A reactogenic "placebo" and the ethics of informed consent in Gardasil HPV vaccine clinical trials: A case study from Denmark.

BACKGROUND: Medical ethics guidelines require of clinical trial investigators and sponsors to inform prospective trial participants of all known and potential risks associated with investigational medical products, and to obtain their free informed consent. These guidelines also require that clinical research be so designed as to minimize harms and maximize benefits. OBJECTIVE: To examine Merck's scientific rationale for using a reactogenic aluminum-containing "placebo" in Gardasil HPV vaccine pre-licensure clinical trials. METHODS: We examined the informed consent form and the recruitment brochure for the FUTURE II Gardasil vaccine trial conducted in Denmark; and we interviewed several FUTURE II trial participants and their treating physicians. We also reviewed regulatory documentation related to Gardasil vaccine approval process and the guidelines on evaluation of adjuvants used in human vaccines. RESULTS: It was found that the vaccine manufacturer Merck made several inaccurate statements to trial participants that compromised their right to informed consent. First, even though the study protocol listed safety testing as one of the study's primary objectives, the recruitment brochure emphasized that FUTURE II was not a safety study, and that the vaccine had already been proven safe. Second, the advertising material for the trial and the informed consent forms stated that the placebo was saline or an inactive substance, when, in fact, it contained Merck's proprietary highly reactogenic aluminum adjuvant which does not appear to have been properly evaluated for safety. Several trial participants experienced chronic disabling symptoms, including some randomized to the adjuvant "placebo" group. CONCLUSION: In our view, the administration of a reactive placebo in Gardasil clinical trials was without any possible benefit, needlessly exposed study subjects to risks, and was therefore a violation of medical ethics. The routine use of aluminum adjuvants as "placebos" in vaccine clinical trials is inappropriate as it hinders the discovery of vaccine-related safety signals.

The Monsanto Papers: Poisoning the scientific well.

OBJECTIVE: Examination of de-classified Monsanto documents from litigation in order to expose the impact of the company's efforts to influence the reporting of scientific studies related to the safety of the herbicide, glyphosate. METHODS: A set of 141 recently de-classified documents, made public during the course of pending toxic tort litigation, In Re Roundup Products Liability Litigation were examined. RESULTS: The documents reveal Monsanto-sponsored ghostwriting of articles published in toxicology journals and the lay media, interference in the peer review process, behind-the-scenes influence on retraction and the creation of a so-called academic website as a front for the defense of Monsanto products. CONCLUSION: The use of third-party academics in the corporate defense of glyhphosate reveals that this practice extends beyond the corruption of medicine and persists in spite of efforts to enforce transparency in industry manipulation.

Industry-corrupted psychiatric trials. / Zjawisko korupcji w badaniach psychiatrycznych.

The goal of this paper is to expose the research misconduct of pharmaceutical industry sponsored clinical trials via three short case studies of corrupted psychiatric trials that were conducted in the United States. We discuss the common elements that enable the misrepresentation of clinical trial results including ghostwriting for medical journals, the role of key opinion leaders as co-conspirators with the pharmaceutical industry and the complicity of top medical journals in failing to uphold standards of science and peer review. We conclude that the corruption of industry-sponsored clinical trials is one of the major obstacles facing evidence-based medicine.

The citalopram CIT-MD-18 pediatric depression trial: Deconstruction of medical ghostwriting, data mischaracterisation and academic malfeasance.

OBJECTIVE: Deconstruction of a ghostwritten report of a randomized, double-blind, placebo-controlled efficacy and safety trial of citalopram in depressed children and adolescents conducted in the United States. METHODS: Approximately 750 documents from the Celexa and Lexapro Marketing and Sales Practices Litigation: Master Docket 09-MD-2067-(NMG) were deconstructed. RESULTS: The published article contained efficacy and safety data inconsistent with the protocol criteria. Procedural deviations went unreported imparting statistical significance to the primary outcome, and an implausible effect size was claimed; positive post hoc measures were introduced and negative secondary outcomes were not reported; and adverse events were misleadingly analysed. Manuscript drafts were prepared by company employees and outside ghostwriters with academic researchers solicited as 'authors'. CONCLUSION: Deconstruction of court documents revealed that protocol-specified outcome measures showed no statistically significant difference between citalopram and placebo. However, the published article concluded that citalopram was safe and significantly more efficacious than placebo for children and adolescents, with possible adverse effects on patient safety.

The paroxetine 352 bipolar trial: A study in medical ghostwriting.

BACKGROUND: The problem of ghostwriting in corporate-sponsored clinical trials is of concern to medicine, bioethics, and government agencies. We present a study of the ghostwritten archival report of an industry-sponsored trial comparing antidepressant treatments for bipolar depression: GlaxoSmithKline (GSK) paroxetine study 352. This analysis is based upon publicly available evidence presented in a complaint of research misconduct filed with the Office of Research Integrity of the Department of Health and Human Services. OBJECTIVES: We performed a deconstruction of the published study to show how primary and secondary outcome analyses were conflated, turning a 'negative' clinical trial into a 'positive' study - with conclusions and recommendations that could adversely affect patient health. METHODS: The paroxetine 352 study was a randomized, double-blind, placebo-controlled, 19-site trial comparing paroxetine and imipramine in 117 patients with bipolar type I major depressive episode which was unresponsive to prior lithium carbonate therapy. RESULTS: Analysis of the primary outcome measures found no statistically significant difference between paroxetine or imipramine versus placebo. However, the published article concluded that both drugs were efficacious versus placebo for a post hoc subgroup of patients. CONCLUSIONS: Few industry-sponsored studies gain public scrutiny. It is important to make these articles transparent to the scientific and medical community.

Conflicted medical journals and the failure of trust.

Journals are failing in their obligation to ensure that research is fairly represented to their readers, and must act decisively to retract fraudulent publications. Recent case reports have exposed how marketing objectives usurped scientific testing and compromised the credibility of academic medicine. But scant attention has been given to the role that journals play in this process, especially when evidence of research fraud fails to elicit corrective measures. Our experience with The Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) illustrates the nature of the problem. The now-infamous Study 329 of paroxetine in adolescent depression was negative for efficacy on all eight protocol-specified outcomes and positive for harm, but JAACAP published a report of this study that concluded that "paroxetine is generally well tolerated and effective for major depression in adolescents." The journal's editors not only failed to exercise critical judgment in accepting the article, but when shown evidence that the article misrepresented the science, refused either to convey this information to the medical community or to retract the article.

Industry-sponsored ghostwriting in clinical trial reporting: a case study.

In this case study from litigation, we show how ghostwriting of clinical trial results can contribute to the manipulation of data to favor the study medication. Study 329 for paroxetine pediatric use was negative for efficacy and positive for harm. Yet the ghostwritten publication from this study concluded that paroxetine provided evidence of efficacy and safety and continues to be influential. Despite the role of named authors in revisions of the manuscript, the sponsor company remained in control of the message.