Industry influences on science

The Remune story (a therapeutic AIDS vaccine)

Phase III clinical trial of clinical efficacy of Remune:

• Primary results paper: Kahn et al November 2000 JAMA paper (pdf file) reporting the study results with a somewhat limited subset of the data
• editorial commentaries on conflict of interest (Korn, de Angelis)
• letters discussing this paper along with the authors' reply
• and a correction (pdf version of correction)
• UCSF contract with Immune Response Corporation to conduct the research
• UCSF press release regarding the 2000 JAMA paper
• Baltimore Sun article on Lagakos and Kahn reporting of an ineffective AIDS vaccine
• DeAngelis commentary on conflict of interest and the public trust noting the reasons for publishing this paper (pdf file)
• Los Angeles Times article (November 1, 2000) presenting the industry side of this story

Phase II clinical trial results of a different Remune study in Thailand:

• Primary results paper: (Churdboonchart paper September 2000; pdf file)
• Glidden et al 2001 CVI commentary on selective reporting in the Churdboonchart et al paper (pdf file) 
• The follow-up author correction noting a financial conflict of interest. (pdf file)
  

Additional accounts:

• The first part of Chapter 5 (p. 103) of University Inc gives a journalistic account of the Remune story
• Scientific secrecy and spin:  The sad, sleazy saga of the trials of Remune by Susan Haack (2006)
• Nature Biotechnology article with discussion of data access and reporting of pre-specified analyses

The Vioxx (Rofecoxib) story

• Peer-reviewed papers or other reports of trial results:
• VIGOR study (Bombardier et al 2000) of gastrointestinal effects for rheumatoid arthritis patients
• Alzheimer's Disease studies:
• Protocol 078
• Protocol 091
• Protocol 126
• APPROVe study results (Bresalier et al 2005) showing increased cardiovascular risk with Rofecoxib
• Expressions of concern and evidence of problems:
• Concerns about myocardial event reporting in the VIGOR study:  Curfman et al (2005) expression of concern; Bombardier et al (2006) response; Curfman et al (2006) reaffirmation of expression of concern
• Psaty and Kronmal (2008) case study of selective reporting in the Alzheimer's disease trials
• Website with supporting documentation for Psaty & Kronmal 2008
• Ross et al (2008) case study of guest authorship and ghostwriting w.r.t. Rofecoxib
• Supporting documentation for Ross et al 2008
• David Madigan fall 2007 UW biostatistics department seminar slides

The Actimmune (subcutaneous interferon gamma-1b) story for treatment of idiopathinc pulmonary fibrosis (IPF)

• pp 404-405 of Tom Fleming's paper "Clinical Trials: Discerning Hype from Substance" gives a brief overview of the Actimune story.
• Chronology of events:
• October 2002 registration of the GIPF-001 study of Actimmune for IPF on ClinicalTrials.gov
• August 2002 press release by InterMune announcing survival benefit from Actimmune for IPF brom GIPF-001
• April 2003 New York Times article about off-label use of Actimmune for IPF
• 2004 New England Journal of Medicine paper giving the primary study results that don't support the survival benefit
• January 2004 registration of the INSPIRE trial on ClinicalTrials.gov for Actimmune treatment of IPF in patients with mild to moderate impairment 
• 2005 paper by Johnson & Raghu in European Respiratory Journal cautioning about choice of outcome measures in IPF trials and citing statistical papers on surrogate endpoints 
• December 2006 Deferred Prosecution Agreement for Actimmune promotion
• March 2007 press release and FDA public health advisory about early stopping of the INSPIRE trial to confirm benefit of Actimmune for IPF
• March 2007 Business Week story about InterMune stock plunging after it halted the Phase III INSPIRE trial of Actimmune for IPF
• January 2008 article in The Recorder giving a succinct summary of the issue with links to the indictment
• March 2008 news story of the indictment of former Intermune CEO for false and misleading advertisement of Actimmune and another in the San Francisco Chronicle
• February 2009 New York Times news story that InterMune stock soars thanks to new results from two trials of a different drug (pirfenidone) to treat IPF.  These trials showed mixed results.

Corporate influences on epidemiology

• Pearce's paper on corporate influences on epidemiology and his response to several commenters
• Chromium:  Egilman D.  Corporate corruption of science – the case of chromium(VI).  International Journal of Occupational and Envrionmental Health  2006; 12:169-176.
• Diesel particulate in underground mines:  Montforton 2006

Managing industry-academia relationships

• Bodenheimer lecture - noting that management of financial conflict of interest is not the only concern.

