Eur. J. Biochem. 270, 3109–3121 (2003) FEBS 2003 Gene regulation by tetracyclinesConstraints of resistance regulation in bacteria shape TetR for applicationin eukaryotes Christian Berens and Wolfgang Hillen Lehrstuhl fu¨r Mikrobiologie, Institut fu¨r Mikrobiologie, Biochemie und Genetik, Friedrich-Alexander Universita¨t Erlangen-Nu¨rnberg;Germany The Tet repressor protein (TetR) regulates transcription
Ismpp.memberclicks.netCorporate Integrity Agreements 2012
Thomas Babcocka, Christopher Rainsb
Scan code to receive aGlobal Publications Group, Shire Specialty Pharma, Wayne, PA, USA;
PDF file of the poster bGlobal Publications Group, Shire Specialty Pharma, Eysins, Switzerland
Objective: US Department of Health & Human Services (HHS) Office of the Inspector
Office of Inspector General (OIG) conducts investigations
General (OIG) works with the Department of Justice (DOJ) investigating alleged Medicare • Civil and criminal and Medicaid service provider misconduct, imposing fines and issuing Corporate Integrity • Of fraud and misconduct Agreements (CIAs) to pharmaceutical companies. We examined CIAs issued in 2012 • Related to Health and Human Services (HHS) programs or their beneficiaries with provisions specific to publications related activities. • Including State False Claims Act reviews
OIG negotiates corporate integrity agreements (CIA) with health care providers
Research Design and Methods: Previous year public records of OIG and DOJ pertaining
to pharmaceutical company CIAs were reviewed.
• Under a variety of civil false claims statutes Results: Four CIAs met criteria. General provisions of the CIAs are similar to those
• Providers or entities agree to certain obligations previous: strict authorship criteria, written authorship agreements, disclosure of funding/ • OIG agrees not to exclude providers or entities from Federal health care programs sponsorship, and needs assessment. Two CIAs went beyond this. Allegations of off-label Department of Justice (DOJ) conducts criminal health care fraud investigations
promotion for one company specified years of dissemination of inaccurate and misleading • Under statutory provisions of the Health Insurance Portability and Accountability Act publications and downplaying safety data, before eventually admitting no evidence of drug benefit. The CIA required future publications not downplay safety, and be balanced and • The Health Care Fraud and Abuse Control Program timely. In another, specifications alleged improper conduct in manuscript development • Coordinates Federal, State, and local enforcement efforts and submission, response to reviewer comments, and subsequent resubmission and • Relating to the delivery of and payment for health care in the United States publication that misrepresented clinical significance and product safety. The CIA required appropriateness, accuracy, and balance in presentation of clinical study results in future publications and educational activities.
Conclusions: DOJ and OIG continue to scrutinize publication activity and include
Internet search of OIG and DOJ web sites
publication-related sanctions in their 2012 CIAs. Two followed investigations that reviewed • Identified OIG pharmaceutical companies CIAs • Dated between January 1 and December 31, 2012 published articles for accuracy and appropriateness of content. They focus on important • Identified associated DOJ press releases components of good publications practices beyond process, i.e. publications are • Located and downloaded DOJ supplemental documents on criminal investigations for responsible and timely, in accordance with established reporting standards.
