it accurately.
Q. Sure. I'll try and help you find it here.
A. If you find before me, please.
Q. I'll let, you know. I'll let you know.
A. Here we go. Page 4 in the first full paragraph. And so I provide some information, Fentanyl gel can be spread over skin areas such as a hundred to a thousand square centimeters, and then I make some calculations based on that. And I follow that by saying that these skin areas are given here as examples.
And so the point is I wanted to show how that calculation would be made. I picked some numbers.
Q. Well, in fairness, you didn't make a calculation. You just picked two numbers, didn't you?
A. Based on those numbers, I in turn made a calculation. But the areas were not calculated.
Q. Right. And then that's what I want to get at. I mean, I wanted to find out what basis, if any, you had for picking the 100 centimeters and 1,000 centimeters. I wanted to understand your thought process in getting to those numbers.
And is it fair to say, from what you just told me, you arbitrarily picked those numbers?
A. Not arbitrarily. I have some experience with, not Fentanyl gel, but other sorts of gels and topical preparations and their spreading on the skin. And so those numbers seem to be useful ones to work with, but — but they are not backed up by experimental data.
Q. Nor are they backed up by any literature citations you can give me, are they?
A. That — that is correct. I am not — I am not standing by these numbers as the correct numbers. They are examples of numbers in a scenario where we just don't know.
(Defendants' Exhibit-V was marked for identification.)
Q. (By Mr. Dean) could you identify Exhibit V for the record?
A. This is a journal article entitled, “Current Status and Future Potential of Transdermal Drug Delivery.” I am one of the authors.
Q. And directing your attention to the second page, to the first paragraph —
A. Starting with Presently Available?
Q. Yeah. I don't want you to read it out loud. Could you just —
A. Shall I read it now and then —
Q. Yeah, let's do that. Let's do that.
A. Okay. I'll take a moment. Okay. I've read the paragraph.
Q. There you describe two basic types of transdermal patch; correct?
A. That's right.
Q. The reservoir patch and the matrix patch; correct?
A. Yes.
Q. You believe — I take it from this paragraph, you believe both are appropriate designs to use for transdermal patches?
A. They are both appropriate designs; depending on the specifics of the drug and what it's being used for, one design might be preferable.
Q. In regard to a drug like Fentanyl, do you have a viewpoint as to which design would be preferable? And if you don't have, tell me.
A. I — I have — I — I — I haven't reached a conclusion about that comparison.
Q. But I do take it from this paragraph that you see a lot of advantages in having a rate control mechanism? Is that fair?
A. The rate control mechanism provides advantages, yes.
Q. Which are what?
A. As — basically what the name says. You — you have a rate-controlling properly built into the patch.
Q. You're not going to offer any criticisms in this case about the design of the Duragesic patch, are you?
A. I — I have not at this point been asked or prepared criticisms.
Q. But as you sit here today, you are generally a supporter of reservoir patch technology; correct?
A. I think reservoir patch technology plays a important role in transdermals.
Q. And you've never written any article suggesting that a reservoir patch technology should not be used in transdermals, have you?
A. I have not.
Q. Let me ask you a question, and you may not have any opinion on it and just tell me that if you don't.
Do you know whether the manufacturing processes for any transdermal product, just in the abstract, can different manufacturing — let me start over.
Can manufacturing process differences affect blood levels?
A. You're going to have to help — help me with that — that question. So if you — if you — the manufacturing process changes, that will, by definition, change the end result that you have. You've made it in a different way and that could very well affect delivery.
Q. I think I won't go back into that.
Go to page 1 of your report, Doctor. It says, under Roman numeral I, subsection 3, “A lethal Fentanyl dose may be achieved individually or by a combination of the effects,” and then they are listed.
My question you to is: Have you read any article at all that involved death from a Duragesic patch?
A. There is a tab No. 2, by Baselt, that addresses Fentanyl levels postmortem in cadavers. So I don't — I don't claim expertise in the toxicology of Fentanyl. I rely on others for that.
