DRUG POLICY OF THE EUROPEAN UNION

SIVIGLIA 15 May 2007

SILVIO GARATTINI

BIAS IN CLINICAL TRIALS

• EUROPEAN LEGISLATION

Institutional location

Industry, consumers or public health?

Quality, efficacy, safety

Necessary, not always sufficient

• IS JUSTIFIED?

• MINORITY POSITION

• REASONS FOR WITHDRAWAL

• RESULTS OF COMMITTMENTS

CONFIDENTIALITY

ADDED VALUE

• TOO MANY TRIALS USE PLACEBO OR NO-CONTROLS

ADDED VALUE

• TOO MANY TRIALS USE PLACEBO OR NO-CONTROLS

• WHEN COMPARISONS ARE MADE DESIGNS OF EQUIVALENCE OR NON INFERIORITY ARE

ADDED VALUE

• TOO MANY TRIALS USE PLACEBO OR NO-CONTROLS

• WHEN COMPARISONS ARE MADE DESIGNS OF EQUIVALENCE OR NON INFERIORITY ARE

• SELECTION OF COMPARATOR IS FREQUENTLY INADEQUATE

ADDED VALUE

• TOO MANY TRIALS USE PLACEBO OR NO-CONTROLS

• WHEN COMPARISONS ARE MADE DESIGNS OF EQUIVALENCE OR NON INFERIORITY ARE

• SELECTION OF COMPARATOR IS FREQUENTLY INADEQUATE

• FOCUS ON SELECTED ADVERSE REACTIONS

ADDED VALUE

• TOO MANY TRIALS USE PLACEBO OR NO-CONTROLS

• WHEN COMPARISONS ARE MADE DESIGNS OF EQUIVALENCE OR NON INFERIORITY ARE

• SELECTION OF COMPARATOR IS FREQUENTLY INADEQUATE

• FOCUS ON SELECTED ADVERSE REACTIONS

• SMALL ADVANTAGES FOR NIGH PRICES

18 ANTICANCER AGENTS

21 INDICATIONS

12 ONLY PHASE II

9 PHASE III

6 EQUIVALENCE OR NON INFERIORITY

3 SUPERIORITY

APOLONE et al., 2005

APOLONE et al., 2005

APOLONE et al., 2005

EQUIVALENCE

OUT OF 383 CLINICAL TRIALS

64 % COULD DETECT A DIFFERENCE > 50 %

84 % COULD DETECT A DIFFERENCE > 25 %

MOHER et al., 1994

BIOTECH SUBSTANCESAPPROVED IN 1995-2003

65

61 61 (15(15))

WITH RCT46 (11)

WITH ACTIVE COMPARATOR

30 (5)

SUPERIORITY13 (4)

WITH HARD ENDPOINTS8 (4)

2 2 (2)(2)

EQUIVALENCE/NON-INFERIORITY

17 (1)

PLACEBO CONTROLLED

16 (5)

WITHOUT DOSE-FINDING33 (8)

UNDER EXCEPTIONALCIRCUMSTANCES

10 (6)

DIAGNOSTICS4

algasidase beta, basilkiximab, infliximab, interferon beta-1b,

laronidase

eptotermin alfa

becaplermin, desirudin, rasburicase, trastuzumab,eptotermin alfa

becaplermin, desirudin, rasburicase, trastuzumab

becaplermin,becaplermin,desirudindesirudin

alemtuzumab, beclapermin, eptotermin alpha, human protein C, interferon beta Ib, laronidase, rituximab, trastuzumab

basiliximab, becaplermin,

desirudin, infliximab

ACUTE RENAL REJECTIONS ARE MINIMIZED WHEN TROUGH LEVELS ARE KEPT BETWEEN 330 - 430 ng/ml

MARGREITER et al., 2002 TRIALCYCLOSPORINE < 300 ng/ml

TACROLIMUS VS CYCLOSPORINE

32.5 % 51.3 %

ACUTE REJECTIONS

Rabinowitz et al., 2001

Favoursatypical

Favourshaloperidol

Drop out rates by dose of comparator drug in trials of patientswith schizophrenia or related disorders (risk difference and95 % confidence intervals)

Geddes et al., 2000

≤ 12 mg haloperidol

> 12 mg haloperidol

-0.5 -0.4 -0.3 -0.2 -0.1 0 0.1

ATYPICAL ANTIPSYCHOTICS

THE REDUCED EFFECT ON EPS IS THE

FOCUS OF ADVERTISEMENT

WEIGHT GAIN AND PROPENSITY TO DIABETES ?