the pharmaceutical companies CIA • To include "Agreed Statements of Facts" and "United States Complaint" • Read CIAs, press releases, and available court documents Four CIAs were identified in 2012; a similar study done last year identified 10 CIAs
between 2007 and 2011
• CIA provisions for 2007–2011 focused on the process of developing publications
• CIA provisions in 2012 also addressed process but we see expansion into publications
Criminal Case #11-10398-RWZ
United States Complaint, October 26, 2011
• The table below summarizes basic process issues in the CIAs
Efficacy for Depression in Children and Adolescents
• Study ran from 1994–1998 • Failed to demonstrate efficacy on the two primary and five secondary predefined variables – Several additional secondary measures added CIA Provisions regarding PROCESS
MED PFZ AZN OMJ AGN FST NOV UCB NND MRK ABB GSK AMG BIP
– Separated from placebo on some of these "Promotional and product related functions" Submitted to JAMA in 1999 • As "safe and ef ective treatment for major depression in adolescents" "Product related functions " • Reviewer comments critical – That treatment effect not much different than placebo – "numerical y superior" used for non-significant dif erences Written agreement Resubmitted to Journal of the American Academy of Child and Adolescent Psychiatry in 2000 Meet ICMJE criteria • Reviewer comments critical Payments at fair market value – Results do not demonstrate efficacy Disclosure of relationship to company, – No a priori primary outcome measure reported financial support Comments not addressed and published in 2001 Disclose writing/ editorial support • Primary endpoints identified in abstract but article did not state failure to show superiority to placebo Scope/breadth of data to authors • Falsely stated paroxetine separated from placebo on "response" when "response" was one of the predefined primary endpoints Needs assessment • Separated from placebo on 3 of 5 secondary measures, misleading by calling these a priori when they were not protocol-defined Needs assessment approved by legal • 1995–1998 and 2000–2001 Needs assessment approved by • Neither study demonstrated efficacy Results not published Publications Plan approved by compliance Safety for Depression in Children and Adolescents
Address authorship • Reviewer for JAMA submission in 1999 Address publications – MS did not note that paroxetine had significantly more serious Publications monitoring adverse events than placebo (and imipramine) • 5 events labeled as "emotional lability" were "suicidal ideation/gestures, Abbreviations: MED=Medicis; PFZ=Pfizer; AZN=AstraZeneca; OMJ=Ortho-McNeil-Janssen; AGN=Allergan; FST=Forest; NOV=Novartis; UCB=UCB; NND=Novo Nordisk; MRK=Merck; ABB=Abbott; GSK=GlaxoSmithKline; AMG=Amgen; BIP=Boehringer Ingelheim Pharmaceuticals • FDA identified 5 additional events as possibly suicide-related • Of 11 serious adverse events reported, only 1 was considered "related" n = no payment permitted for writing/authorship – Events considered "possibly related" were treated as "unrelated" – 5 required hospital admission and were events with known Publications Content in CIAs
association with SSRIs • Content in 2007–2011: Was there a need? Were authors provided data?
Published in Journal of the American Academy of Child and Adolescent • Content in 2012: Was there a need? Were authors provided data? PLUS was it balanced?
Psychiatry in 2000 Accurate? Exaggerated? Appropriate? • As generally well tolerated • Regarding serious adverse events: "Of the 11 patients, only headache 2012 CIAs
(one patient) was considered by the treating investigator to be related to paroxetine treatment." • Two of the CIAs had provisions consistent with those previously reported: – The Boehringer Ingelheim CIA had few comments on publications activity, but all dealt with process Abbott CIA
– The GSK and Amgen CIAs added a provision regarding payment to authors: • With certain limited exceptions, no compensation is paid to Authors for their time May 7, 2012
spent drafting or revising Publications (Amgen CIA p. 36) ". . shal require that scientific publications be published in a timely manner and • For these CIAs, any criminal allegations remain under seal present scientific information in a balanced way that does not exclude or
• For the other 2 CIAs, the criminal cases are not under seal: inappropriately downplay negative safety or health information." (p. 36) – Providing insight regarding CIA content provisions "Abbott's U.S. compliance personnel shall be involved in the review and approval of such annual Publications Plans, including any modification of an approved plan. The purpose of this review shall be to ensure that Publication Activities and related Criminal Case #1.12CR26
events are used for legitimate purposes in accordance with Abbott Policies
Agreed Statements of Fact, May 7, 2012
and Procedures." (p. 36) Mania in Dementia
• FDA expressed reservations about a new or expanded use of divalproex for mania June 28, 2012
• Study was suspended because of increased incidence of adverse events – somnolence and thrombocytopenia "GSK also represents that its human subject research and any resulting publications – dose too high are intended to foster increased understanding of scientific, clinical or
