This testimony was given in February of 2007 in Lusch v. Matrixx Initiatives, Inc., a lawsuit in the federal district court of Oregon.
Personally, I like how the defense expert is put on the spot about using Zicam on his own nose.
Q. Okay. So then tell us, Doctor, what experiments you did on the Zicam cold remedy gel that you personally observed.
What -- what is the -- were the mass and the speed and the distance calculations that you performed?
A. I would say that my study is -- was simply a one-time firing, probably in my office, where I actuated the unit and just looked to see what's the physical form of the spray coming out. So it's -- I did not measure the mass or the velocity or -- there was nothing to measure a distance to.
Q. So the opinion that you gave here today, and you talked in detail about testing and modeling and pharmacodynamics and pharmakinetics, and all of those things; mass, distance, and all that have stuff.
What you did, Doctor, with the product that's in issue in this case, is you sat in your office and you fired it off. Right? One time?
A. I think that I did all of the other things that I talk about in here, which is reviewing the literature.
I just wanted -- I'm curious. I wanted to know what Zicam looked like. I also needed, of course, to look at my observations and see if there's anything fundamentally different from what Dr. Jafek did. In fact, I would say that what I did is, you know, a perfectly reasonable one-off experiment, and carries the same weight as a single one-off experiment with a cadaver. I don't think it's necessary to rely on it, but it's about that level of scientific inquiry.
Q. So you equate sitting in your office in your chair, firing this thing off one time, to a cadaver study?
A. I would say they're not that different. In terms of their utility, there's not much difference.
Q. So then -- then all the discussion you had this afternoon about the nasal passages and -- and, you know, you've said, I guess, now, that you don't really have a superior expert understanding of nasal anatomy, but you testified to it a little bit ago. You said that it's not a straight shot.
That doesn't make any difference?
You can get the same result from firing it up somebody's nose as you can sitting in your chair in your office and shooting the thing, what was it, four to six feet?
A. Sounds about right, yes.
Q. Actually, didn't you say you fired it off and at one -- in one case, didn't you say you fired it off and it hit the ceiling?
A. I can't recall if it did or it didn't, but it certainly is a long, narrow plume that goes up in the air quite a long way.
So my observation is not dissimilar from what Dr. Jafek reports.
Q. Okay. So --
A. And just like Dr. Jafek reported, it was a one-time observation.
Q. Right. So -- so what you did with the product itself --
A. Um-hmm.
Q. -- and what we're talking about here is -- you know, Zicam. Right?
A. Correct.
Q. That's the product.
Okay. What you did is your -- you didn't conduct any calculations about mass and speed and distance and particle size. You didn't measure anything. You sat in your office and fired it off?
A. I did what I was asked to do, which was to answer questions. I think you asked this morning, or Mr. Lazarus asked, you know, what was I asked to do. So I was asked to answer questions. I could, I think, have answered the questions quite appropriately without ever needing to see Zicam, but I'm curious. I mean, I really wanted to see what I'm looking at here.
Q. So you wanted to go the extra mile. You sat in your chair in your office and you fired it towards the ceiling. Right?
A. Well, I think you are not letting me finish the -- the answer.
But I mean, I think have quite a bit of background knowledge, as I outlined for you this morning. I've been doing this for a long time.
So once I've established that Zicam is a nasal product -- and not at all products -- it's not all cut and dry. So I think it's a perfectly reasonable thing to go, to look at.
So, remember that I've been looking at lots of products for a very long period of time here. There are powders that go into the nose. I would go as far as to say that I'm familiar with delivery systems that Dr. Jafek has never seen, but of course I can't know that. But I think it's perfectly reasonable to make sure that I am able to answer questions about the deposition of a nasal spray. And to do that, I can't imagine anything more reasonable than to fire it.
Q. Well, didn't you talk this afternoon about, what was it, gamma scintography studies? And mathematical modeling? And measuring mass and speed and distance? And pharmacodynamics and pharmakinetics?
You talked about all of those things. You didn't do any of that with Zicam, did you?
A. It's true that I did not do any of that with Zicam --
Q. Okay.
A. -- because I think I can actually learn quite a lot from the written description of Zicam, and I can actually see quite a lot from observation of the plume. So I -- I can learn something from that. It's a useful thing to do.
Q. So the sum total of your personal experience with the product is firing it in your office. Right?
A. Yes, I think that's true.
Q. Okay. So you didn't even try the product on your own nose, did you?
A. No, I did not try it on my own those.
Q. And so you don't know, for example -- and I see you've got one sitting up there, and I don't know if you want to try it now. But if you put that thing deep in your those, and you fire it off, you think it would reach your nasal epithelia?
THE COURT: Very well, then. For purposes of this hearing, then, anyone who's going to be called should step out in the hall.
You may come forward, Mr. Dalby.
THE WITNESS: That's fine.
Is this where I'm going?
THE CLERK: Here's fine.
Please raise your right hand.
THE WITNESS: Oh, okay.
(Witness sworn.)
THE CLERK: Please take a seat up here.
Please state your name, and spell your last name for the record.
THE WITNESS: Sure. My name is Richard Dalby. And the last name is spelled D A L B Y.
MR. LAZARUS: Thank you.
THE COURT: Mr. Lazarus.
DIRECT EXAMINATION
BY MR. LAZARUS:
Q. Dr. Dalby, is this your first time testifying in an American courtroom?
A. Yes, it is.
Q. Please be sure to keep your voice up, and try to address the questions as quickly and succinctly as possible.
THE COURT: Same thing for you, for the court reporter.
BY MR. LAZARUS:
Q. Doctor, why don't we start by talking about your background.
Tell me about your educational background, starting with your college.
A. Sure.
I got a professional degree in pharmacy from the University of Nottingham, in England, in 1983. And three years later I graduated, practiced as a pharmacist for approximately a year, then went on to graduate school at the University of Kentucky. I got a PhD in pharmaceutical sciences in 1988. I then went and worked for a pharmaceutical company that specializes in pulmonary medication delivery in the United Kingdom.
About a year after that, I decided to move to the Medical College of Virginia in Richmond. I took an academic position as a research assistant professor.
Q. Let's take it a little more slowly than that.
First of all, you have a PhD in pharmaceutical sciences?
A. Correct.
Q. You earned, then, the distinction of being called a doctor. I'm going to refer to you as “doctor,” given your PhD. Is that all right?
A. That's fine.
Q. Now, Doctor, after your education was completed, you said you practiced for a time as a pharmacist?
A. Correct.
Q. And that was in what area?
A. You mean after my pharmacy degree?
Q. Yes.
A. Just as a general pharmacist, that's the professional license to practice pharmacy in the United Kingdom.
Q. And eventually you went into academia?
A. Correct.
Q. And what institution did you begin teaching at?
A. At the Medical College of Virginia, in Richmond.
Q. How long did you stay there?
A. I stayed there approximately three years before going to the University of Maryland.
Q. What was the focus of your teaching there?
A. The whole time, I have been researching the behavior of small particles, primarily in the lung and the nose.
Q. And did that develop into some sort of specialty in your career?
A. Yes. Almost every aspect of research and professional teaching I do, now, is somehow related to nasal and pulmonary delivery.
Q. Let's continue with your career trajectory.
What did you do after teaching at the university?
A. I moved to the University of Maryland. I took a position as assistant professor of pharmacy.
And then over the years, I moved through the ranks. So I'm now a professor of pharmacy at the same institution. And throughout that period, I've been a teacher and a researcher.
Q. And what has been the focus of your teaching at the University of Maryland?
A. Again, I teach primarily pharmacy students. A little bit of teaching to chemical engineers and dentists, but primarily pharmacy students.
Q. And what subjects do you teach?
A. I teach what's called pharmaceutics, drug delivery systems. I teach compounding and basically things relating to how drugs get to a site of action in order to have any effect.
Q. And have you had a research focus while you were at the University of Maryland?
A. Yes. As a researcher, as I said before, I've focused on the delivery of particles into the lung and into the nose, the types of formulations that are used to deliver those, the types of methodologies that might be used to evaluate where they go.
Q. Now, this specialty in the behavior of small particles in Page 8 the nose and lung, is there a focus in that -- within that specialty on nasal drug deposition?
A. Yes. Although I started out doing a PhD in the behavior of particles that primarily go into the lung, since about 1995 I've also had a lot of interest in where they go when they're inhaled into the nose.
Q. Now, this study of the behavior of small particles in the nose, is that essentially the study of where things go in the nose?
A. Absolutely.
Q. And -- and is it also the study of what the variables are in determining where things travel in the nose?
A. Sure. I'm interested in what determines where a particle goes, and how we might manipulate that to make it go where we want it to.
Q. So a shorthand way of saying that is you focus on studying where particles go in the nose and why that's where they go in the nose. Is that fairly accurate?
A. Yes, I think that's accurate.
Q. Now, I hear that you've been studying this, now, for about the last decade, focusing on the nose, as opposed to other areas of the nasal -- of the airways?
A. That's true.
Q. Why do you study what happens to things in the nose?
A. Well, there are a lot of reasons. But the nose is a very useful target for drugs that might act locally, such as vasoconstrictors or steroids used to suppress inflammation. So that's the sort of historical use of the nose.
But also there's a lot of research interest in whether it might be possible to use the nose as a port of entry into the bloodstream for delivering drugs such as insulin or Calcitonin or Zomig, things that fight migraines. So it's a way of avoiding an injection. So that's one motivation.
There are also a number of patients, unfortunately, who suffer from sinus-related conditions, and so there's interest in how we might be able to reach this particularly difficult target. And also there's speculation about whether it might be possible to get drugs into the brain of patients for treatment of conditions like Alzheimer's disease, which is very difficult right now, going in through the bloodstream.
Q. You used the word -- I want to make sure we understand, here.
You used the word “vasoconstrictors.” What does that mean?
A. A vasoconstrictor is a drug that will essentially reduce the diameter of a blood vessel.
Q. And is the general import of that that it will shrink the tissue?
A. Yes. Of course, if the blood vessel contained in the tissue gets smaller, then the tissue shrinks right along with it. That opens up the airway surrounding that tissue.
Q. Now, before we leave this area of your background, and especially with respect to this specialty, is there anything else in your background that's relevant to your expertise in this specific area?
A. I think I'm -- if I'm understanding you correctly, I mean, my background is unfortunate that I enjoy teaching, and so I've run a lot of teaching workshops over the years. I also run -- one of the co-organizers of the Respiratory Drug Delivery meeting, which is probably the biggest meeting in the world focused on the delivery of particles into the lung, into the nose. So as a headed the proceedings, I'm in a fortunate position to be able to kind of see what other people are doing before it's out in public.
Q. So does this enable you to keep tabs on the literature, as it develops within your scientific community?
A. It's a good way to keep up-to-date, for sure.
Q. Now, you told us that you focus on the behavior of small particles.
Does that include solutions?
A. Yes. The majority of particles can be general solutions, but there are also suspensions or even solid particles.
Q. In this case, in your work in this matter, it was related to a cold remedy called Zicam.
What kind of a substance is Zicam?
A. The formulation itself is a -- is a viscous liquid with a drug dissolved in the formulation and a number of excipients. The major one is to increase the viscosity. So it's sometimes, I think, described on the box as a gel.
Q. You used the word “excipients.” What does that mean?
A. I'm sorry. Excipients are the inactive ingredients that are put in a formulation that are not believed to have any direct pharmacological effect, but they're in there for some other benefit.
A. Correct.
Q. Now, you said that in describing the specialty, that you focus on the behavior of small particles --
A. Um-hmm.
Q. -- in the nose and lung.
Just tell me, what do you mean by behavior in that context?
A. I mean, when -- when you've used the nasal spray pump, for example, you used the delivery system, particles will be generated. And I'm interested in where they go and what's the mechanism by which they might get there.
Q. Doctor, let's talk about the science of nasal drug deposition.
Why is this an area of interest to science? To scientists?
A. Well, as I said before, it's of interest because it provides an alternative way of administering drugs to the bloodstream without the need for an injection. It provides a way of treating regions of the nose that might otherwise be difficult to -- to access.
And then, as I said before, for helping patients to breathe more easily by causing local effects.
Q. How active is this area of scientific research?
A. It's a very active area, driven -- in large part -- by trying to treat some of these conditions that are very difficult to treat and getting drugs into the bloodstream, as I suggested.
So, for example, the last meeting that I helped organize in the United States, there were more than 700 scientists who have an area of explicitly -- an area of interest explicitly related to how you might get things into the lung or into the nose.
Q. And within that community of scientists who are involved in the nasal drug deposition research, what specific scientific disciplines are involved in that study?
A. Well, there's a very big range of people involved. There are folks who are essentially mathematicians or chemical engineers who use mathematical models to predict the behavior of particles in the -- in the geometry of the nose.
There are scientists like me, who sort of come at things from the pharmaceutical end of things, why we look at what you might change about formulations and how you might manipulate where particles go in the nose.
And then, of course, there are clinicians who evaluate, in patients, where particles go in the nose and what effects the drug those particles carry might have on the patient.
Q. And is there a body of literature that's grown up devoted to this area of scientific research concerning the deposition patterns of nasal drugs and how they can be modified?
A. Sure. There's quite a significant body of literature out there now.
Q. Have you contributed to this body of literature?
A. I like to think so, yes.
Q. We'll talk about what studies you've done in the relevant area, as we go along.
Tell me, generally, in the scientific research concerning nasal drug deposition, do the researchers use the scientific method?
A. Yes. I think that's always the intent. They try to.
Q. And what types of data, generally speaking, do researchers in the area of nasal drug deposition rely upon?
A. There are a number of different methodologies that are applied. There is the idea that you can put dye formulations in --
Q. Well, I'm asking more generally. And I'm sorry to interrupt you. But just generally what type of studies you rely upon; scientists in this field.
