Helsinn Healthcare Exhibit 2024
`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PGR2016-00007
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`amongst others.
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`I have presented my research results at multiple national and international
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`forums. I am also on the editorial board for the Journal of the National Comprehensive Cancer
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`Network and Oncopathology, and have received numerous leadership awards from Various
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`organizations such as the National Cancer Institute and American Society of Clinical Oncology.
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`8.
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`I am being compensated for my time consulting in this matter at my usual hourly
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`rate of $500, which is not dependent on the outcome of this case.
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`9.
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`The documents I have relied upon and considered in preparing this report are
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`identified in the report.
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`I have not testified as an expert witness within the preceding four years.
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`A copy of my curriculum vitae is attached as Exhibit 1.
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`II.
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`SUMMARY OF CONCLUSIONS
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`l2.
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`Chemotherapy-induced nausea and vomiting (“CINV”) is a debilitating problem
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`for patients undergoing chemotherapy, and results in lost productivity, distress and delay or
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`complete refusal of further therapy. It can significantly impact the patient’s physical and
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`emotional well—being, nutritional status, ability to withstand treatment rigors and affect overall
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`treatment outcome. While numerous antiemetics were known to be capable of treating acute
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`phase CINV by 2002-2003, there has long been recognition of delayed CINV as a significant
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`problem. In this time period, 5—HT3 antagonists were not shown or thought to be capable of
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`13.
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`Despite this perception in the field, Aloxi®, a new intravenous antieinetic 5-HT3
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`antagonist formulation, provided an unexpected and important advance to efforts to prevent not
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`only acute, but also longer-term, delayed CINV. A single, intravenous dose of Aloxi® given
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`before chemotherapy significantly lowers the risk of antiemetic failure, and provides increased
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`control of both acute and delayed CINV.
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`14.
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`Although Aloxi® is now known to have antiemetic efficacy, this was only
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`established based on the completion and analysis of adequately randomized and controlled Phase
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`3 studies. Such studies are essential to demonstrate the safety and efficacy results of a
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`pharmaceutical drug product.
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`My opinions are based upon my experience in the field of oncology as a
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`practitioner and a researcher, my experience and knowledge in the field of pharmacology, my
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`knowledge of the medical literature and interactions with thousands of patients and other medical
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`professionals.
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`III.
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`OVERVIEW OF CINV TREATMENT AS OF THE RELEVANT TIME PERIOD
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`A.
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`CINV and Its Detrimental Impact
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`16.
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`Both nausea and vomiting are natural responses to noxious stimuli. The ability to
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`respond to tainted foods, ingestion of other toxins and similar experiences by expelling them
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`from the body is very important. When the same pathways are stimulated by medications such
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`as chemotherapy agents, however, the result is stressful and unrelenting, leading to deterioration
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`in both physical and cognitive functions. Nausea, the sensation of needing to vomit, is
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`pervasive, overwhelming and can be disabling.
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`Most chemotherapeutic agents activate chemical pathways that lead to nausea and
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`vomiting. Since chemotherapy was first used to treat cancer, CINV has continuously stood out
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`as a side effect that is particularly burdensome and dreaded by patients and their families, and
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`one of the most significant barriers to the acceptance and/or continuous administration of
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`chemotherapy. In the absence of CINV prevention, nausea and vomiting have been sufficiently
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`severe for many patients to lead to delays or refusal of further treatment, regardless of their
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`understanding of its potential effect on clinical outcome.
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`18.
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`The emetogenicity (i. e., likelihood to cause nausea and Vomiting) of a
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`chemotherapy agent varies, ranging from the highly emetogenic resulting in CINV in 3 90% of
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`patients, to minimally emetogenic agents that result in CINV in < 10% of patients.2 Most
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`chemotherapy agents or combination of agents used in practice are either moderately or highly
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`emetogenic. Moreover, individual patients may be more or less susceptible to the emetogenicity
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`of an agent, with risk factors such as age (younger individuals are more susceptible than older),
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`gender (women more than men), prior exposure and experience with chemotherapy, anxiety,
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`choice of agents, tumor burden, co-morbid conditions, history of motion sickness and genetic
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`factors.3
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`19.
