East Midlands Specialised Commissioning Group

Commissioning Policy for Pre-implantation Genetic Diagnosis (PGD) Reference No:

EMSCGP013V1

Version:

2

Ratified by:

East Midlands Specialised Commissioning Group

Date ratified:

26 November 2010

Name of originator/author:

David Giffard

Name of responsible committee/individual:

EMSCG Clinical Priorities Advisory Group

Date issued:

1 April 2011

Review date:

01/01/2014

Target audience:

PCT Commissioners, Providers of Service

Distributed via:

Postmaster Email Website

Commissioning Policy for Pre-implantation Genetic Diagnosis Version 2

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East Midlands Specialised Commissioning Group Commissioning Policy for Pre-implantation Genetic Diagnosis i. Version Control Sheet Draft

Section/Para/ Appendix

1 2

3 Criteria

Version/Description of Amendments

Date

Author/Amended by

1st Draft

15.2.10

DG

Removal of ‘No living unaffected children from current relationship’

26.3.10

DG

6.9.10

DG

Replace ‘three completed’ with ‘unlimited’ Rewording of welfare of the child statement and movement to rationale section 5 Treatment

Replace ‘a maximum of 3’ with ‘unlimited’ Change of wording in relation to self funded treatment

3

7 Alternatives to PGD

Removal of ‘To adopt a child’ statement

3. Treatment criteria.

Criteria amended to ‘The PGD clinic is working towards CPA Accreditation’. This is because the HFEA are satisfied if they are working towards this, and provide evidence to the HFEA to show this. Criteria amended to: ‘The centre must have a valid HFEA licence which includes the

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provision of PGD, and abides by the HFEA regulations for PGD testing.’ The couple are not infertile has been added. Infertile couples with a genetic condition will be dealt with under the IVF policy criteria (with the allowance for PGD to be conducted in conjunction with IVF if they meet the IVF policy criteria). 5. Treatment

Specific reference to using frozen embryos through self funded IVF in conjunction with PGD. Reference to using other frozen embryos first has been removed. Definition of a complete and abandoned cycle remains. Criteria allowing only one abandoned cycle deleted. Inclusion of HLA Tissue Typing for those conditions licensed by the HFEA

4 5 6 7 8 9 10 11 12

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ii. Policy Statement

Background

This commissioning policy has been produced in order to provide and ensure equity, consistency and clarity in approach towards Pre Implantation Genetic Diagnosis (PGD) in the East Midlands region. Whilst IVF is required as part of the PGD process, it is not, in general used to treat sub-fertility. Therefore the same criteria as per the EMSCG Tertiary Infertility policy will not be used in determining the requirements for PGD This commissioning policy sets out the position of EMSCG PCTs in respect of PGD treatment.

Statement (For further details please refer to the full policy) Each primary care trust to adopt the policy, and incorporate it into Service Level Agreements and contracts with providers. Responsibilities

Clinicians to comply with the policy, and the criteria in the policy. A retrospective audit will be conducted to ensure that these treatments are only commenced for patients who meet the criteria for them. It is anticipated that there will be no exceptions to this policy.

Training

There are no training issues.

Dissemination

To all member PCTs and Trusts who will deal with patients requesting PGD.

Resource

The mechanism for funding will be on a cost by case basis. At present, there is little known from the literature about the acceptability of PGD to couples, nor the likely demand for the technique. So it is proposed that once ratified, a piece of work will need to be completed to estimate the possible financial impact of this policy – and evaluate this prior to any implementation.

implications

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East Midlands Specialised Commissioning Group Commissioning Policy for Pre-implantation Genetic Diagnosis Contents i. ii.

Version control sheet Policy Statement

Section

Page

1

Policy

6

2

Definition

6

3

Criteria

6

4

Rationale

6

5

Treatment

7

6

Epidemiology

7

7

Alternatives to PGD

8

8

Resource Implications

8

9

Evidence Base (and Health Benefits)

8

10

Mechanism for Funding

9

11

Preferred (designated) Provider

9

12

Review

9

13

Glossary

10

14

References

12

Appendix 1

Conditions licensed by the Human Fertilisation and Embryology Authority (HFEA).

13

Appendix 2

Conditions licensed by the HFEA for HLA Tissue Typing

16

Appendix 3

PGD Indication Specific Outcome Rates: ESHRE Consortium Data Collection VIII January to December 2005

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1

Policy Couples who have a proven genetic disorder, and fulfil the following criteria will be eligible for pre-implantation diagnostic services under this agreement.

