Outcome measures for clinical trials in alzheimer's disease: A review on some open issues

Abstract

The methodological discussion which paralleled the long and problematic evolution of tacrine studies ended up in the “Guidelines for the clinical evaluation of antidementia drugs” of the Food and Drug Administration (FDA). To document an antidementia claim, the specific assessment required by the agency is essentially based on a dual outcome assessment strategy: “a performance based objective test instrument providing a comprehensive assessment of cognitive functions” and “a global assessment performed by a skilled clinician” providing a measure of a clinically meaningful effect. After tacrine approval, the “tacrine like study” became almost a must, establishing a kind of orthodoxy. Surely this strategy was a great step forward: beyond the merit of putting research on a rational basis and simplifying it, it had the power to rule out all those trial designs based on aspecific outcomes that populated the literature until then and through which it was possible to demonstrate any kind of pharmacological activity without any predictive value on therapeutic efficacy. But there are also weak points, some probably improvable while others are still subject to discussion in the international harmonization process to arrive at a largely shared consensus. The way the key point of clinical relevance has been addressed, is far from convincing and remains the crucial knot to untangle.