A. Just well -- you know, well-controlled studies in which we can test a particular hypothesis and be able to elicit answers to questions that are sometimes quite difficult to -- to investigate.
Q. You used the term “controlled studies.” What does that mean?
A. That just means we try to -- or at least I try to engage in hypothesis-driven research where we'll try to identify a problem, try to mitigate the other things that could go on to compound the results, so we can look explicitly at what formulation changes affect where particles go.
And obviously, you know, along with that is the necessity to try to make sure that the findings are statistically valid, they're replicated. Where appropriate, they're blinded. Or just trying to make sure that you really are investigating what you believe you're investigating.
Q. And are controlled studies preferred in trying to apply the scientific method to investigate a scientific phenomena?
A. I think that's always true.
I mean, we always try and design studies, to the best of our abilities. Sure.
Q. Now, I cut you off when we were getting a little more detailed about the types of studies that are performed in this area, so I want to give you the opportunity to continue.
What test methods and test procedures are used in the field of -- of nasal drug deposition to investigate drug deposition patterns and principles?
A. There are a number of different methodologies that I use.
You'll see dye studies, where the formulation has some dye to it, or a placebo is dyed to try and visualize the drug in the nasal cavity.
You'll see studies done with a radioisotope in place of a dye. And that radioisotope allows us to visualize where the formulation is going in the nose, without actually having to scope the patient. So it's a noninvasive way. Nonetheless, it still does require cooperation from patients and volunteers.
So another approach to avoid that and be able to study a wider range in variables is to use models. And so we have models derived from nasal casts of cadavers, and we also have models derived from CT scans of patients in life. So those are the types of studies that are done.
And on the model studies you can do very much the same thing as you can in patients. You can use dye formulations or isotope labeled formulations; primarily Technetium-99A.
THE COURT REPORTER: I'm sorry. Primarily, what?
THE WITNESS: Oh, a chemical radio emitter. It's called Technetium-99A. It's a gamma emitter.
BY MR. LAZARUS:
Q. And are there also mathematical modeling exercises that can be done to try to investigate nasal drug deposition patterns?
A. Yes. You can use computational fluid dynamics, which is what I was trying to speak about earlier, when you stopped me, which is the idea you can know something about the geometry of the nose, know something about the behavior of particles traveling within that geometry, and predict where they'll deposit.
Q. Now, the specific research that you've done in the area of nasal drug deposition, what types of investigations have you conducted in this area?
A. I've done at least three studies using gamma ray emitters. So the isotope we spoke of earlier, Technetium-99A, where we will dose volunteers with a formulation, and then externally image where those droplets deposited. And we find that from tracing where the radiation emanated from.
Q. That's always a cue that you're speaking too fast. So if you could try to slow down a little bit.
A. The speed I can do something about. The accent, that will be more of a challenge.
Q. You mentioned that you've done some of these gamma scintigraphy imaging studies.
A. So we talked about ones in volunteers.
MR. JOHNSON: Excuse me. I apologize. I couldn't hear counsel's question.
MR. LAZARUS: I'll repeat it.
BY MR. LAZARUS:
Q. You mentioned that you had performed these gamma scintigraphy studies?
A. Correct. That's gamma scintigraphy studies done in volunteers. I've also done gamma scintigraphy studies in nasal models, which allows us a bit more flexibility. And we can do more replicate testing and have a higher degree of confidence in the answers. And I've also been engaged in dye studies in -- in casts, as well. In nasal casts.
Q. And have your investigations using these techniques resulted in published research?
A. Of course, yes.
Q. And, generally speaking, what has been the focus? If you could give us some examples of the types of research that you conducted using these techniques.
A. Sure. I've looked at, for example, different nasal spray pumps available from different manufacturers. There are different types of pump available. So I've looked to see are two pumps comparable, in terms of the spray they produce.
I've compared different types of delivery systems for nasal administrations, such as a spray pump to a device called a nebulizer. I've also -- also done those kinds of studies in models, silicon models.
And I've also done some studies involving a drug, nicotine, where we have gone one step further and looked not just at the deposition pattern but the resulting appearance of the drug in the bloodstream; so called pharmacokinetics, and then measurable biological response. It's called pharmacodynamics. And it just describes -- you know, can we see a change that we can attribute to the drug, such as a change in blood pressure.
Q. Doctor, I'm going to stop you occasionally and ask you to clarify certain terms that you used, just for all of our benefit.
You used the word “nebulizer.” What is a nebulizer?
A. A nebulizer is an alternative delivery system to a nasal spray pump. And instead of using the patient's hand actuation, hand movement to generate spray, compressed air or vibration of a pisoelectric element generates an aerosol.
But the primary difference between a nebulizer and the spray pump is in the size of the particles that are produced. So nasal spray pump, you're generally talking about quite large particles. A nebulizer, they tend to be much smaller.
Q. And can you put some numbers about the ranges of the sizes of particles that you would see in each of the different devices?
A. Sure. Nebulizers are quite small. I would say small, a good working definition would be somewhere between 1 micron and maybe an upper range of 7 microns.
A nasal spray, there are almost no particles anywhere close to 10 microns. Most of the massive droplets is carried in the -- by particles in the range of 60, 70, all the way up to 100-plus microns.
So in -- in the area that I work, I think of a 100 micron particle as being very large.
Q. Another term you used -- and I would like you to define for us -- is “pharmacodynamics.”
A. Pharmacodynamics just means that we administer a drug, and it has a biological effect that we can measure, that we believe is directly related to the concentration of that drug.
Q. And as I understand your testimony to this point, pharmacodynamics is not really your focus in your specialty?
A. That's correct.
Q. You also used the term “pharmacokinetics.” What does that mean?
A. Pharmacokinetics just means describing the time cause of the appearance of a drug in the bloodstream, primarily, or at some other effect, or something.
Q. And, again, is pharmacokinetics part of your focus within your specialty?
A. I've used it to a limited extent, but not really. I'm kind of very specialized in the area of drug deposition.
Q. Let me ask you, in the area of nasal drug deposition, the types of test procedures that you've described -- gamma scintigraphy within humans and in models, dye tracking studies in humans and in models, mathematical modeling, and computational fluid dynamics procedures -- are these the types of methods generally accepted in the scientific community related to nasal drug deposition to investigate nasal drug deposition patterns?
A. Absolutely. You see quite a number of publications on all of those different areas.
Q. Now, Doctor, I want to switch gears a little bit and talk about your work with respect to Zicam.
A. Okay.
Q. What were you asked to do in connection with the Zicam litigation?
A. I was really asked to answer some fairly fundamental questions about, you know, where this drug is likely -- or where this formulation is likely to go.
Q. Were you asked to bring to bear on answering those questions your background, experience, and knowledge in the field of nasal drug deposition?
A. Yeah, of course. I mean, I think that was the reason I was asked, and I think that's laid out in the deposition that I gave.
Q. And were you asked to review and refamiliarize yourself or familiarize yourself with the literature in the area of nasal drug deposition to answer these questions?
A. Yes, I was.
Q. Were you asked to review any additional scientific evidence that specifically relates to Zicam distribution and deposition?
A. Yes. I was given some additional information about the study done in Pittsburgh, and one done in Spain.
Q. And were you asked to review the packaging that comes with the Zicam product when it is sold in the stores?
A. Yes, I was.
Q. And you were asked to answer specific questions by the attorneys for Matrixx, and did you prepare a report containing those answers?
A. Yes, I did.
MR. LAZARUS: And for the record, your Honor, that report has been marked as Exhibit U to our papers that were submitted in support of our motion.
BY MR. LAZARUS:
Q. Now, Dr. Dalby, are there generally accepted physical principles that govern this question of where things go in the nose?
A. Sure. Actually more general than where things go in the nose. They govern where things go in the lung and the nose as well. Any particle moving through an airstream or any solution moving through an airstream.
Q. Well, focusing specifically on the question before us, which is where things go in the nose, what are the general principles that govern this question?
A. Well, the major things that are going to govern where a particle is going to go in the nose is anything that affects the generation of those particles. So it's going to be things like the geometry of the nose, its internal anatomy. It's going to be the nature of the formulation that's actually sprayed into the nose. It's going to be the nature of the hardware that's used. The spray pump itself and the actuator and the swirl chamber. So the mechanics of what goes into the nose. And, of course, the patient interacts with that by pressing down on the pump. So how hard they press, how long, things like that. We -- so how the pump is actually used in the hands of a given patient.
Q. What is the most important factor that controls where a substance will travel in the -- within the nasal cavity.
A. I think the most important thing, really, is the -- the mass of the particle, which really comes down to the -- well, it's -- well, let me back up.
It's really the momentum of the particle. So that's really speaking about its particle size.
Q. Is there a general rule recognized in the scientific community concerning nasal drug deposition regarding how particle size influences where a substance will travel in the nose?
A. Sure. Particle size, really, combined with how fast a particle is moving governs its momentum.
And so we spend a lot of time worrying about a phenomenon called impaction, which really dictates how a particle goes from moving into an airstream to depositing on a surface. And, of course, depositing on a surface is kind of the precursor for release of drug and ultimately, we hope, some sort of beneficial biological effect on the patient.
Q. So -- I'm sorry. The general rule regarding particle size and its influence on nasal drug deposition, does it have to do with the size of the particles?
A. Of course, yes.
Q. Okay. And is there a general rule you can state for easy reference?
A. I mean, the -- the basic thing that governs a lot of what I do is the notion that large particles are very resistant to changes in direction of travel after they're generated, where smaller particles are much more amenable to a change in direction if some force acts on them to move them. So --
Q. So is it generally recognized in the scientific community that larger particles are more difficult to deliver to the further or higher reached -- reaches of the nasal cavity?
A. Absolutely. I can't imagine really why anybody would try to use a large particle, if you're trying to get deposition high in the nasal cavity.
Q. And the converse of that, is it also true that the smaller the size of the particle, the more likely you will be able to deliver some of the substance to the higher or further reaches of the nasal cavity?
A. That's true. It would be still difficult, but at least more plausible with smaller particles.
Q. What do you mean when you say that it's so difficult to get in the small particle to the further and high reaches of the nasal cavity?
A. I'm sorry. Now it's my turn to ask you to repeat. I couldn't hear because of the cough.
Q. Certainly.
Why is it that even smaller particles are difficult to deliver to the highest or furthest reaches of the nasal cavity?
A. Well, just because it's a very convoluted organ. There's no easy way to reach the upper part of the nose, which is a good thing if you pick your nose.
But the -- you know, it's just difficult to get particles up there.
There's no easy mechanism to particularly get large particles. And even for small ones. They have to avoid capture lower in the nose. They then have to be transported further up into the nasal cavity. So it's just an inaccessible target, with not very many options to get in there.
Q. Are there biological reasons why we want it to be harder to get particles up into the upper reg -- regions of the nose, such as the olfactory area?
A. Well, I think the -- the -- the nose is recognized to have a number of functions in -- in living, breathing human beings. And one is to purify the area, to some extent, before it goes into the lung. It has good defense mechanisms to stop that. And so it's perfectly reasonable that the lung -- sorry, that the nose would be quite an effective capture mechanism for particles.
Q. Now, let me take a step back, and just establish something with you.
The -- the area that we're concerned with in this case, in terms of distribution of the drug, is the olfactory area.
Can you tell us where the olfactory area is within the nasal cavity?
A. Sure. Again, I think I heard the last part of the question. Where it is in the nose?
Q. Where is the olfactory area within the nasal cavity?
A. It is right in the roof of the nasal cavity, towards the back.
Q. So it's at the top-most region of the nose?
A. Correct.
Q. And is that also the region that is hardest to reach for a larger-size particle?
A. Yeah, that's a very inaccessible region, and particularly so for large particles.
Q. Now, this general rule that the larger size the particle, the more difficult it is to make it travel further or higher into the those, can you give us a practical example of how this principle effects strategies for nasal drug delivery?
A. Sure. I mean, if somebody is deliberately, for whatever reason, trying to get drug particles further up into the nasal cavity and to cover a larger percentage of the area in the nasal cavity, all of the approaches that I've seen have been pursued by companies who are interested in treating things like Alzheimer's disease or getting drugs into systemic circulation take the approach of making particles absolutely as small as they can to be able to have those particles follow the airstream and have some mechanism by which they might get high into the nasal cavity in the region of the olfactory area.
Q. And does this influence what devices they are working on to try to get particles higher in the nose?
A. Absolutely. All of the ones that I am familiar with are companies that are trying to get stuff into the brain or get stuff into the sinuses, anything that requires a lot of coverage in the nasal cavity are, without exception, using nebulizers.
Q. Now, this general rule that larger particles are more difficult to deliver to the upper regions, including the olfactory area, does that rule also apply with respect to Zicam, which leaves the container in a stream?
A. Um-hmm. Sure. The formulation of Zicam is very analogous to other nasal formulations. It's more viscous. Therefore, it leaves a stream, as you suggest. But, nonetheless, it's a highly directional stream, moving at a particular velocity as it leaves the spray nozzle. Those are the characteristics of a -- the -- they'll be to impaction. It has a velocity. It has a mass. And a -- quite large, in my estimate. So they are going to be very resistant to change in direction, and, therefore, very likely to deposit low in the nasal cavity.
Q. So is it true, then, that Zicam behaves like a very large particle and more like a large droplet?
A. Sure. I think -- certainly it's a lot more analogous to that than it is to a small particle like you might get from a nebulizer.
Q. Now, the principle that larger particles are more difficult to deliver to the olfactory area, is that principle generally accepted within the scientific community?
A. I don't think anyone would use a large particle to try and target the olfactory region. But, I mean, the principle of impaction, that large particles are resistant to changes in direction and, therefore, carry on, unless they have a reason not to, I think, is very well established.
