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Response to the Human Fertilisation and Embryology Authority's Survey Regulating Mitochondrial Donation: Seeking Expert Views

6 July 2015
This policy document is a response submitted by the Progress Educational Trust (PET) to the Human Fertilisation and Embryology Authority (HFEA)'s Survey Regulating Mitochondrial Donation: Seeking Expert Views.
As well as responding to this survey, PET has also responded to public consultations on mitochondrial donation conducted by the Nuffield Council on Bioethics in February 2012, by the HFEA in December 2012 and by the Department of Health in May 2014, and has drafted briefings for MPs and Peers on the science and ethics of mitochondrial donation.

1. Before a clinic can be licensed to carry out pronucelar transfer (PNT) and/or maternal spindle transfer (MST) they must be able to demonstrate they have the necessary skills and competency. Do you think the proposed approach for assessing the competency of a clinical embryologist is appropriate? Do you have any suggestions for alternative or additional evidence that could demonstrate the competency of a clinical embryologist intending to perform one or both of these techniques?
Since mitochondrial donation is a novel technique, it is important for the HFEA not to create a catch-22 situation where clinicians are only permitted to begin offering mitochondrial donation if they - or someone attesting to their competence - have already performed mitochondrial donation.
It is worth distinguishing between the technical skill of the embryologist, and the framework within which the embryologist will operate. In the past, specific micromanipulation skills have been assessed by direct observation or by examining training records. Where a new service is being introduced, skills have been assessed alongside a clinic's standard operational procedures and other associated documentation.
The HFEA should take into account the fact that a clinical embryologist carrying out a procedure may not be involved in making the relevant clinical decisions. The scientific career structure is moving increasingly towards a culture of separating the decisionmaking from the embryologists.
It is reasonable for the HFEA to suggest that, if an embryologist has received training at another establishment, some reference should be sought from the trainers. But the phrase 'references to support... experience and knowledge' in the background document for this survey (.pdf 205KB) implies something beyond confirmation of skills and training, and it is not clear what this could be.

2 (a). PNT and/or MST can only be carried out for a specific patient where there is a 'particular risk' of the egg or embryo having a mitochondrial abnormality caused by mitochondrial DNA (mtDNA). Do you think the proposed approach for assessing the 'particular' risk by reference to the presence of mutant mitochondria is appropriate? Please provide details of any other relevant measures, evidence, or criteria that could be used to determine the presence of a 'particular' risk.
Yes, we think the proposed approach for assessing the 'particular' risk by reference to the presence of mutant mitochondria is appropriate.

2 (b). Does this proposed process take into account all aspects relevant to the risk, and seriousness, of the disease and mitochondria disease biology? Please provide details of any other relevant information that could support an application for a particular patient.
The way the proposed process is described in the background document for this survey is potentially too inflexible to account for the wide variety of mitochondrial diseases and their manifestations.
All of the types of 'patient-specific information' listed in the background document are potentially relevant, but there will be some instances where some of this information is either not relevant, or cannot be provided. The HFEA's guidance needs to allow for this possibility.
For example, consider scenarios where a deleterious mtDNA mutation is rare, or where there is little previous experience of the mutation load reaching the threshold that will result in symptoms. There may as yet be no scientific literature relevant to the mutation, and evidence from the family may be limited or otherwise qualified.
With regard to the HFEA's assessment of the 'significant risk' of having or developing 'serious mitochondrial disease', it is important to understand that there is a necessarily subjective component to both 'risk' and 'seriousness'. It is impossible to establish either 'risk' or 'seriousness' without soliciting the patients' view, as to the burden that mitochondrial disease would have upon their child (and also, importantly, upon them and the rest of their family).
Risk has two components - the chance or probability of the condition occurring, and the extent of damage or burden to the patient. The former is largely a matter of scientific knowledge and clinical diagnostic skills (although even here there is the subjective element of what constitutes too high a chance in light of the burden), whereas the latter has a considerable subjective element, and can only be arrived at through discussion between patients and clinicians.

