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Spedale v. Constellation Pharmaceutical Inc.

United States District Court, D. Arizona

August 16, 2019

Iris Spedale and Daniel Spedale, Plaintiffs,
v.
Constellation Pharmaceuticals Inc., Defendant.

          ORDER

          HONORABLE JOHN J. TUCHI, UNITED STATES DISTRICT JUDGE

         The Court now considers Defendant Constellation Pharmaceuticals, Inc.'s Motion to Exclude Expert Testimony of Dr. James P. Sutton (Doc. 55, MTE), Motion for Summary Judgment (Doc. 56, MS J), and Objections to Portions of Dr. James P. Sutton's Declaration (See Doc. 68, Reply to MTE Opp'n; Doc. 69, Reply to MSJ Opp'n), as well as Plaintiffs' Motion for Leave to Respond to Defendant's Objections (Doc. 71, MFL) and Motion to Strike the Affidavit of Dr. Robert Sims (Doc. 63, MSJ Opp'n). For the reasons set forth below, the Court grants in part and denies in part Defendant's Motion to Exclude, grants in part and denies in part Defendant's Motion for Summary Judgment, and grants Plaintiffs' Motion to Strike.[1] Additionally, the Court overrules Defendant's Objections and denies Plaintiffs' Motion for Leave as moot.[2]

         I. FACTUAL BACKGROUND

         Defendant is a Massachusetts corporation and developer and manufacturer of pharmaceuticals. (Doc. 64, Pis.' Statement of Add'l Facts & Resp. to Def's Statement of Facts, ("PSOAF")[3] ¶ 20.) Defendant conducts business, including sponsoring clinical trials, in Arizona, where Plaintiffs Iris Spedale and Daniel Spedale reside and the events giving rise to this suit occurred. (Doc. 59-11, Ex. K, Clinical Trial Agreement Between Constellation & Mayo Clinic Arizona ("CTA") at 2; MSJ Opp'n at 2.)

         A. Ms. Spedale's Health

         Ms. Spedale was first diagnosed with multiple myeloma in May 2009, at the age of sixty-six. (Doc. 64-1, Ex. 1, Spedale Medical Records I ("Spedale MR I") at 11.) Ms. Spedale sought treatment from Dr. Rafael Fonseca, M.D., at Mayo Clinic. (Doc. 57, Def's Statement of Facts in Supp. of MSJ ("DSOF") ¶ 3; PSOAF ¶ 5; Doc. 64, PSOAF & Resp. to DSOF ("PSOF")[4] ¶ 3.) At the time of her diagnosis, Ms. Spedale had no prior history of psychological problems; however, while using dexamethasone (a steroid) as part of her cancer treatment regimen, she experienced "steroid-induced mania syndrome." (Doc. 59-15, Ex. O, Daniel Spedale Dep. ("Mr. Spedale Dep.") at 8; PSOAF ¶ 9; Spedale MR I at 27.) In September 2009, Dr. Robert Bright, a Mayo psychiatrist, prescribed Zyprexa Zydis ("olanzapine") to Ms. Spedale to "help restore a normal sleep/wake cycle" and "provide mood stabilization." (Spedale MR I at 27.) By her October 2009 follow-up, Ms. Spedale's mood and sleep cycle had improved significantly. (Id. at 29.) One month later, Ms. Spedale underwent a successful stem-cell transplant, leaving her cancer in remission for three years. (Id. at 35; see Doc. 64-2, Ex. 2, Spedale Medical Records II ("Spedale MR II") at 75-76.) Ms. Spedale was treated for cancer twice more: once in 2013, and again in 2014, though each time with a lower dose of dexamethasone. (See Spedale MR II at 73 (Dr. Fonseca's "Final Report" of Aug. 19, 2013 visit, detailing treatment plan); id. at 59 (Dr. Fonseca's "Final Report" of Oct. 21, 2014 visit, detailing treatment plan).)