2

Definition Pre-implantation Genetic Diagnosis (PGD) uses in vitro fertilisation (IVF) to create embryos, tests one or two cells from each embryo for a specific genetic abnormality and identifies unaffected embryos for transfer to the uterus. The approach through PGD assists couples at risk of an inherited disorder to avoid the birth of an affected child.* Therefore, the reasons for undertaking IVF through PGD are not necessarily due to infertility. * Affected child: This policy uses the conditions licensed by the Human Fertilisation and Embryology Authority (HFEA) to define an affected child, (see appendix 1). The range of genetically transmissible conditions for which testing is possible, are continually increasing.

3

Criteria Mandatory criteria

 

 

  

4

The referral request is supported by the Clinical Genetics Service. Patients will be eligible for unlimited cycles of IVF treatment as part of the PGD process (when patients have received 3 cycles of treatment, a prior approval system will be implemented for any further cycles) Couples to have received genetic counselling from an appropriate genetic counsellor. The laboratory where the test is being carried out is working towards Clinical Pathology accreditation and the HFEA are satisfied of this through the provision of evidence. (Any future equivalents to CP accreditation would need to be assessed against CP accreditation criteria by the EMSCG Board in order to ensure quality and standards are maintained). The PGD clinic must be licensed by the HFEA to carry out a test for the relevant condition and the test must be included in the list of UKGTN approved tests. The centre must have a valid HFEA licence which includes the provision of PGD, and abides by the HFEA regulations for PGD testing. The couple are not infertile. Infertile couples who also have or are carrier(s) of a genetic condition should be assessed under the EMSCG IVF policy criteria. If these criteria are met, then IVF will be offered under the conditions of the EMSCG IVF policy with PGD testing being provided in conjunction with this.

Rationale Pre-implantation genetic diagnosis (PGD) is an extension of prenatal diagnosis. It uses IVF technology to enable couples who are at a high risk of passing a serious genetic disorder to their offspring, from avoiding conception of an affected child using the conditions licensed by the HFEA to define an affected child, (see appendix 1). PGD is deemed to be

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clinically and cost effective in some individual cases after careful counselling and assessment, but should not be regarded as a standard service. The suitability of cases will depend on the inherited disorder concerned and as a result all requests for PGD should be considered individually. For some couples, selection of an unaffected embryo is preferable to pregnancy termination following prenatal testing. Indeed for some couples pre natal testing and termination of pregnancy is unacceptable. If the couple requiring PGD treatment are also sub fertile then they will be assessed against the EMSCG tertiary infertility policy and treated in accordance with that policy. It is a relevant factor to take into account the welfare of any child intended to be born as a result of the process. Thus funding should not be approved unless the PCT are satisfied that proper arrangements which will ensure the child’s welfare will be put in place to care for any child to be born as a result of this process. 5

Treatment Couples meeting the above criteria will be eligible to receive unlimited completed* cycles of IVF/ICSI in conjunction with Pre-implantation Genetic Diagnosis (PGD) treatment. In addition couples who have self funded will be entitled to NHS treatment. Where couples have previously self funded an IVF in conjunction with a PGD cycle and frozen embryos exist, then the couples must utilise the previously frozen embryos, rather than undergo ovarian stimulation, egg retrieval and fertilisation again. HLA Tissue Typing will be permitted for those conditions licensed by the HFEA to be carried out in conjunction with PGD. (These conditions are listed as per appendix 2) *Definition of a completed/abandoned cycle: Completed IVF/ICSI cycle = ovarian stimulation, egg recovery, fertilisation and single fresh embryo transfer. This includes the provision for future transfers of single frozen embryos where the initial procedure does not result in a viable embryo; and the subsequent storage of embryos. Frozen embryos must be transferred within ten years of the initial treatment cycle (HFEA guidance). Abandoned IVF/ICSI cycle = Prior to egg retrieval, usually due to lack of response (where less than 3 mature follicles are present) or excessive response to gonadotrophins; failure of fertilisation; failure of cleavage of embryos and failure to produce any unaffected embryos.

6

Epidemiology It is not possible to make any estimation of prevalence or incidence as PGD may be used for a range of genetic conditions which is continually expanding.

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Alternatives to PGD There are several alternatives to PGD, all of which should be considered by the couple before proceeding with PGD. These are as follows:  

  8

To decide not to have a child. To conceive naturally and have prenatal diagnosis (PND) during the pregnancy (involving the invasive procedures of amniocentesis or chorion villus sampling). If the foetus is found to be affected the parents then have to decide whether to opt for termination of pregnancy (within the provisions of the current legislation). To have a pregnancy without prenatal testing, taking the decision to live with the risks and consequences of an affected child. To consider assisted conception techniques in which one or both partners would not be the biological parent of the child.

