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Human Fertilisation and Embryology Authority

Minutes of the Licence Committee

Meeting held at Finsbury Tower, 103-105 Bunhill Row, London, EC1Y 8HF on 16 July 2015

Minutes – item 2 Centre 0101 (CARE Nottingham) – incident report (IN04125)

Members of the Committee:

Andy Greenfield (Chair, lay) Anita Bharucha (lay) Kate Brian (lay) Margaret Gilmore (lay)

Legal Adviser:

Dawn Brathwaite, Mills & Reeve

Members of the Executive:

Sam Hartley, Head of Governance and Licensing Trent Fisher, Secretary

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:

• HFEA incident investigation report • Relevant supporting documentation

o the clinics root cause analysis investigation report o GGEu’s case investigation report o extracts from patient records o information provided to patients regarding PGD for translocations o Clinical Pathology Accreditation (CPA) investigation report o independent review report o information on number of cycles of PGD performed by the sector

between 2008 and 2014 o a narrative from CARE Nottingham o 2012 European Society of Human Reproduction and Embryology PGD

Consortium report • previous three years of Licence Committee Minutes • correspondence from the PR re publication of the report

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) • HFEA decision trees • guidance for members of the 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 the publication of Authority and committee papers.

Background

1. A Grade A Incident was reported to the HFEA on 19 December 2014 involving a patient who underwent PGD for an unbalanced chromosome translocation. An embryo identified as carrying a balanced translocation was transferred.

2. A subsequent pre-natal diagnosis by chorionic villus sampling showed that the pregnancy was affected by an unbalanced chromosome translocation.

3. A further test of the DNA, originally collected from the transferred embryo,

using a more sensitive testing methodology, next generation sequencing (NGS), found that the embryo was affected by the unbalanced translocation.

4. An investigation by Genesis Genetics (Europe), the centre’s third party PGD

testing laboratory, concluded that the PGD misdiagnosis was due to the testing methodology used.

5. An interim report regarding the incident was considered by the Licence

Committee on 12 March 2015. The committee expressed serious concern and adjourned its decision until the findings from an independent expert review and the CPA misdiagnosis investigation could be presented.

6. The committee also requested further information regarding:

• misdiagnosis rate for other centres that use GGEu; • the literature that the centre provided to patients explaining the risk of

misdiagnosis.

7. A progress update was presented to the Licence Committee on 7 May 2015 for consideration. The committee noted the findings of the UKAS investigation and the preliminary findings from the independent expert review.

8. In considering the progress update the committee requested the following

information: • a narrative from the centre on the decision making process with regard

to which technology was to be used for testing in any particular patient;

• any sop or template document/checklist for recording any conversation that has been had with patients with regard to risks, and how the actual conversation is carried out;

• the advice of a statistical expert on whether 3% risk of PGD misdiagnosis at the centre (compared to the 0.2% rate across the sector) is statistically significant; and

• an update on the number of cycles of PGD across the sector (by clinic), and any further information on misdiagnosis rates by clinic.

Discussion

9. The committee considered responses to the additional information requests made at its previous meetings.

10. The committee noted the reports from CPA, an independent expert reviewer,

GGEu’s investigation report and the root cause analysis undertaken by the centre. The committee agreed that it had sufficient information to make a decision in relation to incident IN04125.

11. The committee also agreed that it had sufficient information to address its

wider concerns about the repeated PGD misdiagnoses at this centre, having noted the response from the centre, the executive’s report and recommendations, and (in particular) the appended ESHRE PGD Consortium analysis.

12. The committee noted the centre’s positive engagement with the HFEA’s

Executive during the course of this incident investigation and further noted that it had been provided with the centre’s patient information, which was acceptable and contained details about the risks involved in PGD treatment.

Decision

13. In relation to the incident under consideration, the committee concluded that the evidence provided by the centre, the CPA and the independent reviewer suggested that the misdiagnosis was as a result of a recognised but rare failure of the testing technology and not the underlying practices or behaviours of the centre or its third party testing facilities.

14. While extremely regrettable for the patients involved, the committee concluded that there was no further action to be taken in relation to the centre’s licence.

15. The committee noted with concern that six of the seven adverse incidents relating to PGD misdiagnosis reported in the UK since 2009 had occurred at this centre. The committee recognised that, taken at face value, it might appear unlikely that such a clustering of incidents in one centre was simply down to chance. However, having considered the evidence provided by the executive regarding the statistical likelihood of misdiagnosis, and the varied laboratories and root causes of those misdiagnoses reported by the centre, the committee was satisfied that there was no evidence provided to suggest that there was any systemic failure that might have contributed to these incidents, or that the centre’s practices are unsuitable.