Q. Is that the only article that you can cite in the materials that would be responsive to a death from a Fentanyl patch — from a Duragesic patch?
A. I have seen some other articles that addressed death from a Fentanyl patch, but this — this was the primary resource that I used.
Q. But you don't have any of those articles with you today, do you?
A. I don't. Again, because the — the toxicological issues have not been my emphasis.
Q. Okay. In paragraph 6 you say, “Quantitative analysis of the effects of various parameters on skin permeability demonstrates the plausibility of achieving serum Fentanyl concentration known to be fatal due to leakage of Fentanyl gel from a Duragesic patch.”
Did I read that correctly?
A. Yes.
Q. And would it be fair to say that what you're saying there is you have a theory which you think is plausible but you have not seen any evidence in the real world in humans to that effect? would that be fair?
A. The analysis that I'm — quantitative analysis that I'm referring to here is if you know what the expected level of Fentanyl should be in the body, based on the extensive clinical trials that have characterized Duragesic performance, and you compare then that number to the level that is seen in the deceased in this case, as well as in some other cases where Fentanyl may have caused death, then you see how much more Fentanyl would you have needed to deliver above the amount that the patch should have delivered.
And the quantitative analysis addresses issues of, in particular, the loss of a rate controlling membrane, the variations in skin permeability that exist between people, and the potential for increased contact area. And those individually and their combination, under what I consider to be reasonable scenarios, can lead you to that level of increase in Fentanyl level.
Q. You think the theory's plausible; right?
A. I — I think it is plausible, yes.
Q. You have not tested it in a laboratory setting with animals, have you?
A. I personally have not. There is extensive literature that looks at Fentanyl absorption, as well as other drugs, and the message is consistent with other drugs, too, Fentanyl is not an outlier, that show these effects of skin permeability in an area and then loss of rate control membrane and that they will very much increase absorption of Fentanyl.
Q. What will increase the absorption?
A. Loss of a rate control membrane, increased skin permeability, and increased area.
Q. You've already told me that the only study that you're aware of where Duragesic gel was actually put on an animal was a rabbit study; correct?
A. Duragesic gel is a — an appropriate formulation, but it is not a magical formulation. So the thousands of papers that inform us about transdermal transport of Fentanyl and other drugs can provide information about what would happen with absorption from Fentanyl gel.
MR. DEAN: Move to strike, nonresponsive.
Q. (By Mr. Dean) would you agree that the only study that you're aware of where actual gel from a Duragesic patch has been placed on an animal is the rabbit study?
A. Yes.
MR. HEBSON: Asked and answered —
Q. (By Mr. Dean) okay. Now —
MR. HEBSON: — four or five times now.
Q. (By Mr. Dean) And you've already agreed that if Duragesic gel were on the skin, there would be evaporation from the ethanol and water.
My question you to is: Did you try to do anything at all to determine the rate of that evaporation?
A. I have not made measurements of that rate of evaporation. I've been informed by the Alza study, and also there are other formulations that involve ethanol and gel — for example, hand cleaners, hand sanitizers — and you get some familiarity with that sort of thing too.
Q. Do any of studies that you cited that we marked as Exhibit C, did they attempt to measure the effect of the evaporation — let me start over.
In Exhibit C, those articles, to the extent that any of them dealt with putting some kind of compound with Fentanyl on the skin, if you limit it to that subset of articles, did any of those articles attempt to measure the rate of evaporation of ethanol or water from the compound that had been placed on the skin?
A. Not quantitatively, but there are a number of studies where a Fentanyl formulation was applied to the skin and it was allowed to evaporate. So we were told that it did evaporate, but it was — we were not given the time of evaporation.
Q. Besides the one that's marked as Exhibit 12, and I think Exhibit 12 just falls in the category you just mentioned. Check and see if I'm right.
