Transcript Diapositiva 1 - EL COMPRIMIDO

DRUG POLICY OF THE EUROPEAN UNION
SILVIO GARATTINI
SIVIGLIA 15 May 2007
BIAS IN CLINICAL TRIALS
• EUROPEAN LEGISLATION
Institutional location
Industry, consumers or public health?
Quality, efficacy, safety
Necessary, not always sufficient
CONFIDENTIALITY
• IS JUSTIFIED?
• MINORITY POSITION
• REASONS FOR WITHDRAWAL
• RESULTS OF COMMITTMENTS
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
9
ONLY PHASE II
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 SUBSTANCES
APPROVED IN 1995-2003
65
DIAGNOSTICS
UNDER EXCEPTIONAL
CIRCUMSTANCES
10 (6)
4
61 (15)
WITHOUT DOSE-FINDING
33 (8)
WITH RCT
46 (11)
PLACEBO
CONTROLLED
16 (5)
algasidase beta, basilkiximab,
infliximab, interferon beta-1b,
laronidase
WITH ACTIVE
COMPARATOR
30 (5)
becaplermin,
desirudin, rasburicase,
trastuzumab,
eptotermin alfa
EQUIVALENCE/
NON-INFERIORITY
17 (1)
SUPERIORITY
13 (4)
eptotermin alfa
alemtuzumab, beclapermin, eptotermin alpha,
human protein C, interferon beta Ib,
laronidase, rituximab, trastuzumab
WITH HARD ENDPOINTS
8 (4)
becaplermin,
desirudin,
rasburicase,
trastuzumab
2 (2)
basiliximab,
becaplermin,
desirudin,
infliximab
becaplermin,
desirudin
TACROLIMUS VS CYCLOSPORINE
32.5 %
51.3 %
ACUTE REJECTIONS
ACUTE RENAL REJECTIONS ARE MINIMIZED
WHEN TROUGH LEVELS ARE KEPT BETWEEN
330 - 430 ng/ml
MARGREITER et al., 2002 TRIAL
CYCLOSPORINE < 300 ng/ml
Rabinowitz et al., 2001
≤ 12 mg haloperidol
> 12 mg haloperidol
-0.5
-0.4
-0.3
-0.2
-0.1
Favours
atypical
0
0.1
Favours
haloperidol
Drop out rates by dose of comparator drug in trials of patients
with schizophrenia or related disorders (risk difference and
95 % confidence intervals)
Geddes et al., 2000
ATYPICAL ANTIPSYCHOTICS
THE REDUCED EFFECT ON EPS IS THE
FOCUS OF ADVERTISEMENT
WEIGHT GAIN AND PROPENSITY TO DIABETES ?
PARAMETER
OLANZAPINE
vs PERPHENAZINE
NEUROLOGIC EFFECTS
14%
17%0
WEIGHT GAIN
30%
12%0
15 ± 20
5.2 ± 200
00.4 ± 0.09
0.1 ± 0.06
CHOLESTEROL (CHANGE)
9.7 ± 2.2
0.5 ± 2.30
TRIGLYCERIDES (CHANGE)
42 ± 8
8 ± 11
BLOOD GLUCOSE (CHANGE)
GLYCOSYLATED Mb
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
Cumulative Incidence of the Primary End Point of a Confirmed
Upper Gastrointestinal Event among All Randomized Patients.
Vigor Study Group. N Engl J Med 2000
Time to cardiovascular adverse events in the VIGOR trial
Mukherjee et al, JAMA, 2001
Cumulative meta-analysis of randomised trials
comparing rofecoxib with control
Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Peter Jüni et al, Lancet 2004
For newly licensed drugs,
confidence about safety can only be provisional
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)
CARDIOVASCULAR
TOXICITY
DICLOFENAC
COXIBs
1
0.92*
(0.81-1.05)
* 26 RCT
Psaty and Weiss, 2007
CARDIOVASCULAR
TOXICITY
NAPROXEN
COXIBs
1
1.57*
(1.21-2.03)
* 42 RCT
Psaty 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 SURVIVAL
n = 209
13.2 mo.
n = 071
13.6 mo.
16.6 mo. NS
17.7 mo. NS
PROGRESSION FREE SURVIVAL
n = 209
5.5 mo.
n = 071
5.2 mo.
9.2 mo. S
9.0 mo. S
TUMOR RESPONSE RATE
n = 209
15.2 %
n = 071
16.7 %
25.2 % S
40.0 % NS
METASTATIC COLORECTAL CARCINOMA
BEVACIZUMAB
OUTCOME
IFL
IFL- BEVACIZUMAB
MEDIAN OVERALL SURVIVAL
n=8P3
15.6 mo.
20.3 mo.
PROGRESSION FREE SURVIVAL
06.2 mo.
10.6 mo.
34.8 %
44.8 %
TUMOR RESPONSE RATE
METASTATIC COLORECTAL CANCER
BEVACIZUMAB
TREATMENT
GRADE 3-4
ADVERSE REACTIONS
GRADE 3-4
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 with
Bevacizumab for Non-Small-Cell Lung Cancer
Sandler 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
n= 329
6.9 mo.
8.5 mo.
n= 347
6.6 mo.
-
n= 057
6.4 mo.
-
n= 138
-
8.4 mo.
MEDIAN OVERALL SURVIVAL
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 CLINICAL
EXCELLENCE
Final Appraisal Determination
Bevacizumab 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.