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PAS-E PLATELET ADDITIVE SOLUTION HAEMOVIGILANCE REPORT, RESIDUAL RISK AND RISK/BENEFIT UPDATE
Chryslain Sumian, Frank Tolksdorf, Ignacio Alvarez
Dr. Frank Tolksdorf, Senior Medical ManagerMacopharma International GmbH, Langen, Germany
Manchester, 11 July 2018
1
• Employee of Macopharma, Langen, Germany
• Macopharma is manufacturer of platelet additive solutions SSP (PAS-B) and SSP+ (PAS-E)
Disclosure
2
„Haemovigilance“
It´s all about Vigilance
„Materiovigilance/Medical Device Vigilance“
„Pharmacovigilance“
„Biovigilance“
3
Legal basis: New Medical Device Regulation (MDR)
2022:IVDR
Regulation (EU)
2017/746
AIMD: Active Implantable Medical DevicesIVD: In Vitro Diagnostic DirectiveMDD: Medical Device DirectiveMDR: Medical Device Regulation
2020
2020:
MDR Regulation
(EU) 2017/745
AIMD
90/385/EEC
MDD
93/42/EEC
IVD
98/79/EC
4
NEW
New
NameCitrate Phosphate Acetate Magnesium Potassium Gluconate Glucose
Alternative
Names
Previous ISBT
128 Name
PAS NS NS NS NS NS NS NS Not named
PAS-A X X X PAS (1) Not named
PAS-B X XPAS-II, PAS-2
SSP, T-SolPAS-II
PAS-C X X XPAS III, PAS-
3, IntersolPAS-III
PAS-D X X X X X Composol PS PASIII-MgK
PAS-E X X X X XPAS IIIM,
SSP+, T-PAS+Not named
PAS-F X X X XPlasmaLyte
A, IsoplateNot named
PAS-G X X X X X X Not named
Terminology of Platelet Additive Solutions
Rice B. ISBT 128 Standard: standard terminology for blood, cellular therapy, and tissue product descriptions, version 6.23. 2016; https://www.iccbba.org/tech-library/international-nomenclature/platelet-additive-solution-pas-3
1. Generation
2. Generation
Platelet Additive Solution (PAS)
5
PAS are buffered electrolyte solutions, designed for partial replacement of plasma in platelet
concentrates to improve:
Safety:
• Reduced risk of plasma-related adverse transfusion reactions
• Enabling ABO-incompatible transfusions
• Reduced risk of using mismatching plasma for resuspension
• Enabling pathogen reduction treatment
Quality:
• Standardisation of platelet products
• Improved storage stability, extended storage time
Stock management/logistics:
• Versatile configurations (volume, connectivity, operational flexibility)
• Improved availability of platelet products (weekends, vacation periods)
• Reduced discard-rate/number of outdated products
• Additional plasma savings6
Platelet Additive Solution (PAS)
7
Research & Development
CE & Approval Commercialisation
Classification& Regulatory
pathway
RiskManagement
Clinical Investigation/ Applications
CE submission
Clinical EvaluationClinical
Investigation/ Evaluation
Post-Market Surveillance
Planning ProductDesign Changes/
Extensions
Pre-/postAudit
Technical File/Design Dossier
Lifecyclemonitoring
Applicationsfor Product/ CE renewal
QM-based interlinked activities
Post-Market Surveillance
(PMS)
Clinical Evaluation
Report (CER)
Risk Management (RM)
Systematic process to collect and analyse experience gained from usage of medical devices in the market, if necessary:• Update benefit/risk assessment • Update design/IFU/labelling • Update clinical evaluation• Identification of needs for preventive,
corrective or field safety corrective action• Improve the usability, performance and safety
Analysis of clinical data (clinical investigation, clinical experience and/or clinical literature review):• Demonstrate conformity with the essential requirements• Demonstrate/confirm clinical safety & performance,
risk/benefit assessment (support labelling claims)
Continuous iterative process throughout the entire lifecycle of a device, requiring regular systematic updating:• Risk Analysis, estimation, evaluation,
assessment, control, residual risk • Impact analysis of any change (design,
production, condition of use, …etc)
QM-based interlinked activities
8
Risk Management Scope
• Market introduction of PAS in 2000
• >10 Million units of Macopharma PAS have been supplied to 55 countries
• PAS is CE class III MD, covering 15 references
• Compliance with current standards for RM
Regular review of Risk Management process related to Design, Production and Usability of PAS:
• Individual/Global residual risk assessment
• Risk reduction and control measures are in place
• Residual risk is considered acceptable
• Risk/Benefit assessment outcome: Clinical benefits outweigh residual risks
R&D
Process/ProductValidation
Industrialization
Distribution, Warehouse
Processing
Application/ Administration
Disposal
Pro
du
ctLi
fe C
ycle
9
• >7 Mio units of PAS included in HV programmesof 15 countries
• 89 Haemovigilance- and related reports reviewed
• State-of-the-art reviews (Databases, Journals, Registries, Presentations/Abstracts, Customer Surveys, etc.)