16. The committee was encouraged by the fact that the centre was fully engaged in the investigation. It urged the centre to continue to take steps to ensure the use of the most suitable technologies and techniques, as available, and the committee noted the centre’s assurances that lessons learnt from such incidents are being addressed in a timely manner.

Signed: Date: 20 July 2015

Andy Greenfield (Chair)

Centre 0101 CARE Nottingham Final incident investigation report IN04125 Trim ref: 2015/011422 1

Purpose of the Report This is the final report of an investigation into an adverse incident involving failure of embryo testing to identify an embryo affected by a serious chromosomal abnormality. Whenever grade A incidents occur, the HFEA, in collaboration with clinics and other regulatory partners, makes sure that systematic and robust investigations are carried out to identify whether improvements are needed to protect patients, their gametes and embryos and ensure that that clinics learn from these incidents and minimise the risk of them happening again. Grade A incidents are the most serious incidents and, for the most part, arise as a result of a unique set of circumstances that are not usually foreseeable. Inspector: Debra Bloor (HFEA) Date of Licence Committee: 16 July 2015 Clinic Name CARE Nottingham

Clinic number

0101

Licence number

L/0101/16/a

Clinic address

John Webster House 6 Lawrence Drive Nottingham Business Park Nottingham, NG8 6PZ

Person Responsible

Lucy Jenner

Licence Holder

Simon Thornton

Date licence issued 01/08/2012

Licence expiry date

31/07/2016

Additional conditions applied to this licence

None

Incident Investigation Report

Licence Committee Papers - July 2015

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Section 1

Introduction

1. This report relates to an incident reported to the HFEA by the clinic, in accordance with the requirements of the Code of Practice, in December 2014. The Executive classified the incident as ‘grade A.’ Reports of grade A incidents are reserved to the Licence Committee.

2. The Executive reported this to Licence Committee first in March 2015, and subsequently on 7 May 2015. On both occasions the Executive sought, and the Licence Committee agreed to, an adjournment on the basis that additional information was necessary to form an overall judgement and if necessary, to inform recommendations to the Licence Committee.

3. This report sets out the details of the incident, investigations and actions

undertaken subsequent to the incident and considers these in the wider context of the clinic’s incident history. This report seeks to document the facts, actions and learning that have resulted from this incident and consider whether it is appropriate to recommend regulatory action.

Brief description of the clinic and its licensing history

4. CARE Nottingham was established in 1985 and is a privately run clinic that provides a wide range of licensed fertility treatments including pre-implantation genetic diagnosis (PGD). The clinic carries out approximately 2000 cycles of licensed treatment a year. In each year of 2012, 2013 and 2014 the clinic carried out circa 50 cycles of treatment involving PGD.

5. Since 2008 the clinic has commissioned various third party testing laboratories to

undertake PGD testing of cells removed from embryos known to be at risk of a serious genetic condition. Whilst the HFEA has no regulatory remit in relation to the testing laboratories the HFEA licensed clinic does have a responsibility to ensure suitable practices are employed by third party laboratories acting on their behalf. The clinic also has a responsibility to ensure that patients who give consent to PGD and fertility treatment are provided with proper information such that the consent they provide is informed.

6. Since 2008 CARE Nottingham has been responsible for six of the seven adverse

incidents relating to treatment involving PGD reported by HFEA licensed clinics.


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Background information on the incident subject of this report 7. A patient underwent PGD for a chromosomal translocation in September 2014.

An embryo identified by the test as balanced for the translocation1 was transferred to the patient. The patient conceived and a scan revealed a twin pregnancy2. Subsequent pre-natal diagnosis by chorionic villus sampling showed that the pregnancy was affected by an unbalanced chromosome translocation. This meant that there had been a failure of embryo testing to identify an embryo affected by a serious chromosomal abnormality. The embryo testing (PGD) was carried out by a third party laboratory, Genesis Genetics Europe (GGEu) on behalf of CARE Nottingham.

8. The incident was reported to the HFEA on 19 December 2014. At the time the incident was reported the clinic confirmed that there were no on-going treatments involving PGD for chromosome translocations and that the next treatment was not due to commence until end January 2015.