A. 12, as well as 14 and 15.
Q. Okay. Any others?
A. AS well as Exhibit u.
Q. Okay. Can I see Exhibit U?
A. Thank you. Let me double check my answers.
Q. Sure. While I'm trying to — I may have the document blown up before I can read it.
A. Let me just see what it says. Certainly these two do. I can verify that one.
Q. Yeah. Why don't you — you have my question in mind; correct?
A. Whether evaporation was measured or at least occurred?
Q. Correct, correct. Okay.
A. Yeah, this one as well. All — in all — so numbers 14, 15 and U, all of those are — are part of the same families of studies.
Q. By that you mean they're from Acrux?
A. That's right. And they've all used a similar protocol of spraying onto the skin for evaporation.
Q. I have not seen Exhibit U before. Could you give me a 90-second overview of what's going on in that study?
A. I'll have to remind myself. This was a study in human subjects where a Fentanyl formulation prepared by the company, Acrux, was sprayed onto the skin of human subjects. The Fentanyl concentration in the blood was then monitored over time as a measure of Fentanyl absorption.
Q. And are drug absorption rates reported there?
A. What's reported is blood concentrations and the characteristics associated with it.
Q. And is there a chart there or are there just values?
A. No. There are a number of graphs, as well as tables.
Q. Okay. And this is some kind of a spray-on; right?
A. This is a spray-on.
Q. Do we — can you tell from the article what the composition of the spray is? I know there's Fentanyl in it, but do we know what else is in it, how strong it is? Does the article tell us?
A. It tells us the total volume in microliters of formulation that was applied to the skin. I don't see information on the composition of that formulation.
Q. I'm not sure I understood your answer, but that's my problem, probably, not yours.
Does that mean we don't know the strength of the Fentanyl in the concentration?
A. That's right. All we know is that a certain volume of material was applied but we don't know how much Fentanyl was in it.
Q. All right. So one couldn't draw a correlation between Fentanyl concentration of blood levels because you wouldn't have the — the Fentanyl concentration is not known; is that fair?
A. Not in this — I don't believe in this study.
Q. Exhibit U?
A. Exhibit u. I believe in their other work they have given that information which enabled me to make some calculations.
Q. So you think in the other work you can draw correlations between the Fentanyl concentration and the reported blood levels; is that correct?
A. It is correct and it is presented at the bottom of page 5 in my report. Oh, no, I'm sorry. I'm pointing you to the wrong place. Page 6. That was a different study. sorry. That was a different study. Page 6. The top of page 6.
Q. And there you say, in that very first paragraph that you just pointed me to, you say, “Based on the skin contact area of 1 centimeter squared, this corresponds to an average flux of 0.5 micrograms” — is that over centimeter squared per hour?
A. Per centimeter squared per hour.
Q. “– which is similar in magnitude to the Duragesic patch.”
And my question you to is: what is your basis for saying that that's similar to the magnitude of the flux in the Duragesic patch? where are you obtaining that number from?
A. That's in the first — second sentence — page 5, last paragraph, the second sentence. From a Duragesic 75, the rate is 2.5 micrograms per centimeter squared per hour.
And so this is certainly smaller than the Duragesic 75, but maybe if you take one of the smaller Duragesics, then the number would probably be much closer. It's a similar number. It's not exactly the same. You wouldn't expect it to be exactly the same.
Q. Well, I'm confused. Is there a footnote to this?
A. I — I just got a number from page 5.
Q. Oh, I have to go back to page 5 for that number?
A. Page 5, yes. My analysis starts here's what Duragesic does, and then look what the first study did and then a second study, which is Acrux, and then I'm comparing among the three of them.
Q. Well, on page — I apologize if I'm confused and I may be, but on page 5, you talk about a flux rate of 2.8 milligrams per centimeter squared per hour?
A. That's right. That is from the sebel study. But if you go to the very top of that paragraph, I first start out by talking about as a point of reference — the second sentence, as a point of reference, Duragesic 75 administers, and if you keep reading on, it gives the flux rate on the third line.
