TTSN Workshop Atlanta May 2008 SARs... · 2018-10-09 · TTSN Workshop Atlanta May 2008. 23 official languages Population: almost 500 million Diverse stages of ... month 20-32 Pilot

Adverse Events and Reactions in Tissues

and Cells: THE EUSTITE PROJECT

Deirdre FehilyItalian National Transplant Centre

Luc NoelWorld Health Organisation

TTSN Workshop Atlanta May2008

23 official

languages

Population: almost

500 million

Diverse stages of

economic development

27 Member States(12 joined since 2004)

The EUSTITE Project

European Union Standards and Training in

the Inspection of Tissue Establishments

– 12 Partners

– 2.5 M Euro (3.2 M dollars) - co-funding

– December 2006 – November 2009

– Website: www.eustite.org

Project Shape

Inspection

Guidelines

Edition 2

Inspector

Training

Survey of AR

and AE systems

Proposed

System for

EU

System Trial

Inspection

Guidelines

Edition 1

V&SMAC

Definitions

& classification

Objectives: Development of a model for the reporting and

investigating of adverse events and reactions associated with the

quality and safety of tissues and cells in the EU (Work Package

4(b))

! month19 Development of the model

! month 20-32 Pilot implementation July 2008 to July 2009

! month 33-36 Report and Recommendation to SANCO

WHO is the leading partner for this workpackage

Vigilance and Surveillance in EUSTITE

EU Directive Definitions

‘Serious Adverse Reaction’ means an unintended response, including

a communicable disease, in the donor or in the recipient associated

with the procurement or human application of tissues and cells that is

fatal, life-threatening,disabling, incapacitating or which results in, or

prolongs, hospitalisation or morbidity

‘Serious Adverse Event’ means any untoward occurrence associated

with the procurement, testing, processing, storage and distribution of

tissues and cells that might lead to the transmission of a

communicable disease, to death or life-threatening, disabling or

incapacitating conditions for patients or which might result in, or

prolong, hospitalisation or morbidity

Vigilance and Surveillance Activity in

the First Year of the Project

• Vigilance and Surveillance systems in the EU and beyond

examined in detail – report available on www.eustite.org

• 2 meetings of EU and Global Experts to explore the best

approach to defining, classifying, reporting, managing and

reacting to adverse events and reactions

• Proposals for EU V&S system advanced

• Madrid, March 2007

• Rome, July 2007

EUSTITE Vigilance and Surveillance

EU and Global

V&S Medical Advisory Committee

EU MAC

+ Non-EU participants from all Regions

EU MACGlobal

V&S MAC

US FDA, CDC

Canada HC, PHAC

Key concepts for an EU Proposal

• Criteria for reporting SAEs to CA

• Severity grading system for SARs with guidance onwhich level to report to CA (based on ISBT systemfor blood)

• Imputability grading system for SARs

• Impact grading system (risk matrix including widersystem implications) for SAEs and SARs

• Guidance on applying these tools

• Guidance on management of SAEs and SARS thathave cross-border implications

V&S Information Flow

within an EU Member State

TE: Tissue Establishment

ORHA: Organization Responsible

for Human Application

PO: Procurement Organization

CA: Competent Authority

EC: European Commission

TE

/ORHAPO

CA

Info

rmati

on

No

tifi

cati

on

SA

E

No

tifi

cati

on

SA

R

Acti

on

oth

er

pro

du

cts

Investi

gati

on

s

Notification SAR

Notification SAE

Key role of Tissue Establishments

Exceptionally, if TE not contactable or mistrust of TE. Direct SAE/R report to CA

which would involve the TE in the ensuing investigation and measures.

V&S information flow between EU

Member States

The provision of a cells or

tissues is shown by a

green arrow

1. from a TE in the same

Member State

2. from a TE in another EU

Member State: report to

this TE and to own CA.

3. from a TE in another EU

Member State, through an

importing TE: report to this

TE and to own CA.

TE

ORHAPO

CATE

CATE

CA

TECA

TECA

TECA

TECA

TECA

TECA

ORHAPO

ORHAPO

ORHAPO

ORHAPO

ORHAPO

ORHAPO

ORHAPO

ORHAPO

EC

12

3

Key role of Competent Authorities

Reporting of Serious Adverse EVENTS

• Adverse events can be detected at any point from donation to

transplantation

• Adverse events include what are commonly called ‘near misses’

• Competent Authorities (National Regulators) will not want to be informed

about every deviation from an SOP within a Tissue Establishment

• EUSTITE proposes the criteria that should be applied when deciding

whether to report an adverse event to the Competent Authority

• EUSTITE proposes an Impact Assessment Tool to be applied for all

reported SAE

Proposed criteria for SAE reporting to

Competent Authorities

Deviations should not be reported as SAEs to CAs unless:

1. Inappropriate tissues or cells have been released for clinical

use (even if not used)

2. The event could have implications for other patients or

donors because of shared practices, services, supplies or

donors

3. The event resulted in loss of any irreplaceable autologous

tissues or cells or any highly matched (i.e. recipient specific)

allogeneic tissues or cells

4. The event resulted in the loss of a significant quantity of

unmatched allogeneic tissues or cells

Some adverse event examples….

