Consequences to patients, clinicians, and manufacturers when very serious adverse drug reactions are identified (1997–2019): A qualitative analysis from the Southern Network on Adverse Reactions (SONAR)

Abstract

Background Adverse drug/device reactions (ADRs) can result in severe patient harm. We define very serious ADRs as being associated with severe toxicity, as measured on the Common Toxicity Criteria Adverse Events (CTCAE)) scale, following use of drugs or devices with large sales, large financial settlements, and large numbers of injured persons. We report on impacts on patients, clinicians, and manufacturers following very serious ADR reporting. Methods We reviewed clinician identified very serious ADRs published between 1997 and 2019. Drugs and devices associated with reports of very serious ADRs were identified. Included drugs or devices had market removal discussed at Food and Drug Advisory (FDA) Advisory Committee meetings, were published by clinicians, had sales > $1 billion, were associated with CTCAE Grade 4 or 5 toxicity effects, and had either >$1 billion in settlements or >1,000 injured patients. Data sources included journals, Congressional transcripts, and news reports. We reviewed data on: 1) timing of ADR reports, Boxed warnings, and product withdrawals, and 2) patient, clinician, and manufacturer impacts. Binomial analysis was used to compare sales pre- and post-FDA Advisory Committee meetings. Findings Twenty very serious ADRs involved fifteen drugs and one device. Legal settlements totaled $38.4 billion for 753,900 injured persons. Eleven of 18 clinicians (61%) reported harms, including verbal threats from manufacturer (five) and loss of a faculty position (one). Annual sales decreased 94% from $29.1 billion pre-FDA meeting to $4.9 billion afterwards ( p <0.0018). Manufacturers of four drugs paid $1.7 billion total in criminal fines for failing to inform the FDA and physicians about very serious ADRs. Following FDA approval, the median time to ADR reporting was 7.5 years (Interquartile range 3,13 years). Twelve drugs received Box warnings and one drug received a warning (median, 7.5 years following ADR reporting (IQR 5,11 years). Six drugs and 1 device were withdrawn from marketing (median, 5 years after ADR reporting (IQR 4,6 years)). Interpretation Because very serious ADRs impacts are so large, policy makers should consider developing independently funded pharmacovigilance centers of excellence to assist with clinician investigations. Funding This work received support from the National Cancer Institute (1R01 CA102713 (CLB), https://www.nih.gov/about-nih/what-we-do/nih-almanac/national-cancer-institute-nci ; and two Pilot Project grants from the American Cancer Society's Institutional Grant Award to the University of South Carolina (IRG-13–043–01) https://www.cancer.org/ (SH; BS).

Davids versus Goliaths: Pharma and academia threats to individual scientists and clinicians

“…This framework was developed with consultant input in our 2019 and 2021 studies on harms of reporting serious adverse drug reactions. 1,2 DATA Data sources for threats included publicly available reports from government agencies, Congressional hearings, and an investigation commissioned by the Canadian Association of University Teachers, documents produced for jury trials and settlement agreements, Department of Justice press releases, and news articles primarily from The New York Times, The Wall Street Journal, The Guardian, The New Yorker, and Science. Data focused on information about manufacturers; clinician and scientist authors' experiences of threats, intimidation, and harms; numbers of persons experiencing toxicities related to drugs or devices that were the focus of communications; payments for injuries/deaths associated with toxicities; and settlements or fines paid to government programs or affected patients.…”

“…For several individuals, threats and intimidations were followed by harms, including: loss of employment, job demotion, delayed academic tenure decisions, personal payments of legal fees for lawsuits filed against individual clinicians and scientists after public communication of clinical or basic science findings, loss of grant funding, and loss of academic positions. 2 Formal documentation of corporate efforts to harm careers The University of Sheffield threatened academic discipline and possible termination. 23 Blumsohn later received a severance agreement.…”

“…Reluctance to report research findings may arise from fear of retaliation from pharmaceutical or device corporations when findings are contrary to corporate interests. 1,2 Research is increasingly funded by pharmaceutical corporations, which introduces bias toward publication of favorable results. 3 We previously reported that actions taken by industry and academic leaders against clinicians who authored adverse drug reaction reports were mostly punitive.…”

“…3 We previously reported that actions taken by industry and academic leaders against clinicians who authored adverse drug reaction reports were mostly punitive. 1,2 Case studies describe threats from pharmaceutical executives to clinicians when findings contrary to corporate interests were communicated. Attacks on scientists' and clinicians' character or their methodologies are threats described in case narratives, although no systematic review of threats and intimidation has been reported.…”

“…1 In our study of eighteen clinicians who authored serious drug reaction reports for drugs with $1 billion or more in annual revenue, 61% experienced professional harms. 2 Our objective is to expand upon case report literature and these two case series on harms to report on threats and intimidations targeted against clinicians and scientists who communicated, or attempted to communicate, findings contrary to corporate interests.…”