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`CIVIL ACTION NUMBER:
` 11-3962
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` TRIAL
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` UNITED STATES DISTRICT COURT
` FOR THE DISTRICT OF NEW JERSEY
`__________________________________
`HELSINN HEALTHCARE, S.A. and
`ROCHE PALO ALTO, LLC,
` Plaintiffs,
` -vs-
`DR. REDDY'S LABORATORIES, LTD.,
`DR. REDDY'S LABORATORIES, INC.,
`TEVA PHARMACEUTICALS USA, INC.,
`and TEVA PHARMACEUTICAL
`INDUSTRIES, LTD.
` Defendants.
`__________________________________
` Clarkson S. Fisher United States Courthouse
` 402 East State Street
` Trenton, New Jersey 08608
` June 12, 2015
`B E F O R E: THE HONORABLE MARY L. COOPER
`
`UNITED STATES DISTRICT JUDGE
`
`Certified as True and Correct as required by Title 28, U.S.C.,
`Section 753
`
`/S/ Regina A. Berenato-Tell, CCR, CRR, RMR, RPR
`/S/ Carol Farrell, CCR, CRR, RMR, CCP, RPR, RSA
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`United States District Court
`Trenton, New Jersey
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`Helsinn Healthcare Exhibit 2010
`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PGR2016-00008
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`Saab - Voir Dire
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`(In open court. June 12, 2015, 9:30 a.m.)
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`THE COURT: Good morning, everyone.
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`ALL: Good morning, your Honor.
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`THE COURT: Okay. We're on the record.
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`I got that stipulation. It looks fine to me. I can't
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`imagine what the remaining issues are, but I'll figure that
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`out or you'll tell me. So I'll sign the stipulation.
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`Thank you.
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`MR. LIZZA: Thank you, your Honor.
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`MR. WONG: Thank you, your Honor.
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`MR. ASHKENAZI: Your Honor, at this time, plaintiffs
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`call Dr. Tanios Bekaii-Saab.
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`(Whereupon, TANIOS BEKAII-SAAB, witness for the
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`Plaintiffs, sworn.)
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`THE DEPUTY CLERK: Please state and spell your full
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`name for the record. Have a seat.
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`THE WITNESS: Tanios Bekaii-Saab.
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`First name T-A-N-I-O-S. My middle name B, like boy,
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`E-K-A-I-I-S-A-A-B, like boy.
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`MR. ASHKENAZI: Your Honor, if I may approach and
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`provide the witness with a binder.
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`THE COURT: Certainly.
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`VOIR DIRE EXAMINATION BY MR. ASHKENAZI:
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`Q.
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`Good morning, Dr. Saab. Could you please turn to PTX-201
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`in the binder in front of you.
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`United States District Court
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`Trenton, New Jersey
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`Saab - Voir Dire
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`5
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`And do you recognize this document, Dr. Saab?
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`Yes. It is my curriculum vitae.
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`And would you please tell us about your educational
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`A.
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`Q.
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`background after high school, please.
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`A.
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`Sure. So, I completed a bachelor in science at McGill
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`University in Montreal, Canada, and then completed my medical
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`degree, so I went back to medical school, at Lebanon, the
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`American University of Beirut.
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`THE COURT: Not loud enough. Not going to work.
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`They can't hear.
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`BY MR. ASHKENAZI:
`
`Q.
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`A.
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`Dr. Saab, if you can get a little closer.
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`I'll get closer.
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`THE COURT: Yes. Closer to the mic.
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`Make sure that it's working, sir.
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`MR. O'MALLEY: Can you just say a word or two?
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`THE WITNESS: Yes. Can you hear me better now?
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`MR. O'MALLEY: Much better.
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`THE WITNESS: Oh, good.
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`THE COURT: Okay, fine.
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`So, we are at medical school in --
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`THE WITNESS: So medical school at the American
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`University of Beirut in Lebanon.
