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HFEA Licence Committee Meeting 7 November 2013

Finsbury Tower, 103-105 Bunhill Row, London, EC1Y 8HF Minutes – Item 8 Centre 0101 (CARE Nottingham) – Grade A Incident IN03434 and the preliminary findings of another reported incident Members of the Committee: Sally Cheshire (lay) Chair Gemma Hobcraft (lay) Bishop Lee Rayfield (lay) (video) Debbie Barber (professional) Andy Greenfield (professional) Committee Secretary: Lauren Crawford

Legal Adviser: Graham Miles, Morgan Cole Observing: Sam Hartley, Head of Governance and Licensing, HFEA Juliet Tizzard, Interim Director of Strategy, HFEA

Declarations of Interest: members of the Committee declared that they had no conflicts of interest in relation to this item. The following papers were considered by the Committee:

Executive Summary HFEA’s root cause analysis Centre’s incident investigation report Person Responsible’s statement regarding the continued

suitability and use of Genesis Genetics Europe Service Level Agreement between centre no 0101 and Genesis

Genetics Europe Genesis Genetics Europe incident report Genesis Genetics Europe audit of 2013 de novo PGD cases

Previous Executive Licensing Panel minutes: a) 14 January 2010 – interim inspection report b) 15 June 2012 – licence renewal report

Previous Licence Committee minutes: 21 January 2010 – grade A incident 30 April 2010 – grade A incident 27 May 2010 – grade A incident 24 June 2010 – grade A incident 11 June 2012 – grade A incident

The Committee also had before it:

HFEA Protocol for the Conduct of Licence Committee Meetings and Hearings

8th edition of the HFEA Code of Practice Human Fertilisation and Embryology Act 1990 (as amended) Decision trees for granting and renewing licences and considering

requests to vary a licence (including the PGD decision tree) Guidance for members of Authority and Committees on the handling of

conflicts of interest approved by the Authority on 21 January 2009. Guidance on periods for which new or renewed licences should be

granted Standing Orders and Instrument of Delegation Indicative Sanctions Guidance HFEA Directions 0000 – 0012 Guide to Licensing Compliance and Enforcement Policy Policy on Publication of Authority and Committee Papers

Consideration

1. The Committee noted that this is an incident reporting a possible PGD

misdiagnosis. The initial incident information relating to the incident being considered here describes a highly specialised diagnostic test (for a de

novo mutation) and not the ‘usual’ PGD analysis.

2. The Committee noted that the centre’s initial investigation revealed that operator error may be the root cause but this was still under investigation.

3. The Committee noted that the centre has previously had a number of PGD

- related incidents. 4. The Committee noted that further to incident IN03434 another possible

misdiagnosis has been reported. The information collected so far for this incident has also been submitted to the Licence Committee.

5. The Committee noted that the Genesis Genetics Europe reported the

incident to its accrediting body, Clinical Pathology Accreditation (CPA). To ensure that the incident was thoroughly considered by the appropriate experts, the executive endeavoured to arrange a joint incident inspection with their accrediting body.

6. The Committee noted that the HFEA Root Cause Analysis (RCA) for incident IN03434 states that the root cause of the incident could be:

Insufficient oversight around the scheduling of a complex test. Staff not adhering to processes documented in SOPs. The absence of formal training and competence assessment of staff in

relation to rarely performed/complex tests. Written and verbal communications not clear in relation to the type of PGD

case (i.e. de novo).

7. The Committee noted that the Executive has taken steps to ensure a full and proper investigation takes place including holding a crisis management meeting to discuss the options for this centre. The Executive has also fully engaged with the Centre and the Clinical Pathology Accreditation (CPA).

8. The Committee noted the receipt of the initial reports for another possible PGD-related incident at the same centre. This information was supplied as it is relevant to incident IN03434.

Decision 9. The Committee noted that, although they had a lot of information before

them, neither incident had been fully investigated as yet. The Committee recognised that incident IN03434 involves specialist techniques and obtaining experts in that field may be adding to time taken to get the report finalised.