NEUROLOGIC EFFECTS 14% 17%0

WEIGHT GAIN 30% 12%0

BLOOD GLUCOSE (CHANGE) 15 ± 20 5.2 ± 200

GLYCOSYLATED Mb 00.4 ± 0.09 0.1 ± 0.06

CHOLESTEROL (CHANGE) 9.7 ± 2.2 0.5 ± 2.30

TRIGLYCERIDES (CHANGE) 42 ± 8 8 ± 11

OLANZAPINE vs

PERPHENAZINE

PARAMETER

CATIE, 2005

IF 4 MILLIONS SCHIZOPHRENIC PEOPLE WERE TREATED

WITH ANTIPSYCHOTIC AGENTS CONFERRING A MEAN

WEIGHT GAIN OF 4 Kg OVER A PERIOD OF 10 YEARS IN

COMPARISON WITH A DRUG WITH LITTLE EFFECT ON

BODY WEIGHT

• ADDITIONAL 24,560 DEATHS

• ADDITIONAL 92,720 CASES OF IMPAIRED GLUCOSE TOLERANCE

• ADDITIONAL 120,760 CASES OF HYPERTENSION

FONTAINE et al., 2001

Vigor Study Group. N Engl J Med 2000

Cumulative Incidence of the Primary End Point of a Confirmed Upper Gastrointestinal Event among All Randomized Patients.

Time to cardiovascular adverse events in the VIGOR trial

Mukherjee et al, JAMA, 2001

Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Peter Jüni et al, Lancet 2004

Cumulative meta-analysis of randomised trials comparing rofecoxib with control

Rofecoxib

•at the time of marketing approval (1999):

safety data based on 5,000 patients

•at the time of withdrawal (2004):

given daily to 2,000,000 patients

(sales in 2003 US $ 2.5 billion)

For newly licensed drugs,confidence about safety can only be provisional

CARDIOVASCULARTOXICITY

DICLOFENAC 1

COXIBs 0.92*(0.81-1.05)

* 26 RCT

Psaty and Weiss, 2007

CARDIOVASCULARTOXICITY

NAPROXEN 1

COXIBs 1.57*(1.21-2.03)

* 42 RCTPsaty and Weiss, 2007

BEVACIZUMAB

RECOMBINANT HUMANISED MONOCLONAL lgG1 ANTIBODY IS AN

INHIBITOR OF h VEGF (ANGIOGENESIS).

LICENSED IN COMBINATION WITH i.v. 5Fu/FA + IRINOTECAN FOR

FIRST-LINE TREATMENT OF METASTATIC COLORECTAL CARCINOMA.

DOSE: 5 mg/kg i.v. ONCE EVERY 14 days

100 mg 0306.76 €

400 mg 1224.55 €

TOTAL COURSE AVERAGE 18.2 DOSES = 21,285.9 €

BEVACIZUMAB

OUTCOME +FU/FA +FU/FA+BEVACIZUMAB

MEDIAN OVERALL SURVIVALn = 209 13.2 mo. 16.6 mo. NSn = 071 13.6 mo. 17.7 mo. NS

PROGRESSION FREE SURVIVALn = 209 5.5 mo. 9.2 mo. Sn = 071 5.2 mo. 9.0 mo. S

TUMOR RESPONSE RATEn = 209 15.2 % 25.2 % Sn = 071 16.7 % 40.0 % NS

METASTATIC COLORECTAL CARCINOMA

BEVACIZUMAB

OUTCOME IFL IFL- BEVACIZUMAB

MEDIAN OVERALL SURVIVAL 15.6 mo. 20.3 mo.n=8P3

PROGRESSION FREE SURVIVAL 06.2 mo. 10.6 mo.

TUMOR RESPONSE RATE 34.8 % 44.8 %

METASTATIC COLORECTAL CANCER

BEVACIZUMAB

TREATMENT GRADE 3-4 GRADE 3-4ADVERSE REACTIONS HYPERTENSION

IFL 74.0 % 02.3 %

IFL+BEVACIZUMAB 84.9 % 11.0 %

5FU/FA 71.0 % 03.0 %

5FU/FA+BEVACIZUMAB 87.0 % 16.0 %

Paclitaxel-Carboplatin Alone or withBevacizumab for Non-Small-Cell Lung CancerSandler et al. N Engl J Med 2006;355:2542-50

Conclusions

The addition of bevacizumab to paclitaxel plus carboplatin in the

treatment of selected patients with non-small-cell lung cancer has a

significant survival benefit with the risk of increased treatment-related

deaths. (ClinicalTrials.gov number, NCT00021060.)