3. Mitochondrial donors will be providing their eggs in the same way as women donating eggs for fertility treatment. What should women donating their mitochondria be screened for?
Women donating mitochondria should be screened for deleterious mutations in their mtDNA via two methods.
First, a family history should be taken from the donor, but this family history should be interpreted in the context of specific expertise in mitochondrial disease. The mitochondrial expert must determine the likelihood that any history of disease in the family is attributable to mtDNA mutations, and will know to be attentive for 'red flags' that warrant investigation. As this is a complex and fast-moving field, the role of the HFEA is not to specify precisely how the mitochondrial expert should interpret the family history, but merely to stipulate that the family history should be taken and interpreted by a mitochondrial expert.
Second, the donor's mitochondrial genome should be sequenced as a matter of course. The small size of the mitochondrial genome (compared with the nuclear genome), combined with the latest advances in next-generation sequencing, mean that this is both a practicable and a reasonable precaution to expect of clinics.
The HFEA should not be prescriptive about the tissue(s) of the body from which cell samples are taken in order to sequence the mitochondrial genome - for example, whether blood cells, urinary epithelial cells or other cells should be sampled. Mitochondrial heteroplasmy means that mutations that pose a risk of mitochondrial disease may not be equally detectable in all tissues, and clinics should take account of this when developing protocols.
The background document for this survey says of mitochondrial donors that 'as their eggs will be processed and used to create embryos, the risk of infectious diseases being transmitted is likely to be the same', and that therefore 'most of the same requirements for laboratory tests and storage... will apply to mitochondrial donors'. There is a potential problem with the assumptions that are being made here.
Screening protocols for donors are based on recommendations by the relevant professional bodies. In the past, recommendations for screening egg donors have been based in large part on recommendations for screening sperm donors, despite the fact that the relevant risks are not necessarily comparable.
If these same recommendations are stretched even further to cover mitochondrial donors, then there is a danger of perpetuating measures that bear only a tenuous relationship to any real risk analysis. After all, the viral load of an insemination sample is unlikely to be comparable to the viral load of cytoplasm in the egg of a mitochondrial donor.
Going forward, the relevant professional bodies should be encouraged to review their guidance in relation to both egg and mitochondrial donors, and to be less reliant on convenient but limited analogy with sperm donors.

4. Age may be an important consideration when selecting mitochondrial donors. Professional guidelines state that eggs for fertility treatment should not be taken from donors aged 36 or over. Do you think the proposed approach to apply the same age limit for women donating their mitochondria is appropriate?
The background document for this survey suggests that the risk of inheriting unhealthy mitochondria from a mitochondrial donor will increase significantly as the donor ages, and that this could be a justification for imposing an age limit of 36 on mitochondrial donors.
This is somewhat convoluted reasoning, for applying the recommended age limit for egg donors to mitochondrial donors. Nonetheless, we agree that it is appropriate to apply the same age limit in the first instance.
Going forward, the relevant professional bodies should be encouraged to review their guidance on age limits for gamete donors - taking into account the latest scientific evidence and clinical developments, and also taking into account the new category of mitochondrial donors and any evidence that is specifically relevant to ageing and mitochondria.

5. The family limit refers to the number of families a single donor can help to create. Sperm and egg donors can donate to create a maximum number of 10 families. Do you think the proposed approach to apply the same 10 family limit to women donating their mitochondria is appropriate? Please provide reasons for your answer.
No, we do not think the proposed approach to apply the same 10 family limit to mitochondrial donors is appropriate.
It is worth pointing out that the 10 family limit on gamete donors is already contentious. But even if one assumes that existing justifications for this limit are valid, it is still not the case that these justifications apply to mitochondrial donors.
Psychosocial justifications for a 10 family limit - that is, arguments that it could be detrimental to a donor-conceived person to learn that they have a large number of genetic relatives - are not applicable to mitochondrial donation. Mitochondrial genetic relatedness is different from nuclear genetic relatedness, and nothing is yet known about the significance people might ascribe to the fact that a large number of people were conceived using the same mitochondrial donor.
In other words, there is no clear analogy to be drawn between gamete donation and mitochondrial donation, and no reason to assume the possibility of a detrimental impact. Mitochondrial donation does not, for most people at the present time, create any psychosocial expectations around a connection of kinship.
Medical justifications for a 10 family limit are similarly tenuous. The small risk of inadvertent consanguinity in gamete donation is not applicable in mitochondrial donation, where mitochondria are inherited solely from the donor (if genetic material is inherited from only one person there can be no consanguinity).
The background document for this survey suggests that a 10 family limit would have the merit of reducing the number of people affected, if it were later discovered that a health problem - undetected during screening - had been inherited from the mitochondrial donor. We are not persuaded that this is significant risk, especially not if the screening regime involves routine sequencing of the whole mitochondrial genome.
We would require a more cogent, evidence-based argument, before we were persuaded that this was a justification for a 10 family limit on mitochondrial donors.

