Charles L Bennett1,2,3, Shamia Hoque4, Nancy Olivieri5, Matthew A Taylor6, David Aboulafia7, Courtney Lubaczewski8, Andrew C Bennett3, Jay Vemula8, Benjamin Schooley4, Bartlett J Witherspoon3, Ashley C Godwin2,3, Paul S Ray3, Paul R Yarnold3, Henry C Ausdenmoore1,2,4,4,8,6,9,10,11,12,13,14,15,16,17,7,18,19, Marc Fishman3, Georgne Herring8, Anne Ventrone8, Juan Aldaco1, William J Hrushesky3, John Restaino2,3, Henrik S Thomsen15, Paul R Yarnold3, Robert Marx9, Cesar Migliorati19, Salvatore Ruggiero18, Chadi Nabhan3,16, Kenneth R Carson13, June M McKoy12, Y Tony Yang20, Martin W Schoen14, Kevin Knopf3,17, Linda Martin3, Oliver Sartor11, Steven Rosen1, William K Smith10. 1. City of Hope National Medical Center in Duarte, California, United States. 2. University of South Carolina College of Pharmacy in Columbia, South Carolina, United States. 3. The SONAR Project of University of South Carolina College of Pharmacy in Columbia, South Carolina, United States. 4. University of South Carolina College of Engineering and Computing in Columbia, South Carolina, United States. 5. University of Toronto in Toronto, Ontario, Canada. 6. University of South Carolina School of Medicine in Columbia, South Carolina, United States. 7. Virginia Mason Medical Center in Seattle, Washington, United States. 8. University of South Carolina College of Arts and Sciences in Columbia, South Carolina, United States. 9. University of Miami Miller School of Medicine in Miami, Florida, United States. 10. Uniformed Services University F. Edward Hebert School of Medicine in Bethesda, Maryland, United States. 11. Tulane University School of Medicine in New Orleans, Louisiana, United States. 12. Northwestern University Feinberg School of Medicine in Chicago, Illinois, United States. 13. Rush University School of Medicine in Chicago, Illinois, United States. 14. Saint Louis University School of Medicine in Saint Louis, Missouri, United States. 15. University of Copenhagen in Copenhagen, Denmark. 16. Caris Life Sciences in Chicago, Illinois, United States. 17. Highland Hospital in Oakland, California, United States. 18. New York Center for Oral and Maxillofacial Surgery in New Hyde Park, New York, United States. 19. University of Florida in Gainesville, Florida, United States. 20. George Washington University School of Nursing and Milken Institute School of Public Health in Washington, District of Columbia, United States.
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).
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).
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