10. The Committee decided to adjourn the item for receipt of further information. This information should include:

a. Final investigation reports for both incidents b. Further information regarding PGD diagnosis error rates across the

sector for comparison c. Further information about Genesis Genetics Europe – including how

many other centres use their labs for PGD; do they have other labs d. Clarity on the status of the patients affected by the incident

11. The Committee noted that although the item was adjourned they would

expect an update on the status of both of these incidents at the next meeting of the Licence Committee (January 2014). The Committee is concerned by the frequency of incidents regarding PGD happening at this centre and the potential risks to current patients and unborn children.

12. The Committee urged the centre and the Executive to provide this extra information as soon as possible, given the serious nature of these incidents.

Signed: Date: 21/11/2013

Sally Cheshire (Chair)

Doc name: Template RCA incident investigation report

Doc reference: CT-14 Version: 1.1 TRIM reference: 2010/03639 Release date: 20 June 2011

Incident Investigation Report

Centre no 0101 – incident number IN03434

Since October 2009 the HFEA has normally published A grade incident reports and the

associated Licence Committee minutes on our website.

Background of the centre and the licencing history CARE Nottingham is a privately run unit and provides a wide range of fertility treatments including pre-implantation genetic screening and diagnosis (PGS and PGD). The centre carries out approximately 2000 cycles of licenced treatment a year. The centre was first established in 1985 and a licence renewal inspection last took place on 28 February – 1 March 2012. At the time of inspection one critical non-compliance, two major non-compliances and seven ‘other’ non-compliances were noted. The Executive Licencing Panel (ELP) granted the centre a four year licence with no additional conditions. The Person Responsible (PR) is also the Laboratory Manager and is an experienced embryologist who has completed the HFEA PR entry programme. In July and November 2009 the centre reported two (unrelated – see footnote) A grade incidents regarding PGD misdiagnosis1. In 2011 the centre reported a further incident initially categorised as an A grade incident resulting from a PGD misdiagnosis. The HFEA understands that those directly affected by the incident are taking legal action. The HFEA is informed that the testing laboratory has since performed further analysis of the samples to suggest that other factors, rather than a PGD misdiagnosis, are relevant to the ultimate outcome of the treatment. This remains under review by the centre and the HFEA. Summary Incident Description & Consequences A couple had a treatment cycle of PGD in July 2013, testing for Neurofibromatosis2. Ten embryos were biopsied on Day 3 and the cells were sent to Genesis Genetics (Europe)3 for analysis. Two biopsies returned a result of unaffected/normal, three indicated the source embryos were affected and 5 provided insufficient data in the report for a result to be given.

1 One incident was a single gene disorder tested for by PCR (polymerase chain reaction), the second was a chromosomal translocation case tested by FISH. The two analyses were carried out at different testing labs – Genesis Genetics Institute and the Bridge Genoma. 2 Neurofibromatosis Type 1 (NF1) also known as von Recklinghausen NF or Peripheral NF is an autosomal dominant disorder occurring in 1:3,500 births. NF1 is characterised by multiple cafe-au-lait spots and fibromatous tumors on or under the skin. Enlargement and deformation of bones and curvature of the spine (scoliosis) may also occur. Occasionally, tumors may develop in the brain, on cranial nerves, or on the spinal cord. About 50% of people with NF also have learning disabilities. 3 Genesis Genetics (Europe) is the European subsidiary of the Genesis Genetics Institute, a large PGD service provider based in Detroit, USA. Genesis Genetics (Europe) provide PGD services to CARE Nottingham through a third party agreement. Genesis Genetics (Europe) occupy laboratory space within the CARE Nottingham building to allow them to do this.



