Obiettivi dello studio e outcomes Outcomes (o end-points)

E
Evidence
 prior knowledge
T
Type of study
 efficacy vs equivalence
Obiettivi dello studio e outcomes
o end-points (= risultato finale, ultimo
fine, fine/scopo/obiettivo)
CLINICAL EPIDEMIOLOGY: HOW TO DO CLINICAL PRACTICE RESEARCH (3rd Edition). RB Haynes, DL Sackett, GH Guyatt & P Tugwell. Philadelphia:
Lippincott Williams & Wilkins, 2005. ISBN 0-7817-4524-1.
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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


Durata di sopravvivenza

R idi
Recidive
Durata di sopravvivenza senza
recidiva

Risposta alla terapia

Comparsa di nuovi casi di
malattia

Miglioramento di un parametro
clinico misurabile
 Effect size






Proporzione di sopravviventi (survival
rate)
Tasso di mortalità
Curve e probabilità di sopravvivenza
Proporzione di recidive
Curve di sopravvivenza prima della
recidiva
Proporzione di risposta
Incidenza
1

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
ifi condition.
diti
 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.
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Scelta degli endpoints
 Pertinenza
 Validità (accuratezza…)
 Precisione (affidiabilità,
 Gerarchia
ripetibilità…)
 Molteplicità
 Surrogazione
 Endpoint primario
 Endpoints secondari
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Endpoints - Gerarchia
Endpoints - Gerarchia
 Ranking
according to importance to
patient (based on utilities)
• I-Death
• II-Critical
• III-Major
• IV-Moderate
• V-Minor
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2
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
i d with
i h smaller
ll treatment effects
ff
than
h iimportant ones””
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

 Implicazioni quando si usano endpoint combinati

Interpretazione fuorviante dell’effetto della terapia
quando c’è eterogeneità tra componenti
 In
 In
base a importanza per il paziente
base a entità dell’effetto



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
p g
il ruolo dei singoli
g componenti,
p
,
necessario programmare dimensione
campionaria adeguata
 Non sempre possibile
 Endpoints secondari (esplorativi)
Bhatt D
DL. NEJM
2006;35
54:1706
Per bassa frequenza
degli endpoint CV
3
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

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
Incluso nella sequenza causale esposizione  endpoint
intermedio  endpoint finale
 Es: Ipertensione (condizione patologica)  Pressione
arteriosa  ictus
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
Endpoints – Surrogazione (esempi)
 HIV/AIDS


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
Endpoints – Surrogazione (cont)
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
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di: sopravvivenza del paziente con
[reverse causation or causal relationship?]
neoplasia
4
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)
HIV Vaccine Efficacy Trial Endpoints
 Domande:
Qual’è la proporzione di effetto del trattamento
sull’endpoint finale spiegata dall’endpoint
intermedio)
 L’effetto del trattamento sull’endpoint
p
intermedio e
sull’endpoint finale è di grandezza comparabile?
 La relazione tra endpoint intermedio e finale è
sostanziale?

Uninfected/
Seronegative
Infected/
Seropositive
 L’evidenza deriva da
Studi epidemiologici
 Studi clinici controllati precedenti / metanalisi

Ideal treatment, surrogate and clinical
outcome relationships
+
Treatment
Z
S
Infection
+
Clinical
Outcome
T
Morbidity/
Mortality
Treatment
Initiation
Mid-term Endpoints:
- Composite (VL, tmt init)
- Biomarker trajectories (VL, CD4)
Problems in Surrogate
Endpoint: Example in HIV
1. Treatments are chosen
based on their anticipated
effect on CD4 count
Surrogate
Marker
Long-term Endpoints:
- vaccine/tmt effects
- CD4
- Morbidity/Mortality
Short-term Endpoints:
- Pre-ART VL
AZT
vs
control
CD4
Lymphocyte
Count
2. Surrogate marker may be
strongly predictive of
the clinical outcome
AIDS
Event or
Death
o
+ positive effect
- negative effect
o no effect
Other Biological
Processes
3. Treatments may
also affect other
biological processes
Other Biological
Processes Affecting
Prognosis
4. Clinical outcome
may be affected
by other biological
processes
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Example in HIV
Example in HIV
False Positive Case
1. Treatments are chosen
based on their anticipated
effect on CD4 count
AZT
vs
control
+
CD4
Lymphocyte
Count
False Negative Case
2. Surrogate marker may be
strongly predictive of
the clinical outcome
Treatment
Effect Cancelled
+
3. Treatments may
also affect other
biological processes
AIDS
Event or
Death
+
Other Biological
Processes Affecting
Prognosis
1. Treatments are chosen
based on their anticipated
effect on CD4 count
AZT
vs
control
3. Treatments may
also affect other
biological processes
AIDS
Event or
Death
o
+
4. Clinical outcome
may be affected
by other biological
processes
CD4
Lymphocyte
Count
2. Surrogate marker may be
strongly predictive of
the clinical outcome
Treatment effect
Not detected
Other Biological
Processes Affecting
Prognosis
+
4. Clinical outcome
may be affected
by other biological
processes
Endpoint
surrogato/
intermedio
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Esempio
The central hypothesis was that the selected outcomes would not differ between the patients of
nurse practitioners and physicians.
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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
y a research nurse
by
 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.
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