• Pre- and post-market clinical studies
Haemovigilance Scope
10
SHOT Report 2016
11
Recommendation• Platelets suspended in platelet additive solution (PAS) are associated with a reduction in allergic response (BSH Estcourt et al. 2017). Hospitals should consider preferential use of readily available pooled platelets suspended in PAS in patients with a history of allergic reactions. This should include paediatric patients where apheresis platelets are usually the platelet component of choice. If reactions continue, despite antihistamine cover, then platelets resuspended in 100% PAS can be supplied
SHOT Report
12
Reactions related to thenumber of issues fromUK Blood Services
Implementation pooledplatelets in PAS-ESHOT Report 2016
13
Rate of allergic reactions 2014 to 2016
SHOT Report
SHOT Report 2016
NZ Blood
14
Annual numberof bloodcomponentstransfused
Annual Report 2016, NZ Blood
Reported events 2009-2014 by type of platelet component transfused (imputability score ≥3):
0.640.59
0.85
0.27
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Plasma PAS
Rat
e a
s%
of
un
its
tran
sf
Adverse events
APC BC
0.36
0.19
0.38
0.15
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Plasma PAS
Rat
e a
s%
of
un
its
tran
sf
Allergic events
APC BC
15
NZ Blood
p = 0.001
Adapted from Annual Report 2014, NZ Blood
APC: Apheresis plateletsBC: Pooled buffy coat platelets
16
Swissmedic HV Report
2008 2009 2010 2011 2012 2013 2014 2015 2016
Platelet units
issued
27,600 29,600 29,900 33,068 34,265 34,750 35,328 36,439 38,374
Adverse
reactions
1/178 No data No data No data ~ 1/350 ~ 1/380 ~ 1/350 ~ 1/350 ~1/350
Allergic
reactions
~ 1/300 ~ 1/670 ~ 1/500 1/568 ~ 1/500 ~ 1/500 ~ 1/500 ~ 1/650 ~1/500
Annual TR reporting rates 2008-2016 related to the number of PCs issued:
Implementation ofuniversal PI
Adapted from Swissmedic HV Reports 2008-2016
Implementation of PAS(-E)
17
Transfusion reactions 2008-2011
PC
2011-2015
PI-PC
Units transfused 93,600 167,200
Risk = 1 reaction per x PC Reports Risk Reports Risk
All high-imputability reports 344 ~ 1/ 270 448 ~ 1/ 375 P<0.001
High-imputability reports,
Grade 3 & 4
33 ~1/ 2800 19 ~ 1/ 8800 P<0.001
Reported transfusion reactions involving conventional and pathogen-inactivated PC:
Swissmedic HV Report
PC: platelet concentrate
PI-PC: pathogen-inactivated platelet concentrate
Adapted from Swissmedic HV Reports 2008-2015
THERAFLEX UV-Platelets
Principle:
• UVC light only, NO photoactive agent needed• DNA/RNA directly absorbs UVC light
Process:
• Platelets suspended in SSP+ (PAS-E)• Agitation + UVC treatment (<1min)• Fast processing and release
Clinical Studies
18
Type of Study Objective(s) Design, Type of control n Study population Ref.
Observational post-
market study
Recovery & CCI of platelets in SSP+
compared with platelets in plasma
Plasma platelets 3940 Txn patients Tardivel et al. ISBT
2012
Recovery and
Survival
post-transfusion recovery and life-span of
platelets in SSP+
Open label;
fresh platelets
12 healthy subjects Cardigan et al.
2008
Recovery and
Survival
post-transfusion recovery and life-span of
platelets in SSP+ treated with UVC-PRT
Open label; Non-treated
fresh platelets
12 healthy subjects Bashir et al.
Transfusion. 2012
Recovery and
Survival
post-transfusion recovery and life-span of
platelets in SSP+ treated with UVC-PRT
Open label; Non-treated
stored platelets
37 healthy subjects Blajchman et al.
2010
Phase I
Safety & Tolerance
safety and tolerance of platelets in SSP+
treated with UVC-PRT;
Open label; Non-
controlled
11 healthy subjects Thiele et al. Vox
sanguinis. 2015
Phase III „CAPTURE“
Efficacy
Efficacy (CCI) and safety of SSP+ platelets
treated with UVC-PRT
RCT, Non-treated
platelets
150 patients ongoing
• Neither adverse reactions, nor antibody formation were observed
• Outlook: Post-Market surveillance studies are planned to evaluatethe safety of THERAFLEX UVC-treated platelets suspended in SSP+
Clinical Studies
19
• Use of platelets suspended in platelet additive solution (PAS) is associated with a reduction in allergic response
• No (s)AE/AR related to PAS-E/SSP+ have been reported in routine use, regardlessof supply volume or extend of use
• No (s)AE/AR related to PAS-E/SSP+ have been reported in clinical studies
• Risk/Benefit ratio has been considered/remains up-to-date and acceptable forboth users and patients
• National HV reports are a valuable source for safety information for transfusion services and manufacturers
Conclusions
20
Thanks for your attention!