Mitochondrial donation: new case application form

1. Introduction

Please use this form if you wish to carry out a mitochondrial donation technique to treat a patient not previously authorised by the HFEA.

Before you begin your application please make sure the following statements are true:

You hold a licence to carry out the mitochondrial donation technique (PNT and/or MST) intended for use in the treatment of this patient.

You have identified a pathogenic mutation in the mtDNA of the patient.

You have evidence that the patient has a significant risk of having a child who will have or go on to develop serious mitochondrial disease.

It is important that the language used in this application is clear and, as far as possible, understandable to non-specialists.

All abbreviations should be explained.

The application form has been designed to ensure that applying centres provide all of the information required to enable the Authority’s Statutory Approvals Committee to make its decision. If the form is completed incorrectly, or does not provide sufficient information, it could delay the decision-making process.

The committee is aware that not all pieces of evidence asked for will be relevant to every case.

An independent assessment of the application may also be sought from clinical experts and may inform the Statutory Approvals Committee’s decision-making process.

Guidance The guidance outlined in the green boxes, has been developed for centres licensed to carry out maternal spindle transfer (MST) and/or pronuclear transfer (PNT), that wish to apply for approval to perform mitochondrial donation for a new patient. Please refer to this as you fill in the application form. These applications are all considered on a case-by-case basis.

2. Current centre information

Person responsible
Centre name
Centre number
Multi-disciplinary team members who have contributed to this application

3. Regulatory requirements

Is this application from a centre licensed to carry out maternal spindle transfer (MST) and/or pronuclear transfer (PNT)?

Licensing requirement for MST and/or PNT Only centres licensed to carry out mitochondrial donation (MST and/or PNT) are permitted to make an application. Please state whether or not the application is from an assisted reproduction clinic, licensed by the HFEA.

☐ MST	☐ PNT	☐ No

Will only an authorised embryologist who is named on the licence carry out the proposed mitochondrial donation technique (MST or PNT)?

Named authorised embryologist Only the authorised embryologists named on the licence are permitted to carry out MST or PNT in treatment. Please confirm that only an authorised embryologist named on your licence will carry out the proposed MST or PNT.

☐ Yes	☐ No

Which technique is intended for the treatment of this patient?

☐ MST	☐ PNT

Has all the diagnostic genetic testing taken place in an accredited laboratory?

Laboratory accreditation Genetic testing should only be carried out by an accredited laboratory. If not, please provide an explanation as to why the genetic testing has not been carried out in an accredited laboratory.

☐ Yes	☐ No

Additional information related to the above points:

As the Person Responsible I confirm that the purpose of the application is to treat a patient with a pathogenic mtDNA mutation, and there is a significant risk of this resulting in a serious mitochondrial disease in their children.

PR confirmation Please confirm that the reason you want to carry out mitochondrial donation is for the statutory purposes.

Please tick the box to confirm acceptance of the above statement: ☐ Confirmed

4. Patient details

Note: This information will be redacted prior to submission to the Statutory Approvals Committee.

Surname
Forename
Patient number

I wish to apply for authorisation for this patient/case ☐ Yes

5. PGD unsuitability

Patient information and confidentiality It is important that you explain to the patient why they are being asked to provide the information given in certain sections of this form on their own medical history and that of their family. Explain to the patient that this information will be disclosed to the HFEA to assist in the Statutory Approvals Committee’s decision-making process and that all information will be treated confidentially by those to whom it is disclosed and will be stored securely.

PGD unsuitability The Committee can only approve applications where the patient has undergone an assessment that deems PGD inappropriate or likely to be unsuccessful. This is in light of the Authority’s decision to approve the use of mitochondrial donation as a risk reduction strategy for patients for whom PGD would be inappropriate. When considering the limitations of PGD for this patient, the Statutory Approvals Committee will take all of the information you provide below into account. Please provide as much evidence as possible so as to explain how your conclusion for this patient was reached.

Has the patient undergone an assessment that deems PGD inappropriate or likely to be unsuccessful?

