DEPARTMENT OF HEALTH HUMAN SERVICES Public Health Service National Institutes of Heaith National institute of Mental Health 6001 Executive Boulevard Bethesda. Maryland 20892 28 November 2017' Mitra Dutta, Vice Chancellor for Research University of Illinois-Chicago 310 Administrative Of?ce Building 1737 West Polk Street Chicago, Iliinois 60612 Re: Adverse Determination and Demand for Payment of Funds on R01MH81019, Mani Pavuluri, M.D., A?cz?ive Neuroscience of Pediatric Bipolar Disorder Dear Dr. Betta: I am writing to notify you of an adverse determination by the National Institute of Mental Health (N IMH) that the University of Illinois-Chicago (University) has violated the terms and conditions on the above referenced grant, awarded by the NIMH to the University, due to the reasons outlined below. As described in this letter, the has independently reviewed the above referenced grant and the associated facts, including ail correspondence and ?ndings from the University that serious and continuing noncompliance with human subjects protections compromised the integrity of this study and has rendered the associated data without merit. NIMI-I is requiring the University to refund $3,079,316, which represents all funds awarded and expended for NIH grant number R01MH81019 for the period January 1, ZOOQ?August l, 2013 due to serious noncompliance with the terms and conditions of grant award. The University?s reports and correspondence with the OHRP and NIMH, the July 2014 OHRP-NIMH site visit, and the information contained in the grant applications and progress reports present the following facts: 1. Beginning in 2006, the University, through Dr. Mani Pavuluri as Principal Investigator (PI), sought research funding for her research application, A?eciive Neuroscience of Bipolar Disorder. During the course of two NIH-peer reviews and consultations by NIMH staff on this initial application, Dr. Pavuluri was made keenly aware of critical human subjects issues, so Dr. Pavuluri ?led a 01A2 resubmission application that resolved the previously identi?ed human subjects issues and other concerns. This 01A2 resubmission then received a third NIH-peer review, and no human subjects concerns were identi?ed because this application had: 4- Addressed previously identi?ed concerns the risks involved with lithium treatment and withdrawal in an age group involving children of ages for which It, I atit (a train Dr. Data, Page 2 28 November 2017 lithium is not FDA approved [under age 12], and that this signi?cant risk was not discussed by Dr. Pavuluri) by excluding children under 13 years of age; It Outlined speci?c exclusion criteria such that any use of medication in the subj act?s lifetime made them ineligible to participate required the subjects to be medication naive); I Deserts ad .. .I ieliacation ofreseai that and clinical roles . .allowing Dr. i?avulul- cc Lazovc; from me direct clinical care of the patients? involved in the study; ano - Included letters of support from NIMH Intramural Staff that underscored the importance L. :.ying medication?naive patients and limiting the age range from 13- . . . so years v? a: The grant as had to are University on December 23, 2008 with a January 1, 2009 star. date. ti Review Bo a (1311i) approval for the associated Protocol 2008-0624 was effective September 17, 2003. On Apri124, 2009, the IRB approved an amendment lowering the age to include 10?12 year-olds. In addition, one IRE-approved inclusion criterion had been changed from ?medication naive? to ?lithium naive.? The .as as: r- o; arose c11..agasto the 2. On January 25, 2013, the University reported an unanticipated problem associated with the above referenced grant to the HHS O?ice for Human Research Protections (OI-IRP) and the NIMH. This report initiated an extended process whereby the University responded to inquiries through extensive correspondence, conducted an audit of the research protocol, and subsequently submitted to OHRP additional reports of unanticipated problems. 3. In its March 22, 2013 letter to the OHRP, the University reported serious non-compliance of the IRB in its review of the grant?s protocol. The ?ndings reported by the University included: - Insuf?cient initial review by the no research protocol was provided at the time of review) and inadequate documentation to support the subsequent exPedited review; disclosure of appropriate alternative procedures or course of treatment was excluded ?rorn the informed consent documents by the investigator and the IRB [repeatedly] failed to identify this omission?; I Failure of the IRB to request or review the rationale for the change in age range (lowering the minimum age to 10 years old) during the review of Amendment #3 (April 24, 2009); I Failure of the IRB to note in the parental permission form that lithium was not FDA-approved for children under the age of 12 during the initial amendment and subsequent reviews of documents; and 0 Failure of the IRB to document and correct multiple inconsistencies between