HISTORY OF "CLINICAL TRIALS“ - 1 1Treatment of yellow fever by bleeding, RUSH, 1794, 1794

“I began to extract a small amount of blood each time. The appearance of the blood and the effect of the intervention made me satisfied on the safety and efficacy of treatment ....... I have never experienced a similar feeling of sublime joy when I was able to contemplate the success of my remedy ..... Thank God, the more than 100 patients that I treated personally or to which I have commanded my attention that day, I have not lost even one "Rush B. An account of the bilious remitting yellow fever as it appeared in the city of Philadelphia in 1793. Philadelphia, Dobson, 1794

HISTORY OF "CLINICAL TRIALS“ - 2 Louis P.C.A. (1835)

Analysis of treatment with "bleeding" in various diseases:

• Pneumonia (78 cases)• Erysipelas (33 cases)

• Inflammation of the chest (23 cases)

• Division into two groups, treated and untreated• Result = no average number of better results of

treatment compared with no treatment

Louis P.C.A.: Recherches sur les Effects de la Saignée, Paris, De Mignaret Ed. 1835

HISTORY OF "CLINICAL TRIALS“ - 3 Lister J. (1870)

Surgical treatment of gangrene according to the traditional method in comparison with the method that involved using antisepsis of the operative field by means of carbolic acid

2 groups of patients 35 and 40 cases:a)Traditional technique mortality = 43%b) New method mortality = 15%

Lister J.: On the effects of the antiseptic system upon the salubrity of a surgical hospital. Lancet, i, 4, 1870

CRITERIA FOR EVALUATION OF A HEALTH INTERVENTION

• EFFICACY• EFFICIENCY• SAFETY

TYPES OF CLINICAL STUDIES ON TREATMENT

• OBSERVATIONAL NOT CONTROLLED STUDIES

a) case series studies b) before-after studies or with historical

controls• QUASI-EXPERIMENTAL STUDIES

a) controlled studies with contemporary controls, but not randomized

• EXPERIMENTAL STUDIESa) randomized controlledb) quasi-randomized controlled

HCT: Historical control trialRCT: Randomized control trialConclusions of "HCT" and "RCT" on 6 different therapeutic problems

HCT HCT after adjustment for

prognostic factors

RCT

Result (outcome)+ -

Result+ -

Result+ -

44 12 21 3 10 40

TREATMENTTREATMENTSS MUST BE MUST BE ASSESSED COMPARATIVELYASSESSED COMPARATIVELY

• Against another treatment, already proven effective, in terms of increased effectiveness, efficiency or safety.

• Against an inert substance (placebo) when there is no proven effective treatment.

CONTEMPORARY ASSESSMENT CONTEMPORARY ASSESSMENT OF THE EFFICACYOF THE EFFICACY

The judgment of efficacy must be based on a comparison between the natural history of the disease in relation to two different treatments:

• experimental treatment• comparator treatment

NEED OF STATISTICSNEED OF STATISTICS

The evaluation of efficacy must depend on comparison of the frequency of significant events in a group of treated subjects and in a control group. The comparison can not disregard a probabilistic assessment and, then, from a statistical analysis of the data.

THE SAMPLE SIZETHE SAMPLE SIZE

THE PROBABILISTIC APPROACH AND SUBSEQUENT USE OF STATISTICS IMPLIES PRE-DETERMINATION OF THE SAMPLE SIZE REQUIRED TO EVALUATE THE EFFECT OF A HEALTH INTERVENTION.

SEVERAL ASPECTS MUST BE TAKEN

INTO ACCOUNT.

The probabilistic approach

• Concept of statistical inference

• 95% confidence intervals

• Significant difference

Whole sample

23 red/64 =35%

Two samples

7 reds/27=25%

16 reds/37=43%

Four samples7 reds/18=22%10 reds/20=50%1 red/10=10%5 reds/15=30%

0 10035

35

0

100

Whole sample

23 reds/64 =35%

26 samplesfrom 1 red/1= 100%to 0 red/3= 0%

0 10035

95% Confidence intervals of the Mean

• The minimum and maximum values that can be found in 95% of our samples

• The larger the sample the more the value found is close to reality

• The larger the sample the more narrow the confidence interval

DIFFERENT STAGES OF DIFFERENT STAGES OF THE CLINICAL DRUG THE CLINICAL DRUG

"TRIAL" "TRIAL" • PHASE I: clinical pharmacology

and toxicology• PHASE II: preliminary clinical

efficacy and safety of treatment, "dose ranging", pharmacokinetics and pharmacodynamics in human.

• PHASE III: definitive study of the effect of treatment-RCT

• PHASE IV: "post-marketing” monitoring

Phase III: Randomized Controlled Trial

• Some preliminary concept: internal /external validity randomization masking power of the study

Phase III: Randomized Controlled Trial

Randomization:

to avoid the "selection bias”

Must be "concealed"

Phase III studies: double blind RCT

Masking: to avoid "bias" in the evaluation

Expectation biasCo-interventionsSingle, double, triple ... better describe

who is blinded to treatment

Phase III studies: Randomized Controlled Trial

• Power of the study No. of patients sufficient to show any

effect of the treatment with a good probability and with few probability of being wrong.

