Communication by scientists contrary to corporate interests Corporate statement (or corporate consultant’s statement) reporting findings contrary to the scientists’ findings or identifying purported methodologic limitations of the scientists’ studies Third party statement on the specific drug or device Retraction of report or statement of concern
Drug or device withdrawn from marketing (n=5)
2001 (rofecoxib): Topol, Mukherjee, Nissen, et al (JAMA) reported increased risk of cardiovascular events with COX-2 inhibitors. (Findings were from clinical trial data from the Bombadier et al study that had not been initially reported.[@129212] 2000: Bombadier et al [NEJM] Merck sponsored clinical trial reports no cardiovascular risk data for rofecoxib.[@129221] 2004: Topol reported to a Senate committee that the 2000 NEJM publication did not include the actual number of deaths in the two arms of the Bombadier NEJM publication in 2000.[@129293] Curfman, Drazen. NEJM (2005). Expression of concern: Bombadier et al[@129223]
1999 (phenylpropanolamine or PPA): Brass communicated safety concerns with PPA-containing cold products to scientists at Roche pharmaceuticals[@129177] 1999: Upon learning that the study by Brass and others found an association of stroke with PPA use, pharmaceutical makers opened an assault on methodology and integrity of the researchers.[@129177] 2004: FDA officials said they did not move faster [to withdraw PPA] because industry's efforts to discredit Yale results delayed the final report. “There were obvious concerns that we weren't getting the data because it was being held up by the people who sponsored the study,” said the director of FDA's Division of Over-the-Counter Drug Products.[@129177] 2004: FDA recommended withdrawal of > 100 PPA products, including popular cough and cold brands such as Robitussin CF and Dimetapp, and appetite suppressants such as Dexatrim and Acutrim.[@129177]
2009 (benfluorex): Frachon reports case series identifying severe valvular disease with benfluorex to France’s Agencie nationale du medicament et des prduits de sante (ANSM).[@129231] 2021: Lawyers for Servier (benfluorex’s manufacturer) stated that they were unaware prior to 2009 of links of benfluorex with heart valve or lung disease.[@129214] Benfluourex was withdrawn from Spain, Italy, the United States, and the European Union (between 1997 and 2004), and France (2009).[@129272] 2021: Servier was found guilty of “aggravated deception” and “manslaughter and involuntary injury” for its benfluorex marketing.[@129230]
2000 (atrazine): Unpublished Syngenta report on adverse effect from atrazine. Hayes was told that his Syngenta contract did not allow him to publish. With NSF funding, Hayes published same findings using independent funding. Male frogs were demasculinized and feminized after atrazine exposure.[@129128; @129246] 2003: Atrazine’s manufacturer (Syngenta)-funded researchers who reported that laboratory treatment of Xenopus laevis at 25 parts per million atrazine, but not at lower concentrations, led to intersex frogs.[@129255] 2003: A special Environment Protection Agency panel concluded that there is inconsistency across studies and more studies are needed.[@129246]
In 2003, European regulators banned atrazine due to an inability to keep atrazine levels in water below 0.1 parts per billion.[@129257]
1982 (amrinone): Wilmshurst communicated lack of benefit and increased risks of serious adverse events with amrinone based on case series to the manufacturer, Sterling Winthrop.[@129165; @129175] 1978: Harvard Medical School cardiologists and Sterling-Winthrop employees and consultants reported improved cardiac function among eight amrinone-treated congestive heart failure patients.[@129175; @129264] 1983: Wilmshurst reported to the Netherland Committee for the Evaluation of Medicine that Sterling-Winthrop had sent the Committee falsified clinical records on amrinone-treated patients with adverse event information deleted.[@129165; @129175] 1985: The Guardian newspaper reported that Sterling-Winthrop submitted fabricated clinical trial data from Wilmhurst’s study to regulatory agencies.[@129175]
Drugs where black box warnings were added to product label (n=5)
2007 (epoetin and darbepoetin): Bennett shared draft manuscript and meta-analysis which identified mortality risks of erythropoiesis stimulating agents with a then Vice-President for Research at an erythropoiesis stimulating agent manufacturer (now a Vice-President for research at a different large pharmaceutical manufacturer)[@129121; @129297] Glaspy et al (2010) published an Amgen sponsored meta-analysis finds no mortality risks with erythropoiesis stimulating agents[@129258] Bohlius et al published a [Lancet] (2009) German Federal Ministry of Education and Research grant-funded meta-analysis identified mortality risks with erythropoiesis stimulating agents.[@129259] FDA 2008 Oncology Drug Advisory Committee (ODAC). Identified mortality risks with erythropoiesis stimulating agents[@129260]
2007 (rosiglitazone): Nissen and Wolski report a meta-analysis in NEJM that identified increased risk of myocardial ischemic events associated with rosiglitazone.[@129211] 2007: GlaxoSmithKline statistician reports at an FDA Advisory Committee meeting results from a meta-analysis that did not identify increased myocardial ischemic risks with rosiglitazone.[@129226] 2007: FDA statisticians report at an FDA Advisory Committee meeting results from a meta-analysis that identified increased risk of myocardial ischemic events associated with rosiglitazone.[@129227] 2010: FDA Statement of concern letter. This letter was addressed to the FDA Commissioner and reported that the “totality of the evidence suggests that GSK was aware of possible cardiac risks associated with rosiglitazone years before such evidence became public.”[@129228]