6. We set out the information that should be provided to fertility patients before consent to treatment is obtained. Before patients give their consent to treatment involving mitochondrial donation, what information should clinics provide?
Because of the way people discover that they are at risk of transmitting mitochondrial disease - ie, they or a member of their family have either had an affected child, or been diagnosed with symptoms of mitochondrial disease themselves - any patient considering treatment with mitochondrial donation will almost certainly have been advised by experts in the field already.
This has an obvious parallel with preimplantation genetic diagnosis, where patients have already received genetic counselling. It is then the role of the clinic to provide more specific information about the procedure, its accuracy and any associated risks.
Therefore, rather than requiring clinics to furnish patients with all relevant information before they consent to be treated with mitochondrial donation, it is more logical for the HFEA to ask patients to confirm that they have already been advised by experts in mitochondrial disease.
It is still reasonable to require clinics to include, in the information that they give to patients, clarification that mitochondrial donation involves novel techniques whose outcome cannot be known with certainty. Obviously, this guidance should be revised in future if mitochondrial donation proves - as it hopefully will - to be safe and effective in practice.
Indeed, it is worth having a sunset provision to ensure that this requirement does not have to remain in the HFEA's guidance beyond a certain point. We suggest five years as a reasonable period for this sunset provision, as our understanding is that any unanticipated health problems due to being conceived via mitochondrial donation are most likely to manifest within the first five years of life.
It is also reasonable to expect clinics to give patients information about the desirability and benefits of families participating in research after they have been treated with mitochondrial donation, and about the desirability of telling the resulting child about the circumstances of their conception when the child is still young.
These two things are intimately connected. Any child who grows up experiencing regular encounters with healthcare professionals, as part of clinical follow-up and research, will be better able to make sense of these experiences if they come to understand the circumstances in which they were conceived. In the longer term, when the child grows up and can make their own decision about whether or not to consent to participation in research, a history of openness about the circumstances of their conception might leave them better disposed to the idea of participating.
Note that the background document for this survey uses the phrase 'the importance of follow-up studies' in relation to this area, but this phrase should be disentangled to distinguish clinical follow-up from longer-term research (see our response to Q8 below).

7. We set out the information that should be provided to prospective sperm, egg and embryo donors before their consent to donation is obtained. Before women give their consent to donating their mitochondria, what information should clinics provide?
Information provided to mitochondrial donors should explain, clearly and concisely, the key medical and legal facts concerning donation and also full details of the compensation to which donors are entitled.
In terms of medical facts, the information should explain what mitochondrial donation is and why it is used, the screening that the mitochondrial donor will undergo and why, and the fact that - according to prevailing scientific evidence - mitochondrial donation creates neither observable nor other shared characteristics between the donor and the person conceived following donation (except for the fact that hopefully, neither donor nor the resulting person will have mitochondrial disease).
In terms of legal facts, the information should explain that donors are not identifiable to recipients or to anyone conceived via their donation, unless known donation is used or unless there is a voluntary exchange of information outside the auspices of the regulator and the clinic. The information should also explain that donating mitochondria does not make the donor a legal relative of, or in any way financially responsible for, anyone conceived via their donation.
It is important not to treat information provided by gamete donors and information provided by mitochondrial donors as equivalent. The Human Fertilisation and Embryology (Mitochondrial Donation) Regulations 2015 make provision for the donor to provide non-identifying information 'with the intention that it be made available to' people conceived via their donation, but this is very different from the pen portraits and goodwill messages provided by gamete donors.
Mitochondria are donated for a very different purpose than gametes, and the genetic relatedness that results from mitochondrial donation is also very different. Furthermore, the mitochondrial donor has a guarantee of anonymity, whereas the gamete donor does not. The fact that both types of donation involve the same process of egg retrieval should not distract us from the fact that they are fundamentally different.
Mitochondrial donation does not, for most people at the present time, create any psychosocial expectations around a connection of kinship, and it is not appropriate for the HFEA to do anything that might encourage such expectations. A mitochondrial donor should not be made to feel that they are under any obligation to provide information that will be given to people conceived via their donation. Any information given to the donor should be neutral on the matter, and on the relevant form it should be made clear that providing such information is optional.
Participants in a workshop organised by the HFEA on 23 June 2015 were shown a draft mitochondrial donor registration form, where the 'optional additional information' section included the words 'this information is not compulsory but it is recommended you provide this information as it can help answer some questions a person conceived from your donation might have'.
This wording places far too much pressure on mitochondrial donors to provide optional information, and should be revised. It is not appropriate for the HFEA to recommend that mitochondrial donors provide this information - after all, we do not yet know what questions (if any) a person conceived from mitochondrial donation might have.

