Below is the text of the deposition taken of Robert Gale, the inventor of the Duragesic fentanyl patch. This deposition was taken in Dicosolo v. Janssen Pharmaceutica, Inc. The Duragesic attorneys who handled this case obtained a verdict of $16.6 million dollars in that case.
THE VIDEOGRAPHER: Good afternoon. We are now on the record.
The time on the screen is 1:16 p.m. Today's date is September 11, 2008.
This is the beginning of videotape number 1 in the deposition of Robert Gale, Volume 1, in the matter of West v ALZA Corp. and other cases, in the Superior Court of the State of California.
We are located at the Westin, Palo Alto, California.
The court reporter is John Squires, in association with Hundt Reporting.
My name is David Manzo, and I'm a Certified Legal Videographer, in association with Hundt Reporting.
Will counsel please state your appearance for the record.
MR. ORR: Jim Orr on behalf of the plaintiffs.
MS. BENEDICT: Mollie Benedict for Defendants ALZA and Janssen.
MS. DAVENPORT: Kirsten Davenport for Defendant Dr. Covington.
THE VIDEOGRAPHER: If there are no stipulations, will the court reporter please swear in the witness.
On Thursday, September 11, 2008, at the hour of 1:16 p.m. of said day, at the Westin Hotel, 675 El Camino Real, Palo Alto, California, before me, JOHN P. SQUIRES, a Certified Shorthand Reporter, personally appeared ROBERT MARTIN GALE, M.S., who was examined as a deponent in said cause.
ROBERT MARTIN GALE, M.S., the deponent herein, having been first duly sworn, was examined and testified as follows:
EXAMINATION
BY MR. ORR:
Q. Could you please state your full name.
A. Robert Martin Gale.
Q. And am I correct that you have an undergraduate degree and a master's degree in chemistry from San Jose State?
A. Yes.
Q. And then you started working for ALZA Corporation in 1971; correct?
A. Correct.
Q. And then you stopped working for ALZA Corporation about when?
A. August of 2006.
Q. And are you still doing some consulting for ALZA Corporation, Janssen or Johnson & Johnson?
A. Indirectly.
Q. And why do you say “indirectly”?
A. Because of severance-pay issues, I work for Tucker & Ellis instead of Johnson & Johnson.
Q. So you're doing consulting with the lawyers for ALZA and Janssen?
A. I am.
Q. In terms of your time, 9:00 to 5:00 on business days, how much of your time are you spending — strike all that.
Are you retired?
A. Yes.
Q. 9:00 to 5:00 the five business days of a week, how much of your time are you spending being retired versus doing some sort of work for an income
A. I work as a consultant for several firms about eight hours a week.
Q. Is that all litigation work?
A. No.
Q. When you say for firms, do you mean law firms or just companies?
A. Companies.
Q. Do you consult with any other law firms other than Tucker Ellis?
A. No, I do not.
Q. And am I correct that you were the original inventor of the form-fill-seal system in 1979?
A. 1984–
Q. 1984?
A. — was the date of the patent.
And it was form-fill-seal Duragesic fentanyl.
Q. It would be fair to say that you were one of the early pioneers in the transdermal industry?
A. Yes.
Q. And you started your work on Duragesic in approximately 1983?
A. Yes.
Q. And did you lead the development team that worked on creating Duragesic?
A. I did.
Q. And essentially you're the primary inventor of the Duragesic patch; fair?
A. Well, there was another series of co-inventors. But I'm the lead.
Q. You were the team leader of all the inventors?
A. I was.
Q. You were the head inventor?
A. Yes.
Q. Given that background, is it fair to say that you are an expert on the subject of the Duragesic patch?
A. That's a fair assessment, right.
Q. And you're also an expert in the area of transdermal drug design; right?
A. Yes.
Q. And you hold over 40 transdermal-related patents?
A. I do.
Q. Do you also have expertise with respect to fentanyl?
A. Expand on that question.
Q. In Duragesic you created a product that is fentanyl based; correct?
A. Right.
Q. And in the process of doing that you worked with fentanyl for years; fair?
A. Yes.
Q. Did you study fentanyl during that time period?
A. Yes.
Q. Given all that, wouldn't it be fair to say that you do have expertise with respect to the drug fentanyl?
MS. BENEDICT: Objection, form.
THE WITNESS: The physical chemistry of fentanyl, what it looks like on a piece of paper, the atomic structure, solubilities, P-chem information, and transport from devices, transdermal devices, I'm an expert in that field.
MR. ORR: What's the objection to the form?
MS. BENEDICT: I think the question is vague.
I think he's answered it to clarify.
MR. ORR: Q. You would agree, wouldn't you that fentanyl is 80 to a hundred times more potent than morphine?
A. Yes.
Q. Now, the original New Drug Application for Duragesic was filed in 1987; is that correct?
A. Yes.
Q. And then that New Drug Application languished for about two and a half years in a newly created pilot division of the FDA; right?
A. It didn't languish until the pilot division was created in 1990.
Q. So when it was originally filed, that pilot division was not in existence?
A. Correct.
Q. And then they created this pilot division, and that division, their first order of business was the Duragesic patch?
A. Yes.
Q. And it was the first drug they approved?
A. That's true.
Q. And it was approved on August 7th, 1990?
A. Yes.
MR. ORR: Okay, I want to go ahead and do some documents now.
MS. BENEDICT: May I see them first?
MR. ORR: Yes.
THE VIDEOGRAPHER: I'm going to go off the record so we can accomplish both at the same time.
We're going off the record at 1:23 p.m.
We're back on the record at 1:26 p.m.
MR. ORR: Q. Mr. Gale, if I could see that.
(Exhibit 1 marked)
MR. ORR: Q. I'm handing you Exhibit Number 1, which is also up on the screen.
Can you identify this document?
A. I believe this is the cover letter that went in with the NDA to the FDA.
Q. And does it look like a true and correct copy of that document?
A. This is the first time I've seen this in 21 years.
It's authentic, I believe.
Q. And what would have accompanied this letter to the FDA?
A. Some number of NDA volumes, the majority of which were clinical study reports, and one of them was the chemistry and manufacturing volume.
Q. And so this is the cover letter that would have accompanied, one, the request that the drug be approved and, two, all of the information that ALZA was relying upon in support of their request that the drug be approved; fair?
A. That's true, yes.
Q. And the whole packet together is called a New Drug Application; is that right?
A. That's correct.
Q. And people commonly refer to that as an NDA?
A. Correct.
Q. And when ALZA requested that Duragesic be approved, am I correct that they represented to the FDA that it was a safe and efficacious product?
MS. BENEDICT: Objection, form. Document speaks for itself.
THE WITNESS: That's correct.
(Exhibit 2 marked)
MR. ORR: Q. I'm handing you what's been marked as Exhibit Number 2.
MS. BENEDICT: Give me a minute to take a look if you would.
MR. ORR: Sure.
MS. BENEDICT: Okay.
MR. ORR: Q. I've handed you what's been marked as Exhibit Number 2 and it's also up on the screen.
Can you identify what Exhibit Number 2 is?
A. Again this has, you know, been 21 years, but I believe this is the first document of the first volume of said NDA that when it's opened, it explains about ALZA technology, pretty much what describes the systems in terms of the components of the system and history of already approved systems by them, the FDA, and what's coming to the FDA. But it pretty much describes the technology and philosophy behind ALZA in general.
Q. And does this appear to be an authentic copy of that section of the NDA?
A. I believe it is, yes.
Q. And the numbers down on the right-hand bottom where it says “1.1/001,” can you interpret those numbers for us?
A. I believe the first number is the volume and the slash — the number that comes after the slash is the page.
Q. What involvement, if any, would you have had in either drafting Exhibit Number 2 or approving it or offering suggestions for it?
A. I don't believe I had a hand in writing this. Other regulatory specialists were in charge of that, they knew what the format of an NDA was and they tried to satisfy that. In short, I didn't write any of this.
Q. Okay. In the first paragraph it says, “Until recently, however, safety hazards, administration problems, and inadequate understanding of factors governing drug permeation through skin have confined transdermal administration to a few drugs of wide therapeutic index.”
Would you agree that that was the case up until recently before this New Drug Application was provided to the FDA?
A. Yes.
Q. And what is meant by this is that before this time you could use drugs on the skin for drugs where it didn't make a big difference in terms of safety if you got a little bit too much of the drug in there or too little of the drug into the body; is that fair?
MS. BENEDICT: Objection, form.