2003 (paroxetine): Mosholder submits a memorandum to FDA supervisors indicating that his analysis of two clinical trials did not identify any benefits of paroxetine for children with depression.[@129241] 2007: GlaxoSmithKline statisticians reported to an FDA Advisory Committee that pooled analysis of the two trials found positive benefit with paroxetine.[@129226] 2007: An FDA statistician reported to an FDA Advisory Committee that his analysis of individual clinical trials identified no benefit with paroxetine for children with depression.[@129227] 2004: New York Attorney General requires GlaxoSmithKline to post entire clinical information for all sponsored trials. NY Attorney General reported GSK had previously withheld data.[@129271]
2007 (gadodiamide): Thomsen reports at a scientific conference 20 cases of gadodiamide-associated nephrogenic systemic fibrosis.[@129241] 2008: Danish Medicines Agency reports that a 2007 White Paper from the manufacturer of gadodiamide (General Electric) identifies no risk of nephrogenic systemic fibrosis 2008: Danish Medicines Agency report on gadodiamide identified several cases of gadodiamide-associated nephrogenic systemic fibrosis.[@129178] 2008: Danish Medicines Agency requested that General Electric respond to allegations that safety-related information had been withheld from radiologists at Herlev Hospital.[@129178]
1991 (paroxetine): Creaney and Healy published two cases of paroxetine-associated suicide.[@129194] 2001: Keller al reported efficacy and no suicide risk with paroxetine treatment of adolescents with depression.[@129263] 2004: FDA reviewer reports meta-analysis identifying increased suicide risks with selective serotonin release inhibitor (SSRI) anti-depressants. This report is leaked to the public by the Alliance for Human Research Protection[@129286] None
Device for which the manufacturer withdrew its application for approval from the FDA (n=1)
2006 (cardiac device): Wilmshurst, a co-principal investigator of the Migraine Intervention with StarFlex Technology (MIST) trial communicated serious safety concerns with the patent foramen ovale closure device.[@129165] 2008: Andre Dowson MD and other NMT Inc funded researchers reported that migraine intervention with STARFlex was beneficial. A co-principal investigator, Wilmshurst, was not a co-author of this report.[@129265] 2006: Wilmshurst and others showed that the manufacturer (NMT Inc) submitted data to the FDA by NMT Inc that were not consistent with the actual clinical findings.[@129257] A review of the original case report forms indicated that data submitted by NMT Inc were falsified.[@129266] 2008: The Guardian newspaper reports that NMT Inc had submitted fraudulent data to the FDA in 2008.[@129165]
Drug for which the manufacturer’s application to the FDA was delayed for several years (n=1)
1996 (deferiprone): Oliveri et al reported to the relevant Research Ethics Board lack of adequate effectiveness and increased hepatic iron concentrations among deferiprone treated persons in clinical trials. This information was also presented at the 1996 American Society of Hematology Conference 1999: A paper by Diav-Citrin et al reports on an Investigation into variability in therapeutic response to deferiprone using selected clinical trial data[@129250] None 2019: The senior author of Diav-Citrin et al was ruled by a University of Toronto committee to have committed research misconduct with respect to this publication.
Request to the University of Toronto for retraction of this paper. Public assurance for this retraction had been initially announced in 2002.[@129283]
Drug for which no regulatory changes were made (n=3)
1999 (thyroxine): Draft report of a study submitted to Boots Pharmaceuticals by Dong et al. finds bioequivalence of generic and branded drug. Mayor et al (1995). Limitations of comparing branded versus generic thyroxine (clinical trial data). Focused on research questions.[@129148] None None
2007 (risedronate): Blumsohn et al report a relationship of fracture risk to bone resorption in a clinical trial study initially reported in 200322 2003: Eastell et al report an abstract with 40% of the clinical trial data purposely omitted. Blumsohn as co-author was unable to see the entire data set. In 2007, Eastall reports a statistical re-analysis of the 2003 data and could not confirm one of the three of findings reported in 2003 from the trial.[@129251; @129252] 2009: Eisman, Lorenzo write that the Journal of Bone Mineral Research did not view itself as an investigative body. They had requested in 2006 that Blumsohn submit a publishable letter and if accepted, Eastell would be asked to respond. Eastell responded to the journal late in 2007. Addressed scientific research considerations.[@129253] Journal of Bone Mineral Research: Statement of concern. [2006] Concern was expressed that a statistical re-analysis of the Eastell 2003 data, as promised in 2006, had not been received.[@129244] This re-analysis was then received in 2007.[@129253]
1997 (textile fibers): Kern submitted a draft version of an abstract to Microfibres that described eight patients with interstitial lung disease following occupational exposure at a textile factory[@129152] 1998: A Microfibres spokesperson noted that the draft abstract listed chemicals for production that they considered proprietary; Kern’s abstract purportedly violated confidentiality agreement; and abstract reached premature conclusions.[@129220] 1997: The Centers for Disease Control and Prevention recognized a new syndrome “Flock Worker’s Lung, based on the abstract information.”[@129219] Not applicable.