9. On receipt of the incident report the executive undertook a formal management

review in accordance with the HFEA’s Compliance and Enforcement Policy to determine whether, in the circumstances, it might be appropriate to consider suspending embryo testing activities at this clinic. The review noted that with immediate effect following the incident, all patients having PGD for the avoidance of inheritance of an unbalanced chromosome translocation were having all biopsied embryos frozen pending the conduct of further confirmatory testing using a more advanced technique (next generation sequencing, NGS). On the basis that the clinic had taken steps to mitigate the risk of recurrence of the incident it was not considered proportionate or in patients’ best interests to take formal action pending the outcome of a more detailed investigation.

Information considered as part of the HFEA incident investigation 10. The following information has been taken into consideration in support of the

HFEA’s incident investigation:

The clinic’s review, GGEu’s review and information provided to patients · The clinic’s root cause analysis investigation report dated 03-04-2015

to 17-06-2015 (annex 1) · GGEu’s case investigation report dated 29-01-15 (annex 2) · Extracts from the patient records documenting the provision of

information about the risks of failure of the treatment (annex 3)

1 A balanced translocation is a condition in which the correct number of chromosomes is present, but two pieces of chromosomal material have switched places. An individual who has a balanced translocation is usually completely healthy. Where a translocation is unbalanced then there is an incorrect number with respect to the chromosomes that have switched places and this can result in a serious genetic abnormality. 2 The pregnancy was confirmed as an identical twin pregnancy indicating that the single embryo divided after transfer.


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· Copies of the information provided to patients regarding PGD for translocations (annex 4)

The report of the laboratory accreditation service

· Clinical Pathology Accreditation (UK) Ltd3 (CPA) investigation report March 2015 (annex 5)

The independent expert review · Report from a Professor in Human Genetics and Embryology

independently reviewing the evidence base of the diagnosis 29-06-2015 (annex 6)

The frequency of PGD incidents · Information requested by the Licence Committee in May 2015 about

the number of cycles of PGD performed by the sector between 2008 and 2014 including information about incidences of misdiagnosis (see annex 7)

· A narrative from CARE Nottingham, requested by the Licence Committee in May 2015: Responses to HFEA minutes of the Licence Committee 20 May 2015 (annex 8)

· A copy of the 2012 ESHRE PGD Consortium’s report on findings of the analysis of 10 years of data collection relating to PGD cycles provided between 1997 and 2007 (annex 9)

The clinic’s review, GGEu’s review and information provided to patients

11. The PR for CARE Nottingham has engaged positively with the HFEA. She conducted a comprehensive root cause analysis (RCA) that also took into account information from the case investigation conducted by GGEu. The report concludes that the incident arose as a result of a recognised but rare failure of the technology used to detect chromosomal rearrangements. It notes that there is no evidence of an embryo mix up in the clinic’s embryology laboratory, data misread, inadvertent natural conception or maternal cell contamination.

12. The RCA documents a review of the information provided to patients and concludes that the patients were provided with appropriate information about the risk of the treatment. Relevant extracts from the patient records were provided to the HFEA and these support a conclusion that patients are counselled and receive clear information: the patient record extracts confirm that the patients were advised that there was a 5% risk associated with their treatment.

13. It was noted in the interim investigation report of 12 March 2015 that the PGD

misdiagnosis rate in HFEA licensed clinics is circa 0.2%. This is consistent with the misdiagnosis rate following PGD for single gene disorders observed by the

3 CPA is part of the UK Accreditation Service (UKAS) and is the accrediting organisation of the testing laboratory


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ESHRE PGD Consortium (see annex 9). It should be noted however that the risks quoted to patients by the clinic incorporate additional factors (such as the incidence of failure to obtain a test result) in addition to the risk of misdiagnosis.

14. With respect to procedures for estimating the risks of treatment, GGEu explained

that prior to undertaking PGD, the testing laboratory has access to standard look up tables that allow the theoretical assessment of whether a particular chromosomal translocation is likely to be detected. GGEu explained that treatment is refused in a small number of cases every year where these tables indicate that a genetic abnormality is not likely to be detected. In this case, on the basis of information provided by the clinical genetics service involved in the referral of the patients, prior to the first cycle of treatment the theoretical chance of detecting the abnormality was assessed as 99% and it was on this basis that the patients were offered treatment. The first PGD cycle provided more accurate information about the particular genetic abnormality than that provided by the genetics service however and on the basis of this more accurate information the theoretical chances of detecting abnormalities in the two switched chromosomes were estimated, by reference to the look up tables, as 88 and 0%. This is referenced in the CPA (UK) report and the HFEA investigation questioned whether the patients were advised of this change in the predicted chance of detecting the genetic abnormality. GGEU advised that they were not: this was because the test conducted by GGEu’s in the first PGD cycle clearly did identity embryos affected by an unbalanced translocation and so the chances of detection were still considered to be in the region of 99% on the basis of this empirical (rather than theoretical) evidence.