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`BY MR. ASHKENAZI:
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`Q.
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`And what year did you graduate medical school?
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`United States District Court
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`Trenton, New Jersey
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`A P P E A R A N C E S:
`
`PAUL HASTINGS
`BY: JOSEPH O'MALLEY, ESQUIRE
` ERIC W. DITTMANN, ESQUIRE
` ISAAC S. ASHKENAZI, ESQUIRE
`SAUL EWING
`BY: CHARLES M. LIZZA, ESQUIRE
`Attorneys for the Plaintiffs
`
`BUDD LARNER
`BY: STUART D. SENDER, ESQUIRE
` MICHAEL H. IMBACUAN, ESQUIRE
` HUA HOWARD WANG, ESQUIRE
` CONSTANCE S. HUTTNER, ESQUIRE
` KENNETH E. CROWELL, ESQUIRE
`Attorneys for the Defendant, Dr. Reddy's Laboratories
`
`WINSTON & STRAWN
`BY: JOVIAL WONG, ESQUIRE
` GEORGE LOMBARDI, ESQUIRE
` JULIA MANO JOHNSON, ESQUIRE
` BRENDAN F. BARKER, ESQUIRE
`LITE DePALMA, GREENBERG, LLC
` BY: MAYRA V. TARANTINO, ESQUIRE
`Attorneys for the Defendant, Teva
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`United States District Court
`Trenton, New Jersey
`
`Colloquy
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`I N D E X
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`2
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`3
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`WITNESS VOIR DIRECT CROSS REDIRECT RECROSS
` DIRE
`TANIOS BEKAII-SAAB
`By Mr. Ashkenazi 4 12 209
`By Mr. Wong 92
`By Mr. Sender 187
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`Saab - Voir Dire
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`It also helps establish guidelines, more specifically,
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`supportive care guidelines of university-wide, at least as
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`pertaining to cancer.
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`Q.
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`Earlier you mentioned that you did research as part of
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`your fellowship. Do you currently conduct any research?
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`A.
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`Q.
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`A.
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`Yes, I do.
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`And what type of research do you currently conduct?
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`Most of my research is focused on what we call
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`translational clinical research, and I get -- most of my
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`involvement is in the Phase I and Phase II, although I've
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`participated in all phases of trials.
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`And the trials are either -- are developed, you know,
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`by myself with grants from the National Cancer Institute or
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`with -- in collaboration with industry.
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`I also -- I'm what you call the local principal
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`investigator of a number of other trials in collaboration with
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`other universities or in collaboration with industry,
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`especially in the Phase III trials.
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`But we work very closely with the National Cancer
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`Institute and with what we call the cooperative groups, which
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`are part of the National Cancer Institute umbrella.
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`Q.
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`Dr. Saab, if you need there should be a bottle of water
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`there.
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`A.
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`Q.
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`No, I think it's my accent a little bit. Sorry.
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`And how many clinical trials have you participated in?
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`essentially, or not.
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`Q.
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`Have you ever served as a reviewer on any peer-reviewed
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`journals?
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`A.
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`Q.
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`Yes, I did.
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`Now, looking at PTX-0201-0007, your CV indicates you
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`received a number of awards, including the National Cancer
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`Institute Clinical Investigator Team award?
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`A.
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`Q.
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`A.
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`Q.
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`Yes.
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`And the ASCO Leadership Program Development award?
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`Yes.
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`Can you explain what the National Cancer Institute
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`Clinical Investigator Team Leadership award is?
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`A.
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`Certainly. So, the National Cancer Institute is the
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`cancer branch of the NIH, and every two years, they actually
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`choose about 10, 10 to 13 clinical investigators from across
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`the United States that they consider as leaders in clinical
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`research and clinical investigation.
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`MR. ASHKENAZI: Your Honor, at this time, plaintiffs
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`proffer Dr. Saab as an expert in the clinical care of cancer
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`patients, including the management of CINV and clinical
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`aspects of drug research and development.