THE WITNESS: That's true for less potent drugs, yes.
MR. ORR: Q. And when it says that it was confined to a few drugs of wide therapeutic index, what does that mean to you?
A. Very few drugs are amenable to transdermal delivery in the first place. They have to have the right melting point, the right molecular weight, the right lipophilic/hydrophilic balance, in other words share both of those domains, and be low doses. Generally, that's less than 10 milligrams per day. So not very many drugs exist in 1987, like I would suggest to you that less than five percent of the drugs in the general realm would be amenable to transdermal delivery.
Q. And prior to the Duragesic New Drug Application, the only ones that were being used for transdermal delivery would be ones where a wide range of blood levels were acceptable and safe. Would that be fair?
MS. BENEDICT: Objection, form.
THE WITNESS: No. I can think of two drugs where that is not the case, Catapres and estradiol. Both have narrow therapeutic index, indices. In fact, those two drugs are more potent than fentanyl, microgram for microgram.
MR. ORR: Q. And what do you mean by “ potent”?
A. Effective doses of Catapres is .1, .2, and .3 milligrams per day, and estradiol is around .05 milligrams per day.
Q. What about in terms of toxicity, would those other medications be as potent as fentanyl?
MS. BENEDICT: Objection. Foundation. Form.
THE WITNESS: I don't know what overdosing Catapres is going to lead to, but estradiol, you can have thrombolytic events.
MR. ORR: Q. So when this New Drug Application says that transdermal administration was only used for a few drugs with wide therapeutic index until recently, the “recently” would include the Catapres and the other drug you mentioned?
A. Estradiol, yes.
Q. So basically when the New Drug Application says that this hasn't been possible until recently, it's referring to recently we have been able to do this for drugs like Catapres and fentanyl — and what's the third one?
A. Estradiol.
Q. Is that correct?
MS. BENEDICT: Objection, form. Foundation.
THE WITNESS: I believe this is referring to a rate-control system controlling the therapeutic amount of drug delivered from the patch into the systemic circulation. It's what ALZA brought to the industry, the concept of rate control.
MR. ORR: Q. And then that concept of rate control allowed, at least in ALZA's mind, the opportunity to transdermally administer more potent drugs with a narrow therapeutic index?
A. Precisely.
Q. And the problem was is that people's skin varies by as much as 10 fold in terms of the permeability; correct?
A. Correct.
Q. And so if you have someone that has extremely — well, strike that.
Is it generally the case that thin skin is more permeable than thick skin?
A. That's an old wife's tale, but I get the point about how skin can vary in permeability due to pigmentation, age, sex, where you're from in the world.
Q. So the idea behind rate control was if someone is a 1 on the scale of 1 to 10 of skin permeability in that their skin is very resistant to permeation, and someone else is a 10, the rate control will keep the person that is a 10 from absorbing a dangerous level of the drug?
A. Correct.
Q. And the person that's a 1, they don't really need the rate control because their skin is already giving them the protection they need?
A. True.
But you can't predict that.
Q. And prior to ALZA getting involved, transdermal therapy was rare because there weren't very many drugs you could use it with; right?
A. True.
Q. And it was confined to drugs that were considered safe?
MS. BENEDICT: Objection, form. Vague.
MR. ORR: Q. Is that right?
A. The first transdermal product approved was Transderm-Scop, and that's truth serum, if you will. An overdose will be lethal. So when Transderm-Scop was designed and eventually approved as the first transdermal system on the market, it was because ALZA targeted the release rate and input to the precise level that would treat nausea without many side effects. So we dose-targeted.
Q. Down at the bottom of the first page of Exhibit Number 2 it says, “Thus transdermal therapy has been a rarity, confined to safe drugs and noncritical situations.”
Are you saying that's not really — that wasn't really the case?
MS. BENEDICT: Objection, form. Foundation.
THE WITNESS: “Noncritical situations” means to me a yacht trip where somebody doesn't want to throw up, so they don't have to go on the yacht.
And then safe drugs, we conferred greater safety by virtue of our dosage forms.
And previously, in the '60s, there was methyl salicylate tapes, which were invented in Japan, and that's safe.
MR. ORR: Q. And when did they first come out with creams and salves and things like that? I mean those have been around for a long time; right?
A. Destined to transdermal delivery, in the '60s, I believe.
The rest of it was topical, like antibiotics and hydrocortisone, meant to be topical.
Q. Those are still considered transdermal therapy, aren't they?
A. Not systemic therapy.
Q. If you could take a look at the fourth page of this document and the bottom paragraph. It says that “All ALZA transdermal systems, including TTS (fentanyl), share two important capabilities. They vest control over systemic drug input in the dosage form.”
Would you agree that that is one of its important capabilities?
A. Yes.
Q. “And they deliver drugs, including those with extremely short half-lives, for durations far exceeding those available with conventional dosage forms.”
Would you agree that's also an important capability?
A. That's true, yes.
Q. And it says, “Control over drug input may reside almost entirely in the dosage form, with the skin exerting little or no control.”
Now, is that referring to the rate-control membrane that's part of Duragesic?
A. Yes.
Q. And so was ALZA representing to the FDA that, the rate-control membrane would almost entirely provide the control over drug input?
MS. BENEDICT: Objection, form. Foundation, the document speaks for itself.
THE WITNESS: In the case of Transderm-Scop, this is an all-encompassing paragraph, all transdermal dosage forms. I believe the rate control is approaching 95 percent.
With fentanyl, it's 50 percent.
With Catapres, it's something like 65 percent.
MR. ORR: Q. So with respect to Duragesic, the control over drug input does not reside almost entirely in the dosage form; instead, it resides 50 percent in the dosage form?
A. Yes.
Q. And then the skin exerts an equal amount of control?
A. Yes, on average.
Q. And we talked about earlier if the person has skin that is not very permeable, then their skin would be providing more of the rate control than the person whose skin is highly permeable.
A. That's true.
Q. Then it says, “Or the dosage form may simply place an upper limit on the total amount of drug delivered within a given time period, regardless of skin permeability.
And that's exactly what the Duragesic patch was intended to do; correct?
MS. BENEDICT: Objection, form. Foundation.
THE WITNESS: Not solely. But that is a correct statement for all dosage forms with rate control.
MR. ORR: Q. And then it says, “Dose dumping is thus prevented.”
What was ALZA telling the FDA, in your opinion, by that?
MS. BENEDICT: Objection, form. Foundation, the document speaks for itself.
THE WITNESS: That the transdermal system would not dump its dose all at once.
MR. ORR: Q. Well, the all-at-once idea doesn't seem to really match with the sentence right before that. Would you agree?
MS. BENEDICT: Objection. Foundation. Form.
He said he didn't write this document. You're asking him for his opinions on a document that he didn't write and you're trying to get him to interpret it. I'm going to object if you keep going along this same line.
MR. ORR: Q. I'm just asking your opinion about what it says.
MS. BENEDICT: He's not been designated as an expert on this document.
The document speaks for itself.
THE WITNESS: I agree.
MR. ORR: Q. And wouldn't you agree that when this document refers to dose-dumping it's referring to the system delivering more drug than the upper limit that it's supposed to deliver over a given time period, regardless of skin permeability?
MS. BENEDICT: Same objections.
THE WITNESS: That's one interpretation, yes.
MR. ORR: Q. Do you agree that's the most reasonable interpretation?
MS. BENEDICT: You don't have to answer that.
MR. ORR: Why doesn't he have to answer that?
MS. BENEDICT: I'm instructing him not to answer.
MR. ORR: And what's the basis for that?
MS. BENEDICT: I just stated my objections.
MR. ORR: Those aren't valid — that's not a valid basis for instructing him not to answer under the Texas Rules of Civil Procedure.
MS. BENEDICT: Okay. I'll add the objection argumentative.
But my understanding is under Texas you just say “form” and that holds all your objections. Right?
MR. ORR: That's right.
Q. On the next page it refers to this dose dumping again. Right here. Is that a term of art in the transdermal industry?
A. Yes.
Q. And what does that term of art mean?
A. I've just described it.
Q. And could you —
A. It's delivery above the intended rate.
Q. Now, when this New Drug Application is submitted, do you know what the FDA does with it?
A. I believe it's parsed out to the different people who are responsible for review, mainly the chemists; medical; preclinical, which is the same thing as toxicology; labeling. That's it. And they look at the appropriate sections or volumes.
