HUMAN FERTILISATION AND EMBRYOLOGY AUTHORITY ETHICS & LAW COMMITTEE PGD/HLA TYPING POLICY RESEARCH

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1 HUMAN FERTILISATION AND EMBRYOLOGY AUTHORITY ETHICS & LAW COMMITTEE PGD/HLA TYPING POLICY RESEARCH Committee: Ethics & Law Committee Meeting Date: June 17, 2004 Agenda Item: 8 Paper Number: ELC (06/04) 04 Paper Title: PGD/HLA typing policy research Author: Paper: Peter Mills Annexes: Christina Panton (B), Charlotte Augst (C), Katy Berry (D), Fran Clift (E), Cathleen Schulte (F). For Information or Decision? Information/comment Resource Implications: None Recommendation to the Committee: The committee is invited to consider the findings of the research and agree a recommendation on these matters to be considered by the Authority in July. Introduction 1. The technique of preimplantation HLA typing allows the selection for transfer of embryos which are capable of providing histocompatible tissue for transplant to an existing, affected child, either as the sole clinical objective or in combination with PGD to exclude the risk of that condition for the child that will result from the treatment. 2. The use of the technique was considered by the HFEA Ethics Committee (EC) in November 2000, January, October 1 and November 2001, and was the subject of an Ethics Committee Opinion dated November 22, This Opinion informed the development of the Authority s current policy on the use of PGD/HLA typing which was agreed at the 113 th meeting of the Authority on November 29, More recently, the Ethics & Law Committee (ELC) has reviewed the HFEA s guidance on the use of the technique in the light of the findings of the Court of Appeal in R. (on the application of Quintavalle) v. HFEA in July and again in December On the last occasion the Committee was of the view that, in the light of developments that had taken place since the original policy was established, the Authority should now review its existing policy, and wished to reaffirm its Opinion of November 2001 with one rider relating to the selection of tissue donors for the benefit of their parents. (The revised Opinion is attached at Annex A.) Finally, in April 2004, the Committee agreed a programme of further research into PGD/HLA 1 Between January and October 2001 the Ethics Committee s consideration of the issue of PGD/HLA typing was suspended to allow the HFEA/HGC Joint Working Party on PGD to produce its recommendations as a result of the 1999 HFEA/ACGT consultation on PGD. These were agreed in June 2001 and finally published in November of that year.

2 typing to assist the Authority in its review of policy. The principal areas to be investigated were the following: safety of embryo biopsy and implications for the resulting child (see also Annex B); experience of families and children in sibling cord and bone marrow donation (see also Annex C); state of the art in stem cell therapy using cord blood and related bone marrow donors (see also Annexes C and D); case law relating to consent/authorisation for procedures involving non- Gillick-competent minors (should bone marrow donation be indicated) (see also Annex E); the development of the debate since the Authority s 2001 decision as expressed in statements and opinions of other ethical and advisory bodies (see also Annex F); public opinion formation on issues related to embryo selection (see also Annex G). 3. The purpose of this paper is to present the findings of this additional research to date and, on the basis of these, to seek recommendations from the ELC. Safety of Embryo Biopsy 4. One factor which distinguishes cases in which the embryo being tested is at risk of inheriting a deleterious condition from cases in which the condition of the affected sibling is either sporadic or one for which there is no known genetic marker (i.e. which distinguishes cases in which PGD would be indicated from those in which the embryos are being tested merely for tissue compatibility) is that in the first case the biopsy is carried out in the medical interest of the child-who-will-be-born whereas in the second it is carried out primarily in the interest of others. If there were a risk to the resulting child arising from the biopsy procedure this would constitute an argument for permitting the first case whilst not permitting the second. The argument goes as follows: Assume that two sets of parents are going to attempt to conceive a child to provide matched tissue for an affected child. One family carries a genetic disease with a regular inheritance pattern for which there is a known genetic marker. The disease present in the other family is not known to be heritable, or there is no known genetic marker for that disease. Assume that there is a small but undefined risk that the biopsy procedure may have adverse medical consequences for the child who will be born. (It need not matter that the risk of these consequences occurring might be relatively low and the consequences significantly less serious than the condition of the existing, affected child.)