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`MR. WONG: No objection.
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`THE COURT: That's fine. Admitted. Thank you.
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`DIRECT EXAMINATION BY MR. ASHKENAZI:
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`Q.
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`Dr. Saab, have you prepared a slide that summarizes your
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`Saab - Voir Dire
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`A.
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`Again, I'm going to give you a conservative number. At
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`least 50. It's probably more than that since 2003.
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`Q.
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`A.
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`And how many articles have you published?
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`Peer-reviewed articles, at least 150. Total articles, or
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`total publications, more than 250 publications.
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`Q.
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`Outside of your research, have you ever served as a
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`consultant to pharmaceutical companies on how to develop
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`drugs?
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`A.
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`Q.
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`A.
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`Yes, I do consult.
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`And what companies have you consulted for?
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`I've actually consulted with a number of different
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`companies from the smaller to the larger ones. As examples:
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`Pfizer, BMS, Celgene, AstraZenica, Merrimack, which is a
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`smaller company, and others.
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`Q.
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`A.
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`What does your consulting work generally involve?
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`Sure. So, there are two -- two types of consulting that
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`I've been involved in. One is essentially working on agents
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`that are in development and essentially help and guide
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`placement of some specific agents into areas of need in
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`specific needs in our, you know, world of gastrointestinal
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`cancers.
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`The others would focus mostly on when agents are near
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`approval or even approved based on large Phase III studies is
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`help companies understand how they would best fit the needs of
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`our patients, how they would make it into the marketplace
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`opinions in this case?
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`A.
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`Yes, sir.
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`MR. ASHKENAZI: Would you put up PDX 502.
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`BY MR. ASHKENAZI:
`
`Q.
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`Could you please walk us through your opinions in this
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`case?
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`A.
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`So, this slide actually summarizes my opinions that in
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`2003, a POSA would be -- would not have pursued the clinical
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`development of yet another 5-HT
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` intravenous drug and that
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`3
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`they would rather focus on NK-1 antagonists for reducing the
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`likelihood of CINV, and that palonosetron provided an
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`unexpected and, I think, important advance in the prevention
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`of CINV, specifically delayed CINV.
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`Q.
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`And, Dr. Saab, you referenced a POSA, which we understand
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`is a person of ordinary skill in the art, correct?
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`A.
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`Q.
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`Correct.
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`Did you provide your opinions in this case from the
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`perspective of that person?
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`A.
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`Q.
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`Correct.
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`What definition of a POSA did you use with respect to
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`your opinions in this case?
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`A.
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`I used essentially the definition that -- that was
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`proposed by Dr. Amidon.
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`MR. ASHKENAZI: Can we please take a look at
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`Plaintiffs' Demonstrative Exhibit 503.
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`BY MR. ASHKENAZI:
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`Q.
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`A.
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`Is this the definition of a POSA that you used?
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`Yes.
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`MR. ASHKENAZI: Your Honor, this is -- you've seen
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`this slide before.
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`THE COURT: That's right.
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`MR. ASHKENAZI: Okay.
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`BY MR. ASHKENAZI:
`
`Q.
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`I'd like to discuss your experience with treating
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`patients for CINV, Dr. Saab.
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`What were the side effects associated with chemotherapy
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`in 2003?
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`A.
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`So, there were a number of different types of toxicities
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`that we deal with with cancer patients, and they go anywhere
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`between fatigue, can go from mild to very severe; nausea,
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`vomiting, diarrhea, drops in the blood counts. Some agents
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`can cause what we call neurotoxicity, so nerve toxicity is
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`numbness and tingling, and there's a variety of other
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`toxicities.
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`Q.
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`And nausea and vomiting associated with chemotherapy is
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`what we have been referring to as CINV, correct?
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`A.
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`Q.
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`A.
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`Yes, sir.
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`How does CINV affect cancer patients in your experience?
