Obiettivi dello studio e outcomes. Outcomes (o end-points) o end-points (= risultato finale, ultimo fine, fine/scopo/obiettivo)

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1 E Evidence prior knowledge Obiettivi dello studio e outcomes o end-points (= risultato finale, ultimo fine, fine/scopo/obiettivo) T Type of study efficacy vs equivalence 1 CLINICAL EPIDEMIOLOGY: HOW TO DO CLINICAL PRACTICE RESEARCH (3rd Edition). RB Haynes, DL Sackett, GH Guyatt & P Tugwell. Philadelphia: Lippincott Williams & Wilkins, ISBN Outcomes (o end-points) Alexander M Clark, et al BMJ 2012 Scelgo la misura specifica per riassumere l obiettivo clinico principale (uno solo) La misura di outcome principale sarà la variazione media dell ematocrito dopo trattamento Scelgo la misura specifica per riassumere gli obiettivi clinici secondari (uno o più) altri endpoints analisi per sottogruppi ESEMPI DI OUTCOMES (end points) Individuali Dello studio Morte Proporzione di sopravviventi (survival rate) Durata di sopravvivenza Recidive Tasso di mortalità Curve e probabilità di sopravvivenza Durata di sopravvivenza senza Proporzione di recidive recidiva Curve di sopravvivenza prima della Risposta alla terapia recidiva Comparsa di nuovi casi di Proporzione di risposta malattia Incidenza Miglioramento di un parametro clinico misurabile Effect size 1

2 development and application of agreed standardised sets of outcomes, known as a core outcome set. represent the minimum that should be measured and reported in all clinical trials, audits of practice or other forms of research for a specific condition. They do not imply that outcomes in a particular study should be restricted to those in the core outcome set. Rather, there is an expectation that the core outcomes will be collected and reported to allow the results of trials and other studies to be compared, contrasted and combined as appropriate; and that researchers will continue to collect and explore other outcomes as well. 7 Scelta degli endpoints Gerarchia Molteplicità Surrogazione Pertinenza Validità (accuratezza ) Precisione (affidiabilità, ripetibilità ) 9 Endpoint primario Endpoints secondari Endpoints - Gerarchia Endpoints - Gerarchia Ranking according to importance to patient (based on utilities) I-Death II-Critical II-Critical III-Major IV-Moderate V-Minor 11 2

3 Problems with use of composite end points in cardiovascular trials: systematic review of randomised controlled trials Ferreira-Gonzalez I, et al.. BMJ 2007;334(7597):786. Endpoints - Gerarchia (cont) Ferreira-Gonzalez I, et al. Problems with use of composite end points in cardiovascular trials: systematic review of randomised controlled trials. BMJ 2007;334(7597):786. The most important components were associated with lower event rates in the control group Components of greater importance to patients were associated with smaller treatment effects than important ones Implicazioni quando si usano endpoint combinati Interpretazione fuorviante dell effetto della terapia quando c è eterogeneità tra componenti In base a importanza per il paziente In base a entità dell effetto Endpoints - Molteplicità La molteplicità degli endpoints aumenta il tasso falsi positivi (l errore di I tipo) Endpoint spesso correlati tra loro e costituiti da una mistura di variabili di tipo diverso (continue, binarie, tempo di sopravvivenza, etc) Soluzioni statistiche Singola misura di outcome (es: all-cause mortality vs cancer specific mortality; patient-and-graft survival vs graft loss) Errore di I tipo suddiviso tra endpoints Endpoint combinato Quando il tasso di eventi per gli endpoints hard è basso (es: ictus + infarto) Analisi del tempo al primo evento aumenta (in genere) la potenza dello studio Altro Endpoints Molteplicità (cont) Endpoints combinati I risultati si applicano al gruppo di eventi in toto e non alle componenti individuali Per spiegare il ruolo dei singoli componenti, necessario programmare dimensione campionaria adeguata Non sempre possibile Endpoints secondari (esplorativi) Bhatt DL. NEJM 2006;35 54:1706 Per bassa frequenza degli endpoint CV 3