Resource Implications A number of centres offer PGD. The table provides a comparison of prices offered at a couple of the centres. Where drugs are charged separately the additional costs will be dependent on the patient’s response to stimulation treatment. (Please note that these prices are purely for information and each patient’s overall treatment cost will differ depending on the exact nature of the treatment).

9

Provider

Cost Per Cycle

CARE Nottingham Guy’s Hospital

£6,895 (drugs charged separately) £7,020 (drugs charged separately)

Evidence Base (and Health Benefits) The eighth report of European Society of Human Reproduction and Embryology (ESHRE) PGD consortium2 published data which includes cumulated information from 39 collaborating centres for the calendar year 2005 reporting 1128 PGD cycles, 227 pregnancies and 194 live-born babies. Around 44% of the cycles were for chromosomal abnormalities (e.g. translocations and aneuploidy risk), 29% X-linked conditions (e.g. Duchenne/Becker’s muscular dystrophy, Fragile X syndrome, haemophilia) 14% autosomal recessive conditions (e.g. cystic fibrosis, thalassaemia, spinal muscular atrophy), 14% autosomal dominant conditions (e.g. myotonic dystrophy, Huntington’s disease) and around 10% for other monogenic (single gene) disorders (e.g. Achondroplasia, Familial adenomatous polyposis, Menkes disease). Success rates for clinical pregnancy were quoted as 20% per oocyte retrieval and 28% per embryo transfer procedure. This is an increase on the cumulative data available since 1999 (18% per oocyte retrieval and 25% per embryo transfer). Data is also provided for the first time on pregnancy and delivery rates for each indication for PGD. Overall delivery rates for PGD within this data collection period were 17% per oocyte retrieval and 24% per embryo transfer. Prenatal diagnosis was performed on 44.6% of the pregnancies identifying three cases of misdiagnosis. Information on congenital malformations was available for 81 children. Several of the abnormalities were unrelated to the PGD. There is little known from the literature about the acceptability of PGD to couples, nor the likely demand for the technique. A study of a small number of PGD patients found that

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over 75% of couples contemplating a future pregnancy would chose to undergo PGD again3. A review in the Journal of Medical Genetics concluded that, after a decade of practical application PGD remained ‘a technically challenging, multi-step, labour intensive procedure which requires the close collaboration of a team of specialists.’4 .

10

Mechanism for Funding Funding decisions resulting from Individual PCT Case Management Panels are the responsibility of the relevant PCT. Funding should be provided on a cost per case basis.

11

Preferred (Designated) Provider: The HFEA currently licenses 13 centres in the UK for PGD: Glasgow RI  Edinburgh Assisted Conception Unit Guy’s Hospital IVF Hammersmith Clarendon Wing Leeds The Lister Fertility Clinic, London  Centre for Reproductive Medicine & Fertility, Sheffield  Newcastle Fertility Centre at Life CARE, Nottingham  The Centre for Reproductive and Genetic Health, London  CARE Manchester  Oxford Fertility Unit  The Bridge Centre, London

12

Review March 2013

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Glossary of terms:

Term amniocentesis

Meaning A test that can be carried out during pregnancy to determine whether the foetus has a specific problem. It is conducted by taking and analysing a sample of amniotic fluid. Blastocytes Any undifferentiated embryonic cell (Lawrence, 2000: 75) Chorionic villus sampling (CVS) This is a test for serious foetal problems. It is available to pregnant women, particularly those with a family history of inherited disorders, or who are over 35. It's an alternative to amniocentesis (where a sample of the mother's amniotic fluid is taken for testing). CVS has the advantage that it can be done earlier than amniocentesis, at about 10 weeks after fertilisation. (NHS Direct b, 2009). Chromosomal Abnormality An abnormality with one or more chromosomes, or in the number of chromosomes. chromosome A structure within cells that contains genetic information. Cleavage stage embryo’s This is when the fertilised cell has started to divide. Congenital malformations A malformation of the developing foetus. In this case it refers to those caused by genetic/chromosomal abnormalities. Embryo A fertilised egg. Foetus The unborn child after the end of the eighth week of pregnancy to the moment of birth.(NSC, 2009) Gonadotrophins Hormones that stimulate the function of the organs in which reproductive cells are produced (Lawrence, 2000; 254) Human Fertlisation and Embryology Authority UK’s independent regulator overseeing the use (HFEA). of gametes and embryos in fertility treatment and research. (HFEA, c, 2009) In Vitro Fertilisation (IVF)

Intra-cytoplasmic Sperm Injection Oocyte

This is a process whereby eggs are removed from the ovaries and fertilised with sperm in the laboratory. It is utilised in the PGD process in order for the fertilised eggs (embryo’s) to be tested for a specific genetic abnormality, with an unaffected embryo subsequently being placed in the woman’s womb. (HFEA, 2009). This is a technique that can be used in IVF whereby a sperm is injected into the egg to assist in fertilisation. (NHS Direct, 2009). A not yet fully developed egg cell.