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`So, CINV had been and remains, but had been then one of
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`Q.
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`Are there any factors that influence whether a patient
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`gets CINV?
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`A.
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`Yes, there are certain at least known factors that may
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`influence that.
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`Q.
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`A.
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`Have you prepared a slide that summarizes those factors?
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`Yes, sir.
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`MR. ASHKENAZI: Could we please look at Plaintiffs'
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`Demonstrative Exhibit 504.
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`BY MR. ASHKENAZI:
`
`Q.
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`Dr. Saab, can you please explain to us what you're trying
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`to illustrate on this slide?
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`A.
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`Sure. So, this represents some of the risk factors for
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`chemotherapy-induced nausea and vomiting, so CINV.
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`So, of course, the choice of the chemotherapeutic agent
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`is a risk factor by itself. Some chemotherapy agents are
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`highly emetogenic, for example, cause CINV in more than
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`90 percent of the patients and some are -- have lower
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`emetogenicity potential, and then most in the middle.
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`It happens that younger patients are actually more
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`susceptible than elderly patients for severe CINV.
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`And women, again, for reasons unknown, mostly unknown
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`to us, are more susceptible than men. And we have a lot of
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`patients that have other diseases -- other diseases, other
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`conditions like diabetes, hypertension or heart conditions,
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`where chemotherapy can induce even a worse profile of
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`the most distressful symptoms that essentially patients could
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`go through.
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`Oftentimes, it was back to the point where patients
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`would stop their chemotherapy midway, but for some patients
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`even that I've actually seen in my clinic along the years,
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`they have been reluctant to accept initiation of any
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`chemotherapy because of either prior experiences or because of
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`a loved one that experienced just severe CINV or a friend or
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`what have you.
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`So, there was incredible reluctance for some patients
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`to pursue that, and for the patients who actually go through
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`the episode, it was sometimes some of the worst and
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`heart-wrenching toxicities you would see.
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`To give you an example at least in clinic, what we used
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`to see patients coming to the hospital with 20 to 30 episodes
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`of vomiting, nonstop for three to four days, occasionally up
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`to a week. And back before 2003, we had to admit them to the
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`hospital, give them intravenous fluids and try everything we
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`had in the day to try to control their emesis and mostly,
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`unfortunately, to no avail.
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`And that usually in some patients would leave a real
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`bad memory, understandably so. And, occasionally, the
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`patients may just decide not to pursue any further
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`chemotherapy.
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`So, it was -- it was pretty distressful to a lot of
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`patients, both mentally and physically.
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`toxicity, including CINV.
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`And, you know, a lot of our patients, understandably
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`so, have the anxiety of being diagnosed with the cancer, the
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`anxiety of going through treatment, and that can actually
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`enhance the risk of CINV. And naturally a history of motion
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`sickness would certainly increase that. And prior exposure to
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`chemotherapy is definitely a risk factor, whether it was in
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`the remote past or patients who had, let's say, what they call
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`in the adjuvant setting, where they have gone through surgery,
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`received chemotherapy, and then two years after, the cancer
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`comes back and then we want to restart them on chemotherapy.
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`They have had a prior bad experience with chemotherapy. That
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`puts them at a high risk for CINV. And this is probably what
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`more related to what we call anticipatory nausea. So,
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`essentially, just thinking about the prior episodes would put
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`them at risk for CINV.
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`Q.
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`I would like to now discuss the treatment and prevention
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`of CINV in 2003. Did you create a slide to help us with this?
`
`A.
`
`Q.
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`Yes, sir.
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`Looking at Plaintiffs' Demonstrative Exhibit 505, can you
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`please walk us through this slide?
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`A.
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`Yes. So, this is -- these are examples of certainly not
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`all, but most commonly used antiemetic strategies for CINV by
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`2003. And we have different -- different categories,
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`depending on the target, so dopamine antagonists, steroids,
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`antianxiety medications, antihistamines, and 5-HT
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` receptor
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`3
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`treating patients for delayed CINV in 2003?
