Improving attribution of adverse events in oncology clinical trials

Goldy C. George, Pedro C. Barata, Alicyn Campbell, Alice Chen, Jorge E. Cortes, David M. Hyman, Lee Jones, Thomas Karagiannis, Sigrid Klaar, Jennifer G. Le-Rademacher, Patricia LoRusso, Sumithra J. Mandrekar, Diana M. Merino, Lori M. Minasian, Sandra A. Mitchell, Sandra Montez, Daniel J. O'Connor, Syril Pettit, Elaine Silk, Jeff A. SloanMark Stewart, Chris H. Takimoto, Gilbert Y. Wong, Timothy A. Yap, Charles S. Cleeland, David S. Hong

Research output: Contribution to journalReview article

Abstract

Attribution of adverse events (AEs) is critical to oncology drug development and the regulatory process. However, processes for determining the causality of AEs are often sub-optimal, unreliable, and inefficient. Thus, we conducted a toxicity-attribution workshop in Silver Springs MD to develop guidance for improving attribution of AEs in oncology clinical trials. Attribution stakeholder experts from regulatory agencies, sponsors and contract research organizations, clinical trial principal investigators, pre-clinical translational scientists, and research staff involved in capturing attribution information participated. We also included patients treated in oncology clinical trials and academic researchers with expertise in attribution. We identified numerous challenges with AE attribution, including the non-informative nature of and burdens associated with the 5-tier system of attribution, increased complexity of trial logistics, costs and time associated with AE attribution data collection, lack of training in attribution for early-career investigators, insufficient baseline assessments, and lack of consistency in the reporting of treatment-related and treatment-emergent AEs in publications and clinical scientific reports. We developed recommendations to improve attribution: we propose transitioning from the present 5-tier system to a 2–3 tier system for attribution, more complete baseline information on patients’ clinical status at trial entry, and mechanisms for more rapid sharing of AE information during trials. Oncology societies should develop recommendations and training in attribution of toxicities. We call for further harmonization and synchronization of recommendations regarding causality safety reporting between FDA, EMA and other regulatory agencies. Finally, we suggest that journals maintain or develop standardized requirements for reporting attribution in oncology clinical trials.

Original languageEnglish (US)
Pages (from-to)33-40
Number of pages8
JournalCancer Treatment Reviews
Volume76
DOIs
StatePublished - Jun 2019
Externally publishedYes

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Keywords

  • Adverse event
  • Attribution
  • Cancer treatment
  • Clinical trial
  • Symptom
  • Toxicity

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging

Cite this

George, G. C., Barata, P. C., Campbell, A., Chen, A., Cortes, J. E., Hyman, D. M., ... Hong, D. S. (2019). Improving attribution of adverse events in oncology clinical trials. Cancer Treatment Reviews, 76, 33-40. https://doi.org/10.1016/j.ctrv.2019.04.004

Improving attribution of adverse events in oncology clinical trials. / George, Goldy C.; Barata, Pedro C.; Campbell, Alicyn; Chen, Alice; Cortes, Jorge E.; Hyman, David M.; Jones, Lee; Karagiannis, Thomas; Klaar, Sigrid; Le-Rademacher, Jennifer G.; LoRusso, Patricia; Mandrekar, Sumithra J.; Merino, Diana M.; Minasian, Lori M.; Mitchell, Sandra A.; Montez, Sandra; O'Connor, Daniel J.; Pettit, Syril; Silk, Elaine; Sloan, Jeff A.; Stewart, Mark; Takimoto, Chris H.; Wong, Gilbert Y.; Yap, Timothy A.; Cleeland, Charles S.; Hong, David S.

In: Cancer Treatment Reviews, Vol. 76, 06.2019, p. 33-40.

Research output: Contribution to journalReview article

George, GC, Barata, PC, Campbell, A, Chen, A, Cortes, JE, Hyman, DM, Jones, L, Karagiannis, T, Klaar, S, Le-Rademacher, JG, LoRusso, P, Mandrekar, SJ, Merino, DM, Minasian, LM, Mitchell, SA, Montez, S, O'Connor, DJ, Pettit, S, Silk, E, Sloan, JA, Stewart, M, Takimoto, CH, Wong, GY, Yap, TA, Cleeland, CS & Hong, DS 2019, 'Improving attribution of adverse events in oncology clinical trials', Cancer Treatment Reviews, vol. 76, pp. 33-40. https://doi.org/10.1016/j.ctrv.2019.04.004
George, Goldy C. ; Barata, Pedro C. ; Campbell, Alicyn ; Chen, Alice ; Cortes, Jorge E. ; Hyman, David M. ; Jones, Lee ; Karagiannis, Thomas ; Klaar, Sigrid ; Le-Rademacher, Jennifer G. ; LoRusso, Patricia ; Mandrekar, Sumithra J. ; Merino, Diana M. ; Minasian, Lori M. ; Mitchell, Sandra A. ; Montez, Sandra ; O'Connor, Daniel J. ; Pettit, Syril ; Silk, Elaine ; Sloan, Jeff A. ; Stewart, Mark ; Takimoto, Chris H. ; Wong, Gilbert Y. ; Yap, Timothy A. ; Cleeland, Charles S. ; Hong, David S. / Improving attribution of adverse events in oncology clinical trials. In: Cancer Treatment Reviews. 2019 ; Vol. 76. pp. 33-40.
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AU - Campbell, Alicyn

AU - Chen, Alice

AU - Cortes, Jorge E.

AU - Hyman, David M.

AU - Jones, Lee

AU - Karagiannis, Thomas

AU - Klaar, Sigrid

AU - Le-Rademacher, Jennifer G.

AU - LoRusso, Patricia

AU - Mandrekar, Sumithra J.

AU - Merino, Diana M.

AU - Minasian, Lori M.

AU - Mitchell, Sandra A.

AU - Montez, Sandra

AU - O'Connor, Daniel J.

AU - Pettit, Syril

AU - Silk, Elaine

AU - Sloan, Jeff A.

AU - Stewart, Mark

AU - Takimoto, Chris H.

AU - Wong, Gilbert Y.

AU - Yap, Timothy A.

AU - Cleeland, Charles S.

AU - Hong, David S.

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N2 - Attribution of adverse events (AEs) is critical to oncology drug development and the regulatory process. However, processes for determining the causality of AEs are often sub-optimal, unreliable, and inefficient. Thus, we conducted a toxicity-attribution workshop in Silver Springs MD to develop guidance for improving attribution of AEs in oncology clinical trials. Attribution stakeholder experts from regulatory agencies, sponsors and contract research organizations, clinical trial principal investigators, pre-clinical translational scientists, and research staff involved in capturing attribution information participated. We also included patients treated in oncology clinical trials and academic researchers with expertise in attribution. We identified numerous challenges with AE attribution, including the non-informative nature of and burdens associated with the 5-tier system of attribution, increased complexity of trial logistics, costs and time associated with AE attribution data collection, lack of training in attribution for early-career investigators, insufficient baseline assessments, and lack of consistency in the reporting of treatment-related and treatment-emergent AEs in publications and clinical scientific reports. We developed recommendations to improve attribution: we propose transitioning from the present 5-tier system to a 2–3 tier system for attribution, more complete baseline information on patients’ clinical status at trial entry, and mechanisms for more rapid sharing of AE information during trials. Oncology societies should develop recommendations and training in attribution of toxicities. We call for further harmonization and synchronization of recommendations regarding causality safety reporting between FDA, EMA and other regulatory agencies. Finally, we suggest that journals maintain or develop standardized requirements for reporting attribution in oncology clinical trials.

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