Q. I'm sorry. Which paragraph are you in?
A. Page 5.
Q. Yeah.
A. Paragraph 3.
Q. Right.
A. And let's go to the third sentence.
Q. Right.
A. “This corresponds –”
Q. Right.
A. “– to a transdermal flux of 2.5 micrograms per centimeter squared per hour.”
Q. Right.
A. So that is the average flux from a Duragesic 75.
Q. And that may get to my question. On the following page, on the third line you've got 0.5. Is that just a typo?
A. No. So that value is 1/5 of the value. It is a smaller value than the Duragesic 75. But this is not formulated to mimic the Duragesic 75, but it's a — it's a number that — it's not, you know, a thousand times off. It's a number that is in the same ballpark.
Q. So you're saying that the 0.5 and the 2.5 is in the same ballpark?
A. They're in the same ballpark.
Q. Is this what you're telling me?
A. Yes.
Q. You say similar in magnitude here; right?
A. (Witness nodded head affirmatively.)
Q. Okay. Do you have any reason to believe that a transdermal flux rate of 2.5 micrograms per centimeter squared per hour represents any health hazard to anyone?
A. It's not my area of expertise, but I would imagine that if we put that patch on, as opiate-naive subjects, we might have a problem with it.
Q. That's true and that's a very fair response and that was a very poorly worded question, so let me rephrase it.
MR. HEBSON: I thought it was pretty good myself.
Q. (By Mr. Dean) People who are on this drug are presumably tolerant to opioids; correct?
A. Yes.
Q. And so assuming that a patient who wears a Duragesic patch is tolerant to opioids, and recognizing, as you said, this may not be your exact area of expertise, did you, in the course of carrying out your assignment in this case, did you read anything to suggest that a transdermal flux rate of 2.5 micrograms per centimeter squared per hour presented a health risk to those patients who normally take Duragesic?
A. If a patient has been correctly prescribed a Duragesic 75, then it shouldn't pose a health risk.
Q. Have you ever harvested skin for an in vitro experimentation?
A. Yes.
Q. Is the technique used in harvesting skin important to achieve appropriate laboratory results?
A. Yes.
Q. How often have you harvested skin yourself? Is that something you usually do in your normal course of —
A. In — in the past, so as a graduate student for over a five-year period or so, I did extensive harvesting of skin. But currently in my job, I supervise others who do that.
Q. Have you — in formulating your opinions in this case, have you had discussions with any other expert witnesses?
A. I had a brief discussion with a toxicologist.
Q. Who was that?
A. That was in the context of the Gingher case. Lewis.
Q. Pardon me?
A. Lewis. I forget his name. As you may have noticed, I'm better at recalling scientific facts than people's names. Can I ask for assistance on the name?
MR. HEBSON: I wouldn't know.
MR. ANGWIN: I think his last name was Lewis. It was one of the experts that clay Robins got a declaration from in the Gingher case.
MR. DEAN: Okay. Thank you.
Q. (By Mr. Dean) Is that the only —
A. The only other expert I've talked to.
Q. — other expert that you've talked with —
A. Yes.
Q. — as you formed your opinions in the Hendelson case?
A. That's right.
Q. Now, we've been sitting here for quite a while today and we've been talking about your report. We've — we've gone over a lot of specific paragraphs of the report. I just want to make sure that I — you've told me this once before but as we've been talking, I want to make sure that this hasn't triggered any more thoughts. But I want to know — I want to make sure that I have all of your — all of your major opinions are written in the report; correct?
A. My major opinions are in this report.
Q. And nothing that we have said back and forth in the last three or four hours is — has changed that answer, has it?
A. That answer has not changed.
Q. And similarly, the — I know not every basis for every opinion is written down, but the major bases are there and nothing we've said in the last three or four hours has reminded you of any other major bases; correct?
A. That's correct.
VIDEOGRAPHER: Off the video record at 1:48 p.m.
(Thereupon, there was an interruption in the proceedings.)
VIDEOGRAPHER: This marks the beginning of Tape No. 4. We're on the video record at 1:57 p.m.