3 Assume also that the primary consideration in reaching a decision is to prevent an adverse medical outcome to the child that will be conceived (setting aside for the moment any emotional or psychological harms or benefits). In the first case (known heritable genetic disease) there are two options: the parents can either conceive naturally, in which case there is a substantial risk that the child who will be born will suffer from a serious genetic disease or they can undergo PGD which will allow them to discount the substantial risk of genetic disease at the expense of introducing the small and undefined risk from the biopsy. Applying game theory, in this case it would clearly be preferable from the point of view of the child who will be born (who has a substantial risk of being severely disabled as a result of inheriting the condition or a small risk of being disabled as a result of the biopsy) for the parents to be offered PGD. In the second case (no known markers for disease in the family) there are also two options: the parents can either attempt to conceive naturally in the hope of having a tissue-matched child, in which case there is no additional risk to any resulting child, or they could undergo preimplantation HLA typing, in which case there is the small risk associated with the biopsy. In this case, if the risk relating to the biopsy is significant and welfare of the resulting child is still the primary consideration, they should not be offered the treatment. 5. Whilst the argument appears to be valid, there is considerable discussion to be had regarding the premises. For example, whilst there is known to be some risk of damage to the embryo as a result of the biopsy procedure (<5%), such damage usually renders the embryo non-viable. In the majority of cases, where the embryo continues to develop following the biopsy, the development of the embryo and subsequent development of the fetus and child is thought to follow a normal path. Nevertheless, although many more children have now been born following blastomere biopsy than existed in 2001 there are no large-cohort follow-up studies of PGD offspring available at present. (Data currently available are attached at Annex B. The outcome of the ESHRE PGD Consortium Data Collections IV and V are expected in Summer 2004.) Consistency with existing HFEA policies and recommendations 6. Where there is no need to produce a tissue donor but there is a diagnosable genetic condition in the family which the parents wish to avoid passing to a future child, if there were a significant risk associated with the biopsy, and the assumption regarding the primacy of the medical welfare of the child were maintained, couples might reasonably be refused PGD. This might be reasonable because it could be argued that it would be preferable for them to remain childless or to have a genetically-unrelated child than to run that risk of adversely affecting the child to be born by the medical intervention required to produce a genetically-related child free from the condition. If the parents insisted on reproducing using their own gametes, it might be considered reasonable to hold them (and not the clinicians who were

4 withholding treatment out of concern for the welfare of the child) responsible for any undesirable outcome. (This, incidentally, if the assumption regarding the risk of biopsy were proven, would certainly constitute the basis for an argument against aneuploidy screening.) 7. However, whilst in cases of ordinary reproduction there would be more than two options (the parents could adopt, remain childless or use donor gametes, for example), where the intention is to produce a tissue compatible sibling, the child must be conceived using the patients own gametes. The alternative to the PGD/HLA procedure, then, if the patients wish to produce a tissue-compatible sibling, is to conceive naturally and to terminate any affected pregnancy (and possibly also seek to abort a healthy fetus that is not tissue compatible). 8. Whilst, therefore, it would arguably be inconsistent with existing HFEA policies (on permitting PGD and aneuploidy screening, for example) to withhold HLA typing on the basis of a risk associated with embryo biopsy, conversely it would be consistent with arguments already made to support the prohibition of sex selection (for non-medical reasons) to withhold the treatment on the basis of the other major consideration that informed the HFEA s 2001 decision, namely psychological harm to the child conceived. 9. There remains, necessarily, very little evidence about psychological outcomes for genetically selected offspring and arguments have been largely speculative. Adopting a precautionary approach may certainly be criticised as incoherent since the precautionary principle can be used to support both sides of the argument: if there is a risk of harm to the child conceived we should err on the side of caution; on the other hand if this harm is merely speculative and the consequence of not undertaking the procedure is the death or suffering of the existing child, the cautious option is to carry out the procedure. 2 Nevertheless, the sex selection recommendation relied also on considerations of risk associated with the techniques of sperm sorting (in the case of flow cytometry, the concern that the laser energy and chromatinbinding dye used could adversely affect the sperm DNA, and in the case of gradient methods, because they do not appear to work) and the speculative argument about psychological consequences was not decisive but merely supportive of the general conclusion. 10. Furthermore, the interests of the patients on one hand and of the responsibility of clinicians involved on the other, not to mention the interests of the children concerned, are different in the two cases. In the case of sex selection the characteristic chosen does not, arguably, serve a purpose that has a positive moral value in itself whereas with HLA typing the characteristic is chosen in order to save the life of a family member. Whereas in the case of HLA typing, although the professional ethics are complicated, there is a good 2 Whilst the incoherence here is generated by adopting different perspectives (different values) on the harm likely to result, the correct perspective to adopt is itself a contested issue. The self-contradictoriness of the precautionary principle in all applications is discussed by Cass Sustein in his Seeley Lectures (Cambridge, 2004?), cited in Runciman, D., The Precautionary Principle, London Review of Books, vol.26, no.7 (April 1, 2004), at p.12.