ISSUES RELATED TO THE SAMPLE ISSUES RELATED TO THE SAMPLE SIZESIZE

• WHICH AIMS HAS THE STUDY? • WHAT MEASURE IS USED FOR EVALUATING THE

OUTCOME OF THE PATIENT? • HOW IS ANALYZED DATA TO IDENTIFY A POSSIBLE

DIFFERENCE BETWEEN TREATMENTS? • WHAT IS THE EXPECTED RESULT OF THE

"STANDARD" TREATMENT OR THE PLACEBO? • WHAT DIFFERENCE BETWEEN THE TWO TYPES OF

TREATMENTS COMPARED IS SUFFICIENT TO CONVINCE US THAT ONE IS BETTER THAN THE OTHER?

• WHAT TYPE I ERROR AND TYPE II ERROR VALUES DO WE DECIDE TO CHOOSE?

EXAMPLE OF THE SAMPLE SIZE CALCULATION

1) WHICH AIMS HAS THE STUDY?

To DETERMINE IF A NEW ANTIPLATELET DRUG IS BETTER THAN “ASA” FOR SECONDARY PREVENTION OF ISCHEMIC STROKE

2) WHAT MEASURE OF "OUTCOME" WOULD YOU LIKE TO USE?MORTALITY + DISABLING STROKE WITHIN 2 YEARS AFTER A PREVIOUS TIA

EXAMPLE OF THE SAMPLE SIZE CALCULATION

3) HOW DO WE ANALYZE DATA FOR ASSESSING THE TREATMENT? ASCERTAINMENT OF NEW STROKES AND DEATHS THROUGH A SYSTEMATIC FOLLOW-UP – COMPARISON OF THE FREQUENCY OF EVENTS IN THE TWO GROUPS.

4) WHICH RESULT IS EXPECTED WITH ASA: MORTALITY + disabling stroke EXPECTED WITHIN 2 YEARS WITH ASA = 10%

EXAMPLE OF THE SAMPLE SIZE CALCULATION

5) WHICH FREQUENCY OF EVENTS DO I EXPECT WITH THE NEW DRUG TO DEFINE IT MORE EFFECTIVE THAN THE COMPARATOR?

EXPECTED RATE OF MORTALITY + EXPECTED RATE OF DISABLING STROKE WITHIN 2 YEARS WITH THE NEW ANTIPLATELET = 5%

6) WHAT IS THE EXPECTED DIFFERENCE OF THE FREQUENCY PERCENTAGE OF EVENTS?

10% (ASA) - 5% (NEW DRUG) = 5%

EXAMPLE OF THE SAMPLE SIZE CALCULATION: ERROR TYPE I

6) WHICH VALUE OF DO I INTEND TO USE?

5 % (p < 0,05)

= probability that the result of the study may be positive due to chance

EXAMPLE OF THE SAMPLE CALCULATION: ERROR TIPE II

7) WHICH VALUE OF ß DO I CHOOSE? 10 %

ß = probability that is possibly negative result of the study due to chance

1- ß = power of the study (90%)

EXAMPLE OF THE SAMPLE SIZE CALCULATION:

Size (N) of each group to be studied = 578 (Total subjects = 1156)

P1 = 10% P2 = 5%= 5% ß = 10%

Classification of RCTs

• According to the intervention aspects you want to check

• According to the manner in which the participants are exposed to be treated

• According to the number of participants

• According to the participants and investigators knowledge about the treatment

• According to the objective

Classification of RCTs

• “explanatory” have the purpose of assessing

whether a treatment works or not independently in other variables

high internal validity• “pragmatic” have the purpose of assessing

whether the treatment works or not in conditions similar to practice

high external validity

“explanatory” trial efficacy

internal validity

“pragmatic trial” effectiveness

external validity

CLASSIFICATION OF RCTsCLASSIFICATION OF RCTs

Classification of RCTs

• Parallel (parallel groups)

• Cross-over

• Factorial

• No. of 1 trial

Clinical Trial

Randomized and Controlled Clinical Trial with parallel groups

Selected sample

Ran

do

mizatio

n

TreatmentA

TreatmentB

Analysis

of

results

Clinical Trial

Randomized and Controlled Clinical Trial with Cross-over

Selected sample

Ran

do

mizatio

n

TreatmentA

TreatmentB

Analysis

of

resultsTreatment

B

TreatmentA

Clinical Trial

Clinical Trial with Factorial Design

Selected sample

Treatment A

Analysis

of

results

Treatment B

Treatment A+B

Placebo

Classification of RCTs

• open

• single-blind

• double-blind

• triple, quadruple blind

Classification of RCTs

• “mega-trial” (very large simple pragmatic trial)

• sequential

• Pre-defined size

Classification of RCTs

• Superiority trials

• Equivalence trials

• Non-inferiority trials

0 Control Better Treatment Better

Difference between treatments

95% confidence interval

P = 0.05

P = 0.2

Demonstrated superiority

Not demonstrated superiority

P = 0.002

Strongly demonstrated superiority

0 Control Better Treatment Better

Difference between treatments

Equivalence not demonstrated

- +

Equivalence Demonstrated

Equivalence margin (10%)

0 Control Better Treatment Better

Difference between treatments

Non-inferiority Not demonstrated

-

Non-inferiority Demonstrated

Non-inferiority margin (5%)

Statistical Analysis

• For protocol• Intention to treat

concept of “drop-out” concept of lost to follow-up

Whole sample100 points35% reds

26 samples from 2 reds/3=66%to1 red/6=16%