8. Many experts recommend that families using mitochondrial donation techniques should be encouraged to take part in long-term follow-up studies to monitor any possible effects on children born and future generations. We propose that clinics must submit their process for following-up children to us. Do you think this approach is appropriate? What do you think this process should cover?
No, we do not think this approach is appropriate. It is reasonable to ask clinics to confirm to the HFEA that they have such processes in place, but it is not reasonable to ask clinics to submit details of the process to the HFEA. It is particularly unreasonable to ask clinics to submit such details on an annual basis, as suggested in the background document for this survey.
Furthermore, the way this question is posed, and the way the relevant section of the background document is framed, is problematic. It conflates two things - clinical follow-up for the specific benefit of the child conceived via mitochondrial donation, and longer-term research for the generic benefit of anyone conceived with or affected by mitochondrial donation.
These two things are related, but are nonetheless distinct. Long-term research involves many complicated challenges, as anyone who has been involved in longitudinal studies will know. There are many different ways in which these challenges might be approached.
Ultimately, such research is entirely contingent upon securing substantial funding. Successful long-term research projects like the Avon Longitudinal Study of Parents and Children only continue to be successful, retaining participants and fostering goodwill among them decades after the project originally launched, because the research benefits from millions of pounds of continued funding year after year.
All of that said, it is certainly appropriate for the HFEA to emphasise the importance of clinical follow-up and longer-term research. The first clinic to apply for a licence to perform mitochondrial donation will already be profoundly aware of and invested in these things, but if we look forward to a time when mitochondrial donation becomes more established, such exhortations to clinics will be valuable. Apart from anything else, researchers may find it useful to cite such HFEA guidance in applications for funding. Still, it is important for the HFEA to understand that there is no guarantee funding will be forthcoming.
As for the proposal in the background document, that it should be regarded as an adverse incident if a child born following mitochondrial donation is found to have a mitochondrial disease, birth defect, or genetic abnormality (that may have been caused by the procedure), we think that this proposal is too simplistic. Certainly it is appropriate for the HFEA to expect clinics to report such an outcome, but that does not necessarily mean that the outcome should be categorised as an adverse incident.
Such an outcome should be categorised as an adverse incident only if the relevant protocol has not been followed. If the relevant protocol has been followed correctly, then what has transpired is actually a known risk. The data is important and valuable in either scenario, but the HFEA should have a mechanism for collecting the data that is not dependent on miscategorising known risks as adverse incidents.

9. Do you have any additional comments about the regulation of mitochondrial donation?
The Third Scientific Review of the Safety and Efficacy of Methods to Avoid Mitochondrial Disease through Assisted Conception (.pdf 997KB) convened by the HFEA recommended 'that consideration is given to mtDNA haplogroup matching when selecting donors, although the panel considers that the risks of not doing so will be very low, and that there may be practical factors preventing it'.
This recommendation was prompted by concern, in some quarters, that there is a possibility of health problems due to mito-nuclear mismatch. However, evidence for this concern is not strong.
Adverse effects from mito-nuclear mismatch have been shown in animal models, but these effects have been mild. Furthermore, the two situations in which such effects have arisen - nuclear material transferred between different species, and nuclear transferred between different populations that have been inbred for many generations and kept separate from one another - are of little or no relevance to mitochondrial donation in humans.
It is reasonable for the HFEA to encourage clinics to keep a watching brief on emerging evidence in this area, but it is not appropriate for the HFEA to be any more prescriptive than this. Haplogroup matching could add undue delay to treatment with mitochondrial donation, and could preclude ethnic minority patients in particular from being treated with mitochondrial donation (because there may be few mitochondrial donors, if any, who belong to the same haplogroup as the patient).
Ultimately, it must be for patients to decide - in discussion with clinicians - whether as-yet-hypothetical risks of mito-nuclear mismatch are acceptable risks to take, when weighed against the non-hypothetical risk of having a child with mitochondrial disease.
Looking more broadly at mitochondrial donation, it cannot be emphasised enough that this is a very different type of donation than gamete donation (notwithstanding the fact that mitochondrial donors will undergo the same egg retrieval procedure as egg donors). The HFEA has done a good initial job of trying to identify areas where its approach to regulation should be different in respect of mitochondrial donation, but we still think more effort should be made to keep the differences in mind.
If an approach suited to gamete donation is misguidedly applied to, for example, the 'additional information' that a mitochondrial donor has the option of providing, then there is a real danger that this will shape people's expectations of mitochondrial genetic relatedness and of the role of mitochondrial DNA. The HFEA should not fall into the trap of shaping expectations and perceptions in this way.
Finally, we would urge the HFEA to strike a balance between making its regulation of mitochondrial donation robust and responsible, and ensuring that what it requires of clinics offering mitochondrial donation is appropriate and proportionate. Parliament has decided unambiguously to permit the use of mitochondrial donation in treatment, and the HFEA should not regulate this form of fertility treatment with particular vigilance just because it is novel and it is criticised by an outspoken minority.
It is especially important for the HFEA to avoid becoming so defensive, that its primary aim in drafting regulation is to withstand judicial review. The purpose of the HFEA's regulation must be to safeguard patients, while giving them and their clinicians the latitude they need to successfully avoid the transmission of mitochondrial disease.