I mean -- and not just in pharmaceutical aerosols. I mean, that's the reason it's hard to drive an SUV around a tight bend at high speed, and yet it's much easier to drive a small sports car around the same bend at lower speed. It's all a question of mass and velocity. And those are the things that -- I mean, they're very basic principles.
And, in fact, I actually use the same principle to size aerosols, according to an instrument called a Cascade Impactor, which causes one impaction after another.
Q. The principle that larger particles have greater difficulty in reaching the higher portions of the nasal cavity, has that been borne out by your research?
A. Absolutely, yes.
Q. And this notion that it's very difficult to get large particles to the olfactory area of the nasal cavity, is that true even when the intent is to deliver particles in that area, as research into delivery to the blood/brain barrier?
A. I don't think anybody really -- at least I'm not aware that anybody would deliberately choose that approach, if you were to try it. But I think it would be very difficult.
MR. JOHNSON: Excuse me, your Honor. May I please just interpose a bit of a foundation objection here?
Counsel has used the term “olfactory area.” The witness has never defined the anatomical structures which are found in that area. I think it would be important for us to have that in the record.
THE COURT: Well, you certainly can do that as part of your cross-examination, unless Mr. Lazarus wants to do it at this time.
MR. JOHNSON: Thank you.
MR. LAZARUS: I would be happy to do it, your Honor.
BY MR. LAZARUS:
Q. Can you see that, Dr. Dalby?
A. Yes, I can.
Q. Okay. Dr. Dalby, does this appear to be a reasonably accurate description of the structures of nasal anatomy?
A. Yeah. It's a lateral view. A schematic of the lateral view through the nose.
Q. When we talk about the olfactory area, as we have within the course of your testimony, can you tell me -- based on the -- the regions identified on this document -- which areas you have in mind?
A. Sure. Do you see anything if I point to the screen, or --
THE COURT: You can point to it, if you want. Mark it with your finger, I believe.
THE WITNESS: Okay. It's sort of up in -- (pointing.)
The arrow is a pretty good representation, although it would appear by a mechanism that I'm not sure how.
THE COURT: You can take a picture of that, if you so chose.
MR. LAZARUS: Yes. That would be helpful, if we could do that.
THE COURT: Jenny, do you want to help them take a picture of that?
THE CLERK: I'll try.
THE COURT: We'll learn together.
THE WITNESS: Do you want me to try again, and hit it -- I mean, it's -- I hit it with my finger, and it drew boxes where I didn't intend in the first. Obviously, I'm not suggesting that the region is outside the nasal cavity.
THE COURT: All right. Why don't we clear that first, Jenny. Clear that.
MR. LAZARUS: We need to clear it, and then he's going to redraw it.
THE COURT: We've got some trouble with our equipment, so we're working on it.
THE WITNESS: As I teach a lot, I'm used to this kind of thing. If it would help, I can put an X on the paper drawing, and you can put it on the screen. Low-tech, but --
MR. LAZARUS: That's a good suggestion, Dr. Dalby. Why don't we do it that way, if it's all right with your Honor.
THE COURT: It's fine with the Court.
MR. LAZARUS: May I approach the witness, your Honor?
THE COURT: You may.
THE WITNESS: I will need a pen from somebody.
(Witness handed document.)
THE WITNESS: Unfortunately it's a blue pen on a dark black area. But I can show you where --
THE COURT: Here, I'll give you a red pen.
THE WITNESS: Thank you.
This is the area I'm talking about.
Still I think you might have trouble. Unfortunately, I don't think it shows up very well.
MR. LAZARUS: If I approach, again, your Honor --
THE COURT: You may. Why don't we mark this defendant's exhibit. Have you marked anything yet?
MR. LAZARUS: No.
THE COURT: All right. Mark this Defendant's 101.
You may proceed.
THE CLERK: Mr. Lazarus, let me put this on it. Thank you.
THE WITNESS: Unfortunately, I'm the one who drew it, and I can barely see it on the diagram.
BY MR. LAZARUS:
Q. Well, we can all see the diagram right now. Why don't you just show us with your finger what portion of the --
THE WITNESS: May I borrow your pen, again?
THE COURT: Sure.
BY MR. LAZARUS:
Q. Showing us the portion that is the olfactory area, as you have been testifying to.
A. No box is appearing. Do I need to do something else?
It disappeared. There's no picture.
THE COURT: If you're going to mark it there -- use it -- he can mark it on the screen, once it's on the display. But he can't do it --
THE WITNESS: (Witness handed document.) So there.
BY MR. LAZARUS:
Q. Thank you, Dr. Dalby.
MR. LAZARUS: And thank you, your Honor, for your patience.
THE WITNESS: So what I tried to indicate there is the roof of the nasal cavity. And then just to make it clearer in the area roughly between those two vertical lines that I drew.
MR. CROW: Oh, the vertical lines.
BY MR. LAZARUS:
Q. Now, Dr. Dalby, just to elaborate on this a little bit, the olfactory area is up near the midline of the eyes?
A. Well, right -- right in the roof of the nose. Yeah, approximately that region.
Q. And it's set back a little ways above a few structures there. And I'm wondering if you could tell us what those three bony-type projections are that are depicted below the olfactory area that you've drawn.
A. Sure. This is a -- you know, as I said, a stylized diagram. But it's showing the arrow or the line that goes to the nasal cavity. That area is the entrance to the nasal cavity through the nose. And then the three structures you you're looking at are the inferior, middle, and superior turbinate.
Q. What are the turbinates, if you could describe them for us.
A. Sure. They're bony projections from the side of the nose that project into the nasal cavity. So they occupy quite a lot of volume within the nose. And the spaces between them are the meatus, the air space through which we breathe air into our lungs.
Q. And what is the anatomical purpose of the turbinates?
A. I can -- I don't have a definitive answer to that. But the speculation is that the increase in surface area, both humidifies and warms the air going through the nose into the lung. And, therefore, helps protect the lungs. So it's like an air-conditioning system.
It also is believed that it laminates the air flow, so we get streamlined flow, which reduces the energy to pull air through that system. Which has the effect of making it easier to breathe, so we don't waste so much energy when we depress the diagram to inhale.
And they also play a significant role in the capture of airborne particles that obviously we would like to avoid getting into the -- getting into the lungs. That's why if you renovate old houses, like I do, and you do a lot of drywall sanding, that's why you have a lot of stuff that accumulates in the nose afterwards. So that's really their functions.
But -- well, I think that's good enough, or I can talk more, if you would like.
Q. So the turbinates are part of this filtration function that the nose carries on?
A. I would call it a protective function, because it's not actually filtration. It has the effect of removing airborne particles from the airstream, but it's not doing it by filtration. It's doing it by impaction.
Q. And these turbinates, these bony structures that are underneath the olfactory area, are they part of the reason why it is difficult to get particles of larger size up to the roof the nasal cavity?
A. Absolutely. They -- they represent a physical barrier, which makes it very difficult to get particles up into the higher regions of the nasal cavity.
Q. Thank you, Doctor.
Doctor, again, turning our attention to Zicam, applying what you've told us, now, to the use of Zicam, what are the critical characteristics that govern the deposition of Zicam in the nasal cavity when the product is used as directed?
A. As I said before, not just Zicam, for all products. But it's going to be a question of what is the mass of the stream coming out, how fast is it moving, and what is the distance between the tip of the spray nozzle and the first oblique surface that that stream of liquid encounters.
Q. And with respect to the example of Zicam used as directed, the mass of the stream -- you've told us that this stream behaves like a large particle. Correct?
A. Correct.
Q. And does that make it less likely that the Zicam will travel to the upper portions of the nasal cavity?
A. For all of the reasons I mentioned, yes. Has a lot of mass. It's moving quite quickly. And if it's used as directed, it's been fired into the lateral wall of the -- of the entrance into the nose. So very unlikely.
Q. Okay. One step ahead of me.
The -- you mentioned the distance to the first oblique surface.
A. Um-hmm.
Q. When Zicam is used as directed --
MR. LAZARUS: Could we have a bottle?
May I approach the witness, your Honor.
THE COURT: You may approach without request any time.
MR. LAZARUS: Thank you, your Honor.
MR. JOHNSON: May we have that marked, your Honor?
THE COURT: Yes. Well, are you going to offer this?
MR. LAZARUS: No.
THE COURT: Then --
MR. LAZARUS: Just use it for demonstrative purposes.
BY MR. LAZARUS:
Q. Doctor, I'm handing you a box of Zicam cold remedy. It contains within it a bottle.
And I want to talk to you about the directions for use and the illustration on the box and how that affects the distribution pattern or the deposition pattern of the drug.
A. Sure.
Q. First of all, if you take the bottle out, can you show us what the bottle looks like?
A. (Indicating.)
Q. Now, with respect to the directions for use, are they -- do they appear on the panel of the box?
A. Yes. They're on the side panel on the outside of the box.
Q. And, for the record, Exhibit U to defendant's moving papers -- which is Dr. Dalby's report -- includes as an attachment a -- a copy of the panel instructions on the box.
Now, Dr. Dalby, what did the instructions tell the user to do?
A. Would you like me to read them or --
Q. Yes.
A. Okay. Directions: 1, remove cap and safety clip.
2, hold with thumb at bottom of bottle and nozzle between your fingers.
3, prior to initial use, prime the pump by holding it upright and depressing several times. Then in parenthesis, Into -- into a tissue, close parenthesis, until gel is dispensed.
4, place the tip of the nozzle just past the nasal opening, parenthesis, approximately one-eighth of an inch.
5, while inside nasal opening, slightly angle nozzle outwards.
6, pump once into each nostril. To help and -- help avoid possible irritation, do not sniff up gel. This product helps put gel in the lower parts of the nose.
7, after application, press lightly on the outside of each nostril for five seconds.
And then for instruction 1, 2, and 3, there's a diagram.
For the first diagram, it simply shows removing the cover and the safety clip.
Second diagram shows the orientation -- or shows how to hold the pump.
And the third diagram shows the pump inhaled, and fired into the fleshy part of the side part of the nose. Those are the instructions on the side of the box (indicating).
Q. Thank you.
Now, in addition to the verbiage that you've told us about, there are specific illustrations or diagrams which show you how to orient the bottle within the nasal cavity?
A. Yes. The -- there is a picture -- I was trying to explain a second ago -- a picture in between Instruction 5 and instruction 6 which shows somebody holding a pump and firing into the outside fleshy part of the external nose.
Q. So, according to the package directions as communicated both in words and in pictures, does it appear to be intended that the location for deposition of the Zicam gel would be in the lower portion of the nasal cavity?
A. I'm -- well, not just -- I mean, it actually says, “Product helps put gel in the lower part of the nose.” So it's labeled on there.
But clearly firing the gel directly into the wall of the nose is very likely to ensure it deposits there. So, yes, I would say that's quite clear.
Q. Now, Dr. Dalby, given the characteristics of Zicam, the physical principles you've told us about that govern nasal drug deposition patterns and these instructions for use, where is the gel most likely to be delivered when the user follows the package instructions?
A. I think if the instructions are followed as they're labeled here, the majority of the gel will be sort in the range that you can -- I know it's kind of gross. But you can reach with your finger, and it will be in the inside of the fleshy part of the nose.
Q. Now, Dr. Dalby, are you familiar with Dr. Jafek's testimony concerning his view that use of Zicam leads to delivery of the gel to the olfactory area?
A. Yes, I have seen Dr. -- the things that you have shown me from Dr. Jafek.
Q. And you're aware, then, that Dr. Jafek bases his -- this view on observations of the distance the gel can travel in the open air? The distance between the nasal opening and the olfactory area and his view that in many people there is a straight pathway from the nasal opening to the olfactory area? MR. JOHNSON: Object. It's leading, your Honor. This is -- this is -- you're aware.
THE COURT: I heard. I sustain the objection.
BY MR. LAZARUS:
Q. Is it your understanding, Doctor, that part of Dr. Jafek's theory is based on the notion that there is a straight pathway between the nasal opening and the olfactory area? MR. JOHNSON: Object, leading.
THE COURT: Again, I'll sustain the objection.
BY MR. LAZARUS:
Q. Doctor, what's your understanding of Dr. Jafek's view of how nasal anatomy influences the delivery of the gel to the olfactory area, in his opinion?
A. It seems to me that Dr. Jafek tries to suggest that there is a direct line of sight between the point of ejection of the spray and where it goes in the nose. And then he builds on that by saying when you fire the nasal spray bottle up into the air, the stream goes quite a long way. Certainly a much bigger distance than the interior of the nose. And so he tries to put those two together and say, okay, the stream is much bigger than the nose. It's highly directional. There's a straight line between the point of ejection and the patient's olfactory region. And so, therefore, I think that's his explanation for how he believes that would happen.
Q. So the purposes of discussing the scientific reliability of Dr. Jafek's opinion and testimony in this area, is that your understanding of what the basis for his opinion is?
A. That's what I believe he is suggesting, yes.
Q. Now, let's break that down.
This notion that there is a straight pathway between the opening of the nose and the olfactory area, have you seen any scientific literature that supports that?
A. No. I -- I have not seen any literature that talks about a straight path between the outside of the nose that's accessible to the formulation that would get you to the olfactory region in the -- in the upper part of the nose.
Q. And is this notion of a straight pathway consistent with the scientific research in the field of nasal drug deposition?
A. I don't believe so. I have never heard that term until -- applied to this area until I heard it -- well, I didn't hear it. I read it in Dr. Jafek's reports.
Q. And if such a straight pathway did exist, given the directions for Zicam use that directs you to release the gel into the lateral wall of the nasal cavity, is it likely that any straight pathway, if it existed, would make a difference on where the Zicam gel would be deposited?
A. In my view, even if it were true -- and I don't believe this to be the case. But even if it were true there were a straight path, the directions are pretty explicit -- at least I believe they are -- to be firing at an angle into the fleshy side of the nose.