Q. (By Mr. Dean) Doctor, what — what is the significance of the — strike that.
To you, what is the significance of the Fiset study which is at tab 3 of the notebook?
A. I evaluated that study primarily in the context of the variability that can exist in the amount of Fentanyl delivered from a patch which can be due, at least in part, to variability in the intrinsic permeability of the skin.
And you asked me the significance, so the significance is that variability can be considerable.
Q. Well, these are — first of all, the Duragesic patch was not being studied in tab 3, was it?
A. The Duragesic patch was not — was not used in that study.
Q. And the Cygnus patch, we can agree, first of all, it had — it had no rate control mechanism; is that correct?
A. There was no rate control.
Q. And isn't it fair, from your reading of the article, that this patch was much stronger than the Duragesic patch?
A. I don't know if it was stronger. Although my main interest in this, my main interest had to do with the variability in the skin's permeability.
Q. Well, how does using two — when you're talking about variability, I assume, correct me if I'm wrong, but I assume you're talking about if you put on a Duragesic patch on ten people, you may not get exactly the same blood level. Is that what you're telling me?
A. Variability would result in different blood levels, yes.
Q. Right, right. But how does writing about a Cygnus patch, which I'll represent to you is much stronger than the Duragesic patch, what does that tell us about variability of the Duragesic patch?
A. It tells us about the variability of skin permeability and this is part of the motivation for the rate control design of the Duragesic patch which can reduce the impact of that variability.
Q. Are you saying that this article establishes that there was variability to the Cygnus patch that was being studied in the article? Is that your testimony?
A. My testimony is it shows that there is variability in the skin's permeability to Fentanyl.
Q. And are you aware that as a result of the study, Cygnus stopped developing this particular patch?
A. I was not aware of that.
Q. Would it surprise you, based upon the results that were obtained there; or is that beyond your expertise?
A. I haven't — I haven't — I haven't thought that through to a conclusion.
Q. Were some of these studies done using skin stripping?
A. Are we still discussing this —
Q. No, no, no. Tab 11. Does tab 11 discuss skin stripping?
A. Tab 11 discusses skin that has been prepared using a common technique which is sometimes referred as stripped cadaver epidermis.
Q. And how did they do it in that article?
A. They used a common technique that I myself have frequently used. The skin is dipped into hot water for a brief time, one minute, and then the upper portion of the skin, called the epidermis, is physically removed from the lower portion of the skin, called the dermis.
Q. And how is that done?
A. The skin is dipped in the hot water, taken out, and then, in this study, they used forceps to mechanically separate the two, to pull the epidermis from the dermis.
Q. What is the relevance in regard to your opinion of the article that appears in tab 8?
A. One of the questions that I thought about in the context of this case is the impact of an evaporating formulation. This study provides information on that impact.
Q. Well, this article does not involve Fentanyl, does it?
A. In this article, a number of drugs, four different drugs, were used. Fentanyl was not one of them.
Q. What was being used here was some type of sex hormones, if I understand right?
A. They were hormones being used, yes.
Q. So I want to understand what you believe the relevance is of this article to your assignment as you articulated your assignment.
A. The skin's permeability, or the amount of drug that goes into the skin, depends, of course, on the drug that's being used. The science has reached the point, however, where it's not some great mystery. We have some understanding about what are the important properties.
So for example, two of the important properties are the size of the drug, its molecular weight, as well as the oiliness of the drug. And for one drug of the same — of a given size and oiliness and another drug that has very similar size and oiliness, their absorption in the skin will be similar. The drugs that are used here are of similar size and oiliness to Fentanyl and, therefore, the conclusions and the trends we can observe in this study are relevant to Fentanyl's performance.
Q. And what is your basis for concluding that these drugs are similar to Fentanyl in the regard you just mentioned?
A. Their molecular weights are similar and their oiliness is similar, their solubility in an oily environment.
Q. Is Fentanyl a steroid?
A. It is not a steroid.
Q. Are some of these drugs steroids?
A. Yes, they are.
Q. If you have a drug that is — if you have a drug that you just spray on, as opposed to a drug — for example, there were spray-ons in articles 14 and 15, as one example.