         B. CPI-0610

         1. Development of CPI-0610

         On June 5, 2013, Defendant submitted an Investigational New Drug ("IND") Application to the FDA for its study drug, CPI-0610, a type of BET inhibitor. (DSOF ¶ 5; PSOF ¶ 5.) The International Conference on Harmonisation ("ICH") guidelines detail the types of studies required to support an IND application, as well as the sequence in which those studies should be performed. (DSOF ¶ 6; PSOF ¶ 6.) The guidelines applicable to pre-clinical safety testing for oncology drugs are known as ICH S9.[5] (Jacobson-Kram Report at 4.) Defendant's regulatory expert, Dr. Jacobson-Kram, [6] has explained the necessity of distinct guidelines with respect to oncology drugs: "[I]nitial doses in phase 1 studies with healthy volunteers generally are below a level that causes a pharmacological effect. When treating oncology patients with advanced disease, it is desirable that patients are initially dosed at levels that have pharmacological effects." (Id.)

         a. Potential Issues with Neurotoxicity

         In his report, Plaintiffs expert, neurologist Dr. James P. Sutton, suggests that Defendant failed to perform adequate preclinical safety testing for neurotoxicity on CPI-0610. (See Doc. 55-2, Ex. A, Dr. James P. Sutton's Expert Report ("Sutton Report") at 9- 10.) Dr. Jacobson-Kram disagrees. (See generally Jacobson-Kram Report.) Dr. Jacobson-Kram currently works as a pharmaceutical consultant specializing in non-clinical safety assessment. (Id. at 3.) Dr. Jacobson-Kram served as head of toxicology in the FDA's Office of New Drugs for 11 years, and vice president of a contract testing laboratory for 15 years. (Id.)

         According to Dr. Jacobson-Kram, Defendant adhered to ICH S9: "[n]o specific safety concerns were identified that would have led to additional studies described in ICH S9." (Id. at 5.) In both rodent and dog studies, "[n]o change in behavioral patterns were observed that might suggest neurological effects."[7] (Id.; see Id. at 5-7.) Nothing in these preclinical studies indicated a risk for neurotoxicity-i.e., that CPI-0610 affected the "normal stereotypical behavior of experimental animals and no histopathology of the central nervous system was seen." (Id. at 8.) Dr. Jacobson-Kram opines: (1) Defendant performed all preclinical studies required by ICH S9; (2) the FDA agreed that the study was safe to proceed since they had declined to issue a clinical hold; and (3) Defendant's preclinical package is standard in the industry and consistent with regulatory guidelines. (Id. at 9.)

         2. 0610-03 Study

         On June 28, 2013, the FDA approved Defendant's IND Application for CPI-0610. (Doc. 59-9, Ex. I, IND Approval at 2.) Defendant and Mayo entered into a Clinical Trial Agreement ("CTA"), agreeing that Defendant would support, and Mayo would conduct, a clinical trial entitled, "A Phase 1 Study of CPI-0610, a Small Molecule Inhibitor of BET Proteins, in Patients with Previously Treated Multiple Myeloma."[8] (CTA at 2.) The CTA defines the relationship between Defendant and Mayo, respectively, Sponsor and Institution, as that of "independent contractor." (DSOF ¶ 17; PSOF ¶ 17.) The CTA identifies Dr. P. Leif Bergsagel, M.D., as Principal Investigator, [9] "responsible for the direction of the Trial in accordance with applicable [Mayo] policies and Applicable Law." (CTA at 2.)

