Advertisement

European Journal of Clinical Pharmacology

, Volume 43, Issue 3, pp 235–244 | Cite as

Surrogate endpoints: A basis for a rational approach

  • J. -P. Boissel
  • J. -P. Collet
  • P. Moleur
  • M. Haugh
Originals

Summary

In clinical trials, the clinical endpoint is often replaced by an intermediate endpoint, known in some instances as a “surrogate” endpoint. The reasons for the substitution are often both practical and financial. At present, no theoretical basis or practical guidelines exist to help in the choice of surrogate endpoints.

An approach is proposed here, based on three provisos which can be verified using one of a series of equations, if sufficient data on the pathophysiology and epidemiology of the disease are available. It is shown that even a strong statistical correlation is not a sufficient criterion for the definition of a surrogate endpoint.

It is apparent that results obtained with the commonly used “surrogate” endpoints should be cautiously considered and that the assessment of treatments should, when possible, be based on clinical rather than intermediate endpoints.

Key words

Surrogate endpoints Clinical trials risk/benefiratio assessment 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Friedman L, Furberg CD, DeMets DL (1984) Fundamentals of clinical trials, 2nd edn. PSG Publishing, LittletonGoogle Scholar
  2. 2.
    Moleur P, Boissel JP (1987) Definition of a surrogate endpoint. Controlled Clinical Trials 8: 304Google Scholar
  3. 3.
    Herson J (1989) The use of surrogate endpoints in clinical trials (an introduction to a series of four papers). Stat Med 8: 403–404Google Scholar
  4. 4.
    Ellenberg SS, Hamilton JM (1989) Surrogate endpoints in clinical trials: cancer. Stat Med 8: 405–413PubMedGoogle Scholar
  5. 5.
    Wittes J, Lakatos L, Probstfield J (1989) Surrogate endpoints in clinical trials: cardiovascular diseases. Stat Med 8: 415–425PubMedGoogle Scholar
  6. 6.
    Hillis A, Seigel D (1989) Surrogate endpoints in clinical trials: ophthalmologic disorders. Stat Med 8: 427–430PubMedGoogle Scholar
  7. 7.
    Ruskin JN (1989) Editorial: the Cardiac Arrhythmia Suppression Trial. New Engl J Med 321: 386–388PubMedGoogle Scholar
  8. 8.
    Winkle RA (1980) Detection of patients at high risk for sudden death: the role of electrocardiographic monitoring. In: Kulbertus HE, Wellens HJJ (eds) Sudden death. Martinus Nijhof, The HagueGoogle Scholar
  9. 9.
    The CAST investigators (1989) Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. New Engl J Med 321: 406–412Google Scholar
  10. 10.
    Kannel WB, Gordon T, Schwartz MJ (1971) Systolic versus diastolic blood pressure and risk of coronary heart disease. The Framingham study. Am J Cardiol 27: 335–346CrossRefPubMedGoogle Scholar
  11. 11.
    Pooling Project Research Group (1978) Relationship of blood pressure, serum cholesterol, smoking habit, relative weight and ECG abnormalities to incidence of major coronary events: final report of the Pooling Project. J Chron Dis 31: 201–306Google Scholar
  12. 12.
    MacMahon S, Petro R, Cutler J, Collins R, Sorlie P, Neaton J, Abbott R, Godwin J, Dyer A, Stamler J (1990) Blood pressure, stroke, and coronary heart disease. Part 1. prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 335: 765–774CrossRefPubMedGoogle Scholar
  13. 13.
    Boissel JP, Gueyffier F (1990) High blood pressure and clinical events linked with atherosclerosis. In: Atkinson J, Capdeville C, Zannad F (eds) Coronary and cerebrovascular effects of antihypertensive drugs. Transmedico Europe Ltd, UK, p 240–252Google Scholar
  14. 14.
    Collins R, Peto R, MacMahon S, Hebert P, Fiebach NH, Eberlein KA, Godwin J, Qizilbash N, Taylor JO, Hennekens CH (1990) Blood pressure, stroke, and coronary heart disease. Part 2. short term reductions in blood pressure: overview of randomized drug trials in epidemiological context. Lancet 335: 827–838PubMedGoogle Scholar
  15. 15.
    Okamoto K, Yamori Y, Nagaoka A (1974) Establishment of the stroke-prone spontaneously hypertensive rat (SHR). Circ Res 34: 1143–1153Google Scholar
  16. 16.
    Lievre M, Leizorovicz A, Boissel JP (1991) Critères intermé diaires et critères de substitution dans le développement des antiarytbmiques. Arch Mal Coeur 84: 27–33PubMedGoogle Scholar
  17. 17.
    Hine LK, Laird NM, Hewitt P, Chalmers TC (1989) Meta analysis of empirical antiarrhythmic therapy after myocardial infarction. J Am Med Assoc 262: 3037–3040CrossRefGoogle Scholar
  18. 18.
    Slater W, Lampert S, Podrid J, Lown B (1988) Clinical predictors of arrhythmia worsening by antiarrhythmic drugs. Am J Cardiol 61: 349–353CrossRefPubMedGoogle Scholar
  19. 19.
    Prentice RL (1989) Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med 8: 431–440PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • J. -P. Boissel
    • 1
  • J. -P. Collet
    • 1
  • P. Moleur
    • 1
  • M. Haugh
    • 1
  1. 1.Unité de Pharmacologie CliniqueHôpital NeurocardiologiqueLyon Cedex 03France

Personalised recommendations