And so the only way to even get into the main part of the nasal cavity would be to fire, you know, much back and up into the nose.
So even if there were a straight path, I don't believe these directions would allow a stream to follow it.
Q. Now, a second component to what you've described as Dr. Jafek's analysis is this observation of the release of gel from the container into the open air. Correct?
A. Yes.
Q. Now, this method of observing the release of the gel into the open air, is that something that is ever done in the field of nasal drug deposition?
A. We do some testing where we'll fire nasal spray products into the open lab, yes. But we're not firing into the constrains of the nose.
Q. Why do scientists in your field do this type of observation, and is there a special name for it?
A. Well, the -- the reason that we do it is to compare one product that's on the market to one -- usually a generic product that wants to receive approval from the FDA. So it's done usually within the context of bioequivalence testing to demonstrate that the two products at least visually appear the same. So I think that's the -- the -- that's really the purpose.
The test itself, look -- looking at the jet or the plume from the side, we would generally refer to as -- as measuring the plume geometry. So the shape of the spray up, or cone shaped. And if we looked from the top, we can also do that. We call that spray pan testing, because historically it was done by spraying onto a solid surface.
So those are the two methods that we can utilize.
Q. Do scientists in the field of nasal drug deposition ever use observations of plume geometry to predict the pattern of drug deposition within the nasal environment?
A. No. There's really no good evidence for what I would term an in vitro/in vivo correlation, whereby we can make some finding from spraying into the open lab to where that formulation is likely to show up in the nose of the patient.
Q. Well, can you reliably predict deposition pattern from an examination of plume geometry?
A. It would be nice to be able to. But, no, I can not.
Q. Why not?
A. Because there's really no literature that demonstrates that it's possible. And on the occasions when I've tried to do that -- because it would be a useful thing -- I was unable to demonstrate that correlation.
Q. So you yourself have studied the question of whether plume geometry correlates to deposition pattern in the nose?
A. Yeah. I've had graduate students in my lab try to correlate the patterns that we see, firing into the open lab, with where things go in both patients and in nasal models.
We've tried on two separate occasions with two different experimental protocols, with multiple patients, well controlled studies, trying to eliminate all sources of variability.
So it's kind of a best-case scenario, and still could not demonstrate a -- any kind of correlation between spray pan, or plume geometry, even though we knew they were different with deposition site in the nose.
Q. Now, finally, Dr. Jafek, in his analysis in his testimony, also relies on an experiment that he performed on a sectioned cadaver.
Are you familiar with that?
A. Yes, I read of that.
Q. I did not hear that type of study described when you were telling me what -- the various methods that are used in the field of nasal drug deposition to predict deposition pattern.
MR. JOHNSON: I'm going to object to -- I don't know if that was a question, your Honor. But, also, there's no foundation that this gentleman -- a very, very fine pharmacist -- is competent to testify to this issue, which is a cadaver study performed by a board certified otolaryngologist.
I think he may be, but I don't think the foundation is there at this point.
THE COURT: Do you wish to question in aid of objection?
MR. JOHNSON: I'm sorry, your Honor?
THE COURT: Do you wish to question in aid of an objection, then?
MR. JOHNSON: I do.
THE COURT: All right. You may.
MR. JOHNSON: Should I do it from here or over there?
THE COURT: Remain seated, is fine with the Court.
MR. JOHNSON: Thanks. Just want to get the protocols down.
Dr. Dalby, have you -- you are not -- you are not a physician. Correct?
THE WITNESS: Correct.
MR. JOHNSON: Not a board certified otolaryngologist. Correct?
THE WITNESS: Absolutely. Correct.
MR. JOHNSON: You do not study or test chemo sensory causes of smell loss. Correct?
THE WITNESS: Correct.
MR. JOHNSON: You've never done a nasal endoscopy?
THE WITNESS: I have never done a nasal endoscopy.
MR. JOHNSON: Never done a cadaver study?
THE WITNESS: I have worked with cadavers on occasion, but I don't really know what you mean explicitly by a cadaver study.
MR. JOHNSON: Why don't you tell us what you've done with cadavers.
THE WITNESS: Sure. As I said, I have a long history of interest of where things go in the lungs and the nose. And obviously a first step, I think, to -- when I started to get into that, I was to learn something about nasal anatomy, I think is the focus here.
So my first approach, obviously, was to go to the textbooks and the literature. I made appointments with researchers in both the medical school at the University of Maryland and the dental school.
And both the gentlemen I spoke to were kind enough to show me -- even though I didn't particularly enjoy the experience -- were kind enough to show me the sectioned human heads -- both -- of a relatively recent lady who had died and also a head that had been sectioned and frozen, I think, in anticipation of a gross anatomy lab.
But you're correct. I have looked at those. I have had structures pointed out to me. I have had a chance to -- to touch things, just to see what they felt like. But I haven't really used them in a study, except for -- I told you I work with models. And I usually now get my models from people who are much better at this stuff than me. But I did, in the early stages, try to power silicon molding fluid into the airways of noses of cadavers. And then, afterwards, to dissect away all of the tissue to be left with the model of the airway that I could use.
MR. JOHNSON: So you have never performed a cadaver study for purposes of testing the nasal deposition of any kind of an aerosol gel or nebulizer and -- and where it ends up in the nasal cavity?
THE WITNESS: I have never used a cadaver to spray a blue solution into them and then try and make inferences about where in life it would go in a patient.
MR. JOHNSON: And you did not do that -- this is subsumed in your answer. You didn't do that with Zicam here, either, did you?
THE WITNESS: Oh, no, I did not.
MR. JOHNSON: So you are -- you are -- with all due respect, sir, a pharmacist who is seeking to testify on whether a board certified otolaryngologist, who specializes in smell loss -- whether his cadaver study that he did determined the deposition of Zicam in the nasal passages -- it is your intention to testify on that issue, the reliability of -- of the methodology by this board certified otolaryngologist in this case?
THE WITNESS: I think --
THE COURT: Before answering that, let's -- do you have an objection, then, Mr. Johnson, to the last question?
MR. JOHNSON: I do not believe he's qualified to give the opinion, your Honor.
THE COURT: All right. I'll sustain the objection.
BY MR. LAZARUS:
Q. Dr. Dalby, are you an expert in what forms of testing are done in the field of nasal drug deposition to investigate patterns and principles of nasal drug deposition?
A. I believe that I am certainly an expert. And I can provide examples of why I believe that is the case, if that will help.
Q. What is the basis for your expertise?
A. Well, I think -- I mean, specifically with reference to the nose, since 1995, I've always had at least two graduate students working on different aspects of nasal drug delivery. I think that's actually more than most people. It's a very -- it's an area that is quite specialized. So I think that, compared to others, I'm quite well qualified to comment on that.
I also -- it's very nice of you to refer to me as a pharmacist, but I haven't practiced as a pharmacist -- even though I teach about 400 at any given time at the University of Maryland, I haven't practiced pharmacy for -- hmmm, since 1984. Something like that. So I've been a professor ever since then.
All of my research has been directed towards the -- the way that particles behave. And as a result of that, I have consulted with probably more than 40 or 50 pharmaceutical companies. I'm the organizer of a meeting that attracts more researchers in this area than any other meeting in the world. And I think that I am pretty well qualified.
Q. Based --
A. I should also mention that I've -- I've consulted with the FDA, who -- at the end of the day -- are the ones who promulgate the regulations that are used to regulate nasally and pulmonarily inhaled products. So I wouldn't be so immodest as to tell you that I'm qualified. But certainly other people -- at least demonstrated by their willingness to invite me to participate, I think, would disagree with your assertion.
Q. Dr. Dalby, the -- the focus of this question, really is --
A. Sorry. Just to -- I'm allowed to answer now, again?
Q. No.
THE COURT: No, you're not.
BY MR. LAZARUS:
Q. I need to pose a question.
Doctor, are you familiar, based on your knowledge, experience, background, and training, and your roles in professional organizations, with the nature of the literature that is generated in the field of nasal drug deposition?
A. Yeah. I think I'm -- I mean, not only because I'm interested and, you know, generally want to do good in that area, I also am one of the three principals that organizes -- like I said -- probably the world's preeminent meeting in this area. And actually my specific role in that is to run -- is to organize the review and editorial oversight of the publications. So whilst I can't remember exactly every year, I'm fortunate that I see maybe -- going back to the last meeting in the U.S., well over 40, maybe 45 presentations at the full-paper level, and I see maybe 150, 160 abstracts. So I think I'm pretty well placed to see the literature.
And then, of course, I see things brought to me by the students that I teach, who include pharmacy students and some other health care professionals. And, of course, I'm lucky that I have good graduate students, as well, who feed information.
So it's certainly not perfect, and there are a lot of things out there that I wish I knew that I don't. But I do believe that I'm qualified.
Q. And the focus of your research, including a lot of the testing and study that you've done, has been focused on this area of nasal drug deposition and how to investigate it with the available scientific techniques. Correct?
A. Absolutely. I mean, I have done -- published studies for a long time before I ever had heard of Zicam. So I have a pretty good history, I think.
Q. In all of your review of literature in this area of nasal drug deposition pattern, have you ever run across any literature which seeks to predict or investigate nasal drug deposition pattern by using a sectioned cadaver head and the Francke-Proetz method that was used by Dr. Jafek in his cadaver study?
A. Up until being shown Dr. -- I don't know. Dr. Jafek's attachments to a deposition, I had never even heard of this method, even though I had been working in this area a long time, and even though I've helped a lot of pharmaceutical companies seek approval with the FDA for these types of products. I have never seen that methodology applied. And I think there are some good reasons why.
Q. Why are those?
MR. JOHNSON: Your Honor, I don't believe he has established a foundation, your Honor. I would object.
He has never conducted a cadaver study.
THE COURT: I understand.
MR. LAZARUS: Your Honor --
THE COURT: I have not -- I'll overrule the objection. You may answer.
MR. JOHNSON: Your Honor, may I then ask that the Court require the witness to identify the specific literature that he is relying on?
MR. LAZARUS: If I can respond to that, your Honor, I think what he's relying on is the lack of literature.
THE COURT: Well, I'll overrule that request, as well.
Doctor, you can testify as to why you believe there's the lack of such studies, as you indicated.
THE WITNESS: I think the study that I read about, which Dr. Jafek had conducted -- I mean, this is a very old study. I don't remember the date. But it was certainly predates me, and I'm 45 now. So it's a lot older than that, and I think it goes back many years before.
It's using a sectioned cadaver head straight down the middle. I believe the cadaver head has been frozen, first, thawed out, then use --
MR. JOHNSON: Excuse me, your Honor. He's going beyond what the Court's allowed him to do. He's testifying about what he believes this study consists of. That wasn't the Court's permission.
THE COURT: I would agree. I'll sustain your objection.
But -- the most recent response by Dr. Dalby will be stricken.
Doctor, just explain why you believe there is the lack of such studies.
THE WITNESS: I think the study is viewed as being essentially meaningless.
BY MR. LAZARUS:
Q. Why is that, Dr. Dalby?
A. Because I don't think -- I think there are much better tools today and have been for a long time to predict where things would go in the nose.
It's not as if there's any shortage of cadavers. It's not that it's difficult to cut them in half, down the middle after they're frozen. It's not that it's difficult to lay a sheet of glass on top. And it's not that it's difficult to insert a formulation and spray it. Those things are perfectly doable. It's just that what you'll learn from that, I think, is very questionable.
MR. JOHNSON: I'm going to object, your Honor. It's nonresponsive, outside the scope, and move to strike.
THE COURT: Well, your motion to strike will be denied, and your objection is overruled. You'll have a continuing objection to that sequence of questions.
All right. Mr. Lazarus, you may proceed.
MR. LAZARUS: Thank you, your Honor.
BY MR. LAZARUS:
Q. Before we just leave this area, Doctor, have you ever seen any other scientists utilize this Francke-Proetz method to investigate nasal drug deposition?
A. I have never seen a -- a publication or an abstract outside of Dr. Jafek. I have been fortunate, as I said, to work with a lot of pharmaceutical companies who have brought products to the market, such as Zomig, or, you know, steroid nasal sprays. And -- so I'm familiar with the types of information that the U.S. FDA has required them to submit. And nobody, to the best of my knowledge, has either been asked to or has chosen to submit data suggesting where a drug might go using a sectioned cadaver head. So guess the short version is no.
Q. Doctor, based on the work you've done, the materials you've reviewed, and your background, experience, and knowledge in the field of nasal drug deposition, do you have an opinion as to the likelihood of the delivery of Zicam gel to the olfactory area when the product is used in general conformity of the package directions?
A. Yes, I think I do have an opinion and a good basis for it.
Q. What is that opinion?
A. Well, that it's very unlikely that -- that Zicam, when you follow these instructions, will reach the -- the roof of the nasal cavity, where the olfactory epithelium is located. I just don't see it.
Q. And based on the work you've done, the materials you've reviewed, and your background, experience, and knowledge in the field of nasal drug deposition, do you have an opinion as to whether there is any reasonable and reliable scientific evidence that any Zicam is likely to reach the olfactory area when the product is used in general conformity with the package directions?
A. No, I don't think it's very likely that there is a way to collect that evidence.
Q. Now, we've talked about the types of evidence that were relied upon by Dr. Jafek.
Are they the types of evidence that are relied on by reasonable scientists in the field of nasal drug deposition to investigate nasal drug deposition patterns?
A. No. As I suggested earlier, you know, Dr. Jafek is the only one, sort of, in recent times that I've seen applying that methodology.
MR. LAZARUS: Thank you very much, Doctor.
THE COURT: Okay. Mr. Johnson, we'll take our afternoon break. We'll take about a 20-minute break. It will be 3:05, by that clock.