On 03 July 2013, in conjunction with the embryo development information, one of the apparently unaffected embryos was transferred to the woman and one was frozen for future use. Three of the ‘no result’ embryos were re-biopsied at the blastocyst stage and frozen for possible future use pending the results of testing of the blastocyst biopsies by Genesis Genetics (Europe). A positive pregnancy test was performed on 15 July 2013. On 16 July 2013, Genesis Genetics (Europe) contacted the PR of the centre to inform her that on re-reading the original testing data from the Day 3 biopsies, they had found that the data had been interpreted incorrectly and the results report issued by Genesis Genetics (Europe) to CARE Nottingham on 2 July 2013 had given an incorrect diagnosis for the embryos. Therefore the embryo that was transferred to the woman and the embryo that was frozen for future use in treatment, which were initially interpreted as being unaffected, were actually affected with the genetic disease, while the three embryos that had been originally interpreted as affected and which had been allowed to perish, were in fact unaffected. Background to PGD analysis for do novo cases Usually in PGD, an affected reference child or close relative is available so that prior to the PGD IVF cycle, the mutated gene can be linked during test optimisation to STR4 markers on the chromosome bearing the mutation, thus identifying the affected allele haplotype. In PGD this is termed ‘setting phase’. This allows testing to investigate the presence of several STR markers linked to the mutation, that is ‘haplotype testing’. This is undertaken to improve the accuracy and reliability of the test. However, in a first cycle de novo5 case such as the case involved in this incident, a reference individual is not available. This prevents phase setting prior to testing of the embryo biopsies on the day the procedure is undertaken. Instead, phase has to be set on the day by performing direct sequencing of the mutation site using whole genome amplified (WGA) DNA from each of the embryo biopsies. The sequencing results are then correlated with the results of informative STR marker testing which is run in parallel. Once an embryo is clearly identified bearing the mutation, the parental STR markers linked to the mutation can be identified. Therefore setting phase on case day is reliant on good quality direct mutation sequencing, which can be complicated by allelic drop out (ADO) because single cell PGD biopsy samples frequently do not amplify all loci. Operator experience and competence is also essential since the sequencing and informative marker testing data must be interpreted on the day of testing to assign phase accurately. Thus de novo PGD haplotype testing is recognised as being more technically demanding than normal PGD testing where setting phase can be accomplished before the case day using samples from affected relatives. Incident type: PGD misdiagnosis

4 A short tandem repeat (STR) is a type of DNA polymorphism where short sequences of DNA are repeated. STRs are

usually considered “junk DNA” because they are introns and do not code for protein. The number of times a DNA sequence is repeated for a given STR is variable between different individuals and thus, STRs are often useful for forensic or genealogical studies.

5 A de novo mutation refers to a genetic mutation that neither parent possessed or transmitted.



Specialty: PGD testing laboratory Effect on patient:

Significant impact on couple who have been informed that an affected embryo has been selected and transferred resulting in an on-going pregnancy.

Severity level: HFEA Grade A Terms of reference To identify the root causes and key learning from this incident and use this information to significantly reduce the likelihood of future harm to patients. Scope and Level of Investigation HFEA Root Cause Analysis Incident inspection including document review Investigation by Genesis Genetics (Europe) (included in the report from centre 0101) The executive has taken longer than usual to schedule the incident inspection in an effort to initiate a joint inspection with the CPA6 . Unfortunately the executive were not able to perform a joint inspection as the CPA was unable to participate at this stage. However the CPA will be carrying out its own investigation and is keen to receive input from the HFEA regarding this incident7. Chronology of events - See table overleaf Notable Practice Actions were taken to inform the couple of the incident in an open and honest way. The incident was reported in line with the HFEA’s incident reporting requirements. The centre ensured that staff from the testing laboratory were available on the day of inspection and all participants contributed positively to the inspection and subsequently. The Laboratory Director from Genesis Genetics Europe carried out an audit of previous de novo cases8. Involvement and support of Patient and Relatives Documentation provided by the PR confirms that contact and communication has been maintained with the patient throughout this investigation. Care and service delivery problems at Genesis Genetics (Europe)

Genesis Genetics (Europe) SOP states that the ‘Case Data Reader’ - a document designed to allow the compilation and display, in an easy to interpret format, of the results of STR marker testing and direct mutation screening for each embryo - should be completed at least 7 days ahead of the receipt of embryo biopsies on the case day. This ensures adequate time to request and receive any missing information and items. Further to this, the SOP states the PGD Pre-Case checklist should be signed off by the laboratory scientist and approved by the laboratory manager once the Case Data Reader is completed.