4 Endpoints Surrogazione Endpoint intermedio (surrogato): variabile che fornisce una misura indiretta dell effetto, in situazioni per cui è difficile/non praticabile/troppo costoso misurare l endpoint finale tempi di follow-up lunghi bassi tassi di eventi elevate numerosità campionarie variabile di risposta che è biologicamente e statisticamente correlata con l outcome clinico finale Incluso nella sequenza causale esposizione endpoint intermedio endpoint finale Es: Ipertensione (condizione patologica) Pressione arteriosa ictus How can we assess the validity of a potential surrogate marker? A strong biological rationale The marker value at a given time is strongly predictive of ultimate survival The effect of treatment on the surrogate endpoint will reliably predict the effect of treatment on survival Introduction to Surrogate Endpoint Why do we use surrogate endpoint? Can be measured earlier Convenient or less invasive Can be measured more frequently Can accelerate the approval process Advantages: May reduce the size of clinical trials May shorten the duration of clinical trials May reduce the cost of clinical trials When is the use of surrogate endpoints justified? Screening For promising new therapies Evaluation of biological activity in phase I/II trials Caution in using surrogate endpoints: Using biological markers as a surrogate endpoint, one may obtain misleading false positive or false negative conclusion when assessing treatment effects of longer term clinical outcome Requirements: Before a surrogate endpoint can replace a primary endpoint, it must be formally validated 23 Endpoints Surrogazione (esempi) HIV/AIDS Aumento della conta delle cellule CD$+ Riduzione viremia plasmatica di HIV Surrogati di: sopravvivenza Cardiologia Scomparsa di aritmie ventricolari Incremento frazione di eiezione Surrogati di: sopravvivenza post-ima Oncologia Regressione del tumore Surrogati di: sopravvivenza del paziente con neoplasia Endpoints Surrogazione (cont) [reverse causation or causal relationship?] 4

5 Endpoints inappropriately characterized as surrogates Quality of life It is an outcome measure (not a surrogate endpoint) Morbidity scale It is a clinical benefit endpoint (not a surrogate endpoint) Endpoints Surrogazione (cont) Domande: Qual è la proporzione di effetto del trattamento sull endpoint finale spiegata dall endpoint intermedio) L effetto del trattamento sull endpoint intermedio e sull endpoint finale è di grandezza comparabile? La relazione tra endpoint intermedio e finale è sostanziale? L evidenza deriva da Studi epidemiologici Studi clinici controllati precedenti / metanalisi HIV Vaccine Efficacy Trial Endpoints Uninfected/ Seronegative Short-term Endpoints: - Pre-ART VL Infected/ Seropositive Infection Treatment Initiation Long-term Endpoints: - vaccine/tmt effects - CD4 - Morbidity/Mortality Mid-term Endpoints: - Composite (VL, tmt init) - Biomarker trajectories (VL, CD4) Morbidity/ Mortality Ideal treatment, surrogate and clinical outcome relationships Problems in Surrogate Endpoint: Example in HIV Treatment Z + positive effect - negative effect o no effect o Surrogate Marker S + + Processes Clinical Outcome T 1. Treatments are chosen based on their anticipated effect on CD4 count AZT vs control 3. Treatments may also affect other biological processes CD4 Lymphocyte Count Processes Affecting Prognosis 2. Surrogate marker may be strongly predictive of the clinical outcome AIDS Event or Death 4. Clinical outcome may be affected by other biological processes 5

6 Example in HIV False Positive Case Example in HIV False Negative Case 1. Treatments are chosen based on their anticipated effect on CD4 count AZT vs control 3. Treatments may also affect other biological processes + CD4 Lymphocyte Count + + Treatment Effect Cancelled Processes Affecting Prognosis 2. Surrogate marker may be strongly predictive of the clinical outcome - AIDS Event or Death 4. Clinical outcome may be affected by other biological processes 1. Treatments are chosen based on their anticipated effect on CD4 count AZT vs control 3. Treatments may also affect other biological processes + o CD4 Lymphocyte Count Treatment effect Not detected Processes Affecting Prognosis 2. Surrogate marker may be strongly predictive of the clinical outcome + AIDS Event or Death 4. Clinical outcome may be affected by other biological processes Endpoint surrogato/ intermedio 33 Esempio The central hypothesis was that the selected outcomes would not differ between the patients of nurse practitioners and physicians. 6

7 Esempio Health status: SF-36 Patient satisfaction: "provider-specific" items from a 15-item satisfaction questionnaire used in the Medical Outcomes Study. Physiologic measures: disease-specific clinical measurements taken by a research nurse Blood pressure for patients with hypertension peak flow for those with asthma glycosylated hemoglobin for those with diabetes. Utilization data: hospitalizations, emergency department visits, urgent care center visits, visits to specialists, and primary care visits within the Columbia Presbyterian Medical Center system. Only visits with a nurse practitioner or physician at a primary care site were counted as primary care. Specialty visits were defined as visits to a medical specialty clinic or specialist physician office. Emergency department and urgent care center visits were combined before analysis. 7