Script 23 April 2007

PACLITAXEL-CARBOPLATIN± BEVACIZUMAB

Sandler et al., NEJM 2006, 355, 2542

SURVIVAL BENEFIT

12 Pts MUST BE TREATED TO HAVE

1 MORE SURVIVAL AT 1 YEAR

AT THE PRICE OF

1 TOXIC DEATH EVERY 24 PATIENTS

TREATED

MEDIAN OVERALL SURVIVAL

12.3 mo. vs 10.3 mo.

BEVACIZUMAB

INCREASE OF SALES BY 76% IN 2006 vs 2005

WITH A TOTAL OF 2.4 Billion $

SCRIPT, 29th March 2007

CETUXIMAB

RECOMBINANT MONOCLONAL ANTIBODY THAT BLOKS EGFR

LICENSED IN COMBINATION WITH IRINOTECAN FOR PATIENTS

EXPRESSING

EGFR IN METASTATIC COLORECTAL CANCER AFTER FAILURE OF

CYTOTOXIC THERAPY THAT INCLUDED IRINOTECAN

DOSE: 400 mg/m2 i.v. (700 mg) FOLLOWED BY 250 mg/m2 (430mg) weekly

100 mg 189.05 €

1,323 € (LOADING DOSE) 842,9 (MAINTENANCE DOSE)

TOTAL COURSE AVERAGE 16.8 DOSES = 13,117.8 €

CETUXIMAB

OUTCOME CETUXIMAB CETUXIMAB+ IRONOTECAN

MEDIAN OVERALL SURVIVAL

n= 329 6.9 mo. 8.5 mo.

n= 347 6.6 mo. -

n= 057 6.4 mo. -

n= 138 - 8.4 mo.

METASTATIC COLORECTAL CANCER

NS

SECOND-LINE TREATMENT IRINOTECAN IRINOTECAN+ CETUXIMAB

OVERALL RESPONSE RATE (%) 2.6 04.0

DISEASE CONTROL (%) 4.2 16.4

MEDIAN PROGRESSION-FREE (MO) 2.6 04.0

OVERALL SURVIVAL (MO) 9.9 10.7

n=1300 patients with colorectal cancer failing first-line oxaliplatin-based therapy

EPIC, 2007

NATIONAL INSTITUTE FOR HEALTH AND CLINICALEXCELLENCE

Final Appraisal DeterminationBevacizumab and cetuximab for metastatic colorectal

Cancer

Bevacizumab in combination with 5-fluorouracil plus folinic acid, with or without

irinotecan, is not recommended for the first-line treatment of metastatic colorectal

cancer.

Cetuximab in combination with irinotecan is not recommended for the secondline

or subsequent treatment of metastatic colorectal cancer.

THERE IS A NEED FOR MORE INDEPENDENT CLINICAL RESEARCH

• AT LEAST ONE PHASE 3 STUDY FOR DRUG APPROVAL SHOULD

BE PERFORMED BY A NON-PROFIT INSTITUTION

• HEAD TO HEAD COMPARISON OF SINGLE DRUGS OR STRATEGIES

THE ROLE OF AIFA

• 54 PROJECTS APPROVED AND FINANCED IN 2006 (35 M €)

• 51 PROJECTS APPROVED IN 2007

EXAMPLES OF APPROVED PROJECTS

A prospective study on long-term outcome and potential

usefulness of an intervention aimed at reducing adverse

effects in patients with refractory epilepsy.

Evaluation of prescribing pattern and safety profile of

antidepressant and antipsychotic medications in italian

general practice.

Pharmacist’s outreach visits and new information formats:

cluster and single-doctor randomised controlled trials for

evaluating their feasibility and impact on knowledge,

attitudes and prescribing practices of general practitioners

in three italian regions.

EXAMPLES OF APPROVED PROJECTS

A randomized, placebo-controlled study of the efficacy of low-dose

aspirin in the prevention of cardiovascular events in subjects with

diabetes mellitus treated with statins.

A randomized prospective, multicenter trial to compare the effect

on chronic allograft nephropathy of mycophenolate mofetil versus

azathioprine as the sole immunosuppressive therapy for kidney

transplant recipients.

A randomized, controlled trial to evaluate the efficacy of

low-molecular-weight heparin on pregnancy outcome of women

with previous pregnancy complications.

EXAMPLES OF APPROVED PROJECTS

First adjuvant trial on all aromates inhibitors in early breast cancer.

A phase 3 study comparing anastrozolo, letrozole and exemestane,

upfront or sequentially.

A randomized clinical trial of trastuzumab optimization in patients with

locally advanced and/or metastatic breast cancer overexpressing her

2 after a first-line chemotherapy plus trastuzumab.

Multicenter randomized controlled study of azathioprine versus

interferon beta in relapsing-remitting multiple sclerosis.