and within the research protocol, informed consent documents, parental permissions and assents, initial review application, grant and other documents. Dr. Dutta, Page 3 28 November 2017 4. In its April 8, 2013 letter to the OHRP, the University reported serious and continuing non?compliance 2; :11: Pl associated with this grant?s human subjects research protocol. Dr. Pavuluri was suspended from all human subjects research pending a minimum of six months training. Speci?c ?ndings reported by the University included: I Failure of the principal investigator to appropriately distinguish her clinical and research activities, primarily related to the medication washout that was not part of the IRE-approved protocol; I Failure to follow the eligibility criteria speci?ed in the IRE?approved protocol. In the University?s May 22, 2013 letter to NIMH, the University reported that 59'; Z: .3 Lied to meet the IRB approved inclusionfexclusion criteria at 3a.; I r?anure to renew L111: mo- approved protocol during the conduct of the study. In the University?s May 22, 2013 letter to NIMH, the University reported that 24/ 103 subjects participated in the non?IRE approved medication washout and that i. . at More miner the lihiaagproved age of 10 at study entry; De?ciencies in the consent, assent, and authorization forms; and I De?ciencies in study documentation. 5. On August 5, 2013, the University relinquished the above referenced grant, effective August 1, 2013, indicating that Dr. Pavuluri?s and the serious and continuing human subjects noocompliance severely compromised the integrity of this study and has renderec. tn. . .1 . :c .-.. vino .13; ntrit. -n the University?s November 27, 2013 letters to Dr. Kristina Box-tor, Director, of Compliance Oversight, OI-IRP, for follow?up on the grants, Dr. Fischer, Director of the Of?ce for the Protection of Research Subjects for the University, indicated that the . .IRB determined in April that all data 35:11-35. 2 - - -- sari 1:341:11): he used for publication.? In the University?s subsequent June 30, 2014 letter to Dr. Borror, the IRB reaffirmed its previous determinations of Serious Non-Compliance related to the ?ve items bulleted above in Item 4 above. Funds awarded for NIH research grants ?shall be expended solely for the purposes for which the funds were granted in accordance with the approved application and budget, the regulations of [42 CFR Part 52], the terms and conditions of the award and the applicable cost principles prescribed in 45 CFR part 75, subpart 42 CFR As a term and condition of award, the NIH Grants Policy Statement (GPS) required prior approval from the NIMH ?for any significant change from the the approved proj ect.? GPS, Prior-Approval Requirements, p. 106 (2003). Here, the application submitted to and approved by NIMH excluded children under 13 years of age from the project and required the subjects to be medication naive. On April 24, 2009, the IRB approved an amendment lowering the age to include 10?12 year-olds. In addition, one [RB-approved inclusion criterion had been changed from ?medication naive? to ?lithium naive.? Both IRE-approved changes represented a ?change in the speci?c aims approved at the time of award? and ?a change from the approved use subjects." GPS, Prior-Approval Requirements, p. 106 (2003). In addition, the changes were signi?cant, because they increased risk to the study subjects, and they represented the same human subjects issues that NIMH had identi?ed during the course of two NIH~peer reviews and consultations by Dr. Dutta, Page 4 23 November 2017 NIMH staff on the initial application, and that NIMH communicated would need to be addressed before the application could be approved for funding. Therefore, NIMH prior approval for the change of scope was required. Contrary to the terms and conditions of the grant award, NIH prior approval for a change of scope was not sought or approved for either of these risk- increasing changes, and the ?rst year?s progress report submitted by Dr. Pavuluri through the University gave no indication of the change in subject ages or inclusion criteria. Further, each subsequent progress report continued to present the study as unaltered from the originally approved protocol. Domsments submitted to NIH consistently referred to ?adolescents," ?individual: betwe 3; 15319 1713* it: years," and "?sychotmpic naive patients.? In the University?s Marci: LL, L. . E, Lotte?. -u 1'th the Quiversiry acinrowledged, . . review of the progress reports does not demonstrate that NlMi-l was informed of the changes to the research.? The GPS speci?cally states, ?Failure to submit complete, accurate, and timely.Ir may result GPS, Reporting, p. 129 (2003). For these reasons, among other concerns, upon an independent review of the grant, including the University?s and the conclusion that Dr. Pavuluri?s and the serious and continuing human subjects noncompliance severely compromised the integrity of this study, rendering the associated data without merit, the NIMH ?nds that the University has violated the terms and conditions of award. Because of the nature, extent, and duration of the violations of the terms and conditions of award discussed above, the NIMI-I has determined that all expenditures that were charged to the grant are not allowable. Accordingly, the NIMI-I seeks to recover all costs awarded for R01MH81019 in the total amount of $3,079,316 (representing Year 1, $577,687; Year Year 3 $708,958; Year 4 - $703,717; and Year 5 - $363,637). Therefore, please be advised that the amount of $3 ,079,3 16 is due and considered a debt owed the Federal government. The debt is subject to the Department of Health and Human Services (HHS) claims collection regulations at 45 CFR Part 30. Interest accrues on the amount due beginning on the date this letter is mailed, 28 November 2019; however, it will not be charged if the debt is satis?ed within 30 days of that date. [Interest will accrue but assessment will be deferred pending the outcome of any appeal. If an appeal is not success?il the interest charges will begin from the date this letter is mailed, not the date of the appeal decision. Interest charges will be computed using the prevailing rate in effect on the date this letter is mailed, as speci?ed by the Department of the Treasury (see hm?whhs. 2. Please make your payment within 30 calendar days from 28 November 2017, the date that this demand letter is mailed, by sending a check made payable to the National Institutes of Health to the following address' A1111: Alan Whatley Government Accounting Branch Of?ce of Financial Management National Institutes of Health 2115 East Jefferson Street, MSC 8500 Suite 43-432 Bethesda, MD 20892-8500 (For courier services, please use Rockville, MD 20852) Dr. Dutta, Page 5 28 November 2017 Please provide the full grant number and the amount returned with your check. If you are unable to make payment in full, you may request an alternative repayment agreement as provided-for in 45 CFR 30.17. Requests for a repayment plan must be made in writing to the Program Support Center (PSC), HHS, with a copy to me at the address provided within this letter. In addition, requests for alternative repayment agreement must include a proposed payment amount, a copy of the institution?s most recent audited ?nancial statements and a good faith payment. mailing address is as follows: Debt Coileciot- . . Program supp; - Accounts Race- 3. 3 . 3 ercnon 141:3: thaUILalC-g - at Rockville, MD $33? If the fLLi'. men; 2. . z. is; a repayment agreement is not received on or before 30 days ?om the can: of .. Mg- 1say-merit is delinquent debt not paid within 30 daysmag?; nu. enforcement collection under 45 CFR Part 30. Private collection agencies, reporung to credit reporting agencies or other collection techniques may be used, if necessary. A debtor delinquent on a debt is ineligible for Government loans, loan guarantees, or loan insurance until the debtor resolves the debt. Knowingly making false statement or bringing frivolous actions may subject a debtor to civil or criminal penalties under 31 U.S.C. 3729-3731, 18 U.S.C. 286, 287, 1001 and 1002 or any other applicable statutory authority. Please be advised that acceptance of this payment should not be construed as a settlement, or any positive determination regarding your instimtion?s compliance status, nor is it an indication of government approval of or acquiescence regarding your ?nancial management of NIH grant awards. Repayment does not relieve your institution of any liability for failure to comply with the terms and conditions of grant awards, nor does it offer a defense to any further admimsm..,te, - n; . a in ateortiance with applicable statutes, This letn: . sprites: . 3; one catef Stunts Management Officer, NIMH. It shall be the ?nal decision of the Department of Health and Human Services unless within 30 days after receiving this decision, you deliver or mail via registered or certi?ed mail, a written notice of appeal in accordance with 42 CFR 50, Subpart to: NIH Grant Appeals Utticer National Institutes of Health 6705 Rockiedge Drive, Room 7963 Bethesda, MD 20892-7963 Dr. Dutta, Page 6 28 November 2017 In accordance with 42 CFR 50, Subpart and NIH GPS 33', Grant Appeals Procedures, please include a copy of this decision, your appeal justi?cation, total amount in dispute, and any material or documentation that will support your position. Finally, the appeal must be signed by the institutional of?cial authorized to sign award applications and must be postmarked no later than 30 days after the postmarked date of this notice. Please let me know if you have an}r questions concerning the information in this letter. My complete contact Lien-nail fciows my signature below. Sincerely, . (7 muck/,Opka/g Rebecca D. Claycamp, M.S., C.R.A Chief Grants Manttgement Of?cer National Institute of Mental Health Execative Boulevard Bethesda, MD 20892 3i". .4433811 Lida foam CC: Dr. Jean Norris: FA Alan G. Whatiey, OFM, NIH Diane Dean, Dfr- DOCS, OPERA, NIH