☐ Yes	☐ No

Evidence for PGD unsuitability Please provide (in the box below) the nature of the assessment done, the rationale for your conclusion, and relevant details of the patient's medical history as well as pregnancy history. How does this demonstrate that PGD is inappropriate for this patient or likely to be unsuccessful? You should explain as fully as possible why you believe PGD would be inappropriate, including any clinical information and tests that informed your conclusion. Ensure you consider the following questions: Has the patient previously had any children affected by mitochondrial disease? If so, what were their symptoms? What was the age of onset? What was the effect on quality of life? Were any treatments available and what effect did they have? Would this manifestation of mitochondrial disease also pass the seriousness test (see section six below)? Has the patient previously undergone preimplantation genetic diagnosis (PGD) to avoid transmission of mitochondrial disease? Was the PGD unsuccessful? What was the mutant mitochondrial load of the embryos tested? Did any of the embryos have a mutant mitochondrial load above the threshold level usually necessary for clinical manifestation of serious mitochondrial disease?

PGD unsuitability - supporting information:

6. Seriousness and significant risk: general information

In this section of the form we would like you to provide information based on scientific literature, which is not patient-specific, about the disease(s) caused by the genetic change which has led to this application, and about the relationship between mutant mitochondrial load and disease manifestation.

Name of disease(s) caused by the genetic change:

Please list any OMIM numbers associated with this mitochondrial disease

OMIM numbers If applicable also provide the OMIM (On Line Mendelian Inheritance in Man System) number(s) for this mitochondrial disease. This is indicated by a hash (#) for phenotypes and a plus sign (+) for the description of a gene of known sequence and a phenotype.

Associated OMIM numbers:

Where information about the disease(s) or genetic abnormality listed above is available:

Lay summary of the condition Please provide a summary of the genetic condition and, if applicable, all the types of the condition in non-technical / lay language (the committee has a lay majority). This should include a description of how the condition affects a person, if known, how mutant mitochondrial load correlates to clinical symptoms and, if applicable, whether any treatments for the condition are available. Please limit the word count for the lay summary to 200 words.

Lay summary:

Evidence from scientific literature When considering the seriousness of a condition, the Statutory Approvals Committee will consider non-case-specific evidence from the scientific literature, which you will provide in this section, as well as the case-specific information given in section seven. Please provide as much information as possible. All of the information you provide will be taken into account by the Committee. Please include all relevant academic references, throughout.

Range of symptoms, including worst possible outcomes:

Age of onset: At what age will the symptoms of the condition start to develop? Is the condition apparent at birth or does it manifest later in life? If so, at what stage – for example, childhood, early adulthood or later? Are symptoms likely to be static, once present, or progressive?

Effect on quality of life: Please provide evidence about the effect the condition has on the quality of life of a child/adult (including the speed of degeneration in progressive disorders together with the extent of any physical and/or intellectual impairment).

Evidence on mutant mtDNA load and severity If there is any evidence from the scientific literature to indicate the effect of mutant mtDNA load on the severity of disease, please include all such information here.

What is the threshold level (or estimated threshold level) of mutant mtDNA necessary to cause symptoms? How does the mutant mtDNA load correlate to clinical symptoms? Are there any studies indicating how high the mutant mitochondrial loads were in women that have had children affected by mitochondrial disease? (please provide full references) What is the lowest mutant mitochondrial load in a woman that has had a child affected by serious mitochondrial disease?

Please list any treatment options available: How invasive is the treatment or likely treatment?

7. Genetic cause and particular risk

Has a pathogenic genetic alteration to the mtDNA been identified in the female patient?

Particular risk Only female patients for whom a pathogenic mtDNA genetic alteration has been identified are considered to be at particular risk of passing on abnormal mtDNA to their children.

☐ Yes	☐ No

Please give a description of this genetic alteration, ie, point mutation, deletion, rearrangement and the tissue this was identified in.

Genetic alteration: Please describe the pathogenic genetic alteration present in the patient’s mtDNA, (eg, T8993T>G in ATP synthase subunit 6 (MTATP6)). Please confirm the condition the patient is at risk of passing on to their children.

8. Significant risk and seriousness: patient information

In this section please provide evidence that is specific to the patient named in this application.

Disclosure of personal medical history It is important that you explain to the patient that information regarding their own medical history and that of their family, will need to be disclosed to the HFEA as part of the application process to assist in the Statutory Approvals Committee’s decision-making, although the patient’s identity will be redacted and so the Committee will not know their name. All information will be treated confidentially by those to whom it is disclosed and will be stored securely.