         Enrollment for the 0610-03 Study began in September 2013. (DSOF ¶¶ 1, 37; PSOF ¶¶ 1, 37.) By its conclusion, 138 patients were evaluated across three trial sites (all Phase I studies), at doses of 6mg to 400mg once per day and 85mg to 110mg twice per day. (DSOF ¶ 38; PSOF ¶ 38.) Of the 138 total patients, 30 patients had multiple myeloma. (DSOF ¶ 38; PSOF ¶ 38.) Ms. Spedale, the 25th patient with multiple myeloma, enrolled at the Arizona trial site (Mayo) on December 1, 2015. (DSOF ¶¶ 1, 39; PSOF ¶¶ 1, 39.) At Mayo, Ms. Spedale was the last of 5 patients with multiple myeloma evaluated at the 150mg dose. (DSOF ¶ 39; PSOF ¶ 39.) Prior to Ms. Spedale's enrollment, two trial sites reported adverse events-Massachusetts General Hospital ("MGH") and The Ohio State University Cancer Center ("OSU").[10] (DSOF ¶ 41; PSOF ¶ 41.) Ms. Spedale discussed her enrollment with Dr. Fonseca, as well as Dr. Bergsagel and Charanjit (J.R.) Singh, Mayo's clinical research coordinator. (DSOF ¶¶ 31-33, 36; PSOF ¶¶ 31-33.) Mr. Singh went over each section of the Informed Consent Document ("ICF") with Ms. Spedale before she signed it. (Doc. 59-24, Ex. X, Charanjit (J.R.) Singh Dep. ("Singh Dep.") at 54-55; PSOF ¶ 35.) Plaintiffs and Defendant disagree as to whether Ms. Spedale was fully aware of the experimental nature of the 0610-03 Study when she signed the ICF.[11] (See DSOF ¶ 35; PSOF ¶ 35 ("Ms. Spedale's deposition testimony is questionable, as her condition may affect her memory and responses. For this reason, her deposition was terminated early."); see also PSOF ¶ 44 ("Mr. Singh would not have been aware of the information that [Defendant] omitted from the protocol.").)

         3. ICF

         Federal regulations require all clinical trials to be approved by an IRB independent of the sponsor. See 45 C.F.R. § 46.107 (defining the composition of an IRB); see also 21 C.F.R § 56.111 (defining criteria for IRB approval of research); (Doc. 59-12, Ex. L, Italo Biaggioni, M.D. Expert Report ("Biaggioni Report") at 3-4).[12] Mayo's internal IRB acted as the "IRB of record" for the 0610-03 Study and reviewed the study's protocol, including its scientific merit and associated risks. (DSOF ¶¶ 22, 47; Biaggioni Report at 4; PSOF ¶¶ 22, 47.) Mayo's IRB was tasked with ensuring the ICF accurately reflected the study's risks, contained important safety-related information, and was written in a manner comprehensible to the target population. (Biaggioni Report at 5-6.) Per the CTA, Mayo was to obtain written informed consent from each trial subject according to protocol approved by the FDA and Mayo's IRB. (CTA at 2, 5.) Dr. Bergsagel testified that he reviewed the proposed ICF and submitted it to the IRB for approval. (DSOF ¶ 25; PSOF ¶ 25.) Plaintiffs, however, claim that "the IRB and investigators were not fully informed of all the risks," resulting in an allegedly deficient ICF. (PSOF ¶ 47.)

         The ICF explains:

The main purpose of this study is to determine the highest dose of CPI-0610 that can be given without causing severe side effects. This is a Phase 1 study, which means that CPI-0610 is in very early stages of testing in humans. Future studies may then test whether or not CPI-0610 is useful against different types of cancer. CPI-0610 is experimental, which means that it is not approved by the [FDA] or other regulatory agencies around the world to treat cancer or for any other disease.

(DSOF ¶ 48; PSOF ¶ 48; Doc. 59-1, Research Participant Consent & Privacy Authorization Form ("ICF") at 4.) Next, the ICF lists five research questions:

• What is the highest dose of CPI-0610 that can be administered to multiple myeloma patients without causing severe side effects?
• What are the side effects of CPI-0610?
• How much CPI-0610 is in the bloodstream at specific times after taking it, and how rapidly does the body get rid of CPI-0610?
• What are the effects of CPI-0610 on the expression of certain genes, both in normal blood cells and multiple myeloma cells?
• Will CPI-0610 help reduce the amount of multiple myeloma in patients bodies?

(DSOF ¶ 49; PSOF ¶ 49.) The section addressing "possible risks or discomforts" associated with the study explains that "risks and discomforts related to CPI-0610 are not well known," and explains findings associated with CPI-0610 animal studies, as well as other potential medical issues. (DSOF ¶ 50; see ICF at 14-17.) The section addressing "possible benefits" of participation states:

There may or may not be medical benefit to you. Other people may benefit from the information that is learned in this study. This is a study to help develop a new therapy for others with a similar condition.

(ICF at 17; see DSOF ¶ 50.)