Q. And then do they produce any sort of written product based on their review?
A. Yes.
(Exhibit 3 marked)
THE WITNESS: Okay.
MR. ORR: Q. I'm going to represent to you that I've handed you what's been marked as Exhibit Number 3, which is a few pages from the Medical Officer Review of Duragesic, particularly Volume 2, Pharmacokinetics and Pharmacodynamics.
Have you seen this document before?
A. Not for 18 years.
Q. But since this project was something you were in charge of, you certainly read the written reviews done by the FDA of your product, didn't you?
A. I believe I read portions. I can't attest to having read them all. I don't remember.
Q. In this document it says in the first paragraph that “there is a large variation in the blood level of the drug supplied by the system in clinical trials and that not all of this variation is due to individual variation in clearance.”
Would you agree that that's what the clinical trials showed?
A. I can't honestly answer that.
Q. Now, when it mentions a variation in clearance, do you know whether or not that would be something that might change with a given person from day to day or if your clearance is one thing today, it's probably going to be something similar, you know, next month?
A. I have no idea. I'm not an M.D.
Q. And down here at the bottom, this Medical Officer, Curtis Wright, M.D., states the opinion that “All systems are reliable enough so that they will not dose-dump,” which he designs as a blood concentration of greater than five nanograms per milliliter.
Would you agree with that definition of dose-dump?
MS. BENEDICT: Objection, form.
THE WITNESS: I believe he is addressing in that same paragraph unrestricted postoperative use and he's coming to grips whether all doses, 25 through a hundred, are suitable for postoperative use and he's leading to the conclusion that 75 and a hundred are not suitable for postoperative use.
MR. ORR: Q. And he says they're not suitable for postoperative use because fentanyl levels over three nanograms per milliliter are generally toxic in opioid-naive people; fair?
MS. BENEDICT: Objection, form.
THE WITNESS: I can't answer that.
MR. ORR: Q. And he says in this sentence right here that if the level is below 5 it should not be toxic for opiate-tolerant individuals in the cancer pain indication. And that's referring to situations other than postoperative use; right?
A. Correct.
Q. So what he's saying here is that all of the systems should deliver less than 5 and thus they should be okay for opiate-tolerant individuals because those people can take up to a 5.
MS. BENEDICT: Objection, form.
MR. ORR: Q. Is that fair?
MS. BENEDICT: Objection, form.
THE WITNESS: That's his opinion, yes.
MR. ORR: Q. And do you agree that he is also of the view that anything over a 5 should be considered a dose-dump?
MS. BENEDICT: Objection, form.
THE WITNESS: I disagree with the concept because there's a variation of clearance and permeability, which could lead to a Cmax of greater than 5 in a low number of people.
MR. ORR: Q. How low?
A. I can't quantitate. At least some of the population.
And multiple patches of a hundred could obviously lead to greater than Cmax of 5.
(Exhibit 4 marked)
THE WITNESS: Have you seen this?
MS. BENEDICT: (Shaking head).
MR. ORR: What?
MS. BENEDICT: Needing it back?
MR. ORR: Q. I'm handing you what's been marked Exhibit Number 4, which is an autopsy of Denise Lawrenz.
Have you ever reviewed any autopsies of people that have passed away from fentanyl intoxication?
A. No, I have not.
Q. Okay. With this particular lady, she was 49 years old and she had —
MS. BENEDICT: You know, I'm going to object to you publishing this before a foundation has been laid.
MR. ORR: I guess I — what do you mean publishing it?
MS. BENEDICT: Well, it seems that you're taking a deposition that you would intend to play for a jury at some point, and by putting it up on the screen you could show it to the jury before it's been admitted or any foundation has been laid.
MR. ORR: Well, I mean obviously it can't be admitted since the judge is not here.
MS. BENEDICT: Right.
But this witness has just said he hasn't reviewed autopsies. He obviously has not seen this one. You're not going to be able to lay a foundation. And I think I'm going to object to him answering any questions about it.
MR. ORR: I mean if you instruct him not to answer, that's — you know, I don't know it's proper under the —
MS. BENEDICT: Well, go ahead and ask your question and we'll see what it is.
But I don't know what this document is or where it came from and it's not for this case.
MR. ORR: Q. In this — strike all that.
With respect to Ms. Lawrenz, according to this autopsy report, she had — she was evidently in the Bay Park Hotel and they sent somebody to check or her because she didn't show up for a scheduled surgery. Would you agree that's a reasonable reading of that?
MS. BENEDICT: Objection. This witness has not seen this document before. Form. The document speaks for itself.
You don't have to answer that.
MR. ORR: You're going to instruct him not to answer?
MS. BENEDICT: Yes, I am.
MR. ORR: Are you going to instruct him not to answer on any autopsy I might question him on?
MS. BENEDICT: Probably, but that depends.
I mean this is not even the autopsy in any of the cases that the deposition is noticed for today. He's not a medical doctor. He doesn't perform autopsies. I'm not sure what relevant testimony you're going to get out of him.
And as far as him just agreeing that it says what it — as you read it to him, you're reading it correctly, I don't know what benefit that gives the case.
MR. ORR: There are other similar incidents. I wanted to show them to him. They're all people that died, they're all people that the autopsy reports indicates they had one patch on, they're all people that have a lethal level of fentanyl, and I'm wanting to ask him what his explanation is for why the patch delivered so much fentanyl to all these people and all these people died.
MS. BENEDICT: I will object to all of those.
MR. ORR: So you'll instruct him not to answer on all that?
MS. BENEDICT: Yes.
They're incomplete hypotheticals — or I guess not hypotheticals, but it's incomplete. He doesn't have the rest of the story or know anything about those people or — even if he did have any basis to answer.
MR. ORR: He's got the autopsy there and we can go over them.
MS. BENEDICT: He's not a doctor.
MR. ORR: So? So what? I mean he doesn't need to be a doctor because they all say — they're all done by a doctor, and the doctor says there's no other explanation for that, they were all ruled they died from fentanyl.
MS. BENEDICT: Well, then you don't need a witness on it, do you?
MR. ORR: Well, will you stipulate to that, I don't need a witness for any of them?
I'm just wanting to ask the primary inventor of the patch what his opinion is as to why this is happening.
MS. BENEDICT: And I'm going to instruct him not to answer those questions.
We can move on.
MR. ORR: Okay.
(Exhibit 5 marked)
MS. BENEDICT: Do you want to take a minute and read that?
THE WITNESS: Yes.
MR. ORR: Q. I'll represent to you that Exhibit Number 5 is a copy of the package insert that came with Duragesic as amended in May of 2003.
A. I see that, yes.
Q. Now, did you have any role in drafting the original package insert that was submitted to the FDA?
A. Only the first half page, that deals with Duragesic and the PK of the compound and the sizes and the dose, the little table.
I wrote — and it was redacted several times — the portion above “CLINICAL PHARMACOLOGY” the bottom of page 2.
And this black box is new, after the original.
Q. Did you have any input as to any of the pharmacokinetic portions of the package insert?
A. No.
Q. Do you know who did that?
A. Suneel Gupta; Stephen Hwang; and Janne Wissel, who was the overall shepherd of the NDA and the interaction with the FDA.
Q. What about the warnings section, do you know who would have been involved in preparing that?
A. I think Janne left in 2004 ALZA. And so she is primarily the person I would name. And Sue Rinne, R-i-n-n-e.
Q. If you could turn to page 17 of the package insert.
Get to that.
This is the section that talks about adverse events; am I correct?
A. Oh. Yes, yes. Table 1, Adverse Effects — Events.
Q. As the lead inventor and designer of the patch, don't you agree that death should be listed as a potential adverse event with the use of Duragesic?
MS. BENEDICT: Objection. Foundation. Form. Argumentative.
You don't have to answer that.
MR. ORR: You're instructing him not to answer that?
MS. BENEDICT: Yes.
MR. ORR: On what basis?
MS. BENEDICT: That's outside his scope.
MR. ORR: This is an individual deposition. There is no such thing as a scope.
MS. BENEDICT: He is a percipient witness. You're asking him outside the area of what he did for his opinions. He's not an expert on this particular area.
MR. ORR: He's an expert on the patch. He's the lead designer, inventor of the patch. Certainly he can have an opinion about whether there should be a warning about death that accompanied the product that he came up with. And I mean that's just not a valid objection. I mean you can object to its admissibility at trial if you think you can get the objection sustained. But it's just not a basis under the Texas Rules of Civil Procedure to instruct him not to answer.
