1. CURRENT ADVERSE EVENTS REPORTING IN HEMOPHILIA
Alfonso Iorio, McMaster University, Canada
Chair, Data and Demographics Committee, WFH
Chair, Canadian Bleeding Disorders Registry
PI, Canadian Hemophilia Surveillance Scheme
Sunday, July 24, 2016
08:30-11:30 PD-S-01
SHOW ME THE DATA! CHALLENGES AND OPPORTUNITIES IN DATA COLLECTION Room: 307
Chair: Alfonso Iorio, Canada

2. Disclosures for: Alfonso Iorio
In compliance with the PIM* policy, WFH requires the following disclosures be made at each presentation
CONFLICT
Disclosure — if conflict of interest exists
Research Support
McMaster receives support for research in hemophilia by Bayer, Biogen, Octapharma, Novo-Nordisk, Pfizer, Shire
Director, Officer, Employee
Data and Demographics committee, WFH
Shareholder
Honoraria
Advisory Committee
McMaster receives support for services in hemophilia by Bayer, Biogen, Octapharma, Novo-Nordisk, Pfizer, Shire
Consultant
* Postgraduate Institute for Medicine 2

3. Click to edit Master title style
FIRST THEME NAME
AGENDA
Click to edit Master title style
What is the evidence?
What is the use we can make of it?
What could everyone role be? 3

4. Clinical Trial Phases Phase Study type Pre-clinical Animal studies 1
Safety in human volunteers 2
Dosing - efficacy 3
Efficacy comparison with gold standard treatment 4
Post marketing surveillance - Pharmacovigilence

5. What you get is related to what you put…
Why RECOMBINANT concentrates cause more cold and headache than PLASMA DERIVED one?
What you get is related to what you put…
Pre-licensure trials use a super-powerful magnifying lens to look at one side only of the whole story..
Add the image of a croach through a lens…
Text appears later 5

6. Monitoring safety after licensing
Post marketing surveillance
Formal requirement
Reporting schemes
EUHASS, CHESS, UKHCDO, FranceCoag, Rodin, ATHN
National schemes
Reporting by doctors, nurses, data managers and patients

7. Monitoring safety after licensing
Post marketing surveillance
Formal requirement
Reporting schemes
EUHASS, CHESS, UKHCDO, FranceCoag, Rodin, ATHN
National schemes
Reporting by doctors, nurses, data managers and patients

8. POST MARKETING SURVEILLANCE
Photo of the air-force one an gorgeous bosy guard

9. POST MARKETING SURVEILLANCE
After RODIN publication, I (as an educated citizen // cumbersome open access ) have accessed the Health Canada database: over 10 years, 6.7 more inhibitor with kogenate (27 vs 4)

10. POST MARKETING SURVEILLANCE
Photo of a toothbrush and toothpaste

11. Post-hoc analysis of post-marketing surveillance studies
Iorio A et al. Patient data meta-analysis of Post-Authorization Safety Surveillance (PASS) studies of haemophilia A patients treated with rAHF-PFM. Haemophilia. 20(6), 777–83 (2014).
Romanov V et al. Evaluation of Safety and Effectiveness of factor VIII treatment in Hemophilia A patients with low titer inhibitors or a personal history of inhibitor. Thromb. Haemost. 114, 56–64 (2015).
Bayesian approach to the assessment of the population specific risk of inhibitors in Hemophilia A patients: a case study. Journal of Blood Medicine, accepted

12. Monitoring safety after licensing
Post marketing surveillance
Formal requirement
Reporting schemes
EUHASS, CHESS, UKHCDO, FranceCoag, Rodin, ATHN
National schemes
Reporting by doctors, nurses, data managers and patients

13. Monitoring safety after licensing
EUHASS
UKHCDO
RODIN
FranceC
ATHN
CHESS
Nat 1
Nat 2

14. Monitoring safety after licensing
Effort
By program characteristics
EUHASS
CHESS
UKHCDO
RODIN
FranceC
ATHN
Nat 1
Nat 2
Size

15. Monitoring safety after licensing
Richness
By data characteristics
EUHASS
CHESS
UKHCDO
RODIN
FranceC
ATHN
Nat 1
Nat 2
Coverage

16. Monitoring safety after licensing
Add images for the concepts

17. EUHASS (European Haemophilia Safety Surveillance)
AE surveillance scheme
All adverse events inc inhibitors
All products
All inherited bleeding disorders
All severities
Prospective (1st Oct 2008)
Sentinel centres in Europe
to Dec 37,675 patients in 78 HTC from 26 EU countries

18. Concentrates Used Jan 2014- Dec 2014 69 Different Products
Recombinant
Advate, 2580
Kogenate/Helixate, 2578
ReFacto AF 1695
BeneFix, 1187

19. EUHASS Patients Under Surveillance Jan 2014- Dec 2014
Total
Severe
Concentrate /FFP treated during the year
Factor V
567
105 38
Factor VII
2491
374
178
Factor X
553 80 69
Factor XI
2913
358 65
Factor XIII
201
116
106

20. SELECTED Events ReportedAE
Year 1-6
Inhibitors – recurrence 35
Thrombosis within 30 days of concentrate 88
Thrombosis with no concentrate in 30 days 59
Malignancies
319
Deaths
563
TOTAL
1064

21. Myocardial infarction / angina 16/3 Stroke/TIA 7/7
Thromboses within 30 days of concentrate: Years 1-6 (Oct 2008-Dec 2014)
Event
Number
Myocardial infarction / angina
16/3
Stroke/TIA
7/7
Venous thromboembolism 33
Port thrombosis 7
Other 15
TOTAL 88

22. Malignancy type Oct 2008-Dec 2014
Number
Hepatocellular carcinoma 68
Gastrointestinal 36
Lung 26
Lymphoma 25
Other
164

23. Large scale studies: Strengths
Large numbers No selection bias Prospective Long duration Earlier results
Quicker identification of danger signals
All products monitored at same time
Not industry led
Less costly than industry studies
Collaboration between participants for other projects

24. Large scale studies: limitations
Accuracy of diagnosis of severe hemophilia (<1% vs 1+%) Uncertainty about reporting of all events No standard protocol for inhibitor testing No central lab inhibitor testing Limited details about risk factors (eg peak treatment moments, genetic analysis etc)
Limited data on inhibitor peak height and persistence
Limited data on inhibitor significance in terms of FVIII recovery
No audit visits
EUHASS model overestimates PUP inhibitor rate for new products
No definite proof that the EUHASS model for PUP inhibitor estimation is accurate

25. Acknowledgements
Mike Makris for the slides on EUHASS EUHASS/CHESS network collaborators Slides at