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Ovarian Stimulation Pre natal diagnosis Pronucleate embryo

The UK Genetic Testing Network (UKGTN)

A technique used in IVF to assist in egg retrieval. Determining if a foetus has a specific problem, by performing a clinical test. Embryo whereby two nuclei (the part of the cell that contains the DNA) from the sperm and the egg are present. (These subsequently fuse together). This advises the NHS on genetic testing across the whole of the UK. It aims to ensure the provision of high quality equitable genetic testing services. (UKGTN A, 2009)

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References 1. DH (2002) Preimplantation Genetic Diagnosis (PGD) – Guiding Principles for Commissioners of NHS services 2. ESHRE PGD Consortium: data collection VIII: cycles from January to December 2005 with pregnancy follow up to October (July 2008). Hum. Reprod. Advance Access published online July 18 2008. Human Reproduction, doi:10.1093/humrep/den238. 3. Lavery SA, Aurell R, Turner C, Castellu C, Veiga A, Barri PN, Winston RM. Preimplantation genetic diagnosis: patients’ experiences and attitudes. Human Reproduction May 2002;17:2464-7. 4. Kanavakis E, Traeger-Synodinos J. Preimplantation genetic diagnosis in clinical practice. J Med Genet 2002;39:6-11. HFEA 2009 plus link HFEA 2009 – IVF NHS Direct ICSPI Hfea c 2009 http://www.hfea.gov.uk/ Lawrence, Eleanor (2000) Henderson’s Dictionary of Biological Terms 12th Edition, London, Prentice Hall. NHS Direct, b, 2009 http://www.nhs.uk/conditions/chorionic-villussampling/Pages/Introduction.aspx UKGTN A http://www.ukgtn.nhs.uk/gtn/Home

NSC, 2009 http://www.screening.nhs.uk/glossary-f

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Appendix 1: Conditions licensed by the Human Fertilisation and Embryology Authority (HFEA)

                                          

Adrenoleukodystrophy (Adrenomyeloneuropathy) Agammaglobulinaemia Alpers Syndrome α thalassaemia/mental retardation syndrome** Alport's Syndrome Alzheimers Disease - early onset Anderson Fabry Disease Androgen Insensitivity Syndrome Aplastic anaemia - severe** Barth Syndrome Battens Disease (infantile) Beta Hydroxyisobuyryl CoA Hydrolase Deficiency (Methacryic Aciduria) Beta Thalassaemia** Bilateral Frontoparietal Polymicrogyria BRCA 1 (increased susceptibility to breast cancer)* Bruton Agammaglobulinemia Tyrosine Kinase Cardiac Valvular Dysplasia Carney Complex* Charcot Marie Tooth Disease Chondrodysplasia Punctata Choroideraemia Chromosomal rearrangements (various) Chronic Granulomatous Disease Coffin-Lowry Syndrome Congenital Adrenal Hyperplasia Congenital Fibrosis of the Extraocular Muscles Congenital Stationary Night Blindness Crouzon Syndrome Cystic Fibrosis Cystinosis* Diamond Blackfan Anaemia** Dystonia 1 Torsion Autosomal Dominant (DYT1) Ectodermal dysplasia (Hypohidrotic) Epidermolysis Bullosa (Hallopeau-Siemens & Herlitz junctional) Facioscapulohumeral Dystrophy Familial Adenomatous polyposis coli Fanconi's Anaemia A** Fanconi's Anaemia C** Fragile X Syndrome Gaucher's Disease (Type II) Gonadal mosaicism Greig's Cephalopolysyndactyly Haemophilia A