MS. BENEDICT: He's not qualified to talk about what adverse event warnings should and shouldn't go in a package insert. That's not his area. You can ask him what he knows about it, but he's not an expert, so you don't get to ask him his opinions on that area where he's not an expert.
MR. ORR: Seems pretty simple to me. I think that if people die from it, they should warn about that death is a possibility. I don't think you need to be any sort of expert to have an opinion about that. And I think he is an expert, also.
So I mean, you know, I don't — you instructing him not to answer is not proper and I mean we're just going to end up having to come back but, you know, obviously he's your witness, so you can do what you want to do.
MS. BENEDICT: He's a percipient witness. You can ask him about his knowledge.
You're asking about his opinions in an area where he's not an expert.
MR. ORR: So that means what, you're instructing him not to answer or you are not instructing him not to answer?
MS. BENEDICT: I'm instructing him not to answer that question.
MR. ORR: Q. Mr. Gale, do you believe that — strike that.
What kind of person would be an expert on this?
MS. BENEDICT: I'm not testifying. We could talk about this.
MR. ORR: I mean you're saying he's not an expert on it, so I mean if you're suggesting that there is somebody that is an expert on whether he should warn people about death when death is a real and not insignificant risk…
So are you going to instruct him not to answer on any questions regarding the package insert?
MS. BENEDICT: No. He can answer questions about what he knows about. I mean he had a role in writing some of it. I certainly think you should be able to ask him about that.
He's told you, you know, who he thinks may have written portions of the rest of it. That's certainly proper.
MR. ORR: So he wrote part of the document, but yet you don't believe he's qualified to have opinions about it. And he invented the product.
MS. BENEDICT: The portions that he wrote are certainly something that you should ask him about if you're interested.
MR. ORR: Q. Do you know who wrote the part that's in the black box on the first page?
A. I can only guess, and I won't.
Q. Do you know what a black box warning is?
A. Yes.
Q. What is it?
A. It's a very serious warning. That's why it's in the position it is, first off.
Q. This very first part in that black box, it says, “BECAUSE SERIOUS OR LIFE-THREATENING HYPOVENTILATION COULD OCCUR, DURAGESIC I CONTRAINDICATED,” and then it lists three contraindications. Would you agree?
MS. BENEDICT: Objection, form. The document speaks for itself.
You can answer.
THE WITNESS: “In the management of acute or post-operative pain, including use in out-patient surgeries.
“In the management of mild or intermittent pain responsive to PRN or non-opioid therapy.”
In doses exceeding 25 micrograms per hour.
MR. ORR: Q. As the primary inventor and designer of the patch, would you agree that this warning is only warning people about life-threatening hypoventilation if they use the patch in one of those three contraindicated ways?
MS. BENEDICT: Objection, form. Vague.
THE WITNESS: Ask me the question again, another way perhaps.
MR. ORR: Q. Would you agree that this part I have zoomed in on, the first section of the black box, it is only warning people about life-threatening hypoventilation if they use the patch in one of the three contraindicated ways that are listed there with the bullet points?
MS. BENEDICT: Same objections.
Do you understand the question?
THE WITNESS: Yes.
Do you want me to answer it?
MS. BENEDICT: You may answer it if you have —
THE WITNESS: Okay.
I believe the capitalized sentences are self-explanatory. This is serious medication and hypoventilation is a cause of death.
MR. ORR: Q. And hypoventilation can occur if you use it in a contraindicated fashion?
A. Right.
Q. But it's not warning anyone about death as a risk if you're using it properly. Fair?
MS. BENEDICT: Objection, form.
THE WITNESS: Proper means doses that start with the 25 microgram an hour and move up, then you are open to hypoventilation. But that's an outcome — well —
MR. ORR: Q. What I'm getting at is if there's a product and it's a prescription drug and you can — and your doctor can write you a prescription for it and your doctor can have properly — its a proper prescription as indicated by the manufacturer of the drug and you can go home and you can use it just as you were instructed and you can die, that the very first sentence in this black box warning should be, hey, you better watch out because you can use this drug as indicated, you can use it as instructed, and there is a real and not insignificant risk of death, and so you better think about how bad that pain is because if you're going to use this product, you're taking on the risk of death. Don't you think something like that should be included in the package insert?
MS. BENEDICT: Objection, form. Foundation.
You don't have to answer that question.
MR. ORR: Q. Would you agree that this section I have highlighted does not warn people that you can die from using this product as indicated and properly?
MS. BENEDICT: Objection, form. Foundation. The document speaks for itself.
You don't have to answer that.
MR. ORR: Q. Ms. Benedict has said several times that “You don't have to answer that.” Are you choosing not to answer that based on her — it's really not an instruction not to answer, it's telling you that if you don't want to, you don't have to answer it. Are you choosing not to answer it?
MS. BENEDICT: I'm instructing the witness not to answer.
He's asking if you're going to follow my instructions when I tell you that you don't need to answer a question.
THE WITNESS: I'm going to follow your instruction and not answer.
MR. ORR: Q. Do you have a lawyer here today representing you?
A. Yes.
Q. Ms. Benedict is representing you for the purposes of this deposition?
A. Yes.
Q. Do you agree that the machines and processes used to make Duragesic are incapable of making 100-percent leak-free patches?
A. I agree.
Q. Don't you think that that should be warned about in the package insert?
MS. BENEDICT: Objection, form. Foundation.
You don't have to answer that.
MR. ORR: Just to be clear, when you're saying “You don't have to answer that,” you're instructing him not to answer; right?
MS. BENEDICT: Yes, I am.
MR. ORR: Okay. And you're going to instruct him not to answer as to similar questions on this package insert and the subsequent package inserts?
MS. BENEDICT: I'm not exactly sure what you mean by “similar questions.”
But if you're asking him to interpret language in the package insert that he didn't write or didn't have input in, yes, I'm not going to have him testify about that.
MR. ORR: And if I ask him about whether he thinks certain warnings should be included in sections that he did not write, you're also going to instruct him to (sic) answer those questions?
MS. BENEDICT: Yes.
MR. ORR: And you're also going to instruct him not to answer questions about his opinion about what the package insert means if it deals with sections he did not write?
MS. BENEDICT: Sections he had no input in that are outside his area of expertise, yes.
MR. ORR: Q. So you had no input into the — strike that.
Did you have any input into the adverse events section?
A. No.
Q. Did you have any input into the black box section?
A. No.
Q. Did you have any input into the warnings section?
A. No.
Q. Did you have any input into the pharmacokinetics section?
A. No.
Q. Did you have any input to the ventilatory effects section?
A. No.
Q. Who wrote most of the package insert?
A. The first, 1990, was a collection of people, pharmacokineticists, regulatory specialists. And in conjunction with the FDA; they had to agree, you know, going along what it looked like. It was so new.
Q. But the FDA doesn't write it. ALZA writes it; correct?
A. Yes.
And the FDA would review drafts. I remember that occurring.
Q. And did you review their comments on the proposed package insert?
A. I saw early drafts of the package insert.
Q. When you say “early drafts,” are you saying that you saw early drafts of what ALZA submitted? Right?
A. Yes.
Q. Did you ever see the FDA's comments on those drafts?
A. I don't believe so.
Q. If someone is using a Duragesic patch per all the instructions in the package insert and they're a proper patient to be using the patch per everything that's in the package insert and they die, in your view — well, and they died from too much fentanyl in their system, in your view would it would proper to call that a, quote, overdose, unquote?
MS. BENEDICT: Objection, form. Incomplete hypothetical, foundation.
MR. ORR: Q. You can go ahead.
A. That sounds like another way of asking what you asked five minutes ago, so I'm not going to answer it.
Q. Well, what I'm trying to get at is to me overdose suggests that someone was taking too much of the drug or they were improperly using it in some way, but if they were using it exactly as instructed, using it properly, only using one patch, using the dosage they were prescribed, and they died from too much fentanyl, do you believe that using the word “overdose” to describe that is probably a misleading term?
MS. BENEDICT: Objection, form. Foundation, incomplete hypothetical, calls for an expert opinion.
You don't have to answer that.
MR. ORR: Q. Let me shorten up my question a little bit. And I'm sure she'll instruct you not to answer, but I just want to make sure that I've got it clear on the record.
My question is, if someone is a proper candidate for the patch and they're properly using the patch and they die from fentanyl poisoning, wouldn't you agree that it is misleading to describe that death as an overdose?
MS. BENEDICT: Same objections and same instruction.
