Analysis

Interpretation of surrogate endpoints in the era of the 21st Century Cures Act

BMJ 2016; 355 doi: https://doi.org/10.1136/bmj.i6286 (Published 30 December 2016) Cite this as: BMJ 2016;355:i6286
  1. Kevin Knopf, director of communications for explanatory analytics division1,
  2. Michael Baum, visiting professor of medical humanities2,
  3. William S Shimp, consultant1,
  4. Charles L Bennett, SmartState chair for medication safety and efficacy3,
  5. Dinah Faith, director of advanced analytics1,
  6. Marc L Fishman, founder and chief executive1,
  7. William J M Hrushesky, chief medical officer4
  1. 1Oncology Analytics, Plantation, Florida, USA
  2. 2University College London, London NW11 7ED, UK
  3. 3University of South Carolina College of Pharmacy and Hollings Cancer Center of the Medical University of South Carolina, Columbia and Charleston, South Carolina, USA
  4. 4Ambulatory Monitoring, Ardsley, New York, USA
  1. Correspondence to: M Baum baum.michael3{at}gmail.com

Surrogate endpoints are commonly used in clinical trials to get quicker results, butKevin Knopf and colleaguesshow how they can lead to both medical and financial harm

The rationale behind medical practice distils to three principles: maintaining health (wellbeing), improving quality of life, and extending length of life. For patients with incurable cancer, quality and length of life are of prime importance and should therefore be the primary outcome measures in all randomised clinical trials of innovative treatments. All other measures are surrogates that do not always translate into improvements in prime outcomes. This concern will only increase as the 21st Century Cures Act is implemented in the United States.

Intersections of efficacy, toxicity, and cost

Although surrogates may be used for legitimate reasons—such as aborting a trial if surrogates point in the wrong direction—they are often used to replace higher order measures to fast track “promising” new (expensive) interventions into clinical practice. The US Food and Drug Administration could already approve drugs with statistically significant outcomes even if life extension was less than six weeks, allowing new agents to enter clinical practice, whatever the price.1 2 With the enactment of the 21st Century Cure Act in 2017, the bar has been changed and the FDA will consider evidence from weaker clinical trial designs and testimonials from patients and families in approval decisions.3 Additionally, FDA approved drugs, particularly for cancer, are often used in off-label settings, where clinical outcomes are untested and financial toxicities abound.4 5 6 With new cancer drugs often costing over $10 000 (£8000; €9000) a month, the finances become unsustainable.

At best, even significant improvements in cancer specific mortality might be abrogated by deaths related to toxicities of treatment, with quality of remaining life impaired by physical, psychological, and financial burden.7 8 At worst, the 21st Century Cures …

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