J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website http://www.jocmr.org

Review

Volume 10, Number 12, December 2018, pages 857-867

Biovigilance for the Quality and Safety of Medical Products of Human Origin

Figure 1. Adverse reactions at the donor requiring report in the member states of the European Union. Source: ARTHIQS [14]. GCSF AT: Reactions due to GCSF in autologous patients; GCSF AL: Reactions due to GCSF responses at allogeneic donors; PBSC AT: Toxicity during peripheral blood collection (PBSC) in autologous donors; PBSC AL: Toxicity during peripheral blood collection (PBSC) in allogeneic donors.

**Table 1.** Allocation Scale of Serious Adverse Reactions (SARs)
Source: ARTHIQS [14].
0	Non-evaluable SAR	Insufficient data for evaluation of allocation
0	Excluded SAR	Reasonable doubts about allocating adverse reaction
0	Unlikely SAR	Evident signs and evidence for allocating to other causes
1	Possible SAR	Evidence is undefined
2	Possible SAR	Evidence is being evaluated in favor of the allocation of SARs to tissues/cells
3	Certain SAR	Conclusion without reasonable doubts about allocation of SARs to tissues/cells

Table 1. Allocation Scale of Serious Adverse Reactions (SARs)

Source: ARTHIQS [14].

Non-evaluable SAR

Insufficient data for evaluation of allocation

Excluded SAR

Reasonable doubts about allocating adverse reaction

Unlikely SAR

Evident signs and evidence for allocating to other causes

Possible SAR

Evidence is undefined

Possible SAR

Evidence is being evaluated in favor of the allocation of SARs to tissues/cells

Certain SAR

Conclusion without reasonable doubts about allocation of SARs to tissues/cells

**Table 2.** Evaluation of Serious Adverse Reactions (SARs)
SAR severity	Comments
Source: ARTHIQS [14].
Unimportant	No damage, no risk, the patient is not informed as there is no risk of damage
Non-severe	Mild clinical/psychological consequences
	There is no hospitalization
	No long-term consequences/disabilities expected
Severe	Hospitalization or prolongation of hospitalization or permanent or significant disability or incapability
	Intervention for permanent damage exclusion
	Sign of serious transmissible disease
	Birth of a child with severe genetic disease after ART with germ cells or embryo from donor
Life-threatening	Notable intervention to prevent death
	Evidence of life-threatening transmissible disease
	Birth of a child with life-threatening genetic disease after ART with germ cells or embryo from donor
Death	Death

Table 2. Evaluation of Serious Adverse Reactions (SARs)

SAR severity

Comments

Source: ARTHIQS [14].

Unimportant

No damage, no risk, the patient is not informed as there is no risk of damage

Non-severe

Mild clinical/psychological consequences

There is no hospitalization

No long-term consequences/disabilities expected

Severe

Hospitalization or prolongation of hospitalization or permanent or significant disability or incapability

Intervention for permanent damage exclusion

Sign of serious transmissible disease

Birth of a child with severe genetic disease after ART with germ cells or embryo from donor

Life-threatening

Notable intervention to prevent death

Evidence of life-threatening transmissible disease

Birth of a child with life-threatening genetic disease after ART with germ cells or embryo from donor

Death

**Table 3.** Evaluation of Adverse Events Severity [1-5]
Event description	Report to competent authority	Reference criterion
Source: The EUSTITE project “European Union Standards and Training in the Inspection of Tissue Establishments” December, 2006 to December, 2009; exercise for inspectors training program; leading organization: Centro Nazionale di Trapianti.
Bacterial infection of tissues or cells distributed for transplantation	Yes	1
Viral infection of tissues or cells distributed for transplantation: retrospective analysis demonstrates viral infection of tissues or cells previously tested and found negative	Yes	1
Documentation-evidence of infection in tissues undergoing the required sterilization procedure, which is used in many tissue establishments-tissues are not distributed	Yes	2
Incorrect type of tissue or cell: a different type of tissue or cell from that intended or requested/provided by the tissue establishment	Yes	1
An ovule has been fertilized with semen from another couple's husband	Yes	3
A bone marrow donation for a particular patient is lost during delivery to the transplantation hospital	Yes	4
Growth of bacteria is detected in an autologous umbilical cord blood collection. The cells are kept in storage in order to treat the patient with antibiotics, if any cells are used in the future	No
	Infection indexes should be reviewed during testing
An entire heart valve bank has been lost due to failure to refill a tank with liquid nitrogen	Yes	5
A cornea is rejected at the tissue establishment due to low cell count	No
	Non-regulatory action

Table 3. Evaluation of Adverse Events Severity [1-5]

Event description

Report to competent authority

Reference criterion

Source: The EUSTITE project “European Union Standards and Training in the Inspection of Tissue Establishments” December, 2006 to December, 2009; exercise for inspectors training program; leading organization: Centro Nazionale di Trapianti.

Bacterial infection of tissues or cells distributed for transplantation

Yes

Viral infection of tissues or cells distributed for transplantation: retrospective analysis demonstrates viral infection of tissues or cells previously tested and found negative

Yes

Documentation-evidence of infection in tissues undergoing the required sterilization procedure, which is used in many tissue establishments-tissues are not distributed

Yes

Incorrect type of tissue or cell: a different type of tissue or cell from that intended or requested/provided by the tissue establishment

Yes

An ovule has been fertilized with semen from another couple's husband

Yes

A bone marrow donation for a particular patient is lost during delivery to the transplantation hospital

Yes

Growth of bacteria is detected in an autologous umbilical cord blood collection. The cells are kept in storage in order to treat the patient with antibiotics, if any cells are used in the future

Infection indexes should be reviewed during testing

An entire heart valve bank has been lost due to failure to refill a tank with liquid nitrogen

Yes

A cornea is rejected at the tissue establishment due to low cell count

Non-regulatory action

**Table 4.** Reporting and Investigation of Adverse Events and Reactions per Institution
Hospital/PO
Detection of suspected SAR and SAE
Report to the tissue establishment
Participation in the investigation with the tissue establishment
Tissue establishment
When receiving a notification or detection for SAREs and SAEs internally: quarantine, recalls of other products, where necessary
Report to CA
Coordination of research in collaboration with clinical users and PO, as necessary
Competent authority
Evaluation and intervention where necessary
Annual report to the European Commission
Notification of relevant information to health care professionals to maximize SANCO update and learning (EC)
Collection and analysis of the annual SARE reports by member states
Publication of collective annual reports
Identification of important trends
Rapid alert issue for tissues and cells of immediate action, when action in more than one Member State is required

Table 4. Reporting and Investigation of Adverse Events and Reactions per Institution

Hospital/PO

Detection of suspected SAR and SAE

Report to the tissue establishment

Participation in the investigation with the tissue establishment

Tissue establishment

When receiving a notification or detection for SAREs and SAEs internally: quarantine, recalls of other products, where necessary

Report to CA

Coordination of research in collaboration with clinical users and PO, as necessary

Competent authority

Evaluation and intervention where necessary

Annual report to the European Commission

Notification of relevant information to health care professionals to maximize SANCO update and learning (EC)

Collection and analysis of the annual SARE reports by member states

Publication of collective annual reports

Identification of important trends

Rapid alert issue for tissues and cells of immediate action, when action in more than one Member State is required