Post-authorisation studies The view from a small academic centre

Post-authorisation studies
The view from a small academic centre
Nicholas Moore
Bordeaux
1
Conflict of interest statement
2
Conflict of interest statement
• Too many to mention
• But not as many as I’d really like
• We have received (some) funding from
regulatory agencies, public research institutes
and the EU
3
Conflict of interest statement
• Too many to mention
• But not as many as I’d really like
• There may be a farfaraway drug company in
another galaxy I haven’t talked with at some
point or another. But I haven’t given up hope.
4
Background
• Pharmacoepi studies are designed to answer a
single specific question per study
• Which is not always obvious
5
“In theory, there is no difference
between theory & practice.
In practice, there is.”
Yogi Berra
Questions
• What is going on?
– What is the target population?
– How is the drug used?
– Does the drug change disease management?
• Does the drug deliver the bang for the buck?
– Are clinical trials reproduced in real life?
– What is the relative benefit of the drug (CE?)
• Is there a safety issue? (RMP or post-alert)
7
Who asks the question?
• CHMP & National registration authorities
– Safety issues
– Drug utilisation: misuse/abuse
• Reimbursement organisms (HTA)
– off-label use
– Comparative effectiveness
– Real-life value
8
Who asks the question?
• Drug company
– To respond to future safety/CER requirements
– To identify/quantify target populations
• Scientific societies, public research
• Or simple curiosity (us)?
9
Who pays for the studies?
10
Who pays the piper?
• Regulatory authorities?
11
Who pays the piper?
• Regulatory authorities?
• Sometimes, but not often and not much
12
Who pays the piper?
• Drug companies
14
Who pays the piper?
• Drug companies
• But they don’t always call the tune
15
Study management
• Drug Company comes with question and $$
• Academic (ENCEPP) Centre provides study
–
–
–
–
With clear contract (submitted as needed)
Independently
With Independent Scientific committee
With protocol submitted to requesting authorities
• Academic centre informs of study progress
– And results, in due course
• Academic centre publishes results
– Whatever the results
16
Data ownership
• Data from database belongs to database
owner.
• Data generated from study is co-owned
– For research and teaching purposes
– For further analysis
• Study report belongs to sponsor
– And is submitted to authorities
18
All of which corresponds to
ENCEPP criteria
19
And at the end of the study,
Company is usually quite happy
20
Because if the study turns out
positive they can deny any
responsibility in this foul deed
21
Types of studies
• Field studies
– Disease-based
– Drug-based
• Database studies
– Medical files
– Claims databases
• Choice is usually obvious from the question
22
Field studies
• Disease-based
– Eole
• Drug-based
– Vesuve
23
EOLE
• Marketing of omega-3 supplement for
secondary prevention of MI
– Does this alter compliance with dietary
recommendations?
– Is the reduction in sudden death found in clinical
trial(s) reproduced in real life?
24
EOLE
• No change in disease management
• Masked study
– Participants blinded to study objectives
• Approved by authorities, EC, DPA, etc.
– Adjudication committee blinded to treatment
25
CIC-P Bordeaux n°0005
Service de
Pharmacologie
ETUDE EOLE
Etude Observationnelle de suivi Long terme du post infarctus du myocardE
Management of acute myocardial infarction:
inclusion results of a national cohort
C Droz (1); C Dureau (1); D Thomas (2); N Danchin (2); J Tricoire (3); J Bénichou (4); F Paillard (5);
P Ducimetière (6); S Hercberg (7); H Maïzi (1); E Guiard (1); M-A Bernard (1); P Blin (1); N Moore (1)
(1)
Bordeaux; (2) Paris; (3) Toulouse; (4) Rouen; (5) Rennes; (6) Villejuif; (7) Bobigny
14ème congrès de la Société Française de Pharmacologie et de Thérapeutique, Bordeaux, 23-25 mars 2010
26
Objectives
• Real-life impact of cardiovascular treatments
and diet recommendations on all-cause
mortality in secondary prevention of MI.
• Secondary objectives
– Major cardiovascular events (MACE)
– Treatment persistence
– Concordance between MD prescription and
reported use of prevention drugs
– Compliance with diet
27
(Apparent) Objectives
• Real-life impact of cardiovascular treatments
and diet recommendations on all-cause
mortality in secondary prevention of MI.