A. And in this article.
Q. And in that article, okay.
As opposed to putting a gel on a skin — not spraying it on, but having a gel-like substance on the skin — is there one that's going to — I'm not talking — leaving Fentanyl out of the equation here, we've got a spray-on application and we've got one that we're putting gel on the skin. Is there one of those which is more likely to have increased drug absorption, just from the manner of application?
A. Just the manner of application is not enough information.
Q. Okay. And specifically on tab 8, I think, if I remember your report right, you said that Fentanyl and testosterone had some similar physiochemical properties; right?
A. I can — I can check whether or not the report said that, but — but I will agree with that.
Q. And my question is: what is your support for that statement?
A. It's the — it's the two properties that I mentioned earlier. Of primary interest are the size, or molecular weight, and the oiliness which is usually described the octanol-water partition coefficient.
Q. Are there dissimilarities between those two drugs?
A. They don't have identical molecular weight and partition coefficient. So they're not — not that — they're not the same drug. Likewise, they have different pharmacological actions, clearly. Although that is probably not directly relevant to skin absorption.
Q. So you're saying that the skin absorption is not directly related to the chemical structure — strike that.
Are you saying that the chemical structure is the key to drug absorption?
A. The chemical structure, in terms of the atoms that make it up, the number, so therefore the molecular weight — can I say strike that too?
Q. Sure. You want to start over?
A. Yeah, let's start over.
Q. Start over.
A. Sorry. Ask the question again.
Q. Are you saying that the chemical structure of a drug is the greatest determiner of its ability to penetrate the skin?
A. Yes, it is.
Q. You read Suneel Gupta's deposition, I know; correct?
A. Yes, yes.
Q. I think you've testified clearly that that didn't really add to your — add to or change your views in what you had written; correct?
A. It did not change my conclusions, correct.
Q. Is there anything — did you read the whole deposition carefully?
A. I did read the whole deposition.
Q. Is there anything in the deposition that you disagreed with?
MR. HEBSON: Do you mean for him to go line by line?
Q. (By Mr. Dean) No, no. As you sit here today — how long ago did you read the deposition?
A. A month ago. It was — it was shortly after it was taken.
Q. But did you read it line by line?
A. I did read the whole thing, yes.
Q. Okay. Within the last month; right?
A. Within the last two months, let's say.
Q. And — and I don't want you to go through it line by line, but I want to know to the best of your — as you sit here today, to the best of your recollection, is there anything in there when you read it, you said that's wrong?
A. There were no — there were no major issues that I would argue with but scientists think about things differently and so, you know, there were, oh, I would have said that differently. I didn't quite agree with that point, but I wouldn't make major criticisms.
Q. Okay. And we've marked a lot of articles here today. Would I be — would it be fair for me to assume that the next time I take your deposition and you bring back the remainder of your material, that we're not going to have that many scientific articles? Is that a fair assumption?
A. Primarily what will come are — are things that come from the record already. And some of them are scientific internal reports.
Q. Okay.
A. But there will not be many more journal articles.
Q. Okay.
MR. HEBSON: Unless a new one comes out in the next few days.
MR. DEAN: Yeah. That's fair, I mean…
THE WITNESS: I didn't bring those other things, in part because I knew you had them already. But I understand that that's not all that's at stake.
Q. (By Mr. Dean) We've already established that if there was Duragesic gel on the skin, there would be ethanol and water that would evaporate.
I'm not sure I asked you specifically, would you agree that that fact of that evaporation would have some impact on drug penetration?
A. It would impact it. It could increase it and it could decrease it.
Q. And how could it decrease it?
A. It could decrease it because over time, there would no longer be a solvent present on the surface of the skin in which the Fentanyl is dissolved.
Q. You understand that the reason ethanol is there is to help drive the Fentanyl into the skin; correct?
A. That — that is one of its roles.
Q. But that's — that's an important role; correct?
A. Yes.
Q. And do you know if — and you may not have any understanding of this, but do you know what drug penetration levels would be from an intact Duragesic patch if there were no ethanol in the product?