You may step down. We'll be in recess.
(Recess taken.)
THE COURT: We should keep those closed, because witnesses were excluded.
Dr. Dalby.
And, again, this is your preference. You can -- you're not required to question from that position.
MR. JOHNSON: I appreciate that. Actually, I may move over in a little bit, here. I feel like I'm about two football fields away from the witness, here.
THE COURT: Three.
You can proceed, Mr. Johnson.
MR. JOHNSON: Thank you, your Honor.
CROSS-EXAMINATION
BY MR. JOHNSON:
Q. Okay. Dr. Dalby, I asked defense counsel if he would leave the drawing up, Defendant's Exhibit 101. I'll take you through a few questions on this, and then we'll move on to some other things. Okay?
A. Sure.
Q. But, first of all, to digress for just a moment, have you ever published anything that's been peer reviewed?
A. Yes, many things.
Q. Many things peer reviewed.
What journals? Just three, as an example.
A. Sure. The primary journal in the area that I work in is the Journal of Pharmaceutical -- it's called Pharmaceutical Research. That's the flagship journal of pharmaceutical sciences.
I've published things in the Journal of Aerosol Medicine, which is really the primary journal that relates to movement of particles in airstreams.
And I have published things in things like journal of drug delivery, and stuff like that, which are much lesser magazines and journals. But certainly Pharmaceutical Research is where I put the -- where I consider the good stuff.
Q. And peer review, in science and medicine, means that the author's work is subjected to scrutiny by other professionals in that area. Correct?
A. It's not always quite as cut and dry as you said. But certainly it's scrutinized by other people who have experience and knowledge, I think, that would qualify them as a reviewer.
Q. In other words -- in other words, the editor of the journal will select perhaps two other professionals in the area to review the author's work and determine whether the methodology -- maybe they don't agree with the conclusions. But at least the methodology is reliable, and it should be published in the journal?
MR. LAZARUS: Objection, your Honor. This is beyond the scope of the direct.
THE COURT: No, I'll -- it comes within the domain of an expert, so I'll overrule the objection.
THE WITNESS: Okay. I think it's fair to say that your description is fairly accurate.
Actually, speaking as somebody who has edited and reviewed fairly frequently, I would say it's fairly typical that an editor would send things out to review more than by two people, because at the end of the day, it's a volunteer activity. Therefore, you won't get reviews back from everyone you send it to. And maybe you won't get them back in a time frame that they're usable to publish the journal. But your point is well taken that that's the approach.
Q. So the editor selects reviewers in that particular area. And they review the methodology, and they decide this article is worthy of being published in the journal, it has been peer reviewed?
A. Again, there is going to be variation.
For example, it's not necessarily likely that an editor would know people qualified in the area. So it's fairly typical that a journal would ask the actual presenter to choose or identify some people who would be appropriate reviewers. The editor then has the option of going to those or going elsewhere.
Usually, if there's controversy -- let's say one reviewer likes it, thinks it's okay; the other one finds it to be unacceptable, you might see things. And certainly I've received things and sent things for tertiary review, where you try to get someone to break the impasse. But, again, I think what you're outlining is a pretty reasonable characterization.
Q. And publication by the journal -- a peer review journal like the one that you -- the first one that you mentioned, which is sort of the -- the -- the top journal in your field.
A. Correct, Pharmaceutical Research.
Q. You know, that indicates the opinion by the editor and the peer reviewers that the methodology is reasonably reliable.
MR. LAZARUS: Objection.
THE COURT: And what's your objection, Mr. Lazarus?
MR. LAZARUS: It's overbroad and lacks foundation.
THE COURT: I'll overrule the objection. You can answer.
THE WITNESS: Okay. Would you mind asking the question one more time, please.
BY MR. JOHNSON:
Q. Well, I don't think we've got a dispute.
You know, the -- the peer review process is intended to have individuals in the -- in the area -- maybe selected by the editor, maybe selected by the author. But individuals with experience -- knowledge, experience, education, and training, in the area to -- to review the article and sign off on the methodology as being reliable.
A. I disagree with you, because --
Q. Okay.
A. The reason I have a difficulty with that is I think it's more committed than that. Because a methodology can be perfectly reliable, for one thing. The question is, does the methodology support the conclusions that the authors draw. So you could have a perfectly good method, but it simply doesn't support the conclusions that are drawn.
So I think that's the -- the bigger issue than simply -- I mean, actually the methods part of things is -- is really, you know, the least of my worries when I'm reviewing. I want to know, are the conclusions valid based on the assertions of the author and the data they present? So personally, when I'm reviewing, unless there is data that I believe in, then, you know, it wouldn't matter if the methods are any good.
I'll give you an example, because I've just reviewed a lot of work for a meeting in Paris.
And there, a number of people will provide, you know, I've seen this observation, and they want to publish it. And my response to that is always the same. Show me the data. Show me replicas of the data. Show me what hypothesis you are testing. Tell me why you believe the conclusion you're drawing fits the data and the methodology you use. So I don't think it's just a method question of methodology.
Q. Okay. So do you think your approach to peer review -- when you a reviewer and not the reviewee -- do you think it's typical?
A. Do you think my approach is typical?
Q. Is typical to what other professionals will do in science and medicine for journals that require peer review before they'll publish an article?
A. Well, within the -- I said before, within the sort of normal variation around that theme, yes, I do. I mean, like for example, you said --
Q. Okay.
A. -- the authors might choose the reviewer. I don't believe that's the case. They might suggest the editor. Or even a computer, in some cases, will simply match up to a database and do the choosing. I don't think I can choose to have you review my paper that directly.
Q. And -- and that is -- I think -- I think I understood your answer to be that, and I apologize. So, yeah, well, that -- that would ensure the independence of the peer review process, which is important. Correct?
A. Correct.
Q. All right. Thank you.
Doctor, let's go back to the depiction of the nasal anatomy that -- the Defendant's Exhibit's 101 and your two little red lines here.
I think that what you testified and what counsel asked you to do was to depict the olfactory area.
A. That's correct.
Q. Okay. And olfactory area is not an anatomical structure, is it?
A. Well, olfactory describes smelling. So it's the area -- at least my interpretation is it's the area responsible for the perception of smell.
But, as we pointed out earlier, I certainly don't have the lock on anatomical knowledge. So this is not my specialty.
Q. Well, you understand that anatomy is an issue -- that the nasal anatomy is an issue in this case.
Is it your testimony that you are not an expert in nasal anatomy?
A. Absolutely not. My -- what I'm trying to convey is that I know the things -- I believe I have a pretty good handle on the things that govern where particles or where objects placed into the nose are going to end up. That certainly requires me to know certain things about the structure of the nose.
But I don't have to understand the nuances between different names that might be applied to certain areas. I think that if I can show you the area in the nose that I believe is at issue here, for the purposes of demonstrating if particles get there, I think I'm very well qualified to do that.
Q. But when you just said -- I just want to clarify.
When you just said absolutely not in answer to my question whether you were an expert in nasal anatomy, that was -- your answer was intended to mean, I am absolutely not an expert in nasal anatomy?
A. No, I think that's not fair.
Q. Oh, that's not -- that's not the correct interpretation? Okay. I want to make sure.
A. Let me --
Q. So are you saying you are an expert in nasal anatomy?
THE COURT: One at a time.
MR. JOHNSON: Sorry.
THE COURT: One at a time.
THE WITNESS: What I'm trying to convey is it is not my role to go looking into different noses, looking for new structures, looking for new cells, looking for new biochemical pathways, looking for the way that bones might generate within the nose, looking for variation between different ethnicities and different ages. So a focus of my research is not identifying anatomy. I'm simply using research that other -- admittedly, very well qualified -- physicians, and other researchers who are not physicians, are able to identify.
It's simply just not what I'm looking at. But I think that I'm perfectly qualified to use it.
As an example, I could not build a car, but I can certainly drive it. I don't believe that driving it qualifies me to build it, but certainly I can use it. And here, I think I'm using it.
Q. Well, you don't -- so you don't have to be an expert in building cars, in your opinion, to drive a car?
A. I think that's fair.
Q. Okay. And so you are not, by your own definition, an expert in nasal anatomy?
A. Again, I think you're -- I -- certainly, I am not a professor of anatomy. Correct.
Q. Well, you're professor of pharmacy?
A. I'm a professor of pharmacy. Correct.
Q. And have you ever conducted a clinical examination of someone who comes to you and says, I've lost my sense of smell, I lost it suddenly, help me figure out why I lost it?
A. I have never been asked to, nor would I do such a thing.
Q. Okay. And you have never done an nasal endoscopy to look up into someone's nose. Correct?
A. I think you asked me that question earlier, and I told you that's correct, yes.
Q. You have not done that?
A. I have not looked, using a nasal scope, up someone's nose.
Q. Okay. So the term that counsel used was “olfactory area.” Defense counsel. And I'm looking at the chart, Exhibit -- or the Exhibit 101. I don't see the term “olfactory area” on that.
So is it your -- is it your testimony that olfactory area consists of more than one nasal anatomical structures?
A. You'll have to tell me -- in order to be able to answer that question, you'll have to tell me a little bit about where you're going with this.
For example, there are two sides on the nose. There is an olfactory capability on both sides of the nose. But assuming you're referring to just, you know, one side of the nose, then there's, within that side, one area to -- to --
Q. Let's -- I'm sorry, let's try to simplify this.
I'm using defense counsel's term, which was “olfactory area.”
A. Um-hmm.
Q. So you tell me what the olfactory area consists of.
A. I think -- I'm looking, then, at half of the nasal cavity, a section down the middle, represented schematically.
So, again, you'll remember, we have difficulty indicating on there. But if you were to project down from those two vertical red lines that I drew, using the pen that the judge was kind enough to loan me, where that intersects with the roof of the nasal cavity is where I'm suggesting to you is the area that's at issue here.
Q. Give me your definition of the olfactory cleft.
A. I think the olfactory tells me that it's the area where you sense smell, and cleft is clearly a description of an anatomical location.
I don't really need to know any more than that to tell you that this is the area of interest, where particles will deposit.
Q. You didn't point out to me on this diagram where the olfactory cleft is. Correct?
A. I could barely point out to you on this diagram where the -- you know, where the roof of the nose was, because it's difficult to indicate because of the color scheme.
But I think that it's fair to say that the olfactory region, as I defined it, is indicated on this diagram to the best of my ability.
Q. No, I don't want you -- I'm sorry, Professor -- or Doctor, I'm sorry. I don't want you to tell me “olfactory region.” I don't want to hear about -- excuse me, if I'm -- you know, “olfactory area.”
I want you to define for me the term “olfactory cleft”, as you understand it.
A. Okay. I have no particular understanding of the term “olfactory cleft,” other than it is a region in the upper part of the nose, which I've tried to identify in the diagram.
Q. And so do you believe that you've identified the olfactory cleft with those two red lines and the space between them?
A. Well, recognizing that it's a crude schematic, I think I've shown you a region that would be a good place to look, yes.
Q. The chart does contain the two words “olfactory epithelium” and with a line pointing to the diagram.
Do you see that, Doctor?
A. Yes, I do.
Q. Okay. Can you define for me “olfactory epithelium”?
A. How would you like me to -- are you asking in words, or to point?
Q. No, no. “Define” means in words.
I see where the arrow goes, I see -- it's set out on the chart. Tell me what the olfactory epithelium is.
A. Okay. It's the region of the nose containing the cells that are capable of perceiving smell.
Q. Okay. And in -- in this case, and in the other cases that you've assisted Matrixx Initiatives in, there have been allegations that the olfactory epithelium was injured by the product.
Do you understand that?
A. I understand, yes.
Q. I know you don't agree with that, but that's the allegation. Right?
A. That's a reasonable understanding, yes.
Q. Okay. Tell me then, Doctor, if the olfactory epithelium is damaged, would that, in your opinion, have any effect on the ability of the person with the damaged olfactory epithelium to smell?
MR. LAZARUS: Objection, beyond -- objection, it's beyond the scope of direct, and it's also beyond his expertise and lacks foundation.
THE COURT: Well, you've got two objections in there.
The first I'll overrule. It's your exhibit, the doctor used it as part of his direct, so it's not beyond the scope of direct. So I'll overrule that.
Now, as to your objection that it's beyond Dr. Dalby's expertise, I'll overrule that objection as well.
You can answer, Doctor, if you can.
THE WITNESS: Would you ask that question, again, please.
BY MR. JOHNSON:
Q. Yeah. The question, Doctor, is if the olfactory epithelium is damaged, that a person could lose or have his or her sense of smell impaired.
A. Well, my reaction to that is my -- my expertise is to know where particles go and droplets go, or liquids in the nose go.
So the answer is, I -- you know, I'm just not qualified to answer.
THE COURT: I said if you can't answer that, you can just say, I can't answer it.
THE WITNESS: I can't answer it.
THE COURT: Okay.
BY MR. JOHNSON:
Q. So Doctor, you testified during your direct exam that one of the things that you relied on was a -- I think you used the term “Pitt study,” PITT?
A. One of the things I was given to take a look at was a study from the University of Pittsburgh, yes.
Q. And that was called the Pitt pilot study?
A. I've been referring to it as the Pittsburg study, but yes, I think we're talking --
Q. Okay. And you -- did you refer to that and rely on it in your opinions?
A. Yes.
Q. In forming your opinions?
A. Yes, I had a chance to look at it, yes.
Q. Okay. And the Pitt pilot study was a cadaver study. Correct?
A. There was one study in Pittsburgh that utilized a cadaver, but actually the one I relied on much more was the Pittsburgh patient study, which looked at patients and normals, and was a much more involved study. I think the cadaver was very limited in many ways, and has the same sort of limitations as we talked about for what Dr. Jafek suggested.
