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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 Six drugs and 1 device were withdrawn from marketing (median, 5 years after ADR reporting (IQR 4,6 years))., Interpretation: Because very serious ADRs impacts are so large, policy makers should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)., Competing Interests: Dr. Sartor reports grants and personal fees from AAA, personal fees from ASTELLAS, grants and personal fees from ASTRAZENECA, grants and personal fees from BAYER, personal fees from BLUE EARTH DIAGNOSTICS, INC., personal fees from EMD SERONO, grants and personal fees from ENDOCYTE, personal fees from PFIZER, grants and personal fees from PROGENICS, grants and personal fees from SANOFI, grants from INVITAE, grants and personal fees from MERCK, grants and personal fees from NOVARTIS, grants and personal fees from JANSSEN, personal fees from CONSTELLATION, personal fees from DENDREON, personal fees from BRISTOL-MYERS SQUIBB, grants from INNOCRIN, grants from SOTIO, other from NRG, other from NCI, personal fees from BRAVARIN NORDIC, personal fees from CLOVIS, personal fees from MYRIAD, personal fees from NORIA THERAPEUTICS, INC., personal fees from NOXOPHARM, personal fees from POINT BIOPHARMA, personal fees from TENEBIO, personal fees from THERAGNOSTICS, personal fees from TELIX, personal fees from CLARITY PHARMACUEITCALS, personal fees from Celegne, personal fees from FUSION, personal fees from ISOTOPEN TECHNOLOGIEN MEUNCHEN, during the conduct of the study. All other authors report no conflict., (© 2020 The Author(s).)