The report of the laboratory accreditation service 15. Clinical Pathology Accreditation (UK) Ltd (CPA) conducted a visit to GGEu on 17

March 2015. The CPA’s Assessment Manager was accompanied by a technical expert with documented competence and current experience in the field of molecular genetics. The CPA assessors were aware of previous incidences of misdiagnosis following testing at GGEu.

16. The CPA investigation concluded that the chromosomal translocation misdiagnosis appears to be the result of technical limitations of the whole genome amplification (WGA) and the array comparative genomic hybridisation (aCGH) technology. The report notes that WGA and aCGH are commonly used by PGD laboratories within the UK and that there was no evidence of human error and or weaknesses in laboratory systems and processes.

17. CPA did not consider there was evidence of systems failure sufficient to

recommend revoking CPA accreditation or to recommend suspending GGEu’s provision of PGD for translocation imbalances, subject to consistent application of the improvement actions identified by GGEu. It was noted that incidents in 2013 and 2014 were attributed to separate causes and both resulted in improvements as required by the CPA Standards.


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The Independent expert review 18. The independent expert reviewer was provided with copies of original documents

by the clinic and GGEu and a copy of GGEu’s case investigation report.

19. On the basis of the review of these documents the reviewer concluded that the incident may have been due to poor amplification of the sample, which sometimes occurs in PGD. This is in line with the conclusion reached by GGEu that poor amplification led to the failure of the test. The reviewer considered there was no fault attributable to the diagnostic laboratory.

20. The reviewer – who has significant experience in reading the results of tests

obtained by the analysis of DNA amplified from a single cell commented as follows: “It is difficult to ascertain what I would have called on the day but in retrospect, analysis of the chromosome 5 result from the biopsied cell does raise some concerns. Ideally in such a case, I would have suggested that the embryo was frozen and further analysis carried out. Genesis Genetics are now performing diagnosis of such cases using NGS which is more sensitive and it is hoped that such ambiguous cases will be a rare event.”

The frequency of PGD incidents 21. A significant component of the consideration of this incident is the nature and

number of previous misdiagnoses or similar PGD-related incidents at this clinic. It has understandably exercised the Committee and the Executive. The HFEA’s vision is high quality care for everyone affected by assisted reproduction. In this case misdiagnosis incidents appear to be clustered and it is necessary to address the question of whether there are systemic issues at play that may indicate that the clinic’s practices and/or those of the testing laboratory acting on their behalf are unsuitable.

22. At its meeting in May 2015 the Licence Committee sought further information on the incidence of misdiagnosis incidents together with advice from a statistical expert on whether the 3% risk of PGD misdiagnosis at the clinic (compared to the 0.2% rate across the sector) is statistically significant.

23. In its report on the analysis of data relating to PGD cycles provided in Europe in

the ten years to 2007, the ESHRE PGD Consortium analysis (see annex 9) notes that most forms of laboratory testing misdiagnosis result from technical or systemic failure (i.e. not failures of IVF clinics). The analysis also notes that the estimates of misdiagnosis after PGD are complex: misdiagnosis can be underestimated because transferred embryos do not result in a pregnancy, some spontaneously abort and others that are mistakenly predicted to be affected are discarded. Conversely, misdiagnoses can be overestimated as pregnancies are always assumed to result from the embryo or embryos that were transferred. Many patients, particularly those having PGD for single gene disorders, are fertile and there is the possibility that a pregnancy could result from a natural conception rather than an embryo that was transferred following PGD.


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24. In its narrative response to the request of the Licence Committee’s made in the minutes of its meeting on 20 May 2015 the clinic discusses the literature surrounding misdiagnosis and these same limitations are also referenced in the responses provided to the HFEA by GGEu.

25. The ESHRE PGD Consortium report notes that with respect to 4534 cycles of

PGD for single gene disorders there were 10 reported misdiagnoses giving an overall misdiagnosis rate of 10/4534 (0.22%). However, the same report notes that 65 PGD cycles, mainly using PCR to determine sex for X-linked disease, resulted in 55 embryo transfers from which 2 misdiagnoses arose giving an overall misdiagnosis rate of 2/65 (3.1%). The report does not comment on misdiagnosis following PGD for detection of a chromosomal translocation but its findings and observations do highlight that the incidence of misdiagnosis may vary significantly depending on the nature of the test and that there may be confounding factors that impact on the reliability of any assessment of the frequency of misdiagnosis.

