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

frank.tolksdorf@macopharma.de

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

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„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• Reduced discard-rate/number of outdated products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)

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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

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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

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• >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

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SHOT Report 2016

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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

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Reactions related to thenumber of issues fromUK Blood Services

Implementation pooledplatelets in PAS-ESHOT Report 2016

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Rate of allergic reactions 2014 to 2016

SHOT Report

SHOT Report 2016

NZ Blood

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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

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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)

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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

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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

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• 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

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Thanks for your attention!