(Exhibit 6 marked)
MR. ORR: Q. I'm handing you what's been marked as Exhibit Number 6.
THE WITNESS: It looks like some kind of ad. No. There's no date.
MR. ORR: Q. I'm going to represent to you that Exhibit Number 6 is a page from a Duragesic brochure that was in use at the time that Ms. West was prescribed Duragesic.
A. That would be 2004?
Q. Yes.
A. Okay.
MS. BENEDICT: Oh. Really?
MR. ORR: Per your e-mail, it was.
MS. BENEDICT: 2004?
MR. ORR: Was it 2003?
MS. BENEDICT: '6?
MR. ORR: I'm sorry. Yes. 2006. You're right.
Q. It was in use all the way — I think starting in 2003 I think this went into use.
A. Okay.
Q. But let me back up.
I'm going to represent to you that Exhibit Number 6 is a page from a Duragesic brochure that was in use in 2006 at the time that Ms. West was prescribed Duragesic.
A. All right.
Q. Have you had a chance to take a look at that?
A. Yes.
Q. Is this document and the representations on the document in line with what ALZA told the FDA about this product to get it improved — to get it approved?
MS. BENEDICT: Objection, form. Foundation, vague.
Can you ask a more specific question?
This is a document he's never seen before from a time when he was no longer with the company. So you're asking him to in general say if the whole document is —
MR. ORR: No. Just this page. I'm just asking him if he could read this page and tell me is there anything on this page that is contrary to what was represented to the FDA to get this drug approved
MS. BENEDICT: Same objections.
You can answer.
THE WITNESS: So you're asking me to remember 1990 and the associated standard deviations being about what they were in 1990.
MS. BENEDICT: If you would need to say something else to answer this question and can't answer it from memory, then tell us that.
THE WITNESS: The words seem correct, but don't know if their graph conforms with the 1990 or 1987 as-produced reports.
MR. ORR: Q. Would you agree that ALZA represented to the FDA to get this product approved that it would provide fewer peaks and troughs than other oral pain medications?
A. That's true.
Q. And ALZA also represented to the FDA to get this product approved that steady-state mean serum concentrations for 72 hours after multiple Duragesic 100 microgram per hour applications — strike that. I just messed that question up.
Would you also agree that ALZA represented to the FDA that Duragesic would produce steady-state mean serum concentrations after multiple applications of the product?
A. Yes.
Q. And that's one of the things that you designed it to do; is that correct?
A. Yes.
Q. And you also designed it to provide fewer peaks and troughs in terms of serum concentrations of fentanyl; right?
A. Yes.
Q. And in looking at that graph, would you agree that the graph represents that with a 100-microgram Duragesic patch that the serum fentanyl concentration never gets above about 3.5 nanograms per milliliter?
MS. BENEDICT: Objection, form.
THE WITNESS: I presume that's the standard deviation associated with the mean from some clinical study. So someone had to be at 6 or 7 nanograms per ML.
MR. ORR: Q. What do you understand these — let me blow up this chart here.
What do you understand this line here to be referring to?
A. Standard deviation of the mean.
Q. One standard deviation?
A. Yes. At steady state, multiple applications.
Q. Okay. So as you sit here today, can you tell us whether or not this chart represents approximately what you intended and designed the patch to do?
MS. BENEDICT: Objection, form. Foundation, vague.
THE WITNESS: Yes.
MR. ORR: Q. It does represent what you intended it to do?
A. True.
(Off the stenographic record)
THE VIDEOGRAPHER: We're going off the record at 2:39 p.m.
(Exhibit 7 marked)
THE VIDEOGRAPHER: We're back on the record at 2:48 p.m.
MR. ORR: Q. I've handed you what's been marked as Exhibit Number 7, which is another page from the brochure, and I wanted to ask you, in your opinion, should Janssen and ALZA be telling physicians and patients that Duragesic has 13 years of proven safety?
MS. BENEDICT: Objection, form. Foundation.
I think again you're getting into an area that's asking for expertise that's outside of his area, rather than either an area where he is an expert or he has percipient knowledge. So I'm going to object and ask him not to answer that.
MR. ORR: Q. Do you know anything about the safety of Duragesic?
MS. BENEDICT: Objection, form.
You can answer.
THE WITNESS: It was designed to be a safe dosage form.
MR. ORR: Q. And in your opinion is it?
A. Yes.
Q. And what's the basis for that opinion?
A. All the material we've already gone over. It's a rate-control dosage form and it comes in four sizes and meters drug to the skin of the user over 72 hours.
Q. And do you know whether or not there have been people passing away while using the patch from fentanyl poisoning?
MS. BENEDICT: Objection, form.
You can answer.
THE WITNESS: I'm sure there have.
MR. ORR: Q. And why do you say that?
A. Cancer, people — people with cancer regularly use the patch, and some forms of cancer involve the liver, which is the major organ of ridding the body of fentanyl excretion, and when that's cancerous, it doesn't do such a good job and blood levels must rise.
Q. What about in non-cancer patients?
MS. BENEDICT: Objection, form. Foundation
THE WITNESS: It's not prescribed for postoperative pain.
MR. ORR: Q. What about for back pain?
MS. BENEDICT: What's your question?
MR. ORR: “What about for back pain” is my question.
MS. BENEDICT: Objection, form. Vague.
I don't understand the question.
MR. ORR: He just said that — he just said that it's not prescribed for postoperative pain, and I said, “What about for back pain?”
MS. BENEDICT: Is it prescribed for back pain? Is that your question?
MR. ORR: Yes.
THE WITNESS: It is, for chronic back pain of a severe nature.
MR. ORR: Q. Have there been people dying from fentanyl poisoning when using the patch for chronic back pain when they weren't abusing or misusing the patch?
A. I don't know.
Q. So how can you say it's a safe drug if you don't know whether or not that's been occurring?
MS. BENEDICT: Objection, form. Argumentative.
THE WITNESS: All I know is it was designed to be safe.
MR. ORR: Q. Do you know anything about the FDA's current investigation into deaths from fentanyl patches?
A. Not for the last two years. I've been retired.
Q. Do you know anything about the pharmacovigilance plan that the FDA mandated that Johnson & Johnson put together and submit to the FDA
A. No. If that was in — within the last two years?
Excuse me.
Q. Well, have you ever heard of the FDA coming to Janssen or ALZA or Johnson & Johnson and saying we're getting reports of a lot of deaths and so we want you to provide to us a plan on how you're going to monitor this situation more in depthly? Have you ever heard of anything like that?
A. In 2005 I believe I did, yes. But I don't know if it got followed through.
Q. Would it be fair to say that as you sit here today you don't have enough information to have an opinion about whether or not the Duragesic patch as being used today by physicians is a safe product?
MS. BENEDICT: Objection. Vague and ambiguous, foundation, calls for an expert opinion.
You don't have to answer that question.
MR. ORR: Q. Would it be fair to say that you don't have enough information to agree or disagree as to whether the Duragesic patch has 13 years of proven safety?
MS. BENEDICT: Objection. Same objections.
And again you don't need to answer.
MR. ORR: Why are you instructing him to (sic) answer?
MS. BENEDICT: Because you're asking him outside his area.
MR. ORR: I'm asking him if he has enough information to offer an opinion.
MS. BENEDICT: Okay.
THE WITNESS: No.
MR. ORR: Q. Do you know anything about who puts together advertising brochures like this?
A. I presume J&J marketing.
Q. Is this something they ever ran by you?
A. No.
Q. Do you know whether or not this would be something they would ever run by someone like Suneel Gupta?
A. I suspect not, because they're up to speed after all these years and they can write what they want.
Q. If there are numerous people dying from fentanyl poisoning when properly using Duragesic patches and upon autopsy it's found that their fentanyl level is above 10 nanograms per milliliter, what would be the possible explanations, in your opinion, for how that would occur?
MS. BENEDICT: Objection. Foundation. Form. Incomplete hypothetical, argumentative, and calls for an expert opinion.
MR. ORR: Q. Go ahead.
MS. BENEDICT: No. You don't need to answer that.
MR. ORR: You can go ahead and shut off the projector. I'm done.
Q. Am I correct that there was a recall in 1993 regarding the rate-control membrane in Duragesic patches?
A. Yes.
Q. And you got involved as an adviser to figure out what went wrong?
A. Yes.
Q. And that was your first involvement with that recall; is that right?
A. Yes.
Q. And that recall concerned rate-control membranes that were going out of specification with regards to how much drug they were releasing?