         4. Ms. Spedale's Participation in the 0610-03 Study

         On November 17, 2015, Dr. Fonseca noted Ms. Spedale's cancer had reappeared in diagnostic tests, and it was time to consider "the next line of treatment in her situation." (DSOF ¶ 27; PSOF ¶ 27.) He wrote, "[t]he logical next step would be the use of carfilzomib," but "[a]nother possibility would be . . . participation] in one of our clinical trials." (DSOF ¶ 27; PSOF ¶ 27.) Dr. Fonseca further stated that he had already communicated with Mayo's study coordinators and was in the process of determining Ms. Spedale's eligibility. (DSOF ¶ 27; PSOF ¶ 27.) On November 23, 2015, Mr. Singh wrote to Plaintiffs, "[Dr. Fonseca] would recommend to first try the study drug (BET inhibitor). . . . Let me know if you want to pursue the trial." (Doc. 59-17, Ex. Q, Nov. 23, 2015 email exchange between Daniel Spedale and J.R. Singh at 2; see DSOF ¶ 29; PSOF ¶ 29.) Mr. Spedale responded affirmatively. (See DSOF ¶ 30; PSOF ¶ 30.)

         On December 10, 2015, Ms. Spedale began the 0610-03 Study's fourteen-day regimen. (DSOF ¶ 2; PSOF ¶ 2.) On December 29, 2015, Ms. Spedale exhibited mild forms of grade 1 mania, which rapidly worsened to grade 3. (DSOF ¶ 3; PSOF ¶ 3.) Ms. Spedale continued to experience manic symptoms into 2017, attributing them to CPI-0610.[13](DSOF ¶ 4; PSOF ¶ 4.)

         II. PROCEDURAL BACKGROUND

         Plaintiffs filed this case on January 13, 2017. (Doc. 1, Compl.) Plaintiffs allege that prior to the 0610-03 Study, Ms. Spedale was "rational," "able to perform her usual duties and provide comfort, society and support to her family." (Id. ¶ 41.) In October 2016, after attempting a complex care plan that included live-in aides and regular fly-in visits from her son and sister, Ms. Spedale "was placed in an assisted living facility, out of concerns for her own safety and security as a result of her mental state." (Id. ¶¶ 44, 47.) Estranged from his wife, [14] Mr. Spedale suffered nerve damage and subsequently underwent back surgery and received multiple spine injections. (Id. ¶¶ 48, 50.) Currently, Mr. Spedale resides in an elder-care facility to receive "assistance with his ongoing physical needs." (Id. ¶ 51.)

         Plaintiffs make four claims. The first three are based on the theory that Defendant knew or should have known of certain neurological risks associated with CPI-0610. First, Plaintiffs allege Defendant negligently drafted the ICF, failing to adequately disclose CPI-0610's risks. (Id. ¶¶ 58-73.) Second, Plaintiffs allege Defendant intentionally, recklessly, and/or negligently enrolled Ms. Spedale in the 0610-03 Study without obtaining her full informed consent. (Id. ¶¶ 74-81.) Third, Plaintiffs allege Defendant is strictly liable for failing to provide adequate warnings with respect to CPI-0610, designing an unreasonably dangerous product, and inadequately testing the product. (Id. ¶¶ 82-88.) Fourth, Plaintiffs allege Defendant caused Mr. Spedale to suffer the loss of his wife's companionship, services, and society. (Id. ¶¶ 89-90.) Plaintiffs also seek punitive damages. (Id. ¶ 91.) Defendant now seeks summary judgment on all causes of action.

         III. MOTION TO STRIKE

         Plaintiffs move to strike the Affidavit of Dr. Robert Sims because "it fails to state that it is made under penalty of perjury" as required by 28 U.S.C. § 1746. (MSJ Opp'n at 4; see Doc. 55-3, Ex. G, Aff of Dr. Robert Sims ("Aff I"); Doc. 59-8, Ex. H, Aff of Dr. Sims ("Aff. II") (identical filing).) The Court agrees. Although the Affidavit is signed, it fails to substantially comply with § 1746, which requires that any affidavit state "under penalty of perjury that the foregoing is true and correct." § 1746; see Schroeder v. McDonald, 55 F.3d 454, 460 n.10 (9th Cir. 1995) (stating pleading substantially complied with § 1746 when plaintiff stated under penalty of perjury that contents were true and correct); Kersting v. United States, 865 F.Supp. 669, 676 (D. Haw. 1994) ("As long as an unsworn declaration contains the phrase 'under penalty of perjury' and states that the document is true, the verification requirements of 28 U.S.C. § 1746 are satisfied."). Here, the Affidavit states: "The foregoing statements made by me are true and correct to the best of my knowledge. I am aware that if the foregoing are willfully false, I am subject to punishment." (Aff. I at 4; Aff. II at 5.) Because the Affidavit makes only one of the two required assertions, the Court grants Plaintiffs' Motion to Strike.