• Results failed to show efficacy in treating signs/symptoms of mania in dementia • Only one secondary measurements showed positive results medical issues" (p. 19)
• Clinical study report concluded this positive result was independent of somnolence ". . the operating practices require the implementation of data dissemination plans • Changed objectives in subsequent trial to target agitation instead of mania that establish prospective publication strategies for GSK-Sponsored Research and Published in Current Therapeutic Research in 2001 address requirements for appropriateness, accuracy, and balance in publications
• ". .did not improve signs and symptoms of mania associated with dementia . . but did improve symptoms of agitation." of GSK-Sponsored Research." (p. 20) Agitation in Dementia
• Study called for lower dosage • Terminated trial for low enrollment • Failed to separate from placebo • CSR reported 2 divalproex groups and placebo group all showed improvement We may consider certain types of communication to be safe harbors,
on all primary and secondary measures protected, peer-to-peer scientific communications
Results not published or disseminated except to FDA • The DOJ criminal investigations have examined the scientific merit of journal • First phase "suggest[ed], but did not prove" divalproex improved agitation in • The DOJ cited FDA comments regarding clinical study reports dementia in spite of no difference vs. placebo • The DOJ cited FDA review of adverse events Partially funded First published in American Journal of Psychiatry in 2001 • The DOJ has cited peer reviewer comments to manuscripts submitted for • 68% of divalproex, 52% of placebo subjects with reduced agitation Second part of study published in The American Journal of Geriatric Psychiatry in 2003 • While the articles in question may have also been distributed inappropriately, • "suggested but did not prove" that "therapy can result in decreased measures the criminal complaint discusses article content separately from distribution The CIAs use terms like appropriateness, accuracy, balance, legitimate
• No benefit over placebo purposes as requirements for the publications
National Institute Published in American Journal of Geriatric Psychiatry in 2005 on Aging funded, • This is consistent with GPP2 section on Reporting standards • Advanced copy to Abbott December 2004 Abbott supplied • No evidence that divalproex was meaningfully different than placebo • Nonadherence to reporting standards may risk loss of safe-harbor status drug product • Abbott continued to distribute "Rochester" study 2003 article until 2006 Augmentation in Acute Exacerbation of Schizophrenia
Corporate Integrity Agreement Between the Office of the Inspector General of the Department of Health and Human Services and Abbott • Divalproex in combination with atypical antipsychotic (ATP) Laboratories, May 7, 2012, accessed online at https://oig.hhs.gov/fraud/cia/agreements/Abbott_Laboratories_05072012.pdf, March 12, 2013.
• Per FDA Abbott failed to meet predefined endpoint [significant improvement at Corporate Integrity Agreement Between the Office of the Inspector General of the Department of Health and Human Services and Amgen Inc., December 14. 2012, accessed online at https://oig.hhs.gov/fraud/cia/agreements/Amgen_12142012.pdf, March 12, 2013 28 days compared to ATP alone] Corporate Integrity Agreement Between the Office of the Inspector General of the Department of Health and Human Services and Boehringer – and did not support application for new indication Ingelheim Pharmaceuticals, Inc., October 22. 2012, accessed online at https://oig.hhs.gov/fraud/cia/agreements/Boehringer_Ingelheim_ Pharmaceuticals_10222012.pdf, March 12, 2013.
Published in Neuropsychopharmacology in 2003 Corporate Integrity Agreement Between the Office of the Inspector General of the Department of Health and Human Services and • Stated combination therapy showed significant improvement day 3 through day GlaxoSmithKline LLC, October 22. 2012, accessed online at http://www.justice.gov/opa/documents/gsk/plea-ex-d.pdf, March 12, 2013. 21 downplaying failure to meet primary endpoint of day 28 United States v. Abbott Laboratories, 2012, Case 1:12-CR-00026-SGW, Document 5-2, Agreed Statement of Facts, accessed online at • Findings "confirmed in post hoc repeated-measures analysis of variance" http://www.justice.gov/opa/abbott-court-docs-2012/StatementofFacts.pdf, March 12, 2013.
United States ex rel, Greg Thorpe, et al. [Consolidated] Plaintif s v GlaxoSmithKline PLC, and GlaxoSmithKline LLC, Defendants, 2012, C.A. • Did not show any significant treatment difference between combination therapy No. 11-10398-RWZ, United States Complaint, accessed online at http://www.justice.gov/opa/documents/gsk/us-complaint.pdf, March 12, 2013.
Published in Neuropsychopharmacology in 2008 Scan code to receive PDF file of the poster • No significant treatment difference Presented at the 9th Annual Meeting of the International Society of Medical Publications Professionals, April 29–May 1, 2013, Baltimore, MD
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