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`CINV is divided into basic categories or phases that describe the pathophysiology
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`of the CINV. Acute CINV is the phase that occurs immediately and within about 24 hours of
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`the administration of chemotherapy. The onset of acute CINV is immediate, can be quite
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`devastating if not prevented, and is largely unresponsive to any treatment other than general
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`supportive measures, such as IV hydration. Delayed CINV is any CINV that occurs more than
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`around 24 hours after chemotherapy. If persistent, it can be as devastating as unprevented acute
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`C]NV. Because of its latency, this problem can go unrecognized and may lead to significant
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`distress to the patient. Additionally, and even in the absence of vomiting, the nausea associated
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`with delayed CINV can significantly curtail the patient’s daily-living activities, impact the
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`patient’s psychological wellbeing, and affect the ability to withstand treatment. Delayed CINV
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`2 Exh. 2,’ Gregory RE and Ettinger DS, 5-HT3 receptor antagonistsfor the prevention of
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`chemotherapy-induced nausea and vomiting, Drugs 55: 173-189, 178 (1998) (“Gregory &
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`Ettinger (1998)”).
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`3 Id. at 177 (Table 111).
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`25.
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`Dopamine antagonists such as metoclopramide were first administered in the late
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`1970s and early 1980s as CINV pathways were becoming better understood. The administration
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`of doses of metoclopramide many times greater than the standard approved dose decreased the
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`risk of CINV, but resulted in serious side effects, including extrapyramidal reactions due to the
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`dopamine blockade (z'.e., various movement disorders, stiffness and tremor), restlessness and
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`anxiety.6 Patients often required admission to the hospital and support for these serious side
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`effects. Prochlorperazine, an older dopamine receptor antagonist, and similar inexpensive
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`medications have also been administered to treat CINV as needed by the patient, although their
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`use is speculative given the absence of significant data to support the use of these medications.
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`26.
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`Antianxiety medications such as lorazepam are also sometimes prescribed in
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`cases of CINV. 7 These agents can be useful in reducing the intensity of nausea and the
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`associated negative experience, but do not affect any of the pathways that are important for
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`preventing CINV. These medications are referred to as adjunct medications, and are more akin
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`27.
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`One turning point in the treatment of CINV was the identification of the 5-HT3
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`pathway, which is activated by the neurotransmitter serotonin. Serotonin is released as a result
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`of the administration of chemotherapy agents both centrally and through direct damage to the
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`I gastrointestinal tract. Serotonin binds to 5-HT3 receptors, and contributes sensory inputs that are
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`implicated in CINV. 5—HT3 receptor antagonists are a class of antiemetics that prevent CINV by
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`blocking 5—HT3 receptors, and disrupting the serotonin pathway. Ondansetron was the first
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`6 Exh. 7, Pendergrass KB, Options in the treatment ofchem0therapy—inVc/uced emesis, Cancer
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`Pract 62276-281 at 278 (1998) (“Pendergrass (1998)”).
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`71d. at 279.
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`5-HT3 receptor antagonist introduced in 1991, and other 5—HT3 receptor antagonists soon
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`followed, including granisetron and dolasetron.
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`28. While the 5-HT3 receptor antagonists were universally thought to significantly
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`advance the treatment of acute CINV, they were not shown or perceived to be effective in
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`improving the treatment of delayed CINV in the relevant time periods Indeed, even though
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`various 5—HT3 receptor antagonists exhibited differences in 5—HT3 receptor binding affinity,
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`serum half—life, and metabolism, they exhibited very similar control on acute CINV compared to
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`ondansetron and had no significant impact on the treatment of delayed emesis.9 Unfortlmately,
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`even use for extended periods and multip1e—dosing regimens did not yield improvements in
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`outcome, and delayed CINV remained a signif1cantprob1em.10
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`29.
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`The NK-1 pathway was another known emetic pathway in the relevant time
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`period. The NK—1 pathway is activated by the release of Substance P, a different
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`neurotransmitter, and its interaction with NK-1 receptors, and was theorized to be more involved
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`8 Id; Exh. 4, de Boer—Dennert (1997) at 1060; Exh. 2, Gregory & Ettinger (1998) at 174.
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`9 Exh. 8, del Giglio A, et al., Granisetron is equivalent to ondansetronfor prophylaxis of
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`chemotherapy-induced nausea and vomiting: results of a meta—analysis ofrandomized controlled
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`trials, Cancer 89:2301—2308 (2000) (“de1Gig1i0 (2000)”); Exh. 2, Gregory & Ettinger (1998) at
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`174; Exh. 7, Pendergrass (1998) at 279.