On the day the biopsies were received from centre 0101, a laboratory scientist at Genesis Genetics (Europe) created the Case Data Reader rather than it being

6Clinical Pathology Accreditation (CPA) is the organisation which accredited Genesis Genetics (Europe). 7 The CPA carried out their inspection on 22 October 2013. 8 Audit looked back at the previous three years’ worth of cases. Copy of audit findings provided in bundle.



completed 7 days in advance of receiving the samples. This is a breach of the laboratory’s SOP. The Day Case Reader was also completed incorrectly since it did not allow the inclusion of direct mutation sequencing data.

A further breach occurred as the completed Pre-Case checklist was not signed off by the laboratory manager at Genesis Genetic (Europe).

The senior member of staff at Genesis Genetics (Europe) who reviewed the Case Data Reader did not read/scroll down the whole document and failed to see the note “mutation is de novo” at the bottom of the document. Therefore this member of staff did not realise this was a de novo case.

The laboratory scientist at Genesis Genetic (Europe) performing the testing incorrectly set phase when interpreting the testing results.

Contributory Factors

At the time of this incident the laboratory staff at Genesis Genetics (Europe) did not undergo specific competency assessment regarding de novo cases.

The senior scientist who carried out the Case Data Reader review and who was available to provide advice to the laboratory scientist performing the test, was working in a Genesis Genetics laboratory in London while the biopsy testing was being performed in a laboratory in Nottingham.

Information explaining this was a de novo case did not alert the senior scientist carrying out the Case Data Reader review, probably because it was not displayed in a prominent position. Nor did any of the e-mail communications between the staff highlight that this was a de novo case.

Root Causes Insufficient oversight around the scheduling of a complex test. Staff not adhering to processes documented in SOPs. The absence of formal training and competence assessment of staff in relation to

rarely performed/complex tests. Written and verbal communications not clear in relation to the type of PGD case (i.e.

de novo). Lessons Learned It is important to ensure a high level of alertness is attached to any rare/unusual test or procedure carried out either for or on a patient. Sufficient information should be communicated to the team carrying out the test/procedure in a timely fashion. This should include reference to the appropriate SOPs, specific task allocation and more importantly to discuss what to do if conditions are not optimal to continue with the test/procedure. Recommendations Genesis Genetics (Europe) has initiated a number of corrective actions to minimise the reoccurrence of a similar incident9:

All staff will be trained to clearly note that for de novo cases, without reference or phase on a previous cycle, phase must be set with direct sequencing analysis of mutation analysis. A specific training event will be scheduled. Only when competence is assured will staff be signed off to analyse data and report results in de novo cases.

9 Please see section 7 – corrective actions of the Genesis Genetics Europe report for full text.



All case family ID for de novo cases will include de novo in the unique family identifier. SOPs and database entries will be amended accordingly.

All de novo cases run by Genesis Genetics (Europe) in future will be performed on biopsy samples from vitrified embryos in order to allow additional case reader proof reading or additional markers/sequencing to be run. Genesis Genetics (Europe) users will be notified by the Laboratory Director and protocols amended.

All de novo Case Data Readers will be created at least one week in advance of case day and will be independently proofed by a senior scientist.

Case notes will be moved to the top of the Case Data Reader. All de novo cases will require a third read by the Genesis Genetics (Europe) laboratory

manager or the Genesis Genetics (Detroit) laboratory manager in their absence. Protocols will be amended.

Further formalised training in sequencing has been requested by a member of staff and Genesis Genetics (Europe) are fully supportive in providing this. This further training will consist of a formal training program in sequencing analysis at Genesis Genetics (Detroit).

