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FAQs on serious adverse events and serious adverse reactions

What you need to know:

What are my obligations in relation to reporting serious adverse events or reactions?

Establishments are required to submit reports of serious adverse events (SAEs) or serious adverse reactions (SARs) ‘without delay’. Establishments should take note that a full investigation of an event or reaction is not required for submitting an initial report. The results of a root cause analysis and corrective preventative actions can be submitted as a follow-up report at a later date.

It is the responsibility of the Designated Individual (DI) to notify the HTA of any suspected SAE or SAR. In the DI’s absence this responsibility can be delegated to other designated members of staff (this process should be supported by a clearly documented procedure outlining such delegated responsibilities).

If you are a third party providing services to a licensed establishment, or if you purchase material from a licensed establishment, then you should report SAEs and SARs directly to the DI of the establishment you are working with. You should advise the DI that they need to report to the HTA on your behalf. (Please note that this system does not replace existing local reporting arrangements.)

What are the obligations of the HTA in relation to serious adverse events and reactions?

The HTA, as a competent authority under the 2007 Regulations implementing the European Tissues and Cell Directive 2004/23/EC, has a statutory obligation to ensure that systems are in place to report, investigate, register and transmit information about SAEs and SARs. This includes a duty to communicate information about any SAEs or SARs to other relevant persons or bodies such as: persons and establishments carrying out human application activities, other competent authorities and to the European Commission. This allows appropriate action to be taken if tissues or cells need to be withdrawn or control measures are required. In compliance with this requirement the HTA issues regulatory alerts if it becomes aware of circumstance affecting a number of tissue establishments.

The authority is also required to keep a register of SAEs and SARs and to make this information available to the public in a manner that it considers appropriate. The HTA has included information about SAEs and SARs in the summary of compliance reports for the Human application sector and is currently considering how best to share further learning from the submitted reports with the sector.

What is a serious adverse event (SAE)?

A serious adverse event is defined as ‘any untoward occurrence which may be associated with the procurement, testing, processing, storage or distribution of tissue or cells intended for human application and which, in relation to a donor of tissue or cells intended for human application or a recipient of tissue or cells: (a) might lead to the transmission of a communicable disease, to death or life-threatening, disabling or incapacitating conditions, or (b) might result in, or prolong, hospitalisation or morbidity.’

What is a serious adverse reaction (SAR)?

A serious adverse reaction is defined as ‘an unintended response, including a communicable disease, in a donor of tissue or cells intended for human application or a recipient of tissue or cells, which may be associated with the procurement or human application of tissue or cells and which is fatal, life-threatening, disabling, incapacitating or which results in, or prolongs, hospitalisation or morbidity.’

How do I report an SAE / SAR to the HTA?

SAE and / or SARs can be reported to the HTA via the adverse event and reaction reporting system

You will require a username and password to log into the system. If you do not have a username and password, please use the form on our website to register.

If you have forgotten your password, you can request a password reminder.

What should I do if I have a problem with the reporting system?

If you have forgotten your login details, you can request a password reminder.

If you are experiencing any other problems with our reporting system, you can contact Veronica Lindop, Regulation Officer for advice on 020 7211 3438 or email veronica.lindop@hta.gov.uk.

Can anyone at the establishment report to the HTA?

It is ultimately the responsibility of the Designated Individual (DI) to notify the HTA of any suspected serious adverse event or reaction. In the DI’s absence this responsibility can be delegated to other designated members of staff (this process should be supported by a clearly documented procedure outlining such delegated responsibilities).

When should I report an SAE / SAR to the HTA?

The DI must notify the HTA of any suspected SAE and / or SAR as soon as possible after the incident has been discovered or after notification by a third party or end user.

The establishment should not wait to conduct an investigation prior to reporting to the HTA. There is a separate form on the notification system which allows further follow-up information to be provided once an investigation has been completed.

Whom else should I report to?

If a serious adverse event or reaction which may influence the quality and safety of tissues and cells has implications for other tissue establishments, e.g. because of a shared donor, the tissue establishment should also notify those other tissue establishments as appropriate without delay.

When is an adverse event reportable to the HTA?

An adverse event can be detected at any stage from donation to transplantation. A suspected SAE should be reported to the HTA when one or more of the following applies:

  • inappropriate tissues / cells have been distributed for clinical use, even if not used;
  • the event could have implications for other patients or donors because of shared practices, services, supplies or donors;
  • the event resulted in loss of any irreplaceable autologous tissues or cells or any highly matched (i.e. recipient specific) allogeneic tissues or cells;
  • the event resulted in the loss of a significant quantity of unmatched allogeneic tissues or cells.

Examples of reportable SAEs are given below.

If you are unsure about whether or not to report an SAE, please contact the HTA for further guidance.

Should ‘near misses' be reported?

Events which are commonly referred to as ‘near misses' should be reported as SAEs if any of the above criteria are met.

When is an adverse reaction reportable to the HTA?

Any serious adverse reaction in a living donor which may influence the quality and / or safety of tissues and cells should be reported to the HTA.

Any serious adverse reaction in a recipient observed during and / or after clinical application which may be linked to the quality and / or safety of tissues and cells should be reported to the HTA.

Suspected serious transmitted infections (e.g. bacterial, fungal, viral, prion, parasitic) should always be reported to the HTA.

Examples of reportable serious adverse reactions are given below.