Q. Okay. I want to make sure I understand.
You did review the Pitt study, which involved squirting Zicam into a cadaver?
A. Yes, I did.
Q. And at one point, at least, in your reports -- in your report, you test -- you -- you included an attachment, and you said you relied on that study. Correct?
A. I think so, yes.
Q. So you relied on a cadaver study, at least in one of your reports --
A. I think --
Q. -- that you did in the Zicam litigation. Correct?
A. No, I think that's not fair. Because I think that what you're suggesting is that, first off, I gave particular importance to that study. Actually, I looked at many studies. I looked at, you know, a lot of literature that I've worked on over the years, and studies that I've done. So to suggest that my findings are somehow related to the validity of that study, I think is not -- is not an accurate representation.
MR. JOHNSON: I'll make this 1. And I marked it.
Now, should I give this to the judge, or -- (pause, conferring with the clerk.)
Okay. Give this to the witness.
(Witness handed document.)
BY MR. JOHNSON:
Q. Dr. Dalby, the clerk is handing you what's been marked as Exhibit 1, and this is one we received from Defense counsel, a report in -- in this litigation, and it was a report done by you.
Do you see this document in front of you, Exhibit 1?
A. Yes, I do.
Q. And it doesn't have your curriculum vitae attached.
But it's the first ten pages of the report, which, at the time you signed this, on -- on -- I think it was January 11th, 2006, this report contained what you relied on and your opinions in the case. Correct?
A. That's correct.
MR. LAZARUS: Excuse me, is there a copy that I can see?
THE COURT: Your exhibit here.
BY MR. JOHNSON:
Q. Okay. Doctor, would you please go to page 2.
A. Certainly.
Q. And one, two, three, four, five, six, seven bullet points down, do you see Matrixx pilot study --
A. Yes.
Q. -- of distribution of Zicam spray?
A. In the passages, by Patricia Hegra (phonetic).
Q. That's right. That's one of the -- that's the cadaver study. Correct?
A. That is a -- a cadaver study, yes.
Q. And that cadaver study consisted of one woman, and they sprayed Zicam in that woman's nasal passages. Correct?
A. I believe that's true.
Q. Okay. And so at the time at least, on January 11th, 2006, you -- one of the things that you reviewed and relied on was a cadaver study. Correct?
A. I think it's -- perhaps you should tell me what you consider to be the difference between reviewed and relied upon.
Q. Well, what I want to know is what forms the basis of your opinions.
A. I think that really my opinion is based on what I believe to be the pretty fundamental principle that's very well accepted, and I don't think you'll find many scientists will quibble with; the notion of how particles move in an air stream. Because at the end of the day, when a patient uses a product that is sprayed into their mouth with the intention of going into their lungs, or into the nose with the intention of keeping the product in the nose, it's those fundamental principles that rely -- that govern where those particles will deposit.
And of course the particle depositing in the right location is -- is kind of the preamble to release of its drug and, we hope, this beneficial biological effect we're looking for.
But I don't think -- you know, if your suggestion is that I'm, you know, particularly compelled by cadaver studies, that is not the case. I find them the weakest of all evidence. But I think it is a reasonable thing to look at, to say that at least it utilized something akin to Zicam. So why would I not at least consider it?
Q. Okay. And so you at least considered the Pitt cadaver study that Zi -- that Matrixx provided you?
A. Yes.
Q. Okay. Doctor, go to the first page of your report here.
A. Okay.
Q. And this was submitted by the attorneys for Matrixx as Exhibit U. And, again, I've got the ten pages of your report, the body of your report, Doctor. I haven't attached your curriculum vitae.
A. Okay.
Q. Doctor, you make the statement, do you not, under the expert testimony paragraph, the first paragraph of your report dated January 11th, 2006, that you are relying on your education, training, research, professional experience.
Do you see that?
A. Just give me a second.
Q. First paragraph.
A. Oh, yes, I see that.
Q. Okay. And just -- so that's one of the things you're relying on; your education, training, professional experience, et cetera?
A. Yes.
Q. And you also say here, Doctor, do you not, that you're relying on your personal observation of a single unit of Zicam cold remedy. No-drip liquid nasal gel, parentheticals, Zicam, and then it gives a lot number. Do you see that?
A. The lot number and the expiration date, yes.
Q. Okay. Doctor, you spoke this morning -- or this afternoon, I'm sorry, about, you know, sort of the particle physics of nasal -- is it deposition or disposition?
A. I prefer deposition, but I will --
Q. Deposition. Okay. I didn't want to get tangled up in a lawyer term there. So it's deposition.
So -- and you talked about your calculation to determine -- is mass -- a calculation of mass, speed, and distance. Correct?
A. Correct.
Q. Okay. So then tell us, Doctor, what experiments you did on the Zicam cold remedy gel that you personally observed.
What -- what is the -- were the mass and the speed and the distance calculations that you performed?
A. I would say that my study is -- was simply a one-time firing, probably in my office, where I actuated the unit and just looked to see what's the physical form of the spray coming out. So it's -- I did not measure the mass or the velocity or -- there was nothing to measure a distance to.
Q. So the opinion that you gave here today, and you talked in detail about testing and modeling and pharmacodynamics and pharmakinetics, and all of those things; mass, distance, and all that have stuff.
What you did, Doctor, with the product that's in issue in this case, is you sat in your office and you fired it off. Right? One time?
A. I think that I did all of the other things that I talk about in here, which is reviewing the literature.
I just wanted -- I'm curious. I wanted to know what Zicam looked like. I also needed, of course, to look at my observations and see if there's anything fundamentally different from what Dr. Jafek did. In fact, I would say that what I did is, you know, a perfectly reasonable one-off experiment, and carries the same weight as a single one-off experiment with a cadaver. I don't think it's necessary to rely on it, but it's about that level of scientific inquiry.
Q. So you equate sitting in your office in your chair, firing this thing off one time, to a cadaver study?
A. I would say they're not that different. In terms of their utility, there's not much difference.
Q. So then -- then all the discussion you had this afternoon about the nasal passages and -- and, you know, you've said, I guess, now, that you don't really have a superior expert understanding of nasal anatomy, but you testified to it a little bit ago. You said that it's not a straight shot.
That doesn't make any difference?
You can get the same result from firing it up somebody's nose as you can sitting in your chair in your office and shooting the thing, what was it, four to six feet?
A. Sounds about right, yes.
Q. Actually, didn't you say you fired it off and at one -- in one case, didn't you say you fired it off and it hit the ceiling?
A. I can't recall if it did or it didn't, but it certainly is a long, narrow plume that goes up in the air quite a long way.
So my observation is not dissimilar from what Dr. Jafek reports.
Q. Okay. So --
A. And just like Dr. Jafek reported, it was a one-time observation.
Q. Right. So -- so what you did with the product itself --
A. Um-hmm.
Q. -- and what we're talking about here is -- you know, Zicam. Right?
A. Correct.
Q. That's the product.
Okay. What you did is your -- you didn't conduct any calculations about mass and speed and distance and particle size. You didn't measure anything. You sat in your office and fired it off?
A. I did what I was asked to do, which was to answer questions. I think you asked this morning, or Mr. Lazarus asked, you know, what was I asked to do. So I was asked to answer questions. I could, I think, have answered the questions quite appropriately without ever needing to see Zicam, but I'm curious. I mean, I really wanted to see what I'm looking at here.
Q. So you wanted to go the extra mile. You sat in your chair in your office and you fired it towards the ceiling. Right?
A. Well, I think you are not letting me finish the -- the answer.
But I mean, I think have quite a bit of background knowledge, as I outlined for you this morning. I've been doing this for a long time.
So once I've established that Zicam is a nasal product -- and not at all products -- it's not all cut and dry. So I think it's a perfectly reasonable thing to go, to look at.
So, remember that I've been looking at lots of products for a very long period of time here. There are powders that go into the nose. I would go as far as to say that I'm familiar with delivery systems that Dr. Jafek has never seen, but of course I can't know that. But I think it's perfectly reasonable to make sure that I am able to answer questions about the deposition of a nasal spray. And to do that, I can't imagine anything more reasonable than to fire it.
Q. Well, didn't you talk this afternoon about, what was it, gamma scintography studies? And mathematical modeling? And measuring mass and speed and distance? And pharmacodynamics and pharmakinetics?
You talked about all of those things. You didn't do any of that with Zicam, did you?
A. It's true that I did not do any of that with Zicam --
Q. Okay.
A. -- because I think I can actually learn quite a lot from the written description of Zicam, and I can actually see quite a lot from observation of the plume. So I -- I can learn something from that. It's a useful thing to do.
Q. So the sum total of your personal experience with the product is firing it in your office. Right?
A. Yes, I think that's true.
Q. Okay. So you didn't even try the product on your own nose, did you?
A. No, I did not try it on my own those.
Q. And so you don't know, for example -- and I see you've got one sitting up there, and I don't know if you want to try it now. But if you put that thing deep in your those, and you fire it off, you think it would reach your nasal epithelia?
A. Can you show me where it's --
Q. Oh, I thought you had it. I'm sorry. I'm sorry.
I mean -- let me ask you a question, Doctor. Before we do this, Doctor. And you don't have to put this in your nose if you don't want to, but what I want you to do -- and this is important.
Your report is based on -- is conditioned on the product being used as directed. Correct?
A. I think -- well, I -- in this report, I think it only addresses use as directed. I have written another report that addresses misuse.
Q. Okay. This report that you gave us in January 2006, your conclusions in this report are based upon using the product as directed?
A. Sure. May I just check?
Q. Sure. You bet.
A. (Pause, referring.)
Yeah, I think you're correct, it's using as directed.
Q. Doctor, do you know if the -- whether at any time when you first -- strike that.
Doctor, do you recall when you first became involved, consulting for Matrixx, for their lawyers?
A. I'm sorry, you're asking the date when I --
Q. Yeah, just -- or approximate. I'm not asking you exactly. When did you first become involved in the -- in the Zicam anosmia cases?
A. I think maybe towards the middle or end of 2005.
Q. Okay. And I think I read a deposition where you had given records in about ten or so cases?
A. I believe that the -- essentially the same report has been used in multiple cases, but I've been given the opportunity to look at some of the depositions of earlier ones, and then include references to them in the later reports.
Q. Well -- and that's correct. You've essentially submitted the same report in multiple cases. Correct?
A. It's been submitted on my behalf, but yes, I think that's true.
Q. There's the Benkwith case, the Russell case. Correct?
A. I believe so, yes.
Q. Johnson case?
A. As I said, I've written one report. I don't -- because my -- what I'm telling you today is quite general, it's not patient specific. I mean, these are pretty basic principles that I think anybody working in the field would know. They don't rely on any given user to be true.
So --
Q. So the Sutherland (phonetic), does that name ring a bell?
A. Yes, it does.
Q. Gillespie ring a bell?
A. Yes, it does.
Q. Hellman?
A. I think that was towards the end, but yes.
Q. Were you involved in the class action in Arizona?
A. Not to the best of my knowledge.
Q. Do you know anything about the class action in Arizona?
MR. LAZARUS: Objection, lacks foundation.
THE COURT: Well, I think it's fair to say, Mr. Johnson, he's identified the report as having been used, so I don't think it's relevant as to which specific case it's been used on.
MR. JOHNSON: I just wanted to find out, though, if he was involved as an expert in the class action in Arizona.
THE WITNESS: I can answer.
I don't believe -- I don't believe so.
BY MR. JOHNSON:
Q. All right. So the dosage of Zicam when -- when -- when you pump this pump, Dr. Dalby, is the dose supposed to be the same every time?
A. Can I ask what you mean by dose, because it's used in different ways?
Q. Thank you. I appreciate -- the amount of the product that comes out of the nozzle, is it supposed to be the same every time.
A. Okay. May I just clarify?
Q. Sure.
A. By -- when one sprays the pump, the pump has a nominal delivery value. So the pump meters by volume, so we talk about volumetric metering. So anyone who is talking about dose but is actually referring to volume is not accurate, and showing they really are missing the boat here.
So we are relying on the concentration of drug in the product, and the volume of the product that's sprayed, and the product of those two things gives you the dose of drug, how much active ingredient goes into the patient.
Q. Right.
A. So I think with that explanation, I think what you're asking is how reliable is the spray metering.
Q. Actually, I appreciate you clearing up my inarticulate use of the dose. When -- when you used the term “dose,” Dr. Dalby, in reference to, for example, the Zicam product, are you talking about the -- the zinc gluconate component of the solution that's delivered?
A. I don't believe I refer to it in here, but I can check if you want.
But when I refer to dose in general, I'm -- at least when I'm behaving myself, I'm referring to the mass of active ingredient. The thing that -- the mass of the agent that we hope will make the patient better.
When I refer to spray weight, I'm talking about the weight of everything that's ejected from the valve when the patient uses it.
The majority of what's ejected from the valve is actually going to be water, so it's going to be the -- that's going to be the biggest weight.
So dose, I'm talking about drug. Formulation or spray weight, I'm talking about everything, which includes the drug.
Q. So is volume the same as spray weight?
A. Of course not. Volume is a measure of volume. Weight is a measure of weight.
Q. And is -- is the volume that's expelled from the Zicam bottle when a customer pumps it and puts it in his or her those, is the volume supposed to be consistent? In other words, is it a metered, measured, consistent amount?
A. Certainly, everybody -- I mean, that's certainly my goal when I set about formulating these products, and making them, and testing them. I would always have that in mind as a goal.
The realty is, it's a mechanical device. It's kind of like your tie. I mean, I'm sure the manufacturer intends that it's always the same length. But of course if your scale of scrutiny is precise enough, and there are some very accurate methods here, there will be variation in that length.
So we talk about a nominal valve volume, which is what the engineering drawings suggest was the target the engineers were aiming at, but there are going to be variations around that. Those variations will come from the manufacturing tolerances of the hardware. These are bits of plastic and springs, and there is shrinkage of the polymer during manufacture.