YES

A dry shipper containing an allogeneic bone marrow

donation being transported for immediate transplant

is stolen from the courier

Examples Report to CA?


NO2 corneas discarded in the TE due to technical error

during dissection from the globe

YES






YESLiquid nitrogen container runs out of LN2, 120 heart

valves thaw out and are discarded

NO2 corneas discarded in the TE due to technical error

during dissection from the globe

YES





More event examples…..

YESBone irradiated twice – grafts released for transplant –

all recalled before use





NO

A cornea is swabbed in theatre prior to being

transplanted – subsequent culture shows growth of

bacteria (previous cultures negative)





NO




YES

All bone and skin tissue from a multi-organ, multi-

tissue donor is contaminated with Clostridium dificile

(organs transplanted, corneas and heart valves in

other banks)





NO




YES

All bone and skin tissue from a multi-organ, multi-

tissue donor is contaminated with Clostridium dificile

(organs transplanted, corneas and heart valves in

other banks)

YES

A frozen femoral head is held by a courier company

for 72 hours in a holding depot rather than being

delivered immediately (Courier company used by

many TEs in the country)


• How to assess SAE and SAR

– Severity grading system for SARs with guidance on which level to

report to CA (based on ISBT system for blood)

– Imputability grading system for SARs

– Impact grading system (risk matrix including wider system

implications) for SAEs and SARs

• Guidance on applying these tools

• Guidance on management of SAEs and SARS that have cross-

border implications

Components of the

EUSTITE V&S Tool Kit

Adverse REACTION Evaluation and

Reporting to the Competent Authority

Each report of a suspected AR received

by a TE should be evaluated using the

following tools:

"Severity

"Imputability

"Impact

Proposed Severity Grading Tool

DeathDeath

The living donor or recipient required major intervention

following procurement or tissue or cell application

(vasopressors, intubation, transfer to intensive care) to

prevent death or there is evidence of a life-threatening

transmissible infection.

Life-threatening

Adverse reaction resulted in:

- hospitalisation or prolongation of hospitalisation and/or

- persistent or significant disability or incapacity or

- medical or surgical intervention to preclude permanent

damage or impairment of a body function or

- there is evidence of a serious transmissible infection

Serious

Mild clincial consequences which do not necessitate

hospitalisation and/or result in long term disability or

consequesces for the recipient or living donor

Non serious

Rep

ort to

CA

Proposed Imputability Assessment Tool

When there is conclusive evidence beyond reaonable doubt

for attributing the adverse reaction to the tissues/cells

3 Definite,

Certain

When the evidence is clearly in favour of attributing the

adverse reaction to the tissues/cells

2 Likely,

Probable

When the evidence is indeterminate for attributing the adverse

reaction either to the tissues/cells or to alternative causes.

1 Possible

When there is conclusive evidence beyond reasonable doubt

for attributing the adverse reaction to alternative causes.


adverse reaction to causes other than the tissues/cells.

0 Excluded:

Unlikely:

When there is insufficient data for imputability assessmentNA

Proposed Impact Assessment Tool

Step 1: Probability of Recurrence

Step 2: Consequences

Step 3: Risk Matrix

Step 4: Response

Step 1 – Assess the probability of

recurrence of the event or reaction

given the controls in place

Difficult to believe it could

happen again

Rare1

Not expected to happen

but possible

Unlikely2

May occur occasionallyPossible3

Probable but not

persistent

Likely4

Likely to occur on many

occasions

Almost certain5

Step 2: Assess consequences

Insignificant impactNo affectInsignificantInsignificant0

Some applications

postponed

Minor damageNon-seriousMinor1

Many applications

cancelled or postponed

Damage to system –

services will be affected

for short period

SeriousSignificant2

Significant no. of

procedures cancelled -

importation required to

make-up short-fall

Major damage to system –

significant time needed to

repair

Life threateningMajor3

All allogeneic

applications cancelled

System destroyed – need

to rebuild

DeathSevere4

Impact on Tissue/cell

supply

Impact on Transplant

or Fertility System

Impact on

individual(s)

Actual (SAR)

Potential (SAE)

Impact

Description

Level

Step 3: Apply Risk Matrix

00000Insignificant

0

12345Minor

1

246810Significant

2

3691215Major

3

48121620Severe

4

Rare

1

Unlikely

2

Possible

3

Likely

4

Almost

certain

5

Probability of

recurrence

Consequences

Step 4: Response

The response of a TE or CA to a specific

SAR/SAE should be proportionate to the

risk indicated by the incident as assessed

by the risk matrix

Application of the EUSTITE V&S Tools:

Example 1 (invented)

• UK cornea recipient develops symptoms of vCJD 5

years after transplant – reported to TE

• SAE or SAR? Suspected SAR

• Need to apply Severity and Imputability tools at TE?

YES

• Severity Grading:

DeathDeath

The living donor or recipient required major intervention

following procurement or tissue or cell application

(vasopressors, intubation, transfer to intensive care) to

prevent death or there is evidence of a life-threatening

transmitted infection.

