Quality and Vigilance Cases

EU Directive Definitions Directive 2004/23/EC Article 2 ‘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 ‘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

SAE or SAR? Bacterial contamination detected in a sample taken at the cornea bank following distribution. Growth detected after transplantation – no symptoms in recipient. SAE Recipient develops HCV after tissue transplant (suspected caused by transplant) SAR Equipment sterilisation failure results in discard of multiple tissues SAE TE discovers that tissues are being procured without consent and medical history by a procurement organisation that supplies to them SAE Wrong valve issued for transplant – discovered immediately before implantation ?SAR

Case 1: Problem with serology testing of cornea donors The analysis of HIV Ab (Chemiluminescent microparticle immunoassay CMIA) gave in positive results in average 11 % when testing post-mortem blood samples of cornea donors. All samples were frozen for transport to the laboratory (LAB 1) because it had a validated method for post-mortem samples. The analysis method most probably gave false positive results since: HIV NAT testing was negative for the same donors At the national level only 0,06% of the population has been diagnosed with HIV infection.

Case 1: Further information Probable reasons for the false positive results: Individual progression of decomposition artefacts, small particles and other unknown factors in post-mortem blood (<24h post mortem). Technical difficulties during the blood sampling procedure. Non-complete clot formulation after blood sampling. Pre-analytical sample handling (cooling time after sampling, centrifugation, separation, freezing, transportation by plane to test lab, thawing, re-centrifugation).

Should the cornea donations be rejected or accepted? What actions should be taken? Case 1 – The Questions

Sample type was changed from plasma to serum, but the change did not decrease the amount of false positive results. During investigation it was concluded that the probable reason for false positive results might be the freezing of the serum which might increase degradation of serum components into even smaller particles interfering with the analysis. The tissue bank decided to change the testing lab because of the false positive results. The new lab (LAB2) is using electrochemiluminescence immunoassay (ECLIA). LAB2 is a local laboratory, so fresh samples (un-frozen serum) can be used. The method is validated only for pre-mortem samples. First 102 post- mortem samples tested were negative for HIV. Likewise NAT analyses were negative for these samples. Case 1 – The Outcome

There was still concern whether the decision was right since according to directive 2006/17/EC “The type of test used must be validated for the purpose in accordance with current scientific knowledge.” When LAB 1 offered to test a new modification of the CMIA free of charge, the tissue bank decided to test serology parallel both in LAB 1 and LAB 2 for 50 consecutive donors. The results of the first four samples were negative in both LAB 1 and LAB2. However already the fifth sample was HIV positive in LAB1. In LAB 2 the result was negative. Also the NAT test was negative. Donor’s medical or social history did not reveal increased risk for HIV. Case 1 – The Outcome contd.

The tissues were released for use on the basis that: LAB2 result and NAT result were negative. Donor’s medical or social history did not reveal increased risk for HIV. LAB1 results have been earlier considered to be clearly false positive. Yes, the tissue bank is planning to validate the LAB2 analysis method for post-mortem samples. Freezing of samples may be problematic Case 1 – The Outcome

Donor of heart valves and corneas. The first determination RPR was negative. But in a second determination, it was TPHA + (IgG +, IgM-). One cornea was already grafted. What would you do? SAE or SAR? CASE 2

Another analysis was performed, and it was also positive. It was a past infection.

The corneas were kept in Optisol® No complication in the recipient.

Case 3 Third person report of a recipient who died of “Mad Cow disease contracted through a corneal transplant.” The deceased had corneal transplant in March 2011 and died May The donor of the cornea had donated ocular and MS tissues. Donor Eligibility determination was appropriate as donor had no risk factors or medical history to be ruled ineligible. The corneal mate had been discarded due to tissue evaluation (quality)

Case Study 3: The question What should you do? SAE/SAR?

Case 3: The Investigation Contact partner tissue organization Work with regulators Autopsy performed and brain sent to National Prion Disease Pathology Surveillance Center Notify to regulator and/or other vigilance system Review sterilization of Instrumentation

Abnormal protease resistant prion protein (PrPSc) positive CJD not likely transmitted through corneal transplant due to: incubation time too short patient in high risk age group for sporadic CJD donor chart review revealed no elevated risk of transmission

The results of the anatomical pathology informed that a tissue donor had an adenocarcinoma. It was a heart valve and ocular tissue donor. One cornea was grafted, the other was discarded due to quality reasons. Heart valves were stored at the bank. What would you do? SAE or SAR? CASE 4

Follow up of the recipient. He hasn’t developed any reaction.

During an internal audit of an eye procurement programme it is discovered that over a 5 month period a batch of solution that was being used for xxxx was not intended for use for this purpose. It was of low purity, non-sterile and labelled ‘not for human use’ and had been purchased by a neighbouring research laboratory. During this time, 45 pairs of corneas were procured. Case 5 – What happened

Case 5 – The Questions Would your report this incident? If so, to whom? What would be the key points of the investigation and follow-up? SAE/SAR?

Case 5 – The Key Points Full root cause analysis required – (e.g. Map the process and use fish- bone?) Sharing lessons learned – no blame

Case 5: SAE investigation – establish root cause e.g. fishbone diagram SAE Factor Possible cause

Case 6: What happened: A problem with donor family interviews A tissue procurement organisation conducts donor family interviews by telephone They decide to audit the procedure by listening to a selection of interview recordings They discover that one co-ordinator routinely omits to ask certain questions, always entering ‘no’ on the donor history form for those questions or doesn’t correctly document the answers What should be done? SAE/SAR?

A focused and expanded sampling of this coordinator’s work was performed. It was determined that a full review of all cases she had been involved in needed to be reviewed – 52 donors. The full review was completed by listening to all recorded conversations where a donation was recovered and transplantable tissue was processed. Based on those findings it was determined that many of the families/historians involved needed to be contacted again for additional information to adequately complete required information.

Some challenges... High number of donors involved (52) How to document the second interview? What to say to families/ historians? The cause analysis was challenging because the coordinator involved was no longer employed Finally, all tissue (except from one donor) were considered suitable – that donor’s tissues were not released

Key Learning Points Perform more frequent audits Use larger sample sizes per coordinator Revisions needed to the donor risk assessment interview questionnaire structure and format. The donor risk assessment questionnaire was revised to eliminate the multi-part questions with the use of capture questions. All staff persons in the organization were retrained on expectations when interviewing and were trained on use of the new form.

A cornea recovery doctor has completed recovery of corneas from 4 donors and is returning to the eye bank. He stops during the 3 hour journey to have coffee and use the bathroom. While he is in the service station, the vehicle is stolen with the donation inside it. Case 7: A Surprise for some thieves!

Case 7 – The Questions 1. Would you report this incident? If so, to whom? SAE/SAR? 2. What other actions would you take? 3. Would you inform the donor family? Or the media?

Case 7 – The Key Points Maintenance of public confidence is critical to supporting donation programmes Transparency and openness are always the best approach when there is a serious adverse incident Procedures and training should make it clear that donated tissues and cells should never be left unattended!

A nurse goes to take 4 recovered corneas and their associated blood samples from a refrigerator in the hospital for transport to the eye bank She discovers that the regrigerator also contains a old half-eaten ham sandwich! What should happen next? Case 8 – A tasty snack?