However as the HFEA has no direct regulatory powers as regards (notwithstanding the centre’s third party agreement) Genesis Genetics (Europe) the executive recommends that the PR provides to the Licence Committee a written statement explaining why she, as the PR at the centre, is satisfied in allowing Genesis Genetics (Europe) to continue to PGD analysis on behalf of CARE Nottingham patients. The PR has now provided a written statement as to why she is satisfied that Genesis Genetics Europe is a safe and suitable laboratory to carry out embryo testing on the centre’s behalf. The executive consider that this is insufficient. The statement does not include information on how the PR will monitor and consider as complete the corrective actions10 Genesis Genetics intend to carry out in relation to this incident. Further work should be undertaken in relation to this issue. For the PR to demonstrate that Genesis Genetics Europe is carrying out suitable practices11 in the course of the activities they carry out on behalf of the centre, the executive recommend that the PR provides;

an action plan as to how she will monitor the laboratory’s progress against their remedial actions

this action plan should contain well defined timeframes to ensure that these actions are monitored in a timely fashion

a suitable audit trail of evidence as referenced from Genesis Genetics’ investigation report

Although it is not entirely clear at this point what the root cause of one of the incidents at Genesis Genetics was, it is clear from the evidence contained in this report that in at least one of the two incidents that have been reported to the HFEA, there were some shortcomings in the processes at Genesis Genetics. In light of this and the lack of assurance, in the executive’s view, that these inadequacies have been properly addressed and therefore the

10 The corrective actions are mentioned in this section of the report and in full in Genesis Genetics Europe report (section 7) 11 The PR under SLC T2 has a duty to ensure that suitable practices are being used in the course of activities authorised by her licence



likelihood of any further serious incidents of this nature are reduced, the Executive recommends that the PR provides further assurances. The executive consider it would be disproportionate and unfair to CARE patients to suspend the centre’s PGD/PGS programme. However the continued use of Genesis Genetics in the absence of assurances that the remedial actions have been properly implemented and thus the possibility that further patients and their embryos may face similar risks to those patient’s affected by the reported incidents, the executive recommends that the Licence Committee make a direction using their powers under section 24(13)(a) and (b) of the HFE Act 1990 (as amended) to direct the PR not to use the services of Genesis Genetics Europe for the purpose of embryo testing (for PGD & PGS). When this evidence is provided to the satisfaction of the executive we will submit the evidence to the Licence Committee with an appropriate recommendation. Authors Paula Nolan (Clinical Governance

Lead/Inspector)

Date 17 September 2013



Chronology of events

Date & Time Event

06/12/2012 Couple were counselled by Genesis Genetics Institute (Detroit, USA) counsellor on the limitations of setting genetic phase day.

28/06/2013 Patient undergoes oocyte retrieval.

01/07/2013 Embryo biopsy performed and 10 embryos were biopsied. The cells were sent to Genesis Genetics Europe for testing. Two of these returned a result of unaffected/normal, 3 results shown to be affected and 5 had insufficient data on the report for a result to be given.

03/07/2013 In conjunction with the embryo development information one of the unaffected embryos was transferred, and one was frozen for future use.

15/07/2013 Positive pregnancy test.

16/07/2013 The testing lab, Genesis Genetics Europe, contacted the PR of the centre to inform her that on re-reading the original data from the Day 3 biopsy they had found that the results had been interpreted incorrectly and the results report issued had given incorrect diagnosis for the embryos.

17/07/2013 Centre report incident to the HFEA.



17/07/2013 Patient was contacted to invite her and her partner to attend a meeting with the Medical Director and the Nurse Manager/PGD Nurse.

19/07/2013 Couple attended centre and situation explained to them.

22/07/2013 HFEA Management Review.

22/07/2013 Telephone discussion with the PR (with the HFEA Clinical Governance Lead/Inspector). How is she, as the PR, assured that an incident of this nature will not happen again? What reassurance/changes in practice have the testing lab provided to minimise the risk of reoccurrence? The PR to provide written reassurance to the Executive as a matter of urgency.

24/07/2013 E-mail from PR with further information about the incident including assurances from the Genesis Genetics Europe, laboratory manager, explaining what further measure have been put in place to minimise the reoccurrence of a similar incident raking place.

2/08/2013 Preliminary incident report received from the PR.

2/09/2013 Full report including Genesis Genetics Europe investigation sent by the PR.

13/09/2013 HFEA incident inspection.

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