Risk and seriousness The Committee may only approve the use of mitochondrial donation if it is satisfied that there is a particular risk that any egg extracted from the ovaries of the patient, or any embryo created with those eggs, may have mitochondrial abnormalities caused by mitochondrial DNA. The committee must also be satisfied that there is a significant risk that a person with those abnormalities will have or develop serious mitochondrial disease. The Committee may also only approve applications for patients who are (or are predicted to be) highly heteroplasmic or homoplasmic for a particular mtDNA mutation in their germ line. When considering risk and seriousness, the Statutory Approvals Committee will take all of the information you provide below into account. Please provide as much evidence as possible.

Is there a significant risk that a child born without mitochondrial donation will have or go on to develop a serious mitochondrial disease?

☐ Yes	☐ No

Is the patient (or is the patient predicted to be) highly heteroplasmic or homoplasmic for a particular mtDNA mutation in their germ line?

☐ Yes	☐ No

Please explain why you think the patient's child, if conceived naturally, is at significant risk of having or developing a serious mitochondrial disease. You should include a full explanation of how you have drawn that conclusion (including information on the patient’s medical history and symptoms, relevant tests and results, and the family’s medical history).

Patient mtDNA load Has the patient's mutant mtDNA load been assessed? How does it provide evidence of risk and seriousness? In your response, please ensure you address the following questions: Is the patient homoplasmic or heteroplasmic for the mutation? What is the patient’s mutant mtDNA load and in which tissues? Have patients with similar mutant mtDNA loads had children affected by serious mitochondrial disease? How does the patient’s mutant mitochondrial load compare to the threshold level for clinical manifestation, if known? Please include specific predictions and risk calculations for the patient in relation to mutation load.

Please provide information on the patient’s mutant mtDNA load:

Patient family history of mitochondrial disease You should consider the following: Does the patient have a family history of mitochondrial disease? How prevalent is mitochondrial disease in the family? How serious was the disease in affected family members: what were the symptoms, what was the age of onset, what was the effect on quality of life, were any treatments available and what effect did they have? What were the mutant mitochondrial loads of affected family members with severe mitochondrial disease and what were the mutant mitochondrial loads of their mothers? Are the mutant mitochondrial loads of female family members who have had severely affected children comparable to the patient? Describe the symptoms of affected family members, age of onset, effect on quality of life, their mutant mitochondrial load, if any treatment was available, what it was and what effect it had. Note: Please ensure that you have either obtained consent before providing disclosure of family medical history that is capable of identifying an individual in the family, or take measures to ensure that confidentiality is not breached by providing family history as a narrative rather than describing individuals to a degree that they might be identified from your description.

Please provide information on the patient’s family history of mitochondrial disease How does the family history provide evidence of risk and seriousness?

Additional evidence relating to risk and seriousness If there is any additional information you feel provides evidence of risk and seriousness, please include it here. For example, you may wish to include a statement from the patient’s genetic counsellor, outlining the impact that mitochondrial disease has had on them and why they feel mitochondrial donation is the most appropriate treatment for them.

Please provide any additional information to support this application:

9. Declarations

I consent to the HFEA processing the data that I have provided on this form and any supporting documentation submitted with it, for the purposes of considering my application; statistical analysis; and quality control.

I further consent to the HFEA sharing these data with any other body with whom there is an agreement to undertake inspections or other regulatory functions on behalf of, or in conjunction with, the HFEA.

I understand that these data will be stored securely by the HFEA and saved in accordance with the HFEA's published retention and disposal schedule.

I further understand that the HFEA will not disclose these data to any third parties except as specified above, or as permitted or required by law, and in particular by the requirements of the Data Protection Act 1998 and the Freedom of Information Act 2000.

Persons submitting this application should note that by Section 18(2) of the Human Fertilisation and Embryology Act 1990 (as amended) the Authority may revoke a licence if it is satisfied that any information given for the purposes of application for the grant of licence was in any material respect false or misleading. They should also note that under Section 41(3) provision of false or misleading information, knowingly or in a reckless manner is a criminal offence.

The information provided on this form is to the best of my knowledge true and accurate.

Declaration Please tick the box to confirm the declaration. This must be completed by the Person Responsible of the licensed centre applying for the treatment.

Check the box to confirm acceptance of the above statement	☐