BIAS IN CONTROLLED

CLINICAL TRIALS

Ljubljana 19 March 2012

SILVIO GARATTINI

METHODOLOGICAL REQUIREMENTS

FOR CLINICAL TRIALS

Ask important questions…

…answer them reliably

The objective is the patient,

the goal is his benefit

Yusuf S, Collins R, Peto R.

Why do we need some large, simple randomized trials? Stat Med 1984; 3: 409-420

PATIENTS CAN BE INVOLVED IN CLINICAL

TRIALS ONLY IF THERE IS A REASONABLE

POTENTIAL ADVANTAGE. FOR THEM OR

FOR FUTURE PATIENTS THE ADVANTAGE

COULD BE INCREASED EFFICACY,

DECREASED TOXICITY, DIFFERENT TOXIC

PROFILES, BETTER COMPLIANCE.

LONGER DURATION OF ACTION, etc.

MEDIANA 0,097 QALY

51% < 0,1 QALY

12% > 1,0 QALY

MIGLIORAMENTI INDOTTI

DA 281 NUOVI FARMACI

Basic Clin Pharmacol

2009, 105, Suppl. 1, 032

Walker et al., 2009

• THE EXCESSIVE USE OF PLACEBO

PLACEBO SHOULD BE USED ONLY WHEN

THERE ARE NO EFFECTIVE DRUGS FOR

A GIVEN INDICATION INAPPROPIATE USE

OF PLACEBO MAY LEAD TO AN OPTIMISTIC

EVALUATION OF A NEW DRUG

DENOSUMAB (ANTI-RANK LIGAND MAB)

HAS BEEN TESTED AGAINST PLACEBO IN

POST-MENOPAUSAL WOMEN WHEN THERE ARE

AVAILABLE SEVERAL ANTI-OSTEOPOROTIC AGENTS

Scrip 19/9/08

Giovannoni et al., 2010

Kappos et al., 2010

ADD-ON DESIGN

NEW DRUG PLACEBO

BASIC TREATMENT

+ +

Zinman et al., 2007

A FAIR COMPARISON WOULD HAVE

BEEN TO USE INSTEAD OF PLACEBO

ONE OF THE MANY ANTIADIBETIC

AGENTS AVAILABLE ON THE MARKET

Pratley et al., 2010

Effect of Noninsulin Antidiabetic Drugs Added

to Metformin Therapy on Glycemic Control,

Weight Gain, and Hypoglycemia

in Type 2 Diabetes Olivia J. Phung, PharmD

Jennifer M. Scholle, PharmD

Mehak Talwar, BS

Craig I. Coleman, PharmD

Conclusion When added to maximal metformin therapy, all noninsulin

antidiabetic drugs were associated with similar HbA1c reductions but

differed in their associations with weight gain and risk of hypoglycemia.

JAMA. 2010;303(14):1410-1418

Phung et al., 2010

• DESIGN OF CLINICAL TRIALS

CLINICAL TRIALS MAY BE

DESIGNED TO DEMONSTRATE

• SUPERIORITY

• EQUIVALENCE

• NON INFERIORITY

IN THE NON-INFERIOR TYPE OF TRIAL WITH AN ACTIVE

CONTROL, INVESTIGATORS ARE TESTING THE NULL

HYPOTHESIS THAT A NEW DRUG IS WORSE THAN THE

ACTIVE CONTROL (STANDARD) AND WHEN THEY CAN

REJECT THE NULL HYPOTHESIS THEY ACCEPT THE

ALTERNATIVE, THAT THE NEW DRUG IS NOT WORSE

THAN THE ACTIVE CONTROL.

ARAS, 2001 DRUG INFORMATION J.35,1157

SUPERIORITY

EQUIVALENCE

NON

INFERIORITY

CONTROL BETTER NEW AGENT BETTER 0 - +

Are there specific reasons for allowing a

non-inferiority approach?

• There may be non-responders to current treatments

and products with comparable activity may offer a

useful alternative.

If the target is non-responders to current

treatments, why not test their superiority over

drugs with little effect in this subset of patients?

18 ANTICANCER AGENTS

21 INDICATIONS

12 ONLY PHASE II

9 PHASE III

6 EQUIVALENCE OR NON INFERIORITY

3 SUPERIORITY

Fueglistaler et al., 2007

A B C Therapy

Eff

icacy %

OUT OF 383 CLINICAL TRIALS

64 % COULD DETECT A DIFFERENCE > 50 %

84 % COULD DETECT A DIFFERENCE > 25 %

MOHER et al., 1994

Between 2002 and 2009, of 43 NDAs

containing data from at least one noninferiority

trial, the FDA approved 18 on the basis of

pivotal evidence from noninferiority trials but

found nine NDAs had poorly designed

noninferiority trials that could not be used to

establish the efficacy of the new drug.