A. Yes.
Q. And you looked into that, and your conclusion — you reached a conclusion as to what went wrong; right?
A. Yes.
Q. And your conclusion was that the blown-film extrusion oriented the molecules too much and so that it was more permeable than the conventional extrusion?
A. Yes.
Q. And what does that mean in laymen's terms?
A. The polymer strands when you blow film, it's a continuous process, you're forming a bubble that's taken up 20 feet up in the air, and a circular dye is aligning the molecules this way and it becomes more permeable for that reason.
The other extrusion is a dye which extrudes a river of film, more randomly aligning the molecules, and so it's more prone to crystallize and be less permeable.
Q. Okay. Are you saying that there were two different methods that were used to make the membrane?
A. Yes.
Q. And both of those were being used?
A. We validated using the latter process, the second process — I forget. Conventional extrusion dye and calendar.
Q. Well, which one was being used when the problem developed with the membrane and its release of drug?
A. The former process, the blown film.
And in fact, two different methods of manufacturing the EVA control membrane were mixed in four or six lots of twenty-fives.
Q. So what you're saying is that there was one process used to make this membrane and then you started to mix in with that a different process. And were you in the process of moving to that new process?
MS. BENEDICT: Objection, form. It's vague.
You can answer it.
Assumes facts not in evidence.
THE WITNESS: Okay.
MS. BENEDICT: You can answer.
THE WITNESS: I became aware of the problem by invitation. The lots of twenty-fives were placed on stability, and within three months of stability shelf life the product was out of spec for six lots — a portion of six lots. And then I learned that a purchasing agent made an independent decision to get film made cheaper by another process.
MR. ORR: Q. Now I think I understand.
The problem that you discovered in connection with that 1993 membrane recall was that the rate-control membrane was being made with one process and then at some point an employee of ALZA made an independent decision to buy membrane from someone else that used a different process?
A. Yes.
Q. And that process basically just didn't do the job as good as it needed to be done; right?
A. Correct.
Q. And so then you didn't buy any more film or membrane from that vendor?
A. Correct.
Q. And you went back to how it was — to the vendor that was using the process that you had been using all along?
A. Right, for 10 years.
Q. Am I correct that the patent for Duragesic was issued to ALZA?
A. Yes.
Q. And that was in 1986?
A. Yes.
Q. And then ALZA sold the rights to the patent to Janssen?
A. Yes.
Q. Do you know who owns it now?
A. It's expired, so the universe owns it.
Q. Expired in 2005; right?
A. Yes.
Q. Okay. And that patent was set to expire in May of 2004 and then ALZA got a six-month extension to January of 2005 for pediatric exclusivity; is that correct?
A. Correct.
Q. And was it thought by ALZA that they could cover the matrix fentanyl patch with that 280 patent?
MS. BENEDICT: Objection, form.
But you can answer if you know.
THE WITNESS: I believe the patent was general enough to cover all types and forms of fentanyl transdermal delivery, so we had to get creative about the matrix patent.
MR. ORR: Q. And so did ALZA make application for a separate patent that covered specifically the matrix product?
A. Yes, we did.
Q. And that was never approved?
A. It's still in process.
Q. Do you have any opinion about what's going to happen with that?
A. As time goes by, it's less likely to be approved.
It's a real mess out there. It's competitive.
Q. And if it was approved, then Mylan would have to stop making their patches?
A. I don't know what Mylan's status is about their patch. It's definitely a monolith of matrix.
Q. Speaking of a matrix patch, am I correct that — is it Cygnus first developed the matrix fentanyl system?
A. Yes.
Q. And that was in 1993 or 1994?
A. Yes.
Q. But the matrix technology was available and known in the '80s; is that right?
A. Yes.
Q. And when you first got involved in transdermals, that was again in the late '70s; is that right?
A. Yes.
Q. There were basically — well, strike that.
In the '80s, when you were working with developing transdermal technology, is it correct that there were three types of delivery mechanisms that were available, the multilaminate, the matrix and the form-fill seal?
A. That's correct.
In my mind, the multilaminate equals the form-fill seal. It's just the form is different, a gel versus a solid-state reservoir.
Q. And what would be the benefit of a multilaminate over a form-fill seal?
A. No true benefit. The pereation enhancer, ethanol, is a liquid, so that drives you to make a form-fill seal system, because the ethanol would evaporate out the edges of a solid-state multilaminate.
Q. And what's the difference between a multilaminate and a matrix?
A. In its simplest form, nothing. It's got the backing, the reservoir, the rate-control membrane, the adhesive and the liner, five layers. Both types of systems have those five layers.
MS. BENEDICT: I think you misunderstood the question.
THE WITNESS: Oh, okay.
MR. ORR: Q. The multilaminate and the form-fill seal — am I saying that right? It's form-fill seal?
A. Yes.
Q. Okay. They all have five layers? They both have five layers?
A. Right.
Q. But the matrix is different?
A. Right.
Q. And the only difference between the multilaminate and the form-fill seal is that the form-fill seal has a seal around the edge and then the drug in the reservoir is not a solid state?
A. It's a liquid.
Q. Right.
A. Yeah.
Q. And in the multilaminate it wouldn't be a liquid?
A. Correct.
Q. Could you have a seal with the multilaminate?
A. Yes, if you wanted to.
Q. Would there bean any reason to —
A. It's an extra production step, yes.
Q. But if the substance containing the drug is solid, would there be any purpose for a seal?
A. None that I can see.
Q. About 10 years after the NDA for Duragesic was submitted to the FDA did you become involved in discussion about Johnson & Johnson making a matrix patch?
A. Yes.
Q. And you began working on that, but it did not progress very fast because you were having problems getting the right adhesive to use with a matrix patch; is that right?
A. That's true.
Q. And the reason why Johnson & Johnson was looking at a matrix patch, in your view, was because there was a second-generation product that was coming on line, the Mylan matrix patch, after expiration of the patent on Duragesic?
A. Correct.
Q. And Johnson & Johnson was worried about losing market share to the Mylan patch when the patent for Duragesic expired; is that fair?
A. Yes.
Q. And it's also your understanding that there was a general belief at Johnson & Johnson that a small dosage form would sell better, it was more desirable?
A. And elegant, yeah.
Q. And the matrix patch is smaller than the Duragesic patch?
A. Yes, and more flexible and more discrete.
Q. And then finally, in 2000, did the company give you the go-ahead to try and produce a matrix system?
A. Yes.
Q. And then at that time did you start to scale up the matrix product?
A. Yes.
Q. And for those of us not in the pharmaceutical business, what does “scaling up” mean?
A. Producing more per unit time. From tens to hundreds to ten thousands.
Q. And during the scaling-up process, is it fair to say that the company was excited about the project?
MS. BENEDICT: Objection, form.
THE WITNESS: Both companies were excited, to the point where Johnson & Johnson bought ALZA in 2001.
MR. ORR: Q. Did Johnson & Johnson have any involvement with ALZA before 2001?
MS. BENEDICT: Objection, form. Vague.
THE WITNESS: Janssen signed a contract in 1988 to distribute Duragesic. So Janssen is a major portion of the pharmaceutical arm of Johnson & Johnson.
MR. ORR: Q. So prior to 2001 there was a contractual working relationship between ALZA and subsidiary of Johnson & Johnson?
A. Correct.
Q. And then in 2001 ALZA itself also became a subsidiary of Johnson & Johnson?
A. Correct.
Q. So since Johnson & Johnson was selling the fentanyl patches, at least their subsidiary Janssen was, that's why they were involved with giving the go-ahead in 2000 to scale up the matrix patch?
A. That's true.
Q. And is it correct that by the end of 2000 the ALZA matrix patch was already developed and it was just waiting on production?
A. Yes. The production was at the pilot plant scale. A thousand systems was the lot size at that point.
Production scale-up to the commercial level was an extensive process, which had yet to be approved.
Q. And it's your conclusion, isn't it, that the matrix fentanyl patch and the form-fill seal fentanyl patch are bioequivalent; is that right?
A. Correct.
Q. And to your knowledge, all the tests that have been done, all the studies that have been done so far support this?
A. Yes.
Duragesic became the reference product to which generics had to match the blood profile.