Life-threatening

Adverse reaction resulted in:

- hospitalisation or prolongation of hospitalisation and/or

- persistent or significant disability or incapacity or

- medical or surgical intervention to preclude permanent

damage or impairment of a body function or

- there is evidence of a serious transmitted infection

Serious

Mild clincial consequences which do not necessitate

hospitalisation and/or result in long term disability or

consequesces for the recipient or living donor

Non serious







YES

• Severity Grading: 4 (death) – Report to CA

• Imputability Grading:

When there is conclusive evidence beyond reaonable

doubt for attributing the adverse reaction to the

tissues/cells

3 Definite,

Certain


adverse reaction to the tissues/cells

2 Likely,

Probable

When the evidence is indeterminate for attributing the

adverse reaction either to the tissues/cells or to

alternative causes.

1 Possible

When there is conclusive evidence beyond reasonable

doubt for attributing the adverse reaction to alternative

causes.


adverse reaction to causes other than the tissues/cells.

0 Excluded:

Unlikely:

When there is insufficient data for imputability

assessment

NA







YES

• Severity Grading: Death – Report to CA

• Imputability Grading: 1 (possible)

• Need to apply the impact tool - YES

Application of the EUSTITE V&S

Tools: Example 1

Step 1 – Assess the probability of recurrence (UK

Context):

4 (likely)


happen again

Rare1

Not expected to happen but

possible

Unlikely2


Probable but not persistentLikely4


occasions

Almost certain5


Tools: Example 1

Step 2 – Assess the consequences:


Some applications

postponed


Many applications

cancelled or

postponed


services will be affected

for short period

SeriousModerate2

Significant no. of

procedures cancelled

-importation required

to make-up short-fall

Major damage to system

– significant time needed

to repair

Life-threateningMajor3

All allogeneic


System destroyed –

need to rebuild

DeathSevere4

Impact on

Tissue/cell supply


or Fertility System

Impact on

individual(s)

Actual (SAR)

Potential (SAE)

Impact

Description

Level

4 (severe)


Tools: Example 1

00000Insignificant

0

12345Minor

1

246810Moderate

2

3691215Major

3

48121620Severe

4

Rare

1

Unlikely

2

Possible

3

Likely

4

Almost

certain

5

Probability of

recurrence

Consequences

Step 1:

Assess the

Probability of

Recurrence:

4

Step 2:

Assess the

Consequences:

4

Step 3:

Apply the Matrix:

16Major active

response by CA


Tools: Example 2 (invented)

• Fracture in an irradiated massive allograft

(femur) 2 months after transplant


• Need to apply Severity and Imputability

tools at TE? YES

• Severity Grading: Serious

• Imputability Grading: 2 (likely/probable)

• Need to apply the impact tool - YES


Tools: Example 3

Step 1 – Assess the probability of recurrence:


happen again

Rare1

Not expected to happen but

possible

Unlikely2


Probable but not persistentLikely4


occasions

Almost certain5

4 (Likely)


Tools: Example 3

Step 2 – Assess the consequences:

1 (minor)


Some applications

postponed


Many applications

cancelled or postponed


services will be affected for

short period

SeriousModerate2

Significant no of

procedures cancelled -

importation required to

make-up short-fall

Major damage to system –

significant time needed to

repair

Life-threateningMajor3

All allogeneic


System destroyed – need to

rebuildDeathSevere4

Impact on

Tissue/cell supply


or Fertility System

Impact on

individual(s)

Impact

Description

Level


Tools: Example 3

Step 1 – Assess the

probability of

recurrence:

4 (likely)

Step 2 – Assess the

impact if the

event recurs:

1 (minor)

Step 3 - Risk Matrix

4 (yellow)

– active limited

response by CA00000Insignificant

0

12345Minor

1

246810Moderate

2

3691215Major

3

48121620Severe

4

Rare

1

Unlikely

2

Possible

3

Likely

4

Almost

certain

5

Probability of

recurrence

Consequences

CA Vigilance Action

How Competent Authorities respond to SAR/E by

– Routine Responses to SAE/R Reports

• From ‘watching brief’ to ‘urgent action’

– Rapid Alerts

• Incident of a serious or potentially serious nature

• Potential risk to other individuals across member states

• Wider public health implications

– Regulatory Action Notices

• Based on serious incidents or trends

• Lessons learnt from investigations of SAR/E sharedthroughout the professional community

EUSTITE proposes criteria for the evaluation of a V&S systems

EUSTITE Vigilance and

Surveillance Pilot

• The approved EUSTITE ‘tool kit’ and reportingsystem will be piloted in partner countries and in anyother MS that wish to participate for 1 year from July2008

• All SAEs and SARs will be collated and theirmanagement and outcome reviewed and reported

• The project will make recommendations to SANCOon future management of V&S of tissues and cells inthe EU

• WHO will publish global recommendations onmanagement of V&S in transplantation

Deirdre Fehily

Italian National Transplant

Centre

[email protected]

Documents

TTSN Workshop Atlanta May 2008 SARs... · 2018-10-09 · TTSN Workshop Atlanta May 2008. 23 official languages Population: almost 500 million Diverse stages of ... month 20-32 Pilot