Nature Medicine 2010, 16, 1049

THE DESIGN OF N.I. TRAILS REQUIRES

ALWAYS THE USE OF STANDARD AND

PLACEBO WILE A SUPERIORITY DESIGN

REQUIRES ONLY THE USE OF STANDARD.

Garattini S, Bertele’ V.

How can research ethics committees protect patients

better?

BMJ 2003; 326:1199-201

Draft informed consent

“Let us treat you with something

that at best is the same as what

you would have had before, but

might also reduce - though this is

unlikely - most of the advantages

previously attained in your

condition. It might even benefit

you more than any current

therapy but, should that actually

happen, we shall not be able to

prove it. Nor have we enough

chance to let you know whether

the new treatment may somehow

bother or even harm you more

than the standard one”.

NON-INFERIORITY TRIALS

FEW PATIENTS WOULD AGREE TO

PARTICIPATE IF THIS MESSAGE IS

CLEAR IN THE INFORMED CONSENT FORM.

THREE ARM TRIAL

RANDOMIZATION

PLACEBO COMPARATOR NEW DRUG

PLACEBO IS NOT NECESSARY IN THE DESIGN OF SUPERIORITY

• SURROGATE END POINTS

QUALITY OF LIFE, MORBILITY, MORTALITY

SHOULD BE THE FINAL OBJECTIVES

OF CLINICAL TRIALS

• ENCAINIDE AND FLECAINIDE DECREASE ARRHYTHMIAS

BUT INCREASE MORTALITY

• OESTROGENS INCREASE HDL-CHOLESTEROL

BUT DO NOT PREVENT CARDIOVASCULAR EVENTS

• TORCETRAPIB INCREASES HDL-CHOLESTEROL

BUT INCREASES MORTALITY

HbA1c IS NOT A SURROGATE END-POINT FOR

CARDIOVASCULAR DISEASES IN TYPE 2 DIABETES

SULFONYLUREAS HbA1C MYOCARDIAL INFARCTION

ROSIGLITAZONE HbA1C HEART FAILURE

NEED TO EVALUATE PARAMETERS IMPORTANT FOR PATIENTS

Arguedas et al., 2009

RIMONABANT

antagonist of cannabinoid-1 receptor

• DECREASE OF BODY WEIGHT

• INCREASE OF HDL, ADIPONECTIN

• DECREASE OF TRIGLYCERIDES, BLOOD

GLUCOSE, FASTING INSULIN, LEPTIN

• DECREASE OF TOTAL VOLUME ATHEROMA

Topol et al., 2010

CRESCENDO TRIAL

• UTILIZATION OF COMPOSITE END-POINTS

Lapostolle et al., 2007

Ferreira-Gonzàlez et al., 2007

• SELECTIVE PUBLICATIONS

SELECTIVE PUBLICATIONS

OF 5 SSRI

• 21 STUDIES SHOW DRUG BETTER THAN PLACEBO

• 19 PRIMARY PUBLICATIONS

IN TOTAL 42 STUDIES

Sweedish Drug Regulatory Authority Melander et al., BMJ 2003

SELECTIVE PUBLICATIONS

OF 5 SSRI

• 21 STUDIES SHOW DRUG BETTER THAN PLACEBO

• 19 PRIMARY PUBLICATIONS

IN TOTAL 42 STUDIES

• 21 STUDIES SHOW NEGATIVE RESULTS

• 6 PRIMARY PUBLICATIONS

Sweedish Drug Regulatory Authority Melander et al., BMJ 2003

SELECTIVE PUBLICATIONS

OF 5 SSRI

• 21 STUDIES SHOW DRUG BETTER THAN PLACEBO

• 19 PRIMARY PUBLICATIONS

EVIDENCE

B(I)ASED

MEDICINE

IN TOTAL 42 STUDIES

• 21 STUDIES SHOW NEGATIVE RESULTS

• 6 PRIMARY PUBLICATIONS

Sweedish Drug Regulatory Authority Melander et al., BMJ 2003

Kirsch et al., 2008

Eyding et al., 2010

Eyding et al., 2010

SELECTIVE REPORTING OF CLINICAL TRIALS MAY

BIAS META-ANALYSES AND MISDIRECT GUIDE-LINE.

IN A RETROSPECTIVE REVIEW OF 130 TRIALS,

THOSE WITH POSITIVE RESULTS WERE THREE

TIMES MORE LIKELY TO BE PUBLISHED WITH A

SIGNIFICANT SHORTER TIME TO PUBLICATION THAN

THOSE WITH NEGATIVE RESULTS.

STERN, SIMES, 1997