balancing benefits and risks after marketing · 4/21/2016 · balancing benefits and risks after...
TRANSCRIPT
Balancing Benefits andRisks after marketing
Marieke De BruinCORS/Biopeople Workshop, Copenhagen, April 21, 2016
Declaration of Interest
• Assistant Professor of Pharmacoepidemiology, Utrecht Institute of Pharmaceutical Sciences, Utrecht University
• Pharmacovigilance expert at the Dutch Medicines Evaluation Board (MEB)
• Independent Scientific Expert at the Pharmacovigilance Risk Assessment Committee (PRAC) - European Medicines Agency
• Professor in Regulatory Science, Copenhagen Institute for Regulatory Science (as of August 15, 2016)
This talk reflects my personal views
2000-2010, 200 new medicines, 19.5% orphans
PLoS Med 2013; 10: e1001407.
PhV system has many PhV tools
• Routine/Addtitional PhV
– Spontaneous reporting
– PSURs/PSUSAs
– PASS/PAES
– SOBs (e.g. CMA)
• Routine/Additional RMM
– SmPC
– Educational material
– DHPCs
– PPPs
• RMPs
• Referrals
• Renewals
• PRAC
Intended effect:
Public Health
Balancing Benefits and Risks after marketing
• Routine/Addtitional PhV
– Spontaneous reporting
– PSURs/PSUSAs
– PASS/PAES
– SOBs (e.g. CMA)
• Routine/Additional RMM
– SmPC
– Educational material
– DHPCs
– PPPs
• RMPs
• Referrals
• Renewals
• PRAC
2 examples
Study aim
To examine the development of the RMP after approval, to provide insight into
the knowledge gain over time, by quantifying changes in listed safety concerns
and study factors associated with change
Clin Pharmacol Ther 2014
Study methods: Cohort study
• New medicinal products EU (Nov ‘05 - Dec ‘09): baseline RMP
- Type of product , type & nature of concern, additional activities
• Subsequent RMP updates through EMA, follow-up until Dec ’12
- Outcomes of interest: Change in type of concern / Newly added concerns
• Analysis: - Time to first change (all concerns), time to resolve uncertainties
- Type & nature of newly added concerns
Results – RMPs at authorisation
• 48 medicinal products included in study cohort
- 31 small molecule drugs and 17 biologicals
• Comprising 640 concerns at authorization (baseline)
- 152 identified risks, 246 potential risks, and 242 missing information
Safety concerns at authorization, median (IQR)
Small molecules
(n=31)
Biologicals
(n=17)
All products
(n=48)
Important identified risks 4 (2-5) 3 (2-4) 3 (2-4.5)
Important potential risks 5 (4-7) 6 (4-8) 5 (4-7)
Missing information 4 (3-6) 5 (4-8) 5 (3-7)
Total 12 (10-16) 15 (11-19) 13 (10-16)
→ more uncertainties with biologicals
Results – Resolved uncertainties
• Cumulatively, 85 of the 489 (17.4%) uncertainties were resolved over time
- No difference observed between small-molecules and biologicals:
Rates = 0.04/ product-year
Log-rank p=0.95
Results – newly added information
•During follow-up, 157 concerns newly added for the 48 products
– Median 3 per product (IQR: 1 – 4.75)
•Type of concerns
– 45 identified risks
– 69 potential risks
– 43 missing information
•Approximately half related to change in context of use
New uncertainties (n=112)
Results – newly added information
Characteristics and follow-
up of post-marketing studies
of conditionally authorised
medicines in the EU
J Hoekman, TT Klamer, AK Mantel-
Teeuwisse, HGM Leufkens, ML De Bruin
[Online Early DOI: 10.1111/bcp.12940]
Conditional Marketing Authorisation (CMA)
“In order to meet unmet medical needs...it may be necessary togrant marketing authorisation on the base of less complete data than is normally the case” (Commission Regulation 726/2006)
Pathway design:• Benefit of quick access should outweigh potential risks related
to uncertainty• Medicine should have positive B/R • Post-marketing obligations and yearly renewal of licence
Specific obligations (SOBs):• “The holder is required to complete or initiate certain studies
with a view to confirming that the risk-benefit balance is positive and resolving any questions relating to the quality, safety and efficacy of the product” (Commission Regulation726/2006)
26
2006 2007 2008 2009 2010 2011 2012 2013 2014
sunitinib
stiripentol
darunavir
panitumumab
etravirine
raltegravir
lapatinib
everolimus
aztreonam
H1N1vaccine
ofatumumab
H1N1vaccine
pazopanib
fampridine
vandetanib
pixantrone
crizotinib
brentuximab
bosutinib
vismodegib
2015
bedaquiline
cabozantinib
Cancer
13 (50%)
HIV
3 (12%)Influenza
2 (8%)
Other
8 (30%)
delamanid
2016
ataluren
holoclar
ceritinib
Data Lock Point Nov 2015
Conditional MA in Europe
Aims & Methods
To examine characteristics and follow-up of post-marketing (PM) studies related to specific obligations (SOBs) of medicines that were granted a conditional marketing authorisation (CMA) in the EU
• Study population: CMA products 2006-2014, their SOBs and PM-studies
• Study outcomes
Characteristics: indication, objective, design, status
Follow-up until August 1, 2015
• Time to fullfill obligation
• Time to convert CMA in standard MA
21 medicines with CMA
59 post-marketing studies
23 medicines with CMA
2 vaccines excluded
5 (8%) observational
studies
44 (75%) interventional
studies
34 (58%) with due date before August
1, 2015
11 (19%) with due date after July 31,
2015
33 (56%) matches with online register
1 (2%) not matched
3 (5%) with due date before August
1, 2015
2 (3%) with due date after July 31,
2015
1 (2%) match with online register
2 (3%) not matched
10 (17%) other post-marketing
obligations
Analysis of characteristics
Analysis of follow-up
1 obligation excluded
61 specific obligations
Medicines (n=21)
Number (%)
Indication
Cancer 13 (62%)
HIV/AIDS 3 (14%)
Epilepsy 2 (9%)
Multiple Sclerosis 1 (5%)
Cystic Fibrosis 1 (5%)
Tuberculosis 1 (5%)
Orphan designation 10 (48%)
Pro-active request for CMA by MAA 8 (38%)
Characteristics of CMA medicines
Studies (n=59)
Number (%)
Design
Interventional studies 44 (75%)
Observational studies 5 (8%)
Other obligations 11 (17%)
General objective
Additional Efficacy data 25 (42%)
Additional Safety data 9 (15%)
Additional Efficacy/Safety data 25 (42%)
New studies (after MA) 23 (39%)
Expected time to completion in days 575 (IQR 204-1287)
Characteristics of post-marketing studies
Time to completion(studies)/conversion (license)
Delay (n=26/34): 275 days [IQR -121; 773] Delay (n=14/23): 470 days [IQR 114; 1295]
50% 29%
Discussion & Conclusions
• Obligations are started, registered and eventually completed
• Half of all studies have substantial delays
• Lack of incentive or closing a window of opportunity?
• With annual renewal of license regulators are probably aware
• Patients exposed to unnecessary treatment risks
• Difficult to balance B/R with limited data
More work to be done