On Clinically Relevant Differences and Shifted Nullhypotheses ^[*]

Summary

The currently usual one value for the judgement of the clinical relevance of therapeutic effects frequently does not suffice to adequately formulate the problems of clinical studies, and the statistical standard procedure (the testing of the classical nullhypothesis) fails to take this value duly into account.

Therefore, it is proposed to judge the clinical relevance and importance by means of four values, fixed in discussions with the clinician before commencement of the study, and to proceed by testing non-zero nullhypotheses (shifted nullhypotheses) where the “clinically relevant difference” is the shift parameter.

Methodical problems resulting from the shifting of the nullhypothesis are discussed, and other possibilities to take into account the clinically relevant difference (introduction of criteria of success) are considered.

Die derzeit übliche eine Größe zur Wertung der klinischen Relevanz von Therapieeffekten reicht zur sachgerechten Problembeschreibung in Therapiestudien oft nicht aus und wird durch das statistische Standardvorgehen (Test der klassischen Nullhypothese) nicht problemadäquat berücksichtigt. Deshalb wird vorgeschlagen, die klinische Relevanz und Bedeutung anhand von vier in Diskussionen mit dem Kliniker vor Studienbeginn festzulegenden Größen zu beurteilen und verschobene Nullhypothesen zu testen, in die die “klinisch relevante Differenz” als Verschiebungsparameter eingeht. Methodische Probleme, die sich aus der Verschiebung der Nullhypothese ergeben, werden aufgezeigt und andere Möglichkeiten zur Berücksichtigung der klinisch relevanten Differenz (Konstruktion von Erfolgskriterien) diskutiert.

Key-Words

Clinical Trials - Clinically Relevant Difference - Shifted Nullhypothesis - Effect and Efficacy

Schlüssel-Wörter

Therapiestudien - klinisch relevante Differenz - verschobene Nullhypothese - Wirkung und Wirksamkeit

^* Dedicated to the memory of Prof. Edward Walter

• REFERENCES

• 1 Dunnett C. W, Gent M. Significance testing to establish equivalence between treatments, with special reference of data in the form of 2 x 2 tables. Biometrics 1977; 33: 593-602.
• 2 Freedman L. S, Lowe D, Macaskill P. C. Stopping rules for clinical trials incorporating clinical opinion. Biometrics 1984; 40: 575-586.
• 3 Gart J. J. The comparison of proportions: A review of significance tests, confidence intervals and adjustment for stratification. Rev. Internat. Statist. Inst 1971; 39: 148-169.
• 4 Kirkwood T. B. L. Bioequivalence testing – A need to rethink. With response from W. J. Westlake and a note by the editor. Biometrics 1981; 37: 589-594.
• 5 Mandallaz D, Mau J. Comparison of different methods for decision making in bioequivalence assessment. Biometrics 1981; 37: 213-222.
• 6 Mau J. A statistical assessment of clinical equivalence. Tech. Rep. No. 4/86, SFB 175 University of Tübingen; 1986
• 7 Mehta C. R, Patel N. R, Tsiatis A. A. Exact significance testing to establish treatment equivalence with ordered categorical data. Biometrics 1984; 40: 819-825.
• 8 Moussa M. A. A. Clinical trial size: Fixed versus group-sequential designs. Meth. Inform. Med 1986; 25: 233-236.
• 9 Nurminen M. Confidence intervals for the ratio and difference of two binomial proportions (Letter to the Editor). Biometrics 1986; 42: 675-676.
• 10 Schwartz D, Flamant R, Lellouch J. L’essai Thérapeutique chez l’Homme.. Paris: Flammarion; 1970
• 11 Spiegelhalter D. J, Freedman L. S. A predictive approach to selecting the size of a clinical trial, based on subjective clinical opinion. Statist. Med 1986; 5: 1-13.
• 12 Westlake W. J. Use of confidence intervals in analysis of comparative bioavailability trials. J. Pharm. Sci 1972; 61: 1390-1391.
• 13 Westlake W. J. Symmetrical confidence intervals for bioequivalence trials. Biometrics 1976; 32: 741-744.