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                                             

Haemophilia B Hereditary diffuse gastric cancer* Hereditary motor and sensory neuropathies Homozygous Familial Hypercholesterolaemia Hunters Syndrome Huntington’s Disease Hydrocephalus Hydroxyisobuyryl CoA Hydrolase Deficiency Hyper IgM Syndrome - Hypogammaglobulinaemia** Hypospadias (severe) Ichthyosis Incontinentia Pigmenti Juvenile Retinoschisis Krabbe Disease Leber's hereditary optic neuropathy / Lebers Optic atrophy Leigh's (subacute necrotising encephalopathy of childhood) Lenz syndrome Lesch Nyhan Syndrome Leukocyte Adhesion Deficiency (Type I)** Li-Fraumeni Syndrome Lymphoproliferative Syndrome Lynch Syndrome (MLH 2)* Lynch syndrome (MLH 1)* Macular Dystrophy (childhood onset - variant of Retinitis pigmentosa) Marfan Syndrome Medium-chain acyl-Co A dehydrogenase MELAS (Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) Menkes Syndrome Myoclonic epilepsy and ragged red fibres (MERFF) Metachromatic Leukodystrophy Multiple Endocrine Neoplasia (Type I) Multiple Exostoses Muscular Dystrophy (Beckers) Muscular Dystrophy (Duchenne) Muscular dystrophy (Occulopharangeal) Myotonic Dystrophy Myotublar myopathy Neurogenic muscle weakness, ataxia, retinitis pigmentosa (NARP) Neurofibromatosis type I Neurofibromatosis type II Niemann Pick Disease Type C Ornithine carbamoyl transferase Deficiency (OTC) Ornithine transcarbamylase deficiency (OTD) Osteogenesis Imperfecta (Type II) Ostheopathia Striata with Cranial Sclerosis Otopalatodigital syndrome (Type 2)

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                          

Partial Lipodystrophy, Familial (Type 2) Pelizaeus Merzbacher Disease Phenylketonuria (PKU) Plakophilin 1 (PKP1) associated ectodermal dysplasia syndrome Polycystic kidney disease Pompe Disease (early onset) Prader Willi Syndrome Pyrodoxine-dependent seizures Recurrent Digynic Triploidy Recurrent hydatitiform mole Retinitis Pigmentosa Retinoblastoma Retinoschisis (Juvenile) Sandhoff Disease Sensorineural deafness - autosomal recessive non-syndromic Severe Combined Immune Deficiency (x-linked) Sickle Cell Anaemia** Spastic paraplegia Spinal Muscular Atrophy (SMA1) Tay Sachs Disease (infantile onset) Torsion Dystonia Treacher Collins Syndrome Tuberous Sclerosis (TSC2)* Turner's syndrome (Mosaic) Von Hippel Lindau Syndrome Wiscott-Aldrich Syndrome** Wolman's Disease (Acid Lipase Deficiency)

Please note: This is not an exhaustive list. PGD is also available for some chromosomal re arrangements. This list shows most but not all of the conditions currently licensed by the HFEA for PGD testing. Some are not included here because their rarity means there is a risk of patient identification. In addition there are some conditions that are awaiting consideration by the HFEA. Further information regarding the indications available can be found on the HFEA website at http://www.hfea.gov.uk/pgd-screening.html

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Appendix 2

The HFEA has licensed HLA tissue typing with PGD for the following diseases:           

Beta thalassaemia Alpha thalassaemia Diamond Blackfan Anaemia Severe Aplastic Anaemia x-linked hyper IgM Syndrome Fanconi's Anaemia A Fanconi's Anaemia C Wiscott-Aldrich Syndrome Sickle cell disease Leukocyte Adhesion deficiency Type 1 Acquired Aplastic Anaemia

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Appendix 3: PGD Indication Specific Outcome Rates: ESHRE Consortium Data Collection VIII January to December 2005

Indication

Number of Cycles to Oocyte Retrieval (OR)

Embryo Transfer (ET) Procedure (%)

Clinical Pregnancy per OR (%)

Clinical Pregnancy per ET (%)

Delivery Rate per OR (%)

Delivery Rate per ET (%)

Spontaneous Abortions (%)

Chromosomal Abnormalities

520

328/520 (63)

94/520 (18)

94/328 (29)

81/520 (16)

81/328 (25)

12/931 (13)

X-linked Diseases (sexing)

108

83/108 (77)

24/108 (22)

24/83 (29)

18/108 (17)

18/83 (22)

5/23 (22)

Autosomal Recessive Diseases

161

134/161 (83)

44/161 (27)

44/134 (33)

36/161 (22)

36/134 (27)

4/322 (13)

Autosomal Dominant Disease

160

126/160 (79)

27/160 (17)

27/126 (21)

27/160 (17)

27/126 (21)

0

69

51/69 (74)

8/69 (12)

8/51 (16)

7/69 (10)

7/51 (14)

01

110

94/110 ((85)

30/110 (27)

30/94 (32)

25/110 (23)

25/94 (27)

5 (17)

Specific Linked Diseases Other Monogenic Diseases

X-

1. One pregnancy lost to follow-up

2. Four pregnancies lost to follow-up

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