         IV. MOTION TO EXCLUDE

         A. Legal Standard

         Rule 702 provides:

A witness who is qualified as an expert by knowledge, skill, experience, training, or education may testify in the form of an opinion or otherwise if:
(a) the expert's scientific, technical, or other specialized knowledge will help the trier of fact to understand the evidence or to determine a fact in issue;
(b) the testimony is based on sufficient facts or data;
(c) the testimony is the product of reliable principles and methods; and (d) the expert has reliably applied the principles and methods to the facts of the case.

Fed. R. Evid. 702. Under Rule 702, the trial court acts as "gatekeeper," ensuring proffered scientific testimony meets certain standards of relevance and reliability before admission. Daubert v. Merrell Dow Pharm., Inc. ("Daubert F), 509 U.S. 579, 590-95 (1993).

         1. Reliability

         An expert opinion is reliable if based on proper methods and procedures rather than "subjective belief or unsupported speculation." Id. at 590. The test for reliability '"is not the correctness of the expert's conclusions but the soundness of his methodology.'" Stilwell v. Smith & Nephew, Inc., 482 F.3d 1187, 1192 (9th Cir. 2007) (quoting Daubert v. Merrell Dow Pharm., Inc. “Daubert II”), 43 F.3d 1311, 1318 (9th Cir. 1995)). Alternative or opposing opinions or tests do not "preclude the admission of the expert's testimony-they go to the weight, not the admissibility." Kennedy v. Collagen Corp., 161 F.3d 1226, 1231 (9th Cir. 1998). The same is true of "[d]isputes as to the strength of [an expert's] credentials, faults in his use of [a particular] methodology, or lack of textual authority for his opinion . . . ." Id. (quotation omitted).

         The proffering party must demonstrate expert testimony's admissibility by a preponderance of the evidence. Daubert I, 509 U.S. at 592 n. 10. The district court considers four factors to determine whether the testimony will assist the trier of fact: "(i) whether the expert is qualified; (ii) whether the subject matter of the testimony is proper for the jury's consideration; (iii) whether the testimony conforms to a generally accepted explanatory theory; and (iv) whether the probative value of the testimony outweighs its prejudicial effect." Scott v. Ross, 140 F.3d 1275, 1285-86 (9th Cir. 1998) (citations omitted). Whether an expert seeks to "testify about matters growing naturally and directly out of research they have conducted independent of the litigation, or whether they have developed their opinions expressly for the purpose of testifying" is highly significant. Daubert II, 43 F.3d at 1317. If the proposed testimony is not based on independent research, the court may rely on "other objective, verifiable evidence that the testimony is based on 'scientifically valid principles.'" Id. at 1317-18. Ultimately, "judges are entitled to broad discretion when discharging their gatekeeping function." United States v. Hankey, 203 F.3d 1160, 1168 (9th Cir. 2000) (citing Kumho Tire Co. v. Carmichael, 562 U.S. 137, 149-153 (1999)).

         2. Relevance

         The district court must exclude proffered scientific evidence unless it is "convinced that it speaks clearly and directly to an issue in dispute in the case, and that it will not mislead the jury." Cloudy. Pfizer Inc., 198 F.Supp.2d 1118, 1130 (D. Ariz. 2001) (citing Daubert II, 43 F.3d at 1321). The district court "assessing a professor of expert scientific testimony . . . should also be mindful of other applicable rules," including Federal Rule of Evidence 403, which allows "exclusion of relevant evidence 'if its probative value is substantially outweighed by the ...


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