So I think anybody who works in the area would realize that it's a -- there's a target, a nominal value, and there is a specification around that target. And the FDA requires that you agree with any specification, and then all products meet that specification.
Q. And the -- what is the target amount of this product? In other words, what is the target volume when -- when the dose is -- or strike that.
When the spray is expelled, how much are we talking about?
A. I believe that nominal target is 140 microliters.
Q. 140 microliters?
A. Correct.
Q. And I'm assuming that -- strike that. I'm not going to assume anything.
How much gets up actually into the nose?
A. In my estimation -- you're talking about for Zicam specifically?
Q. Right.
A. I think it's all going to be -- used as directed, in the fleshy part of the bottom of the nose, I suspect very little of that volume even gets beyond the entrance to the nasal cavity.
Q. But what I'm asking you is if you use the product as directed, 140 microliters gets up into the nose?
A. I think your characterization of “gets up into the nose” is not sufficiently accurate a description for me to give you a good answer.
I mean, do I think it ejects from the tip of the spray nozzle?
Unless the user does what we call a partial actuation or a misfire, I think it's quite likely that somewhere around 140 microliters, plus or minus. Typically these pumps are accurate to, you know, just a few percent.
So when you take patient variability out of the picture, they're pretty precise. So I'm pretty sure the pump metering is very precise. Where it goes afterwards, that's a more difficult question. But my view is that the majority of it is probably deposited very close to where it came out from the tip. I do not believe, therefore, that it goes what you've described as “up into the nose.” I think it goes into the nose, and actually pretty low in the nose.
Q. Have you -- I think you said that you -- you -- you've reviewed that -- the Pitt cadaver study, but you've also reviewed an additional Pitt study. Correct?
A. Correct.
Q. And was that study done on live people?
A. Yes, it was.
Q. Okay. Because -- ‘cause I think the one thing you and I can agree on this afternoon, cadavers don't sniff?
A. I've think we can agree on more than that, but I absolutely agree with you that cadavers do not sniff.
Q. All right. And I'll approach here.
A. (Handed document.) Thank you.
Q. Dr. Dalby, this is a page that's contained in Exhibit 1D, and it's a document we obtained from Zicam. And you'll see in the lower right-hand corner it says, ZM143248.
Do you see that?
A. Yes, I do.
Q. That's a Zicam stamp. And you see that this is Exhibit D1. This is page 36 of 62, so I'm handing you one page from the University of Pittsburg studies.
Have you seen this before?
A. Yes, I have.
Q. Okay. And would you go to the second paragraph, where it starts out, Ten additional normal subjects.
A. Okay. I'm there.
Q. Okay. And the last sentence of that paragraph says -- correct me if I'm wrong -- Two of ten incorrectly administered reached the olfactory cleft, and three of ten reached the upper one-third middle turbinate.
Do you see that?
A. Yes, I do. May I just take a second to read the whole paragraph, just for the context?
Q. Yes.
A. Okay. When you're ready.
Q. And -- and you've seen this before?
A. Yes.
Q. Okay. And you know this was a study that was -- that was financed by who?
A. I think I was told that it was financed by Zicam. So --
Q. Okay. And did -- did you review -- before we ask you some questions about this, did you review any safety studies of Zicam that the company did prior to releasing this product on to the market?
A. I do not believe so.
Q. And do you know whether or not Matrixx, Zicam did any safety studies?
A. I really don't know.
Q. So as an inquiring scientist who wants to go the extra mile in these cases and find out all the best evidence, are you telling us that you never asked the company whether they did any safety studies?
MR. LAZARUS: Objection, argumentative.
THE COURT: Yeah, he can rephrase. I'll sustain the objection.
BY MR. JOHNSON:
Q. Did you ask the company whether they did any safety studies?
A. I would have no need to ask the company, because I was asked to comment on where things go in the nose.
And in much of my research I have no need to utilize a drug. I would never want to unnecessarily expose you or any other patient, you know, to a drug if I didn't need to. It simply produces no useful benefit in terms of risk to benefit ratio. So I don't understand when I'm asked to comment about deposition, why you would do that.
Actually, just -- just so you realize, as a graduate student I volunteered actually for quite a lot of studies, so I have seen this from both ends. And so I appreciate researchers who don't unnecessarily expose patients to drugs, both as a scientist with a record in the field and also as a volunteer in studies.
Q. Doctor, do you have enough grasp of nasal anatomy to tell us whether the olfactory cleft includes the olfactory epithelium?
A. Again, I think that I've told you, at least tried to indicate on the diagram, you know, I was asked to answer certain specific questions. And I think if you refer to the deposition, you know, I can see what those questions were. You know, what factors and variables affect the extent of nasal drug delivery with nasal spray.
So what is the extent, and then some follow-up questions. I was not asked to go into cadavers or patients and identify the olfactory cleft located in the olfactory epithelium.
So, no, I couldn't do that, because I don't look up the noses of patients, as you pointed out earlier.
Q. So you cannot tell us, as you sit here today, that -- whether -- if the drug reaches the olfactory cleft, whether it would also reach the olfactory epithelium?
A. I think that's a fair statement.
That's a level of precision that's really not necessary, for me at least, to answer the question of does the drug get up into that general region, which I've tried to identify for the judge and the rest of the court. And as long as that's the question I'm asking, as long as the region of interest falls up there, that's about the level of precision that I feel I need to know to be able to answer, you know, the general question.
Q. But didn't you testify here -- you testified here today, I believe, that if -- if the product is used as inconsist -- consistently with the directions on the bottle, that the product will not reach the olfactory cleft?
A. I think what I'm trying to testify to is when you engage in certain modes of use, or certain modes of misuse, where in the nasal cavity will droplets deposit.
I'm not qualified to say what will be the effect of drugs contained in those droplets, nor am I qualified to break down at a very microscopic level different regions of the anatomy. It would seem to me that a nasal surgeon would need to know that stuff.
I would basically say that does somebody using a nasal spray need the same in-depth knowledge of nasal sprays that I believe I have? Including Dr. Jafek. I mean, he is utilizing something that I know quite a bit about. And he's using it, I think, for a -- you know, an intended purpose. Likewise, I'm utilizing the knowledge of other people to try and be able to direct the formulation which contains the drug to the right region of the nose.
MR. JOHNSON: Move to strike as nonresponsive, your Honor. I think the question was very narrow. And did he not testify here, earlier this afternoon, that if the drug -- if the product is used consistently with the instructions, that it will not reach the olfactory cleft.
THE COURT: Do you wish to be heard, Mr. Lazarus?
MR. LAZARUS: I believe he has answered the question, your Honor.
THE COURT: It was lengthy, but I'll overrule the objection, and I'll deny your Motion to Strike.
BY MR. JOHNSON:
Q. Do you believe that Zicam, when used properly, can reach the olfactory cleft?
A. I do not believe that if you follow the instructions on the side of the box, that I read you earlier, that it is going to get up into the region of the nose that I indicated for you in the diagram. I don't know how else to answer, because you keep answer about the olfactory cleft, repeatedly. And I haven't learned anything in the last five minutes, so I still can't answer.
Q. Well, I'm sorry I haven't educated you on the medicine, Doctor, but I thought -- you know, you gave the opinion that the product wouldn't reach the olfactory cleft, but you cannot define olfactory cleft for us, can you?
MR. LAZARUS: Objection, argumentative.
THE COURT: I agree, and I think the record's clear as to where Dr. Dalby has defined the olfactory area, slash region, parenthe, cleft, as he has testified.
So I think it's clear as to where he's indicating.
BY MR. JOHNSON:
Q. Okay. And so directing your attention to the University of Pittsburg document before you, Dr. Dalby, paragraph 2.
A. Okay.
Q. This is the last sentence of paragraph 2 of this Matrixx funded study. The statement is made, Two of ten incorrectly administered reached the olfactory cleft, and three of ten reached the upper middle turbinate. Correct?
A. That's -- that's what the sentence says, yes.
THE COURT: It says one-third middle.
BY MR. JOHNSON:
Q. I'm sorry, the upper one-third middle turbinate. Thank you.
So, out of ten patients, Dr. Dalby, who used the product incorrectly, the product did reach the olfactory cleft. Correct?
A. Well, the study -- you're talking about the ten additional patients that were done in the study. I think in total, there were 23 patients in the study. But, yes, it does say that two of ten incorrectly administered reached the olfactory cleft, and three of ten reached the upper third of the middle turbinate.
Q. And so if the olfactory cleft includes the nasal epithelium -- strike that. If the olfactory cleft includes the olfactory epithelium, and accepting as true Zicam's University of Pittsburg study, if the product is used incorrectly, there is a 20 percent chance that the product will reach the olfactory epithelium.
MR. LAZARUS: Objection, your Honor, vague and ambiguous and lacks foundation. It's also irrelevant on this record, where the only question is proper use, which is all the testimony we got from plaintiff concerning how she used the product.
THE COURT: Mr. Johnson?
MR. JOHNSON: Well, I think he -- he -- he is trying to back off the medicine that he testified to. But clearly he gave the opinion that it can't reach the -- I think he said the olfactory cleft.
They tried to keep it as vague as possible. First they said olfactory area and olfactory region.
But this is -- this is a study that he says he relied on, or he was given. It was a study done by Matrixx, and it shows that two of ten incorrectly administered reached the olfactory cleft.
So if he -- if -- if -- my question is, he -- you know, he -- either the opinions have to be stricken or I have to be able to conduct some type of a medical discourse with this gentleman, because he said the product can't reach the area we're saying it reached.
THE COURT: Well, Mr. Lazarus, if I understood his objection correctly, is that this exhibit and your area of questioning goes to an improper use of the Zicam, and there's nothing in the record that would support an improper use. Therefore, your questions are not relevant.
I don't know what evidence there is insofar as how Ms. Lusch used the product, but unless there is going to be some evidence of improper use, then I would sustain the objection as to your last series of questions.
MR. JOHNSON: Well, there's two reasons for the -- and I understand that, your Honor.
First of all, the record establishes Ms. Lusch's deposition testimony that she -- she is not certain how she used it, but she felt an immediate burning sensation. Which, as the Court will learn in the next couple of days, is classic of the people that subsequently develop anosmia.
And so she thinks she used it as directed, but after she used it and she felt the burning, she went to the box to see; maybe she did something wrong.
And so the record is that, you know, we don't know for sure because when people have used a product for a while, as the Court knows, you might not, you know, every single occasion, take cognizance of exactly how you used it. And so the record, I think, establishes from Ms. Lusch's testimony at deposition that she's not certain.
And so this is -- this is a chain of causation, basically, we're trying to link, where she felt the burning, lost her sense of smell the next day. So we're trying to make a temporal connection.
But I think if he's going to testify that -- you know, product misuse is foreseeable, I believe, under Oregon law. So if he's going to testify that his -- limit his opinions to the fact that, you know, if it's used -- if it can't reach the olfactory cleft if used properly, I think we should be able to explore the foreseeable misuse issue, and -- and ask him whether this in fact contradicts, you know, you -- you incorporate this additional fact, the incorrect use, that it can reach the nasal epithelia contained in the olfactory cleft.
I'm sorry, that was way too lengthy, and I apologize.
THE COURT: Why not just ask him that question, then.
MR. JOHNSON: I think I did.
THE COURT: No, I don't think you have.
MR. LAZARUS: Your Honor --
THE COURT: Mr. Lazarus?
MR. LAZARUS: Under Rule 7020, one of the requirements is fit between the testimony of the experts and the facts of the case.
In this case, Ms. Lusch testified unequivocally that she used the product as directed. Dr. Dalby's report, as Mr. Johnson has already established, was limited to the scenario of use as directed and what happens under that scenario.
At page 43 of Ms. Lusch's deposition, she said the following.
Question: So you read the instructions?
Answer: Um-hmm.
Question: You understood the instructions?
Answer: (Nodding head.)
Question: And you -- did you use the product in accordance with the instructions?
Answer: Yes.
Question: And tell me how you used it.
Answer: I sprayed it in the side of my nostril.
Question: Each nostril?
Answer: Yes.
Skipping down, she says --
And then what did you do? Did you sniff?
Answer: No, I held my nose.
(Court reporter interrupts.)
MR. LAZARUS: No, I held my nose.
Question: The instructions told you not to sniff, did they?
Answer: Yes.
Question: And so you didn't?
Answer: No.
The misuse protocol that's discussed in this exhibit has to do with people sniffing, inserting the bottle much further than they were directed to on the package, and -- and sniffing while they were using it. That is not the situation that she testified to in her deposition.
Taking him far afield from his -- the scenario that he considered, I think is unfair to the expert and irrelevant for this proceeding.
MR. JOHNSON: May I address?
THE COURT: Certainly.
MR. JOHNSON: You know, she felt the instant burning after she used the product, which led her to believe she may have used it incorrectly. And the burning is the absolute signal event in the Zicam anosmia cases.
And one of the exhibits in the record, your Honor, the Alexander and Davidson study from the University of California, San Diego, 17 patients used -- came to the -- and this is a very good study. 17 patients presented to the University of California, San Diego, with anosmia. 15 of them, the researchers -- peer-reviewed journal -- concluded that they had lost their sense of smell due to the inhalation of Zicam. Every single one, 15 out of 15, felt the burning. And every single one sniffed.
So it is reasonable to conclude, based on the peer-reviewed Alexander and Davidson study, the fact -- and 15 out of 15 experienced burning, and that Ms. Lusch experienced burning, that she did use the product incorrectly. She just simply didn't recall specifically.
And hopefully -- (pause, referring to document.)
The deposition -- this is from page 51 of her deposition. But again, your Honor, we're trying to -- you know. And we think we're entitled to put this together circumstantially with all of the other evidence in the case.