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REFERENCES

Remune

Kahn JO, Cherng DW, Mayer K, Murray H, Lagakos S  Evaluation of HIV-1 immunogen, an immunologic modifier, administered to patients infected with HIV having 300 to 549 x 10(6)/L CD4 cell counts: A randomized controlled trial.  JAMA. 2000 Nov 1;284(17):2193-202.

Churdboonchart, V., C. Sakondhavat, S. Kulpradist, B. Isarangkura Na Ayudthya, V. Chandeying, S. Rugpao, C. Boonshuyar, W. Sukeepaisarncharoen, W. Sirawaraporn, D. J. Carlo, and R. Moss. 2000. A double-blind, adjuvant-controlled trial of human immunodeficiency virus type 1 (HIV-1) immunogen (Remune) monotherapy in asymptomatic, HIV-1-infected Thai subjects with CD4-cell counts of >300. Clin. Diagn Lab Immunol. 7:728-733

Glidden D, Kim S, Lagakos S.  Effectiveness of Remune.  Clin Diagn Lab Immunol. 2001 Mar;8(2):468-9.

LINK Research Agreement between the UCSF and Immune Response Corporation..

Birch. D, Cohn. G, Standing up to Industry. Chicago Tribune 2001, June 26.

DeAngelis C, Conflict of Interest and the Public Trust. JAMA 2000 April; 284(17):2237-2238

Niiler E, Business and Regulatory News, Company, Academics Argue Over Data. Nature America Inc. 2000 Dec; 8

Vioxx

Avorn J.; Evaluating Drug Effects in the Post-Vioxx World: There Must Be a Better Way; Circulation 2006:113:2173-2176

DeAngelis C.; Fontanarosa P.; Impugning the Integrity of Medical Science: The Adverse Effects of Industry Influence; JAMA 2008 Nov; 299(15):1833-1835

LINK Merck Withdraws Vioxx; FDA Issues Public Health Advisory; FDA Consumer magazine 2004 Dec.

Horton R.; Vioxx, the implosion of Merck, and aftershock at the FDA; Lancet 2004 Dec; 364:1995-1996

Juni P.; Nartey L.; Reichenbach S.; Sterchi R.; Dieepe P.; Egger M.; Risk of cardiovascular events and rofecoxib: cumulative meta-analysis; Lancet 2004; 364:2021-2029

LINK Vioxx: an unequal partnership between safety and efficacy; Lancet 2004 Oct; 364:1287-1288

Maxwell S.; Webb D.; COX-2 selective inhibitors-important lessons learned; Lanchet 2005 Feb; 365:451-449

Psaty B.; Kronmal R.; Reporting Mortality Findings in Trials of Rofecoxib for Alzheimer Disease or Cognitive Impairment: A Case Study Based on Documents From Rofecoxib Litigation; JAMA 2008 Nov; 299(15):1813-1817

Curfman G.; Morrissey S.; Drazen J.; Expression of Concern Reaffirmed; N Engl J Med 2006 Mar; 354(11):1193

Bombardier C.; Laine L.; Burgos-Vargas R.; Davis B.; Day R.; Ferraz M.; Hawkey C.; Hochberg M; Kvien T.; Schnitzer T.; Weaver A.; Response to Expression of Concern Regarding VIGOR Study; N Engl J Med 2006 Mar; 354(11):1196-1199

Ross J.; Hill K.; Egilman D.; Guest Authorship and Ghostwriting in Publications Related to Rofecoxib: A Case Study of Industry Documents From Rofecoxib Litigation; JAMA 2008 Nov; 299(15):1800-1812

Roth-Cline M.; Clinical Trials in the Wake of Vioxx: Requiring Statistically Extreme Evidence of Benefit to Ensure the Safety of New Drugs; Circulation 2006;113:2253-2259

Topol E.; Failing the Public Health-Rofecoxib, Merck, and the FDA; N Engl J Med 2004 Oct; 352(17):1707-1709

Bombardier C.; Laine L.; Reicin A.; Shapiro D.; Burgos-Vargas R.; Davis B.; Day R.; Ferraz M.; Hawkey C.; Hochberg M.; Kvien T.; Schnitzer T.; Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naprozen in Patients with Rheumatoid Arthritis; N Engl J Med 2000 Nov; 343(21):1520-1528

Curfman G.; Morrissey S.; Drazen J.; Expression of Concern: Bombardier et al., “Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naprozen in Patrients with Rheumatoi Arthritis,” N Engl Med 2000; 343:1520-8;N Engl Med 2005 Dec

Madigan D.; Secrets of Vioxx, Drug safety in the drug development process; Columbia Univ

Madigan D.; Safe and Effective? Drug safety in the drug development process; Columbia Univ.