TY - JOUR
T1 - Consequences to patients, clinicians, and manufacturers when very serious adverse drug reactions are identified (1997–2019)
T2 - A qualitative analysis from the Southern Network on Adverse Reactions (SONAR)
AU - Bennett, Charles L.
AU - Hoque, Shamia
AU - Olivieri, Nancy
AU - Taylor, Matthew A.
AU - Aboulafia, David
AU - Lubaczewski, Courtney
AU - Bennett, Andrew C.
AU - Vemula, Jay
AU - Schooley, Benjamin
AU - Witherspoon, Bartlett J.
AU - Godwin, Ashley C.
AU - Ray, Paul S.
AU - Yarnold, Paul R.
AU - Ausdenmoore, Henry C.
AU - Fishman, Marc
AU - Herring, Georgne
AU - Ventrone, Anne
AU - Aldaco, Juan
AU - Hrushesky, William J.
AU - Restaino, John
AU - Thomsen, Henrik S.
AU - Marx, Robert
AU - Migliorati, Cesar
AU - Ruggiero, Salvatore
AU - Nabhan, Chadi
AU - Carson, Kenneth R.
AU - McKoy, June M.
AU - Yang, Y. Tony
AU - Schoen, Martin W.
AU - Knopf, Kevin
AU - Martin, Linda
AU - Sartor, Oliver
AU - Rosen, Steven
AU - Smith, William K.
N1 - Funding Information:
Role of funding agencies: This study was conducted by physicians, pharmacists, nurses, epidemiologists, statisticians, attorneys, and research assistants who are affiliated with a decades-old National Institutes of Health R01 funded pharmacovigilance network called the Southern Network on Adverse Reactions (SONAR) [5] . SONAR does not accept funds from pharmaceutical manufacturers. Neither of the two funding agencies (the National Cancer Institute of Health or the American Cancer Society) had any input into the design, text, drafts, analyses, or submitted versions of the manuscript.
Funding Information:
We are particularly indebted to the long series of conversations and guidance on this project from the late Robert C. Kane, MD, the 2016 Frances Kelsey Award Recipient from the Food and Drug Administration who died in 2018 before completion of this manuscript. We would like to thank clinicians and pharmacovigilance experts who have worked closely with the National Institutes of Health-funded R01 grants, the Southern Network on Adverse Reactions (SONAR) and the Research on Adverse Drug Events and Reports (RADAR) projects from 1997 to 2019 at: the University of South Carolina, Columbia, South Carolina; the Medical University of South Carolina, Charleston, South Carolina; Duke University, Durham, North Carolina, University of North Carolina, Chapel Hill North Carolina, Tulane University and the Louisiana State University, New Orleans, Louisiana, the University of Miami, the University of Texas, San Antonio, Texas; the University of New Mexico, Albuquerque, New Mexico; Nara Medical University, Kashihira, Nara, Japan; the Japan Institute of Pharmacovigilance, Tennoji-ku, Osaka, Japan, the MD Anderson Cancer Center, Houston, Texas; Johns Hopkins University, Baltimore, Maryland; the University of Nebraska School of Medicine, Omaha, Nebraska; Baylor University, Houston, Texas; the University of Chicago, Chicago, Illinois’ the University of Illinois/Chicago, Chicago, Illinois; Indiana University, Indianapolis, Indiana; Case Western Reserve University, Cleveland, Ohio; Albert Einstein College of Medicine, Bronx, New York; the Mission Saint Joseph's Hospital, Asheville, North Carolina; University of Copenhagen, Copenhagen, Denmark; Yale University, New Haven, Connecticut; University College, London, England; University of Modena and Regio Emillia, Modena, Italy; the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health, Bethesda, Maryland; the Food and Drug Administration; Silver Spring, Maryland; the University of Copenhagen, Copenhagen, Denmark; McGill University, Montreal, Canada; the University of Pennsylvania, Philadelphia, Pennsylvania; Rutgers University, Piscataway, New Jersey; Washington University, Saint Louis, Missouri; Memorial Sloan Kettering Cancer Center, New York, New York; the Midwest Center for Health Services Research and Policy Studies, Maywood, Illinois; Tenon Hospital and Pierre and Marie Curie University, Paris France; Singapore General Hospital, Singapore; Hotel-Dieu, Paris, France; Queen's University, Kingston, Ontario; the University of California at Los Angeles, Los Angeles, California; A Manzoni Hospital, Lecco, Italy; the University of Utah, Salt Lake City, Utah; Oregon Health Sciences University, Portland, Oregon; the Therapeutics Good Administration, Cabrera, Australia; Long Island Jewish Medical Center, New Hyde Park, New York; the Veterans Administration Cooperative Studies Program Clinical Research Pharmacy, Albuquerque, New Mexico; University of Pisa, Pisa, Italy; Stanford University, Palo Alto, California; the University of Pisa, Pisa, Italy; the University of Melbourne, East Melbourne, Australia; the Dana Farber Cancer Institute, Boston, Massachusetts; the Neoplastic and autoimmune diseases research institute, Rancho Santa Fe, New Mexico; the Southern Illinois College of Medicine, Springfield, Illinois. The names of the individual investigators are not included to protect the confidentiality and anonymity of collaborators of RADAR and SONAR. We also acknowledge editorial support from Virginia Green PhD of the Benaroya Research Institute at Virginia Mason in Seattle, Washington.
Publisher Copyright:
© 2020 The Author(s)
PY - 2021/1
Y1 - 2021/1
N2 - 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).
AB - 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).
KW - Adverse drug reaction
KW - Liability
KW - Patient harm
KW - Toxicity
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U2 - 10.1016/j.eclinm.2020.100693
DO - 10.1016/j.eclinm.2020.100693
M3 - Article
AN - SCOPUS:85099819860
VL - 31
JO - EClinicalMedicine
JF - EClinicalMedicine
SN - 2589-5370
M1 - 100693
ER -