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`antagonists, such as ondansetron, granisetron, and dolasetron.
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`A.
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`Well, as I said, we didn't have real good strategies at
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`Q.
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`Now, for the 5-HT
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` antagonists when were each of those
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`3
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`the time to actually prevent or treat delayed CINV, although I
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`available, commercially available?
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`should say that controlling well acute CINV would help with
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`A.
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`So, as I show on the slide, so '91 for ondansetron, '93
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`some cases from spilling into delayed CINV, but for the
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`for granisetron, and '97 for dolasetron.
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`majority we didn't have any -- any good strategies to prevent
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`Q.
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`Okay. How effective were these 5-HT
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` antagonists for
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`3
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`or treat.
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`reducing the likelihood of CINV as of January 2003?
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`Q.
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`I would like to talk a little bit now, Dr. Saab about
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`A.
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`You know, they were a very welcome addition to our
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`half-life. We have heard a little bit about that during this
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`armamentarium in terms of how we treat patients or prevent
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`trial. Can you please explain to us what the term "half-life"
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`CINV. They were effective in helping with the acute episodes
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`means?
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`and very effective in doing so and helped us a lot, actually,
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`A.
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`Certainly. So, half-life of a drug means essentially in
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`going through a lot of the chemotherapy. So, they were a very
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`simple terms that this is the time where 50 percent of the
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`welcome addition before 2003 and helped us a lot with a lot of
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`agent that's administered is not present anymore in your
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`patients in the acute setting.
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`system.
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`Q.
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`You mentioned the "acute setting." Are there two
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`Q.
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`Now, we heard a little bit about half-life and 5-HT
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`3
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`different types of settings for CINV?
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`antagonists during this trial. In 2003 what impact, if any,
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`A.
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`Yes. So the division line between what you call acute
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`would the longer half-life of a 5-HT
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` antagonist have been
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`and delayed CINV is 24 hours. I don't know exactly why it is
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`thought to have on reducing the likelihood of delayed CINV?
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`24 hours, but it is around that time. And the first 24 hours
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`A.
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`So, at least most of the body of the literature at the
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`we call this acute CINV. Any nausea and vomiting that occurs
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`time suggested that prolongation of exposure to 5-HT
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`3
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`beyond 24 hours is essentially delayed, whether it is a
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`inhibitors would not actually affect delayed CINV. So, in
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`continuation of acute, so an acute that's not controlled and
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`other words, just prolonging half-life or prolonging exposure
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`spills over beyond 24 hours, or nausea and vomiting that
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`to 5-HT
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` inhibitors would not have significant effect on
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`occurs beyond 24 hours. And I can tell you I have by examples
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`of patients of mine across the years that essentially left the
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`infusion center with no evidence of nausea and vomiting and
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`two, three days after they come back with these severe
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`episodes of refractory nausea and vomiting, and that falls
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`within this category of delayed CINV.
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`THE COURT: Why do you call it "refractory"?
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`THE WITNESS: Thank you. Refractory, once --
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`THE COURT: What does that mean?
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`THE WITNESS: "Refractory" meaning it is resistant to
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`all types of treatments, all attempts to actually control it.
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`THE COURT: Okay.
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`THE WITNESS: So, most of these patients will present
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`with severe episodes of nausea and vomiting up to 20, 30
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`times, as I said, and we have tried all types of chemicals,
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`and, essentially, all you do is keep them in the hospital
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`supported with I.V. fluids for up to a week and before they
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`actually just settle on their own.
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`BY MR. ASHKENAZI:
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`Q.
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`Now, why is there this distinction between acute and
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`delayed CINV?
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`A.
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`Because we do believe, although until today I can't say
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`that we really understand it fully, we do believe that there's
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`a difference in the the mechanisms that actually initiate the
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`acute reaction versus the chronic reaction.