And the burning is the signal event. But she says she was in Los Angeles.
I just remember it being a -- different than it was in the way it burned. A lot.
This is page 51 of her deposition.
What kind of sensation did you have?
Answer: Just like a really painful burning.
Where?
It was like up in my nose.
Higher in your nose than where you normally put the spray. Is that correct?
Well, it felt different. Instead of being here, it was just like a burning here.
And she sprayed each nostril, and -- and -- at first -- it asked if she sprayed each nostril.
She said, I can't tell you for sure if I sprayed both nostrils. I don't remember.
But the point is -- and then the next morning, she noticed that there was a smell in the house, a bad smell in the house. And her friend actually thought that -- the way Barbara complained, her friend felt that the -- perhaps one of her dogs had had an accident in the house.
So she felt this burning which is characteristic of people -- in the 15 patients, at least, in the Alexander and Davidson study. And all of those people sniffed. And all of those people, Alexander and Davidson linked to -- linked their anosmia to Zicam. Zinc-induced anosmia syndrome.
MR. LAZARUS: Your Honor, if I may be heard.
THE COURT: All right, Mr. Lazarus.
MR. LAZARUS: I don't want to prolong this, but there is no foundation for believing that burning is tied to misuse, and there's no foundation for believing that burning is tied to causation.
Now, in this case, what we're looking at is the reliability of the scientific opinions on causation that are being proffered by the plaintiff. If the plaintiff's experts are really relying on a foundation that was just described for their causation opinions, which includes ignoring the clear deposition testimony of Ms. Lusch that she used the product properly, and instead assuming that she used it improperly because there was burning or because she had doubts in the aftermath, then I would suggest that that itself is evidence of the unreliability of their scientific analysis. It simply is not a foundation for scientific opinion in this case.
Be that as it may, Dr. Dalby is on the stand now. He assumed, based on the deposition record that he was given, that fact scenario of use as directed. That's what he limited his analysis to. And to the facts of this case. I therefore think that it's irrelevant and it's beyond the scope for them to be talking to him about some scenario that they speculate about but really isn't supported by any evidence.
MR. JOHNSON: He used this -- he said he relied on this Pitt report. He's seen it.
THE COURT: No, I don't think he said he relied on it. I think he said he reviewed it.
MR. JOHNSON: Okay.
THE COURT: I think that's what's his testimony; that he was aware of it, he reviewed it. I think he even called it to someone's attention, that there's a difference between review and rely.
And the question before the Court is defendant's Motion for Summary Judgment. I think you're well aware of the body of case law that says that you cannot try and substitute testimony to contradict a prior deposition of a party.
So if what Mr. Lazarus read is your client's depositional testimony as to how she used it, then that's what is in the record.
Now, as you've read, as she says she used it, she received this burning sensation, then that's also a record. But that doesn't mean you can go back and say she used the product in a fashion that is different than what she said at the time of her deposition.
MR. JOHNSON: Well, what she said is -- the question was, Did you sniff? And she said, I don't remember. But she felt the burning.
And if -- if you use that in conjunction with the Alexander and Davidson study, where every -- where 15 out of 15 individuals who lost their sense of smell after using Zicam sniffed and felt the burning, that's the connection.
THE COURT: But I also agree with Mr. Lazarus that Dr. Dalby was basing his testimony on the description on the box as to the proper method of use. And based on that, it's his opinion that the Zicam would not reach the area that he marked on Exhibit 101.
Therefore, I believe the questions that go to the improper use as described in this exhibit would not be relevant.
So I'll sustain the objection, in that respect.
MR. JOHNSON: May I ask a few follow-up questions about the extent to which he incorporated this in his opinions? The -- the -- the Pitt study?
THE COURT: Very well. Go ahead.
MR. JOHNSON: Just -- just --
BY MR. JOHNSON:
Q. And that is a question, Dr. Dalby.
To what extent did you incorporate the -- Exhibit 2, the Pitt study that you referenced, that you looked at this afternoon, into your opinions?
A. Well, I think I really viewed this study, and also a study from Spain, as confirming an opinion that I already held, which is the likely location of deposition.
So I think, as I said, from -- from a knowledge of what causes particles to both travel in the direction of, ultimately come into contact with, and stay in contact with a biological membrane, doesn't really -- there's nothing in these studies that contradicts really what I would have said before.
So they reinforce my opinion. They don't -- they're not the basis for it.
Q. This study is not the basis of your opinion?
A. I -- I don't know how to be clearer.
I mean, it -- to me, the study is pretty well -- you know, it's a -- it's a relatively small study. It certainly has things you could quibble with about the design of the study.
But it's, broadly speaking, looking at the -- you know, what really amounts to, I think, 23 patients with -- as you said, two of the ten incorrectly administered, so three of the ten reached the upper third of the middle turbinate.
So, you know, what I take away from that is, in the majority of cases, that didn't happen.
So I -- I view it as confirming what I've told you before, which is I think this type of formulation, sprayed as we -- I thought we agreed from my reading of the box, it's just not likely to go to the region of the nose that I identified.
Q. But you would also agree that if -- if this study is correct, two of ten, 20 percent of incorrectly administered doses of Zicam reached the olfactory cleft?
MR. LAZARUS: Your Honor, objection. Objection, your Honor. It's the same -- it's the same problem. And also, I have a problem with the questions that go to this study without specifying further.
For the Court's understanding, this study had two different protocols, one in which the patients used the product properly and one in which the patients used the product mis--under a misuse protocol. These two out of ten that he's talking about are in the misuse protocol.
So to the extent that Dr. Dalby may be relying or considering important the results of the proper use protocol, that's different from any reliance or use on the irrelevant protocol to this case, which was a misuse protocol.
THE COURT: Well, is this Exhibit 1D or Exhibit 2?
MR. JOHNSON: Well, it -- your Honor, it was submitted in the materials in opposition to the summary judgment motion as D1, but I had it marked --
THE COURT: As Exhibit 2 today?
MR. JOHNSON: That's correct.
THE COURT: Okay. And it says what it says. All right? If you're asking the doctor to do the math insofar as whether it's 20 percent, I think you can do that. But it says it. So I don't know the purpose of your asking him that.
MR. JOHNSON: Understood. Thank you.
THE COURT: All right.
BY MR. JOHNSON:
Q. Dr. Dalby, you -- have you reviewed -- and obviously, this -- this Pitt study, Exhibit 2, was not listed in the materials in your report that we received in January of 2006.
Did you review, in the interim, any medical records or any studies regarding Barbara Lusch personally?
A. I think I have -- I don't know exactly when, but I have had a chance to look at some of Dr. Jafek's testimony. And I think in some cases that does talk about, I think, his examination of Ms. Lusch.
Q. And you have no reason, I assume, to doubt that Ms. Lusch did in February of 2004 suffer a loss of a sense of smell suddenly?
A. Up until today, I --
MR. LAZARUS: Objection, foundation.
THE WITNESS: -- never had an opportunity to meet or see Ms. Lusch, so I just have no -- you know, no opinion at all.
But, again, that wasn't something that I was asked about, nor am I really qualified to speak on it.
I can tell you, you know, an awful lot, and I'm trying to help to understand the -- where particles go in the nose.
What they do when they get there, I think, is, you know, moving out of my area of expertise. So I'm not trying to be difficult, I'm just trying to tell you what I know.
MR. JOHNSON: Okay. Thank you. No further questions.
THE COURT: Anything further, Mr. Lazarus?
MR. LAZARUS: Just a few, your Honor.
REDIRECT EXAMINATION
BY MR. LAZARUS:
Q. Dr. Dalby, you were asked some questions about the peer review process.
Is it your understanding that all peer-review journals are peer reviewed in the same way?
A. There's a variation, but the basic idea is to have somebody else who we hope will be impartial, but at least qualified and knowledgeable to be able to offer an opinion as to whether what's been presented is sensible.
Q. Do you know anything specific about the process for peer review that's utilized by the American Journal of Rhinology, the publication that published Dr. Jafek's case series?
A. No, I do not.
Q. In your role as a peer reviewer, do you depend on the author to provide you with accurate and honest information about the procedures used in the study and his bias or interest?
A. Well, I rely on what the author submits in writing with their manuscript. Only if I thought something were really confusing that I couldn't even expect to review it or understand it might I ask, you know, for some sort of clarification.
So what I'm always looking at is what is submitted in the manuscript.
Q. Now, in the report that's been marked as Exhibit 1, you've listed in that report a great number of materials.
Is that list the materials that you relied on to form your opinion, or is that list the materials you reviewed and considered in your work on the case?
A. It's things that I was asked to review and to consider.
Q. For example, did you review and consider Dr. Jafek's cadaver study?
A. Absolutely. I read it. And I looked up, you know, what he had to say.
Q. You're not basing your opinion as to where Zicam reaches in the nasal cavity based on Dr. Jafek's cadaver study, are you?
A. No. As I tried to suggest earlier, I'm basing it on, you know, other studies that I think are much more compelling, that have been replicated much better, that involve statistical analysis, that are more than a one-off observation using a technique that I think is simply old and dated.
Q. And is there a distinction in your mind between something that you read and considered, and what you relied on to form a scientific conclusion?
A. I'm sorry, could you say that again?
Q. Is there a distinction in your mind between things that you read and considered and, on another hand, things that you rely upon to form a scientific conclusion?
A. Yes, there is. There's a lot of things written that I don't necessarily find to be useful or -- or to be true.
Q. I just want to very briefly make sure that the record is clear on the University of Pittsburg cadaver study. That is something you reviewed and considered during your work on the case, because it was provided to you for your information. Correct?
A. Correct.
Q. Is that something that you relied upon in forming your conclusion as to where Zicam is likely to be deposited when used as directed?
A. No. As I tried to make clear earlier, when I was asked, I -- I looked at it, and I think that it is, you know, not the most compelling piece of data. I didn't rely on it. I'm relying on other papers, other experiences, but not specifically that study.
Q. Mention was made during your cross-examination of the Spanish study and of this University of Pittsburg study that was the subject of some discussion.
Now, the Spanish study and the University of Pittsburg study were both studies that were funded by Matrixx and specifically looked at the question of where Zicam is deposited when the product is used in various different ways.
Is that your understanding?
A. Yes, I do understand that both studies were funded by Matrixx.
Q. And both of them included, as I described earlier, a proper use protocol and a protocol in which the patients were directed to misuse it egregiously. Correct?
MR. JOHNSON: Your Honor, I'm going to object. He's leading --
THE COURT: I'll sustain the objection.
BY MR. LAZARUS:
Q. Doctor, what's your understanding of protocol of the Spanish and Pittsburg studies with respect to proper and misuse of this product?
A. The studies have one -- one -- one arm in which one nostril is utilized to -- or the formulation is sprayed into the nose using the direction -- or according to the directions that are on the package.
The other protocol has varying degrees of what we -- I can't remember who introduced the term “misuse,” but have different things which are not included in the protocol.
And actually I think you gave a comprehensive list before, except I think you forgot to mention multiple sprays or two sprays into one nostril, rather than one.
So it looked at -- it added sniffing, which is not on the label. It added two sprays, which is not on the label. Had a depth of insertion which I don't think is suggested by the label.
So there were multiple modes of misuse employed.
Q. What was the data revealed by those studies, in terms of where Zicam gel is likely to be deposited when the product is used according to the package directions?
A. I think in total in these two studies -- and this is why I was equivocal about the 20 percent. I think in the two studies together, I think the Spanish study was around -- I think they had planned to recruit -- although they may not have completed 40 patients. There were 23 patients in this study. And from the best of my memory all of the ones who used it according to the normal use protocol that I tried to outline for you earlier, I don't believe in any of those cases that Zicam was recovered in the top third of the nasal cavity.
MR. LAZARUS: Thank you very much, Doctor.
THE COURT: Anything further, Mr. Johnson?
MR. JOHNSON: A very short recross, your Honor.
RECROSS-EXAMINATION
BY MR. JOHNSON:
Q. You understand that Zicam, Matrixx financed both the Pitt study that you and I discussed and the Spanish study that's been alluded to. Correct?
A. Yes, I did.
Q. And neither of those studies were peer reviewed or published. Correct --
A. I think I actually had the -- for -- just to be clear for the Spanish study, I don't speak Spanish, so I read an English translation of it. But the paper was on the front of it.
I honestly don't recall whether, you know, what I was looking at was a proof or the final version. But in -- in either case I did understand, certainly, that they were funded by Matrixx.
But just to point out, the -- in the area that I work, which is sort of away from the basic science that NIH funds, and more in the direction of things as they're actually used by patients, that's true for the majority of studies. I mean, the funding by the company that wants to learn an answer to the question -- and clearly Matrixx was going out of its way to learn the answer here -- is normal.
I don't think the study would have been done, had Matrixx not paid for it.
Q. But my question is very specific.
A. Okay.
Q. To your knowledge, neither study was peer reviewed or published?
A. I honestly can't recall.
Q. Okay. And -- and both studies were done after Matrixx had been made aware of complaints by patients, by customers, of burning sensation and smell loss after using the product?
A. Well, if you can let me break it into two parts, I -- I -- you know, don't know what Matrixx's motivation was. But certainly I think the studies were -- you know, were done on the behest of Matrixx.
Does that answer your question?
Q. No.
A. Sorry, I'm --
Q. I think my question was pretty clear. I'll make it shorter.
Both studies were done after the commencement of litigation against Matrixx?
A. Well, I honestly don't know when -- I actually don't know what's the definition of beginning of litigation by Matrixx. But I think they were done to try and answer questions that at least arose during the litigation. I just simply don't know when it started.
MR. JOHNSON: Thank you. No further questions.
THE COURT: All right. Thank you, Dr. Dalby. You may step down.
We have another witness?