• Secondary objectives
– Major cardiovascular events (MACE)
– Treatment persistence
– Concordance between MD prescription and
reported use of prevention drugs
– Compliance with diet
28
Methods
• Recruitment of patients by cardiologists
– 5000 patients followed 6 years
• EOLE1 3000 pts April 2006 - March 2008
• EOLE2 2000 pts March 2008-June 2009
– After recent MI (<3 months)
29
Data
• Cardiologist data
– Cardiovascular morbidity
– Risk factors
– Prescribed treatments
• Patient data
– Diet (EOLE-1 only)
– Treatments taken
– Hospital admissions
30
Study organisation
2006
2007
QM : Questionnaire Médical, AQ : Auto-questionnaire patient
2013
2009
2012
2014
2008
2010
2011
QMi
6 mois
mois QM
AQi QM
AQ 6
AQ 22 ans
ans AQ 3 ans AQ 4 ans
ans
AQ 5 ans
AQ 6
Suivi du dernier patient inclus EOLE 1
QMi
AQi AQ 6 mois
AQ 2 ans
AQ 3 ans
AQ 4 ans
Suivi du dernier patient inclus EOLE 2
31
AQ 5 ans
AQ 6 ans
2015
Study organisation
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
Relances médecins / patients
Monitorage / Saisie / Archivage / Contrôle qualité
Réunions du Comité Scientifique
Validation des évènements par le Comité de Validation des évènements
EOLE 1
Rapport intermédiaire
« suivi traitement et règles
hygiéno-diététiques à 6 mois
»
n≈3000
EOLE 1
Rapport final
« suivi traitement et règles
hygiéno-diététiques à 2 ans »
n≈3000
EOLE 1 + 2
Rapport final « inclusion »
n≈5000
EOLE 1 + 2
Rapport
« Mortalité à 3,5 ans »
n≈5000
32
EOLE 1 + 2
Rapport FINAL
« Mortalité à 6 ans »
n≈5000
Inclusion results
How are post-MI patients managed
in real life?
33
General characteristics of patients at inclusion
34
Management of inclusion MI
n = 5540
Présence de critères caractéristiques de l’IDM (%)
Critère symptomatique
Critère électrique
Critère enzymatique
97.2
81.7
91.6
Délai entre l'IDM d'inclusion et la consultation d'inclusion (jours) (médiane)
30.0
Reperfusion au stade aigu (%)
58.6
Angioplastie coronaire suite à l’IDM (%)
81.5
Pontage coronaire suite à l’IDM (%)
5.0
35
Secondary prevention treatments at inclusion
36
36
Recommended preventive treatments at inclusion
n = 5540
number of recommended secondary prevention
treatments (%)
0
1
2
3
4
5
0.1
0.4
3.4
20.8
62.3
13.0
Cardiovascular rehabilitation program (%)
40.5
37
Main characteristics at inclusion / to exposure to O3
without oméga 3
n = 1768
with oméga 3
n = 244
p brut
Patient age (années)
Moyenne (± e-t)
Médiane
[p25% - p75%]
[Min - Max]
63.3 (12.9)
63.0
[54.0;74.0]
[23.0;95.0]
59.5 (12.2)
58.0
[50.5;70.0]
[34.0;86.0]
Male, %
77.9
81.6
ns
Previous MI, %
13.0
10.2
ns
Inclusion MI, %
typical pain
At least 2 Q-waves
ST elevation
Acute reperfusion/thrombolysis
97.6
61.0
71.0
15.3
99.6
68.9
81.1
27.9
ns
<0.01
<0.001
<0.001
Never spoked %
38.1
35.2
ns
Large abdominal circumference*, n (%)
<0.001
1097 (62.0)
163 (66.8)
ns
*: ≥94cm in men, ≥80cm in women;
38
Main characteristics at inclusion / to exposure to O3
Without omega 3
n = 1768
Secondary prevention treatments), n (%)
Bêtablockers
Aspirin (or other antiplatelets)
ACE (or ARA)
Statins (or other LLA)
Omega 3
number of secondary prevention drugs, n (%)
0
1
2
3
4
Cardiac rehabilitation program, n (%)
1545
1754
1410
1699
0
(87.4)
(99.2)
(79.8)
(96.1)
(0.0)
With omega 3
n = 244
p brut
221 (90.6)
243 (99.6)
215 (88.1)
238 (97.5)
244 (100.0)
ns
ns
<0.001
ns
<0.001
4 (0.2)
6 (0.3)