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`Q.
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`Now, what challenges, if any, were associated with
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`delaying CINV. And, again, I have to put my clinician hat on
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`here and tell you my own experience if you don't mind. My own
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`experience with -- with strategies of administering setrons,
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`because we have done that before 2003. We had to do all
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`desperate measures to actually treat patients who came in with
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`delayed CINV.
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`As I said, a lot of them were refractory, so we had to
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`throw what we call the kitchen sink approach, which is
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`anything we had on hand, any drug that had any antiemetic
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`activity we have used, any strategy that even had a glimmer of
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`a hope, we actually have used. I mean, you have to be there
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`seeing those patients just on rounds just retching and
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`vomiting between every word, and it was just not certainly a
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`pleasant thing for patients.
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`And, so, we tried actually using setrons in clinic for
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`two to three days after chemotherapy, and at least in my --
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`THE COURT: You mean readministering it on a daily
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`basis?
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`THE WITNESS: Yes. So we would give the patients --
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`we would give the patients a prescription for three days or we
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`even when they get admitted we give them a prolonged course of
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`5-HT
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`s in the hospital. And none of these strategies seemed
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`to work, so, you know, at least at the time in my -- in my
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`mind in just analyzing the literature, as well as our own
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`experience, I would say that, you know, this didn't seem like
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`a strategy.
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`BY MR. ASHKENAZI:
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`Q.
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`Dr. Saab, when we talk about the dosages in terms of
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`milligrams, what does that mean with respect to these setrons?
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`A.
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`Q.
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`A.
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`The clinically used dosages?
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`Yes.
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`Each agent has a different dosage that it works optimally
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`at. You really can't compare them. So the dose itself
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`milligram-per-milligram you can't compare two drugs
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`milligram-per-milligram because this is not how you think
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`about a drug. Certain drugs like granisetron may function at
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`a much lower dose because of a certain level of, say, potency
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`and other factors, as well. A drug like ondansetron may work
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`best at a higher dose. But these are the safe and effective
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`doses that you would use. One happens at 8 or 16 or
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`32 milligrams, one happens to be at 1 milligrams, but they're
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`equally effective and equally safe at the approved dosage.
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`Q.
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`So, the fact that one is at 8 milligrams and one is at 32
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`doesn't -- what difference, if any, does that make in terms of
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`safety?
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`A.
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`Q.
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`It does not make any difference.
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`Now --
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`THE COURT: As long as you're working with the
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`approved dosages in the package insert?
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`THE WITNESS: Absolutely. As long as you stay within
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`the confines of the approved dose that works and is safe. You
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`and, thus, we will be able to actually control beyond
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`24 hours.
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`THE COURT: And it might result in a further
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`indication being approved by the FDA?
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`THE WITNESS: Yes.
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`THE COURT: Thank you.
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`THE WITNESS: So, then they were hoping for an
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`indication in the delayed setting where they had the
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`indication in the acute setting. So to add to this
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`indication.
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`THE COURT: Also, doctors can prescribe off-label, so
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`they could go on prescribing their multiple doses multiple
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`days even without the FDA-approved label indication, right?
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`THE WITNESS: Guilty as charged. I have done that,
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`yes.
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`THE COURT: "Guilty as charged," I'm sure you use
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`that only as a figure of speech because --
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`THE WITNESS: Yes.
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`THE COURT: -- that's part of your clinical
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`on-the-job research, right?
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`THE WITNESS: Absolutely so. Like I said, you know,
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`we have -- oftentimes, I mean, when you're in clinic or on the
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`ward with a patient who is vomiting nonstop, we have used
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`these strategies. We were hoping if there is a one-in-40
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`chance it will work that that one patient will be one-in-40,
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`don't want to experiment with larger doses one way or the
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`other.
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`BY MR. ASHKENAZI:
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`Q.