A. There is information on the degree which ethanol increases the skin's permeability to Fentanyl, and I'm trying to remember if I have something about that in the report or if that's just in some other — I think it might not be in the report but is in other documents. Let me check. No, there is. I do make — make a point about it. So I should have something about ethanol.
Well, what I'm finding now has to do with the study by Sebel, et al., No. 12. This was a study that was done using Fentanyl in water. There was not ethanol present. The Fentanyl in water was applied to the skin of human subjects. The water evaporated and a large fraction of the Fentanyl was absorbed into the skin in the absence of ethanol.
Q. My question was: Do you know whether — what the impact would be on the drug penetration of Fentanyl from an intact Duragesic patch if you removed the ethanol from the product?
A. You ask a complicated question, because if you remove the ethanol, the Fentanyl will not be as soluble. And so you've changed two things. You've also changed the concentration.
So I'm anticipating what you would like to ask, assuming the concentration of Fentanyl didn't change and the only thing you've changed is ethanol's effect on the skin, what impact would that have? Have I restated your question appropriately?
Q. Let me accept that and go ahead and answer your question.
A. Okay. In that case, I would expect either no effect or a reduction in the rate of Fentanyl delivery from a Duragesic patch.
Q. I want to go back to your — I asked you about what the impact would be from evaporation of ethanol and water from gel on the skin and you said it could either increase or decrease in the blood level.
I want to go back and ask you: How would it decrease? How could it decrease it?
A. It could decrease it, the item that I mentioned originally was that over time, there would no longer be a Fentanyl solution on the skin because the solvent would disappear and there would be nothing to dissolve the Fentanyl in anymore.
Another aspect that you brought up was that Fentanyl would — sorry, that ethanol would disappear, and so although ethanol can have long-lived effects on the skin, it would not be continuously applied.
Q. How do you think that gel on the skin could increase the blood level?
A. One of the parameters that controls the rate of delivery into the skin is the concentration of Fentanyl in the gel on the skin's surface. So as you evaporate solvent, the Fentanyl concentration goes up and as it goes up, you therefore get a higher rate of delivery.
Q. And what article or articles do you have to support that notion?
A. The — the fact that the rate of drug transport, including Fentanyl, across the skin scales with the concentration of the Fentanyl in the reservoir contacting the skin, can be supported with thousands of articles.
Q. I'm not talking about gel in a reservoir. I'm talking about gel on a — on the skin outside of the patch.
A. So I mean, yeah, I — the term “reservoir” can mean different things to different people. So let me — let me restate it. I think it doesn't mean the same thing to us both.
But it is certainly — I think undisputed and very clear in the literature that the rate at which a drug will cross the skin will scale directly with its concentration contacting the skin.
Q. And what's going to happen to the concentration of Duragesic gel on the skin as evaporation happens? Do you know that?
A. The concentration will increase.
Q. And why would you say that there could be decreased drug penetration as a possibility, in light of your last answer?
A. It would come later. So initially, the solvent is evaporating. So concentration is the amount of drug per volume of solvent — per amount of solvent. So there's less solvent, the concentration goes up. Eventually there is no solvent, and then the cons — then the delivery goes down.
Q. Is what you're saying is that you would initially get a peak in blood levels but over some course of time you get a decrease over what you anticipate if the drug was in the pouch? Is that a fair characterization of what you said?
A. Let me explain how I — how I'm thinking the process through a little bit further, and I'm happy to come back to your question. But there's — we've only talked about the rate at which it enters the blood and there's a difference and that's why I'm pausing.
So the skin has a very outer layer called stratum corneum, which is very oily. Fentanyl is able to go into that layer more readily than, say, a watery later. Below that is a watery level of skin and then ultimately you come to the blood vessels.