83 (4.7)
464 (26.2)
1211 (68.5)
0 (0.0)
0 (0.0)
4 (1.6)
51 (20.9)
189 (77.5)
665 (37.6)
118 (48.4)
<0.01
39
Differences between exposed / not
exposed
• Construction of propensity scores
• Adjustement or matching
40
Adjusted on PS
41
Matched on PS
42
3. Diet and other lifestyle adjustments
• Smoking cessation between inclusion and 6 months :
3,9% of non-O3 patients
2,5% of O3 patients
no difference
• Non Smokers at 6 months:
89,9% of non-O3 patients
90,8% of O3 patients
No difference
• Increased rapid walking duration from inclusion to 6 months :
37,8% of non-O3 patients
44,1% of O3 patients
No difference
43
3. Diet and other lifestyle adjustments
• No difference in the changes in the use of different foodstuff classes
• Foodstuff most reduced at 6 months
« non O3 » / « O3 »
Charcuterie :
74%
Salted products :
68%
Pastries:
66%
Sweet products:
64%
Butter:
62%
Added salt:
57%
Liquors and spirits: 53%
/
/
/
/
/
/
/
77%
75%
71%
66%
64%
57%
53%
• Foodstuffs most increased at 6 months
« non O3 » / « O3 »
Fresh fruit:
48% /
48%
44
Advantage of field study
• Information not found in claims or medical
files
– Dietary data
– Lifestyle data
– Quality of life
• Comparison of prescription by GP with use by
patients
45
Drug based study: VESUVE
46
The question
• Bortezomib in Multiple Myeloma
• Drug was put on the market after limited
clinical trials
– 30% survival in phase 2 study
• Do we have the same in real life?
47
Study Objectives
• Measure survival and response in MM
patients treated with bortezomib
• Describe the characteristics of patients
starting B.
– demographics, previous treatments, indication
– Compared to CT data?
• Describe treatment characteristics
– Dose, number and rhythm of treatment cycles
48
Methods
• Identification of patients from hospital
pharmacy records
– Expensive treatment with nominative
dispensation
– Patient/physician acceptance
• 36-month follow-up from treatment onset.
49
Study population
n = 1310 patients
Identified by pharmacies
n = 386 patients
Non participating MD
n = 924 patients
Participating MD
n = 9 patients
refused or data not found
n = 915 patients
Inclusion data
N = 117 patients
Not incluable: other indications,
clinical trials, …
N = 798 patients
Followed and validated
50
Results : Indications for bortezomib
Indications
Multiple myeloma
N = 915 (100%)
842 (92,1%)
Lymphoma
58 (6,3%)
Other indications
13 (1,4%)
(leukemia, plasmocytoma,
melanoma, …)
unknown
2 (0,2%)
51
Results : Characteristics at inclusion
Characteristics
N = 798 (100%)
Age (ET)
65,6 years(10)
Women
373 (46,7%)
Type of myéloma
Ig (G, A, M, D, biclonaux)
Light chain
Not secreting
666 (83,5%)
119 (14,9%)
13 ( 1,6%)
Previous treatments (at least once)
Conventional Chemotherapy
Graft (allo-, auto-)
Thalidomide (alone or associated)
Other (interferon, lenalidomide, …)
566 (70,9%)
417 (52,3%)
545 (68,3%)
70 ( 8,8%)
52
Results : characteristics at initiation of bortezomib
Caractéristiques
N = 798 (100%)
Ligne de traitement
1ère ligne
2ème ligne
3ème ligne
4ème ligne
5ème ligne +
4 (0,5%)
141 (17,7%)
266 (33,3%)
168 (21,1%)
219 (27,4%)
Posologie à l’initiation
≤1 mg/m2
= 1,3 mg/m2
Non renseignée
71 ( 8,9%)
604 (75,7%)
123 (15,4%)
Traitements associés
Monothérapie
Bithérapie *
Trithérapie et +
342 (42,9%)
381 (47,7%)
75 ( 9,4%)
* Dexamethasone : 343 patients (90% des bithérapies)
