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Balancing Accelerated Approval for Drugs With Accelerated Withdrawal—Reply

Balancing Accelerated Approval for Drugs With Accelerated Withdrawal—Reply In Reply We thank Drs Braillon and Menkes for their letter. Indeed, in our investigation we found that the majority of new cancer drug approvals are made on the basis of a surrogate.1 Surrogate end points were used both in cases of accelerated (or provisional) approvals, as well as in cases of traditional (or regular) approvals. The use of surrogates in the context of traditional approvals is particularly troubling because, practically speaking, marketing authorization is unlikely to be revoked if efficacy on the patient centered outcomes (ie, survival or quality of life) is subsequently not demonstrated. We believe that all cancer drugs approved on the basis of a surrogate should have postmarketing commitments to establish efficacy against patient-centered outcomes. For this reason, we would advise caution with the use of surrogates to support traditional approval. For instance, everolimus was approved for metastatic breast cancer in combination with exemestane based on a prolongation of progression-free survival, but it later became clear the drug does not improve overall survival.2 Yet, because it received traditional approval, it appears unlikely that approval will be revoked. The repeated failure of everolimus to improve survival for at least 3 cancer indications is the subject of a recent piece of investigative journalism.3 Drs Braillon and Menkes are correct. If we want to benefit from the rapid approval of drugs in dire settings with few treatment options based on improvements in surrogate end points, we must ensure that drugs that subsequently do not work are rapidly removed from the market. A 2015 Government Accountability Office report provides more evidence that the US Food and Drug Administration (FDA) has failed to enforce this standard.4 We urge the FDA to set concrete postmarketing standards and enforce them without fail. Back to top Article Information Corresponding Author: Vinay Prasad, MD, MPH, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239 (prasad@ohsu.edu). Conflict of Interest Disclosures: None reported. References 1. Kim C, Prasad V. Cancer drugs approved on the basis of a surrogate end point and subsequent overall survival: an analysis of 5 years of US Food and Drug Administration approvals. JAMA Intern Med. 2015;175(12):1992-1994.PubMedGoogle ScholarCrossref 2. Piccart M, Hortobagyi GN, Campone M, et al. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2. Ann Oncol. 2014;25(12):2357-2362.PubMedGoogle ScholarCrossref 3. Fauber J. FDA repeatedly approved cancer drug Afinitor without proof it extended life. Journal Sentinel. December 12, 2015. http://www.jsonline.com/watchdog/watchdogreports/fda-repeatedly-approved-cancer-drug-afinitor-without-proof-it-extended-life-b99628814z1-361607291.html. Accessed January 18, 2016. 4. United States Government Accountability Office. FDA Expedites Many Applications, But Data for Postapproval Oversight Need Improvement. 2015. http://www.gao.gov/assets/680/674183.pdf. Accessed February 4, 2016. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Internal Medicine American Medical Association

Balancing Accelerated Approval for Drugs With Accelerated Withdrawal—Reply

JAMA Internal Medicine , Volume 176 (4) – Apr 1, 2016

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Publisher
American Medical Association
Copyright
Copyright © 2016 American Medical Association. All Rights Reserved.
ISSN
2168-6106
eISSN
2168-6114
DOI
10.1001/jamainternmed.2016.0374
Publisher site
See Article on Publisher Site

Abstract

In Reply We thank Drs Braillon and Menkes for their letter. Indeed, in our investigation we found that the majority of new cancer drug approvals are made on the basis of a surrogate.1 Surrogate end points were used both in cases of accelerated (or provisional) approvals, as well as in cases of traditional (or regular) approvals. The use of surrogates in the context of traditional approvals is particularly troubling because, practically speaking, marketing authorization is unlikely to be revoked if efficacy on the patient centered outcomes (ie, survival or quality of life) is subsequently not demonstrated. We believe that all cancer drugs approved on the basis of a surrogate should have postmarketing commitments to establish efficacy against patient-centered outcomes. For this reason, we would advise caution with the use of surrogates to support traditional approval. For instance, everolimus was approved for metastatic breast cancer in combination with exemestane based on a prolongation of progression-free survival, but it later became clear the drug does not improve overall survival.2 Yet, because it received traditional approval, it appears unlikely that approval will be revoked. The repeated failure of everolimus to improve survival for at least 3 cancer indications is the subject of a recent piece of investigative journalism.3 Drs Braillon and Menkes are correct. If we want to benefit from the rapid approval of drugs in dire settings with few treatment options based on improvements in surrogate end points, we must ensure that drugs that subsequently do not work are rapidly removed from the market. A 2015 Government Accountability Office report provides more evidence that the US Food and Drug Administration (FDA) has failed to enforce this standard.4 We urge the FDA to set concrete postmarketing standards and enforce them without fail. Back to top Article Information Corresponding Author: Vinay Prasad, MD, MPH, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239 (prasad@ohsu.edu). Conflict of Interest Disclosures: None reported. References 1. Kim C, Prasad V. Cancer drugs approved on the basis of a surrogate end point and subsequent overall survival: an analysis of 5 years of US Food and Drug Administration approvals. JAMA Intern Med. 2015;175(12):1992-1994.PubMedGoogle ScholarCrossref 2. Piccart M, Hortobagyi GN, Campone M, et al. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2. Ann Oncol. 2014;25(12):2357-2362.PubMedGoogle ScholarCrossref 3. Fauber J. FDA repeatedly approved cancer drug Afinitor without proof it extended life. Journal Sentinel. December 12, 2015. http://www.jsonline.com/watchdog/watchdogreports/fda-repeatedly-approved-cancer-drug-afinitor-without-proof-it-extended-life-b99628814z1-361607291.html. Accessed January 18, 2016. 4. United States Government Accountability Office. FDA Expedites Many Applications, But Data for Postapproval Oversight Need Improvement. 2015. http://www.gao.gov/assets/680/674183.pdf. Accessed February 4, 2016.

Journal

JAMA Internal MedicineAmerican Medical Association

Published: Apr 1, 2016

References