Intended for healthcare professionals


Raising the bar for using surrogate endpoints in drug regulation and health technology assessment

BMJ 2021; 374 doi: (Published 16 September 2021) Cite this as: BMJ 2021;374:n2191

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Should regulatory authorities approve drugs based on surrogate endpoints?

  1. Dalia Dawoud, senior scientific adviser1,
  2. Huseyin Naci, associate professor of health policy2,
  3. Oriana Ciani, associate professor of practice34,
  4. Sylwia Bujkiewicz, professor of biostatistics5
  1. 1Science, Evidence and Analytics Directorate, Science Policy and Research Programme, National Institute for Health and Care Excellence, London, UK
  2. 2Department of Health Policy, London School of Economics and Political Science, London, UK
  3. 3Centre for Research on Health and Social Care Management, SDA Bocconi, Milan, Italy
  4. 4College of Medicine and Health, University of Exeter, Exeter, UK
  5. 5Biostatistics Research Group, Department of Health Sciences, University of Leicester, Leicester, UK
  1. Correspondence to: H Naci H.Naci{at}

Surrogate endpoints provide no guarantee of clinical benefit, and Dalia Dawoud and colleagues argue they should be used only as a last resort in drug trials

In June 2021, the US Food and Drug Administration granted accelerated approval to aducanumab for treating Alzheimer’s disease based on the drug’s amyloid reducing effects. This was despite evidence from several earlier studies that shrinkage of β-amyloid protein plaques does not predictably delay cognitive impairment.1 The controversial decision has drawn attention to the use of surrogate endpoints—laboratory values, radiographic images, or other physical measures that may serve as indicators of clinical outcomes such as symptom control or mortality—in clinical trials of new drugs.2 In fact, the approval of aducanumab is only the latest example of growing regulatory reliance on surrogate endpoints, even though their use can cause problems for patients, clinicians, drug regulators, and health technology assessment bodies.

We argue for more selective use of surrogate endpoints when evaluating new drugs, restricting their use to chronic diseases, especially when collecting data on patient relevant clinical outcomes requires trials with unattainably long follow up.

The problem with surrogates

Using surrogate endpoints to measure whether a new drug works can reduce the duration, cost, and complexity of clinical trials before regulatory assessment and facilitate faster patient access to new therapies, especially for chronic diseases.3 For example, in early stage gastric cancer, clinical outcomes such as overall survival—how long patients live after receiving treatment—are of primary interest to patients, but surrogate endpoints such as disease-free survival can potentially provide earlier indications of a drug’s effect.4 In a recent evaluation, using surrogate endpoints in cancer drug trials reduced clinical development time by about 11 months compared with measuring overall survival.3 However, the use of such endpoints can also have negative implications.

Regulatory reliance on surrogate endpoints makes …

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