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`10 Exh. 7, Pendergrass (1998) at 279; Exh. 9, Goedhals L, et al., Control ofdelayed nausea and
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`vomiting with granisetron plus dexamethasone or dexamethasone alone in patients receiving
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`highly emetogenic chemotherapy.‘ A double-blind, placebo-controlled, comparative study, Ann
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`Oncol 9:661-666 (1998) (“Goedhals (1998)”); Exh. 10, Latreille J, et al., Use of dexamethasone
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`and granisetron in the control ofdelayed emesis for patients who receive highly emetogenic
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`chemotherapy, J Clin Oncol 16:1174-1178 (1998) (“Latreille (1998)”); Exh. 11, Tsukada H, et
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`al., Randomized comparison ofondansetron plus dexamethasone with dexamethasone alonefor
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`the control ofdelayed cisplatin—induced emesis, Eur J Cancer 37:2398—2404 (2001) (“Tsukada
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`(2001)”); Exh. 12, Geling O and Eichler HG, Should 5-hydroxytryptamine-3 receptor
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`antagonists be administered beyond 24 hours after chemotherapy to prevent delayed emesis?
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`Systematic re—evaluation of clinical evidence and drug cost implications, J Clin Oncol 2311289-
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`1294 (2005) (“Geling & Eichler (2005)”).
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`HIGHLY CONFIDENTIAL — OUTSIDE COUNSEL EYES ONLY
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`in the development of delayed Cl_NV.” In View of the poor efficacy of the 5-HT3 receptor
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`antagonists for the prevention of delayed CINV, NK-1 antagonists, which counteract the
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`Substance P—NK-1 pathway, became the subject of intense research focus with respect to delayed
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`CINV and, by 2002-2003, were being tested and developed by a number ofpharmaceutical
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`companies.”
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`C.
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`Problems of Patient Non-Adherence
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`30.
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`During clinical trials for any medication under development, patients are followed
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`very closely and continuously encouraged to be adherent. After a medication is approved and
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`marketed, however, data indicate that adherence becomes rapidly problematic for take-home,
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`multi—day medications.” There are many reasons for patient non-adherence, and may include
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`barriers in communication, lack of support and cultural sensitivities.
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`31.
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`Adherence is particularly problematic for CINV medications. These agents are
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`aimed at preventing CINV. It has been my experience, and the experience of many of my
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`11 Exh. 13, Kris MG, et al., Use ofan NK] receptor antagonist to prevent delayed emesis after
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`cisplatin, J Natl Cancer Inst 89:817-818 (1997) (“Kris (1997)”); Exh. 14, Gale JD, et al.,
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`Tachykinin NK1 receptor antagonists for the control of chemotherapy—induced nausea and
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`vomiting, Exp Opin Ther Pat 11: 1837-1847 at 1838-1839 (2001) (“Gale (200l)”); Exh. 15,
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`Hesketh PJ, Potential role of the NK1 receptor antagonists in chemotherapy-induced nausea and
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`vomiting, Support Care Cancer 9:350—354 (2001) (“Hesketh (2001)”); Exh. 16, Roila F, et al.,
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`Delayed emesis: incidence, pattern, prognostic factors and optimal treatment, Support Care
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`Cancer 10:88-95 at 93 (2002) (“Roila (2002)”).
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`12 Exh. 14, Gale (2001); Exh. 13, Kris (1997); Exh. 15, Hesketh (2001); Exh. 16, Roila (2002) at
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`93; Exh. 17, Rizk AN and Hesketh PJ, Antiemetics for cancer chemotherapy-induced nausea and
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`vomiting: A review of agents in development, Drugs R&D 2:229-235 (1999) (“Rizk & Hesketh
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`(1999)”); Exh. 18, Eglen RM and Bonhaus DW, 5-Hydroxytryptamine (5-HT)3 Receptors:
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`Molecular Biology, Pharmacology and Therapeutic Importance, Curr Pharm Design 2:367-374
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`at 373 (1996).
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`13 Exh. 19, Osterberg L and Blaschke T, Adherence to medication, N Engl J Med 353:487~497
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`(2005).
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`12
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`HIGHLY CONFIDENTIAL — OUTSIDE COUNSEL EYES ONLY
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`55.
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`It is well established that, in order to be clinically relevant, all pharmaceutical
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`agents must strike a balance between safety and efficacy. Phase 1 and Phase 2 studies provide
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`important information during the process of developing a potential pharmaceutical product to
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`help determine any dose and schedule that may warrant further investigation in Phase 3 studies.
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`Only Phase 3 trials are designed to provide definitive conclusions regarding the safety and
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`efficacy of a potential new pharmaceutical product. For that purpose, it is critical to obtain and
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`fully analyze the complete Phase 3 results for the intended clinical indications.
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`Tanios Bekaii-Saab, M.D.
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`Date: October 25, 2013
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