Q. Now, you're the one that came up with the composition of the gel that goes into the Duragesic patch; is that right?
A. The initial? Yes.
Q. Did anyone change it after you came up with it?
A. No.
Q. Still the same today?
A. Yes.
Q. And the Sandoz patch is exactly like the Duragesic patch; is that right?
A. Yes.
Q. And the gel is approximately one percent fentanyl, two percent gelling agent, 23 percent ethanol, and the rest water?
A. Correct.
Q. And that gel is about the consistency of honey?
A. Yes.
Q. Now, to come up with the amount of ethanol 23 percent you did kind of a trial and error — strike that.
To come up with the decision to make the gel 23 percent ethanol, you tried other levels of ethanol in the gel; is that right?
A. Yes, in a designed-experiments format.
Q. And did you do that with the flux cell?
A. Yes.
Q. And the flux cell is the device where you have a couple of tubes with some cadaver skins in between them?
A. Yes. And the tubes are blocked off on the ends.
Q. And one end of the tube measures the flux and the other end of the tube you put the gel in?
A. Correct.
Q. And why did you decide upon 23 percent?
A. It was an optimal level to get the fentanyl soluble enough to handle but not — any greater would use too much fentanyl to get the saturated solution. So that's why the solubility was selected about one percent. 47-weight ethanol, for instance, was 10 percent fentanyl to get a saturated solution, and that was too much.
Q. So you had one percent fentanyl, two percent gelling agent, 40 percent ethanol and the rest water, what would happen?
A. We would need to place 10 percent fentanyl base instead of one percent base to get a saturated solution, which was the gold standard —
Q. Because the ethanol does not dissolve the fentanyl as well as the water?
A. Quite the opposite. The good solvent is ethanol. It's extremely insoluble in water.
Q. So why would you need more fentanyl if you have more ethanol?
A. To get a saturated solution, which is a constant driving force throughout the lifetime of the product. That's what gives the constant blood levels in the end. So it's not subsaturated, it's saturated with excess. And then as you lose ethanol, the solubility drops and the fentanyl is still crystalline which is saturated. So it gives a constant driving force.
Q. What is the definition of “saturated”?
A. Enough solute is present to be at saturation with excess crystals in the bottom of the beaker. The crystals are more dense than water or the solvent. Saturated with excess.
Q. So saturated means that — I think I understand what you're saying.
Saturated means that not all of the drug can be dissolved; there's crystal form of the drug in the solution?
A. Correct.
Q. So if you have too much alcohol — or ethanol in there, all the drug would be dissolved?
A. Correct.
Q. And if all the drug were dissolved, then you'd have a much greater fentanyl flux?
MS. BENEDICT: Objection, form. Incomplete hypothetical.
THE WITNESS: If you had 47 percent ethanol which is what we tried, the ethanol would, number one, irritate the skin and, number two, you would have to add so much fentanyl to create a saturated state that, you know, it — it was quickly discarded as a viable concentration of ethanol.
MR. ORR: Q. So when you did the 47 percent were you getting more flux of the drug?
A. Yes. Gel and the skin. The Pharmaceutical Development Report, which we've gone over, that was the maximum flux shown of the different ethanol concentrations we tried.
Q. And so did it lose all the drug early on and then — if you have 40 percent ethanol, would — you said there was a much greater flux of the drug.
A. Yes.
Q. So what would that do in terms of the drug delivery on day two, day three? Would the drug already be all gone?
A. Effectively, it's getting depleted faster, so the blood levels would be like this instead of constant. It's spending — you know, it's high to low.
Q. So you needed just the right amount of ethanol in there to where you would keep a lot of the drug in crystal form, and then as the drug entered the skin, that would then allow room for some of the crystallized drug to then dissolve?
A. Yes.
Q. So you needed something that would force a large portion of the fentanyl to wait?
A. Yes, until day three, for instance.
Q. Right.
A. Yes.
Q. And if you had 47 percent alcohol — or ethanol, all the drug would be dissolved and it would just enter the skin early on in the process and you wouldn't have three days of drug delivery?
A. Correct.
You would, however, have a small patch.
Q. Was there ever any thought to a different day, you know, like a two-day patch or a one-day patch?
A. Yes. Trouble is, patients need to remember when to replace the patch, and every other day you might forget, and twice a week is at the outer edge of, oh, memory, change it Thursday and Sunday, for instance.
Once a week or once a day was highly popular. Change it on Sunday night or every day.
Q. Did ALZA do any research on that?
A. It was just a feeling by the marketing people.
Q. So did you ever take any steps towards a one-day patch?
A. It would be too expensive in the end. Fentanyl was an expensive compound in 1982. It's come down, but it's still a very expensive drug.
Q. The Lavipharm product, is that a multilaminate patch?
A. Yes, to my understanding.
Q. So that's a solid-state patch with a rate-control membrane?
A. That's what it has been described to me.
MR. ORR: We need to change tape.
THE VIDEOGRAPHER: We're going off the record at 3:26 p.m. This marks the end of tape number 1 in the deposition of Robert Gale.
We're back on the record at 3:29 p.m. This marks the start of tape number 2 in the deposition of Robert Gale.
MR. ORR: Q. To your understanding, the Lavipharm patch has the fentanyl in polymer?
A. Yes.
Q. And what is polymer?
A. It's high-molecular-weight gum-like substance.
Q. And the Lavipharm design, in your view, would have been a technologically feasible design as of when?
A. I don't know enough about the Lavipharm system to make a cogent comment. But they must no have permeation enhancers, whereas — to keep the size down. So without a permeation enhancer, we could have been doing that in 1982.
Q. And with a permeation enhancer, you could have been — you could have made one when?
A. It depends on if it's a liquid, semisolid or solid permeation enhancer. They come in all sizes and shapes.
A solid one, 1982.
A liquid one, 1982 with a form-fill seal system.
Q. Certainly you could have made a multilaminate fentanyl patch in the late '90s? Fair?
A. Yes.
Q. And if you were going to design a patch today, that's the design you would use?
MS. BENEDICT: Objection, form.
THE WITNESS: In my personal opinion, yes.
MR. ORR: Q. Would you agree that the Duragesic patch was designed to and intended to avoid any type of buildup of fentanyl in the patient's blood upon repeat applications?
A. That's true.
Q. It's supposed to achieve a steady state and maintain that state over time and over multiple applications?
A. Correct.
Q. And that's what you intended for it to do?
A. Yes.
Q. And you would agree, wouldn't you, that most individuals using Duragesic are also on other medications?
MS. BENEDICT: Objection. Foundation. Form.
THE WITNESS: It varies is my understanding
MR. ORR: Q. Well, do you have any understanding of the typical or common Duragesic patient?
MS. BENEDICT: Objection, form. Foundation.
MR. ORR: Cancer and back pain of a chronic nature.
It was never designed or intended to be the only medication,
MR. ORR: Okay. I'll pass the witness.
EXAMINATION
BY MS. BENEDICT:
Q. How many years did you work on the design of the Duragesic patch?
A. Three or four.
Q. At the time, did you consider other designs?
A. Yes.
Q. Why did you go with the form-fill seal design that is in the Duragesic patch?
A. Well, to make a matrix where we didn't have the correct adhesive for another 18 years, so —
Q. You mean it wasn't available on the market?
A. Yes. And we only had polyisobutylene and silicon, and both are unsuitable, low solubility of fentanyl. And so we wanted to make the product as small as we could because it was expected to be more elegant if it was smaller. So we needed a permeation enhancer to make that true.
And ethanol was used in the Estraderm, and form-fill seal technology was with us on Estraderm and Transderm-Nitro, so form-fill seal machinery was not novel to ALZA. So it was an easy selection to go form-fill seal.
Q. Did you participate in meetings with the FDA before the patch was approved to discuss the design of the Duragesic patch?
A. Yes. I was in one meeting, the initial meeting with the FDA, with other ALZAns.
Q. Was it your understanding that the FDA wanted the patch to include a rate-control membrane
A. Yes, because we had had approval of Transderm-Nitro, which was rate-controlled estradiol which was rate control and scopolamine. So they became used to it, semi-demanding it, unless we had good reason not to have rate control.
Q. Were there any other reasons, to your knowledge, that a form-fill seal design was used rather than a matrix or a multilaminate?
A. Multilaminate was not considered because we didn't know enough about permeation enhancers that could be effectively kept in a multilaminate without heat-sealing the edge. That was a novel thing to think of.
Matrix without rate control concerned us and the FDA, so it became secondary to rate control form-fill seal.
