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Poster Discussion session - Public health policy

4001 - Magnitude of Clinical Benefit of Trials Supporting US Food and Drug Administration (FDA) Approval of Breakthrough and Non-breakthrough Drugs


20 Oct 2018


Poster Discussion session - Public health policy


Bioethical Principles and GCP

Tumour Site


Consolacion Molto Valiente


Annals of Oncology (2018) 29 (suppl_8): viii562-viii575. 10.1093/annonc/mdy297


C. Molto Valiente1, M. Borrell1, T. Hwang2, I. Gich Saladich3, A. Barnadas1, E. Amir4, A. Kesselheim5, A. Tibau1

Author affiliations

  • 1 Oncology Department, Hospital de la Santa Creu i Sant Pau and Universitat Autònoma de Barcelona, 8026 - Barcelona/ES
  • 2 Program On Regulation, Therapeutics, And Law (portal), Brigham and Women's Hospital and Harvard Medical School, 2115 - Boston/US
  • 3 Department Of Epidemiology, Hospital de la Santa Creu i Sant Pau and Universitat Autònoma de Barcelona, 8026 - Barcelona/ES
  • 4 Division Of Medical Oncology & Hematology, Department Of Medicine, Princess Margaret Cancer Centre and the University of Toronto, M5G2M9 - Toronto/CA
  • 5 Program On Regulation, Therapeutics, And Law (portal), Brigham and Women's Hospital and Harvard Medical School, 02215 - Boston/US


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Abstract 4001


The Breakthrough Therapy program was established in July 2012 to expedite drug development and approval in the US, although it is unclear if cancer drugs qualifying for this program are more effective or safer than non-breakthrough-designated drugs. The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) is a validated tool to assess the clinical benefit of cancer drugs. Here, we compare the magnitude of clinical benefit of clinical trials leading to FDA approval of breakthrough-designated and non-breakthrough-designated cancer drugs.


We searched the Drugs@FDA website to identify anticancer drugs for solid tumors approved by the FDA between July 2012 and December 2017. For each drug, we collected data on breakthrough therapy designation, pivotal trial design, efficacy, safety, and quality of life outcomes, and applied ESMO-MCBS v1.1 grades. Substantial benefit was defined as a grade of A or B for trials of curative intent and 4 or 5 for those of palliative intent. Trial characteristics and ESMO-MCBS grades were compared using Chi squared or Mann Whitney U tests.


We identified 110 trials supporting the approval of 52 individual drugs for 96 indications. Of these indications, 49% received breakthrough designation. Compared to non-breakthrough drugs, trials supporting breakthrough drugs had a smaller sample size (median 401 vs 604, P=.047), were less likely to evaluate experimental cytotoxic chemotherapy or endocrine therapy than targeted therapy (0% vs 10%, P=.004), and were less often randomized (60% vs 84%; P=.009) or double-blind (15% vs 46%, P=.001). A similar proportion of trials supporting breakthrough and non-breakthrough drugs approved for palliative intent showed substantial clinical benefit using ESMO-MCBS v1.1 (36% vs 29%; P=.45). There were too few trials performed with curative intent (n = 10) to perform statistical testing.


Compared to non-breakthrough drugs, trials of breakthrough drugs are smaller and more likely to be single-arm and not double-blinded. A similarly low proportion of breakthrough and non-breakthrough cancer drugs met the standard of substantial clinical benefit as applied in ESMO-MCBS v1.1.

Clinical trial identification

Legal entity responsible for the study

Hospital de la Santa Creu i Sant Pau.


Has not received any funding.

Editorial Acknowledgement


All authors have declared no conflicts of interest.

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