53
Results: Characteristics of treatment during follow-up
Caractéristiques
Nombre de cycles
Médiane [p25 %-p75%]
< 8 cycles
8 cycles
> 8 cycles
N = 798 (100%)
4 (3 - 7)
630 (78,9%)
118 (14,8%)
50 (6,3%)
Au moins un cycle non standard*
558 (69,9%)
Au moins un traitement concomitant **
574 (71,9%
Durée de traitement cumulée de bortezomib
(mois) Médiane (p25 %-p75%]
2,6 [1,1-4,5]
* Posologie réduite, cycles tronqués, arythmiques, retardés
** 545 (94,9 %) dexaméthasone
54
Results: treatment outcomes
Response*
N = 798 (100%)
Complete Response
13 (1,6%)
Very good partial response
78 (9,8%
Partial Response
255 (32,0%)
Stable disease
210 (26,3%
Progression
Not evaluable
single cycle
Missing lab data
37 (4,6%)
205 (25,7%)
79 ( 9,9%)
126 (15,8%)
* Best response during initial line with B
55
Results: global survival, %
(IC 95%)
Clinical trials & other observational studies
62% - 82%
38% - 69%
61.1% (57.6-64.4)
43% - 58%
42.2% (38.7-45.7)
31.1% (27.8-34.4)
VESUVE : Median : 19.2 mois (16.5-21.5)
56
Results: progression-free survival %, (IC 95%)
Clinical trials: median progression-free survival : 6,5 months
26,6% (25,4-31,8)
11,8% (9,7-14,2)
7,8% (6,0 – 9,8)
Vesuve, median progression-free survival : 7,1 months (6,6 -7,5)
57
Conclusion
• Large cohort
• Recruitment from hospital pharmacies:
– Representativity, exhaustivity
– Recruitment after initial prescription
• Non-invasive follow-up
• Use conforms to recommendations
• Real-life performance as expected from RCT
58
Conclusion
• 2 studies with different designs
– Recruitment by MD, access to patients (diet, use
of medication, outcomes)
– Recruitment from dispensation record, data from
medical file (standardized F/U by specialist depts)
• In both cases, results as expected, and drug
readmitted to reimbursement without change
59
Some other studies
• Drug-based
–
–
–
–
CADEUS (NSAIDs and COX2 inhibitors) (DB+F)
EULEV (levetiracetam persistence) (DB+F)
ETNA (bevacizumab/CRC)(F) (public funding)
SANTORIN (Antiangiogenics in renal cancer)(F) *
• Disease-based (CE)
–
–
–
–
–
ABSINTHE (sinusitis)
THEATRE (AECB)
COLCHIC (CRC) (not funded)
SALT: Study of Acute Liver Transplant (NSAID hepatotox)
Psolemee: cost of psoriasis *
60
Some other studies
• Claims database
– PCR-PRH: target populations for Biologicals
– NSAID+PPI: combination drug?
– URRS: use of dopamine agonist in restless legs
syndrome
– GROC: Insulin and risk of cancer
• And many other studies
– 10K to 7G €
61
Conclusion
• Many different Sponsors
– European/national regulators
– Pharmaceutical companies
– Ourselves
• For many different purposes
– Safety
– Effectiveness
– Value for money (reimbursement or HTA)
– Fun
62
Different Safety purposes
• Respond to alert
– SALT
– GROC
• Prevent problems
– RMP – risk minimisation
• Understand context
– Drug utilisation
– Disease definition
63
Conclusion
• High quality
– Depending on requirements
– And investment
• Very Cheap
– Compared to RCT
– Considering returns:
• Drug still reimbursed or not taken off the market
• Knowledge generation on
– Background risk
– Disease environment
64
One last question
• Could some studies be mutualised between
companies and/or public funding?
– Especially disease-based studies
• EOLE: post MI data
• SALT: drug-related liver transplant in Europe
65
“You can observe a lot by
just watching”
Yogi Berra