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`Now, could we please take a look at Plaintiffs'
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`Demonstrative Exhibit -- sorry, Plaintiffs' Trial Exhibit 212.
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`And what is this document, Dr. Saab?
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`A.
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`So, this is another -- another trial actually looking at
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`granisetron, a setron with dexamethasone, the steroid
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`dexamethasone, alone in patients receiving highly emetogenic
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`chemotherapy. This was a double-blind placebo-controlled
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`comparative -- excuse me, comparative study.
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`Q.
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`A.
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`Q.
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`And what year was this article published?
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`This was, again, in 1998.
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`Now --
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`THE COURT: Why do they do these extra studies after
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`Phase III is long over and the drug -- both of these drugs are
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`approved? What's the context of that kind of research?
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`THE WITNESS: So, these -- these agents were approved
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`in what we call the acute -- acute controlled setting, and
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`there was no data on these agents in the delayed setting, so
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`beyond the 24 hours. And, so, those studies, again, under the
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`thought that if we give repetitive doses of these setrons at,
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`you know, multiple times a day or over multiple days,
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`depending on their half-life, that we will overcome the
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`limitations of the half-life, maximize exposure over time,
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`so absolutely.
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`THE COURT: And then you're going to report out what
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`you find if you have enough of these cases to make it worth
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`reporting?
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`THE WITNESS: Yes, absolutely.
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`THE COURT: Okay.
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`BY MR. ASHKENAZI:
`
`Q.
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`With respect to this article, Dr. Saab, have you created
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`a slide summarizing the conclusions of this study?
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`A.
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`Q.
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`Yes, sir.
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`If we can look at Plaintiffs' Demonstrative Exhibit 508.
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`And can you please explain to us what the conclusions
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`of this study was?
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`A.
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`So, this is again from Goedhals, et al. published in '98.
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`So, the results of the study, at least in the conclusions, are
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`in agreement of those of other studies of cisplatin-induced
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`delayed emesis, so this is in the delayed emesis setting, and
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`show no difference in the control of delayed nausea and
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`vomiting between setron, ondansetron, and ondansetron plus
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`dexamethasone, or if you look at dexamethasone alone plus
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`granisetron, dexamethasone plus metoclopramide, so a number of
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`studies, again, using this multiple dosing of setrons
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`strategies that have consistently proven to be ineffective
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`from this conclusion for delayed CINV.
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`Q.
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`I'll read the last blowout into the record. "In
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`conclusion, the balance of evidence to date from this and
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`previous studies does not suggest that granisetron can add to
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`the efficacy of the corticosteroids currently used in the
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`treatment of delayed emesis, though the combination of
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`dexamethasone and granisetron is well tolerated."
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`Dr. Saab, I would like to look at one more study.
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`DTX-0047. It should be in your binder. If we could put up
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`DTX-47-0004.
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`What is this document, Dr. Saab?
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`A.
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`So, this is another study, another randomized trial that
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`looked at ondansetron, so another setron plus dexamethasone
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`with dexamethasone alone for the control of delayed
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`cisplatin-induced emesis. Again, focusing on the delayed
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`emesis.
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`Q.
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`A.
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`Q.
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`And what year was this study published?
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`This was in 2001 in the European Journal of Cancer.
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`And, again, have you prepared a slide that summarizes the
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`conclusions of this study?
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`A.
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`Q.
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`Yes, sir.
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`And --
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`THE COURT: And it is actually a Japanese study
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`published in the European journal, right?
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`THE WITNESS: Yes.
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`BY MR. ASHKENAZI:
`
`Q.
`
`If we can take a look at Plaintiffs' Demonstrative
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`actually, it is close to 1, which means it is statistically
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`not significant, so the differences are not statistically
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`significant. Typically it is 0.01 or 0.05 or less to be able
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`to see any statistical significance.
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`THE COURT: Thank you.
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`BY MR. ASHKENAZI:
`
`Q.