Q. Do you know if the abuse potential of the patches was considered?
A. Not at the initial meeting, but it became more of a concern as the approval became evident in 1990. The DEA asked questions: What makes your product non-abusable? And our answer is that it's no more abusable than morphine orally. And that went long way towards satisfying.
Q. Is there any reason that a form-fill seal design is less abusable than either a matrix or a multilaminate design?
A. We did a whole boatload of experiments on the form-fill seal versus the matrix, and basically at the end the DEA and the FDA agreed that the form-fill seal was less abusable than the matrix.
Q. And can you explain that reasoning?
A. No.
Q. Okay.
A. It's a matter of opinion —
Q. Okay.
A. — in the end.
Q. Did it have to do with the fact that a matrix or a multilaminate could be cut up into smaller portions and someone looking to abuse it could divide a patch and use certain sections of it, whereas the Duragesic patch once cut could not be used?
A. One-time use, yes, that was discussed.
Q. Is it fair to say to say that all drugs — all prescription medications have risk?
A. Yes.
Q. So when a prescription medication is considered safe, it doesn't mean that it's risk free; correct?
MR. ORR: Objection, form.
THE WITNESS: Yes.
MS. BENEDICT: Q. There were numerous test performed both in vivo and in vitro on Duragesic and the gel before it was submitted to the FDA in the NDA; is that correct?
A. Correct.
Q. And how long was that testing process?
A. A good five years.
Q. And is that, in part, the basis for — your understanding of the basis for the statement in the NDA submission that Duragesic was safe and effective or would be safe and effective when used as directed?
A. Yes.
Q. And ultimately the FDA agreed with that statement and approved it for market; correct?
A. Yes.
MS. BENEDICT: I have no further questions.
MS. DAVENPORT: We'll reserve.
MR. ORR: A couple more questions.
Could I see the exhibits.
FURTHER EXAMINATION
BY MR. ORR:
Q. Back to Exhibit Number 7. As I indicated, Exhibit Number 7 is from a Duragesic brochure that was being used at the time Ms. West was prescribed the Duragesic patch that she was wearing at the time of her death. And you have seen the portion at the bottom, haven't you, where it says “13 years of proven efficacy and safety”?
A. Yes.
Q. So that's clearly saying that it's a safe product, not an unsafe product; fair?
MS. BENEDICT: Objection, form.
THE WITNESS: Used as prescribed, I believe it's safe.
(Exhibit 8 marked)
MR. ORR: Q. I'm handing you what's been marked as Exhibit Number 8, which is a pleading that has been filed by ALZA and Janssen.
MS. BENEDICT: May I see it?
MR. ORR: Yes.
Q. If you could look on what's marked as page 15 of this pleading. If you could — do you see there where it says “Duragesic is plainly an ‘unavoidably unsafe’ drug”?
A. Yes, because it's highlighted.
Q. Could you turn to the last page of this exhibit.
Do you see where this is signed and submitted by attorneys for Janssen and ALZA Corporation?
A. Yes.
Q. Do you know why these companies would tell the public in Exhibit Number 7 and tell doctors in Exhibit Number 7 that this is a safe product and then in litigation over someone that died from the use of this product they would try and say that it's just unavoidably unsafe?
MS. BENEDICT: Objection, form. Argumentative, foundation.
You do not have to answer that question.
MR. ORR: Q. Do you agree that Duragesic carries a risk of respiratory depression that can lead to, in severe cases, respiratory failure and death, even when used as prescribed?
MS. BENEDICT: Objection. Incomplete hypothetical, foundation. Form. When he doesn't know how it's being prescribed.
MR. ORR: Well, you elicited testimony from him that it was a safe product when used as prescribed. That's what he just testified to when you were questioning him. Now I get to cross-examine him on that.
MS. BENEDICT: Well, how is it being prescribed in your question? He's not a doctor.
MR. ORR: When he said it's safe as prescribed, that's what I'm talking about, whatever he said.
MS. BENEDICT: Well, I object that the question is vague.
MR. ORR: Can you read back my question.
(The reporter read the record as follows: “Do you agree that Duragesic carries a risk of respiratory depression that can lead to, in severe cases, respiratory failure and death, even when used as prescribed?”)
MS. BENEDICT: Same objections.
You're questioning him about a pleading from a different case that he has not seen before or authored.
MR. ORR: My question didn't mention the pleading.
MS. BENEDICT: You're quoting from the pleading after putting it in front of his face. It's argumentative.
MR. ORR: Q. You can go ahead and answer.
MS. BENEDICT: You don't have to answer that question.
MR. ORR: Mollie, you elicited testimony from him that this is a safe product as prescribed.
MS. BENEDICT: If you thought my question is vague, you could have objected to it.
MR. ORR: No, I didn't think your question was vague.
MS. BENEDICT: Okay. Well, maybe it was. Maybe I should have objected to it.
MR. ORR: But you can't instruct him not to answer because of a vague question. That's against rules. That's not allowed.
MS. BENEDICT: Which rules? This deposition is being taken in 11 different cases, so we've got a lot of rules to comply with here.
MR. ORR: I'm taking the — I only noticed it in one deposition (sic).
MS. BENEDICT: Well, it's going forward in 11, so — of cases that you brought, not other cases that other plaintiff attorneys brought.
MR. ORR: So I'm taking this deposition under the Texas Rules of Civil Procedure because that's what I noticed it in.
MS. BENEDICT: It was also noticed in 10 other cases. You didn't object to that. There are other rules of procedure that apply.
MR. ORR: For the part that you're conducting of the deposition.
MS. BENEDICT: No. The whole deposition is for all the cases.
MR. ORR: So you're instructing him not to answer that question?
MS. BENEDICT: Yeah. I'm not going to let him answer about a pleading from a case in Chicago.
MR. ORR: I didn't ask him about the pleading.
MS. BENEDICT: You put the pleading in front of him, you highlighted a section, you quoted from it and you asked him about it.
MR. ORR: What's your objection to my question?
MS. BENEDICT: Form.
MR. ORR: And so you're instructing him not to answer because of form?
MS. BENEDICT: Yes.
MR. ORR: Q. Do you agree that Duragesic is plainly and unavoidably an unsafe drug even if used as prescribed?
MS. BENEDICT: Same objections, same instruction.
MR. ORR: Q. What do you think about the credibility of Janssen and ALZA now that you don't work for them anymore when they're telling the public and doctors that it's a safe drug but they're telling the court that it's an unavoidably unsafe drug?
MS. BENEDICT: Objection, form. Argumentative, foundation.
You can answer.
THE WITNESS: I would want to take time to read this entire thing, not just the highlighted sections.
MR. ORR: Q. Well, I mean I can represent to you that I included everything that discusses this topic in here, pages 14 — everything before page 14 didn't have anything to do with that subject. And I included all the way through the end of that subject, which is at the bottom of page 16.
MS. BENEDICT: Also object that it calls for a legal conclusion.
MR. ORR: Q. But I'm asking you without even considering this document —
MS. BENEDICT: “Unavoidably unsafe” is a legal term of art that has certain consequences in that jurisdiction.
MR. ORR: Q. I'm not asking about any legal terms.
I'm just asking in the ordinary Webster's meaning of the words, do you agree that Duragesic is a plainly and unavoidably unsafe drug when used as prescribed?
A. No.
Q. Do you agree that it carries a risk of respiratory depression that can lead to death, even when used as prescribed?
MS. BENEDICT: Objection, form. Foundation, incomplete hypothetical.
You can answer.
THE WITNESS: Yes.
MR. ORR: Q. And if that's the case, certainly you could agree, can't you, that that's something that should be warned about in the package insert; fair?
MS. BENEDICT: Objection. Foundation. Form. It's outside of his area of expertise. It calls for an expert opinion.
I'm instructing him not to answer, consistent with my prior instruction.
MR. ORR: I'll pass the witness.
MS. BENEDICT: I have no other questions.
MR. ORR: Okay. I want to say on the record that obviously I, you know, reserve my right to reconvene the deposition and go into all the areas where Mr. Gale was instructed not to answer. We don't believe that he was — any valid instruction not to answer — strike that.
We don't believe that there was any valid basis to instruct Mr. Gale not to answer under the Texas Rules of Civil Procedure and, for that matter, under the Rules of Civil Procedure in any of the other cases that Ms. Benedict noticed this deposition in. So we reserve all our rights in that regard.
That's it.
THE VIDEOGRAPHER: This concludes video 2 2 in today's proceedings.
The master videotapes will be retained by Hundt Reporting.
We are now off the record at 3:52 p.m.