26. Information drawn from the HFEA Register of treatments (annex 7) identifies that

since 2008 3840 PGD cycles were performed by HFEA licensed clinics with 275 (or 7%) of the cycles performed at CARE Nottingham. Seven incidents following PGD treatment have been reported to the HFEA in that time, six of which were reported by CARE Nottingham. This raises concerns about clustering of incidents at CARE Nottingham and it is necessary to review information relating to previous incidents reported to the HFEA by the clinic to address these concerns.

27. Information provided in the course of this investigation concludes that two of the

six PGD incidents reported by CARE Nottingham in 2011 and 2013 (this latter report related to embryo testing carried out in 2008) may have been the result of natural conception.

28. In July and November 2009 the clinic reported two grade A incidents involving

PGD misdiagnosis.

· The first incident involved the misdiagnosis of a single gene disorder. It was identified that contamination of the sample by maternal cells was the cause of the misdiagnosis. In this case, the test was carried out by Genesis Genetics International (USA) (not GGEu).

· The second case was a PGD translocation case that was considered most likely to have arisen as a result of a recognised limitation of the testing methodology (fluorescence in situ hybridization (FISH)) used in relation to this treatment. In this case, the test was carried out by Bridge Genoma (again, not GGEu).

29. In November 2011 the clinic reported another incident, categorised at the time as

a grade A incident relating to an apparent PGD misdiagnosis following testing by (GGEu). The HFEA has been informed that following investigations and further testing of the amplified products and of the DNA of the child GGEu have concluded that the embryo that formed the baby was not one of the embryos created in the IVF cycle. This case is the subject of ongoing litigation.


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30. In July 2013, a further incident involving a PGD misdiagnosis occurred following

embryo testing for Neurofibromatosis. In this case, the HFEA and Clinical Pathology Accreditation (CPA) investigations both concluded that the incident was the result of operator error on the part of the third party testing laboratory (GGEu), rather than any systemic failure of laboratory procedures or processes at CARE Nottingham. The corrective actions proposed by the testing laboratory were considered likely to minimise the risk of such failures occurring in the future.

31. In October 2013, the clinic reported an incident to the HFEA following the birth of

a child affected by sickle cell anaemia. The child’s parents had undergone PGD treatment in 2008 (with testing by GGEu) that did not result in a pregnancy. In 2012 the patients transferred their remaining two frozen embryos to a clinic based in London and underwent a frozen embryo transfer. This treatment resulted in the birth of a child affected by sickle cell anaemia. Further information provided in the course of the current investigation states that the testing laboratory considers that the pregnancy in this case is likely to have been the result of a natural conception as the original GGEu test data confirms the presence of “healthy” paternal gene in the frozen embryo. However, it is not possible to confirm this.

32. The information on previous PGD related incidents reported by CARE

Nottingham is summarised below:

Date reported Conclusion Testing laboratory 1. Embryo created 2008 -

transferred 2013 Possible natural conception

GGEu

2. July 2009 Maternal cell contamination

Genesis Genetics International (USA)

3. November 2009 Testing limitation Bridge Genoma 4. November 2011 Natural conception GGEu 5. July 2013 Operator error GGEu 6. December 2014 Subject of this report GGEu 33. It appears highly unlikely that the clustering of incidents with respect to CARE

Nottingham is the result of chance. However, the analysis of information about the specific incidents and their distribution across several third party testing laboratories shows that the root causes are specific to each incident.

34. This investigation has not identified a pattern that suggests the clinic’s practices are unsuitable. It would therefore be unsafe to draw a conclusion with respect to any statistical significance of the apparent clustering.


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Investigation conclusions 35. The Executive considers that there is sufficient evidence to support a conclusion

that: · this incident arose as a result of a recognised but rare failure of the

testing technology; · that there is no evidence of human error and or weakness in the

testing laboratories systems and processes and that in consideration of this, the PR for CARE Nottingham has ensured that the clinic commissioning of the laboratory as a third party provider is compliant with HFEA requirements;

· that acceptable, bespoke information about risks was provided to the patients before they were provided with treatment

· that the learning from this incident and those relating to previous incidents is expected to mitigate the likelihood of incidents recurring for the same reasons.

Recommendation to the Licence Committee

36. It is recommended that the clinic’s licence should continue without additional

conditions.


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Additional information from the Person Responsible


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