`
`We have just taken a look at three studies that evaluate
`
`multidosing of 5-HT
`
` antagonists for treating delayed CINV.
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`3
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`Are there any other studies that were available as of 2003
`
`that addressed this issue?
`
`A.
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`Well, I mean, this was a very active researched area, you
`
`know, the multiple dose of setrons, so there are a number of
`
`other studies. If I recall, there's at least 10 studies that
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`went on around that time. There could have been even,
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`perhaps, even more than 10 studies in the same setting.
`
`Q.
`
`If we can please look at Defendant's Trial Exhibit 48,
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`and specifically if we can put up Plaintiffs' Trial
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`Exhibit 0048-0002.
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`Dr. Saab, do you recognize this document?
`
`A.
`
`Q.
`
`A.
`
`Yes, sir.
`
`And what is it?
`
`So, this is actually by a Canadian group, although it was
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`not a study, it was a meta-analysis, meaning it looks at a
`
`composite of different studies and analyzes the results of all
`
`these studies combined. And the main question of this study
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`Exhibit 507.
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`And can you please explain to us what you're
`
`illustrating on this slide?
`
`A.
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`Sure. This is the study by Tsukada, et al. published in
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`2001. And it is very similar to the other studies looking in
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`multiple dosing of setrons. They found no significant
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`difference between the two arms in either the total number of
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`vomiting episodes or worst -- we say worst grade of nausea
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`intensity during the delayed phase, two to four -- days two to
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`four.
`
`Q.
`
`And at the bottom it says, "In conclusion, there does not
`
`appear to be sufficient evidence to support the prolonged use
`
`of 5-HT
`
` receptor antagonists after 24 hours of
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`3
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`cisplatin-containing chemotherapy."
`
`Did I read that?
`
`A.
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`Which is consistent, again, with most of the body of the
`
`literature at the time.
`
`Q.
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`And that was consistent, also, with your clinical
`
`practice, as well?
`
`A.
`
`Q.
`
`Yes, sir.
`
`Now --
`
`THE COURT: This parenthetical that you see in the
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`upper highlighted box, "P = 0.8716," is that a statistical
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`mark?
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`THE WITNESS: Yes. So, that's the p-value, and,
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`was should 5 hydroxytryptamine
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`3
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` receptors -- or 5-HT
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` receptor
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`3
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`antagonists, or the setrons, be administered beyond 24 hours
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`after chemotherapy to prevent delayed emesis?
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`And, so, what they looked at, which I think is great,
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`is systemic --
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`THE COURT: What's the date of this one?
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`THE WITNESS: 2005.
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`THE COURT: Oh, okay. But it is a meta-analysis?
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`THE WITNESS: Yes.
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`BY MR. ASHKENAZI:
`
`Q.
`
`Why don't we take a look at the Table 1 on DTX-0048-0004.
`
`That may help us. We can blow up that portion of the table.
`
`Dr. Saab, what studies were they -- what was the
`
`meta-analysis evaluating?
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`A.
`
`So, there were 10 studies included in this meta-analysis,
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`all dating prior to the year 2000. So, the meta-analysis was
`
`in 2005. It is essentially all the studies that were included
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`were, naturally, the ones before 2000.
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`And on the top, the top five studies were actually with
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`a 5-HT
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` antagonists alone without steroids, and the top, which
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`3
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`is more reflective of what we do in clinic, are those with
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`5-HT
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` antagonists as adjunct to dexamethasone or a steroid.
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`3
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`And, so --
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`THE COURT: So, in clinic you would tend to use a
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`combination?
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`THE WITNESS: Yes.
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`THE COURT: Adjunct?
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`THE WITNESS: Adjunct.
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`THE COURT: Setron and something else?
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`THE WITNESS: And steroids.
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`THE COURT: So, there's a whole box on that type of
`
`literature in this chart?
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`THE WITNESS: Yes. Absolutely. And, so -- and in
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`this art