If you are unsure about whether or not to report a serious adverse reaction, please contact the HTA for further guidance.

What will the HTA do when it receives the report?

When the HTA receives the report, a member of the serious adverse events and reactions team will review the information provided and contact you if further information is required.  When you submit the follow-up report, it will be reviewed and a member of the team may advise if any further actions are required.

Depending on the assessed impact of the event or reaction, the HTA may offer advice and guidance to the establishment, and / or participate in the development of corrective and preventative actions or a product recall. The HTA may also use the information to adjust an establishment's risk rating which could prompt a site visit inspection. Where required, the HTA may issue a regulatory alert to inform other human application establishments, and / or competent authorities in other EU member states where there may be implications for establishments outside the UK.

What does the HTA do with the information it receives on SAE/SARs?

The HTA retains a register of the notifications it receives from establishments. The HTA has a statutory obligation to report annually to the European Commission on the notifications it has received. Additionally, the HTA is participating in a pilot on surveillance and vigilance as part of the EUSTITE project, more information about this project can be found at www.eustite.org

The 2008/09 summary of compliance report for the human application sector contains an overview of notifications received by the HTA during the 2008/09 business year.

The HTA is currently developing a communications plan to determine the best ways of sharing wider learning from SAEs or SARs, to the human application sector. Once finalised, details will be available on this website.

What happens if an SAE or SAR is discovered by a third party?

If a suspected SAE or SAR is discovered by a third party, this should be reported to the licensed tissue establishment without delay. This requirement should be detailed in the appropriate third party agreement. It is of prime importance that third parties are made aware of the need to report SAEs and SARs to the relevant licensed establishment. The licensed tissue establishment should then report this event or reaction to the HTA using the online reporting system.

What happens if an SAE or SAR is discovered by an end user?

If a suspected serious adverse event or reaction is discovered by an end user, this should be reported to the licensed tissue establishment who provided the tissues / cells without delay. This requirement should be detailed in the appropriate agreement with the end user. It is of prime importance that Third Party are made aware of the need to report SAEs and SAR to the relevant licensed establishment. The licensed tissue establishment should then report this event or reaction to the HTA using the online reporting system.

I am only licensed for procurement, whom should I report to?

If you are licensed by the HTA for procurement, you should report any suspected SAEs or SARs, which may influence the quality and safety of tissues and / or cells, directly to the HTA. You should also notify any tissue establishments who have received the tissue and / or cells as appropriate.

My product has been classified as an ATMP and I am licensed by the HTA only for procurement and testing – do I still report to the HTA?

If the suspected SAE or SAR is linked to donor selection, procurement or donor testing then you should notify the HTA.

I import tissue / cells from another EEA state – do I still report to the HTA?

Yes, if the SAE or SAR occurred in the UK, or en route to the UK (i.e. during distribution to the UK), you should report to the HTA.  You should also report to any organisations in other countries if there are implications for donors or because of shared practices.

I export tissue / cells to a tissue establishment in another EEA state - do I still report to the HTA?

Yes, if the suspected SAE or SAR occurred in the UK, you should report to the HTA. You should also report to any organisations in other countries to which you have supplied implicated tissues / cells.

When should I submit a follow-up report?

A follow-up report should be submitted using the online system without delay following completion of the internal investigation.

What information should be included in the follow-up report?

For SAEs, the follow-up report should include details of the investigation, including a root cause analysis and details of any corrective or preventative measures identified.

For SARs, the follow-up report should include details of the investigation, including confirmation of whether it was an SAR, clinical outcome, outcome of the investigation and final conclusions and any corrective and preventative measures identified.

Examples of serious adverse events with explanations

Positive microbial test result on stem cells detected at a tissue establishment post transplantation. No adverse reaction detected in the recipient.

  • reportable as a suspected SAE as inappropriate tissues may have been distributed for use.

A dry shipper containing an allogeneic bone marrow donation being transported for immediate transplant is stolen from the courier.

  • reportable as a suspected SAE as there has been a loss of irreplaceable autologous cells.

Liquid nitrogen container runs out of LN2, 120 heart valves thaw and are discarded.

  • reportable as a suspected SAE as there has been a loss of a significant quantity of allogeneic tissue which could have an impact on supply.

Cryopreserved skin past its expiry date is distributed and used on a burns patient. Discovered after the procedure.

  • reportable as a suspected SAE as inappropriate tissue may have been distributed for use.

Significant loss (80%) of stem cells in an allogeneic bone marrow graft following freezing / thawing (viability and CD34+ measured). Graft infused as there is no other option.

  • reportable as a suspected SAE as there has been a loss of irreplaceable autologous cells. This case could become a SAR depending on the outcome in the donor / recipient.

Examples of serious adverse reactions with explanations

Skin graft recipient tests positive for hepatitis B six months after the skin grafting procedure. 

  • reportable as a suspected SAR (communicable disease which may be linked to the quality and safety of the tissue).

Stem cell recipient exhibits fever post infusion, haemoculture matches bacterium discovered in the bone marrow product.

  • reportable as a suspected SAR (communicable disease which may be linked to the quality and safety of the tissue).

Defective packaging results in exposure of a heart valve outside the sterile field in theatre – heart valve not implanted. Patient already anaesthetised.  Surgery rescheduled.

  • reportable as a suspected SAR (recipient has prolonged hospitalisation and second general anaesthetic).