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Review
November 11, 2019

US Food and Drug Administration Recommendations on the Use of Surrogate Measures as End Points in New Anti-infective Drug Approvals

Author Affiliations
  • 1Program on Regulation, Therapeutics, and Law, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 2Harvard Center for Bioethics, Harvard Medical School, Boston, Massachusetts
  • 3Harvard Faculty of Arts and Sciences, Cambridge, Massachusetts
  • 4Division of Infectious Diseases, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
  • 5Department of Medicine, George Washington University School of Medicine, Rockville, Maryland
JAMA Intern Med. 2020;180(1):131-138. doi:10.1001/jamainternmed.2019.5451
Key Points

Question  What primary end points do US Food and Drug Administration guidance documents recommend for pivotal clinical trials of new anti-infective drugs?

Findings  In this systematic review, 21 of 27 guidance documents for anti-infective drug approvals recommended indirect outcomes, such as change in microbial culture status, rather than clinical outcomes, such as symptom resolution or survival, as primary end points. None of the recommendations for use of indirect measures matched the regulatory and scientific conditions favoring indirect outcomes in place of clinical outcomes.

Meaning  Existing guidance documents for anti-infective drug approvals should be updated and revised to recommend appropriate clinical outcomes consistent with general scientific and regulatory parameters.

Abstract

Importance  Regulatory and scientific guidelines stipulate that indirect, surrogate measures of patient benefit, such as a change in microbial culture status, should be used as primary end points only in pivotal trials of chronic conditions that are serious or life threatening and when the experimental therapy is expected to offer substantial benefit compared with available therapy. However, many recent US Food and Drug Administration (FDA) anti-infective drug approvals for acute and/or non–life-threatening diseases have been based on pivotal trials using surrogate measures as primary end points rather than clinical outcomes, such as symptom resolution or survival.

Objectives  To review FDA recommendations for primary end points in pivotal trials of new anti-infective drugs and assess the concordance of those recommendations with the regulatory and scientific conditions for the appropriate use of surrogate measures as primary trial outcomes.

Evidence Review  All guidance documents for antimicrobial drug development hosted on the FDA website were searched in November 2017; the search was updated in June 2018. For each document, 2 reviewers independently extracted data on the recommended primary end points for a pivotal or phase 3 trial.

Findings  Twenty-two FDA guidance documents met the inclusion criteria, which included recommendations for primary end points in pivotal clinical trials in 27 infectious disease indications. Twenty-one of 27 indications recommended surrogate outcomes as either the sole primary end point or as components of composite end points. None of the recommendations for the use of surrogate measures matched the regulatory and scientific conditions favoring indirect outcomes in place of clinical outcomes.

Conclusions and Relevance  The FDA guidance documents for developing new anti-infective agents frequently recommend indirect measures of patient benefit, rather than direct measures of patient benefit, as sole primary end points or components of primary end points. Existing guidance documents should be updated and revised to recommend appropriate clinical outcomes consistent with general scientific and regulatory parameters.

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