So it is much easier for Fentanyl to leave the skin's surface and enter this oily stratum corneum than it is for it, in turn, to leave the stratum corneum and enter the watery internal regions. So I would expect as the ethanol is evaporating, there can be a surge of Fentanyl delivery into this upper layer of the skin.
Once the ethanol and water are completely evaporated, at that point I would not expect — I would expect Fentanyl to enter the skin at a much slower rate. However, there can be a very large depot of Fentanyl formed within the stratum corneum and that can leach into the blood over a much longer time.
Q. Do you have any expertise in how long it takes Fentanyl to get from the stratum corneum to the bloodstream?
A. There is some information on that in some of the papers that we have here.
Q. My question is: Do you have expertise on that?
A. I have expertise from what I read in the papers.
Q. What papers address that issue?
A. One of them is the Sebel paper.
Q. What other paper?
A. The — the three studies from Acrux.
Q. That's all I have for you. I'll take your deposition later in the month. But when I do, I want you to bring everything else with you; okay?
A. Okay.
Q. Correspondence, court documents, whatever stray articles you may have. Stray scientific articles, because I think we've gotten most of the scientific articles, but for today, that will be it. Thank you very much.
VIDEOGRAPHER: This concludes the deposition. We are off the record at 2:25 p.m.
(Deposition concluded at 2:25 p.m.)
DESCRIPTION OF EXHIBITS
EXHIBIT … IDENTIFICATION
B … Expert Report from Mark R. Prausnitz, Ph.D.
A … Amended Notice
B … Report of Mark R. Prausnitz. Ph.D.
C … Notebook
E … Printout of Prescribing Information for the Duragesic Patch
F … Transdermal and Topical Drug Delivery, Adrian C. Williams
G … Comparison of Fentanyl Concentrations in unembalmed and Embalmed Liver Samples
H … -226 Patent
I … Transdermal Delivery of Narcotic Analgesics Comparative Permeabilities of Narcotic Analgesic through Human Cadaver Skin
DESCRIPTION OF EXHIBITS
EXHIBIT … IDENTIFICATION
J … Physical Chemical Determinants of skin Absorption
K … Compositie Exhibit
K … Documents, K1 through K7
L … Internet Printout, Patient Information, Duragesic
M … Internet Articles
N … Internet Printout from the US FDA 2004 Safety Alert for Duragesic
O … Internet Document, Duragesic Patch and the Recall and Issues Related
P … Collection of Abstracts
Q … Inter- and Interindividual variabilities in Pharmacokinetics…
R … Article, Clinical Pharmacokinetics of Transdermal Opioids
DESCRIPTION OF EXHIBITS (Continued)
EXHIBIT … IDENTIFICATION
S … Pharmacokinetics of Transdermal Fentanyl
T … Urgent Expanded Product Recall
U … Pharmacokinetic Characterization of a Novel…
V … Current Status and Future Potential of Transdermal Drug Delivery
(Original Exhibits A through D are attached to the Original transcript. copies of Exhibits E through V are attached to the Original transcript. original Exhibits E through v were sent back to Mark Prausnitz, Ph.D.)
STATE OF GEORGIA:
COUNTY OF FULTON:
I hereby certify that the foregoing transcript was reported, as stated in the caption, and the questions and answers thereto were reduced to typewriting under my direction; that the foregoing pages represent a true, complete, and correct transcript of the evidence given upon said hearing, and I further certify that I am not of kin or counsel to the parties in the case; am not in the employ of counsel for any of said parties; nor am I in any way interested in the result of said case.
Disclosure Pursuant to Article 8(B) of the Rules and Regulations of the Board of Court Reporting of the Judicial council of Georgia, I make the following disclosure:
I am a Georgia Certified court Reporter, here as a representative of Brown & Gallo, L.L.C., to report the foregoing matter. Brown & Gallo, L.L.C., is not taking this deposition under any contract that is prohibited by O.C.G.A. 5-14-37 (a) and (b).
Brown & Gallo, L.L.C., will be charging its usual and customary rates for this transcript.
LEE ANN BARNES, RPR.