5 argument that the parents have a strong claim on the assistance of professionals since their object is a genuine therapeutic one (to save the life of a child who might otherwise die); in the case of sex selection, on the other hand, the responsibility of clinicians to provide treatment is diminished in relation to the strength of the claim on their professional beneficence of those seeking it (simple sex preference). In the case of sex selection, then, if there is the possibility of an adverse, or even suboptimal, outcome that compromises the welfare of the child, clinicians cannot attenuate their professional responsibility for this by claiming that they were merely a tool in the service of the parents. Finally, one might be justified in imputing to a child an interest in being born with characteristics that allow it to save the life of a family member whereas it is much less clear that a child might, ex hypothesi, have an interest in being of one sex rather than the other. Families experience of sibling bone marrow and cord blood donation 11. Experts who were canvassed on this topic pointed to the paucity of existing evidence relating to the long-term psycho-social outcomes for those involved. Their opinions indicate, however, that where there is bone marrow donation within a family, this tends to intensify family relationships without, however, necessarily changing them for the worse. These experts identify a number of risk and resilience factors which may indicate how those involved will respond to the circumstances of donation. They are also critical of the expectation that child donors will give free consent to the treatment, although they stress the importance of the child s assent and involvement in the decision making process. 12. With particular reference to cases in which a child is conceived to be a tissue donor, both experts pointed to concerns about the welfare of the child as well as the welfare of the mother undergoing IVF during at an already stressful time. There was no indication that the concerns relating to the child s welfare would differ depending on whether the child was conceived by IVF or naturally. 13. Overall the opinions of the experts canvassed would seem to continue to support the model of constrained parental decision making recommended in the original Ethics Committee Opinion. 14. Further information may be found in the document attached at Annex C. Current state of the art of cord blood transplantation in context of alternative therapeutic options 15. Although the Authority is only required to address itself to the issue of whether HLA typing can be a proper (necessary or desirable) use of the technologies of assisted conception and not to the appropriateness of different treatment options considered by specialists caring for an affected child (or to disputes among paediatricians and haematologists about the relative value of these options) some consideration of the current state of the art in tissue may be useful to contextualise the main issue.

6 16. Related cord blood transplantation: Expert opinion has been sought from paediatricians and haematologists working with cord blood and bone marrow transplant patients in the UK. Written responses have not yet been obtained but further information can be found at Annex C which also contains a report of a discussion of PGD/HLA typing at the UK Childhood Cancer Study Group meeting on May Literature reviewed by policy staff reports the use of cord blood to treat blood malignancies, immunodeficiency, bone marrow diseases and storage diseases. Successful treatment has been documented in both children and adults. Further information, including abstracts of published articles, is attached at Annex D. 18. Related bone marrow transplantation: Bone marrow transplantation is a relatively well-established procedure for the treatment of certain conditions. Depending on the condition to be treated, closer human leukocyte antigen (HLA) matching it is generally more important for successful treatment using bone marrow transplantation than when cord blood is used. 19. The findings of a selective literature review relating to bone marrow transplantation are included in the document attached at Annex D. Legal research 20. R. (on the application of Quintavalle) v. HFEA: Following the HFEA s announcement of its policy decision in December 2001, the interest group Comment on Reproductive Ethics (CORE) sought permission to apply for judicial review, claiming the decision was ultra vires the 1990 Act. The claim was upheld at first instance but an appeal, in which the HFEA was joined by the Department of Health, was allowed in May As the law currently stands it appears that the HFEA has the power to license preimplantation HLA typing, with or without PGD to avoid serious disease. The claimant in this case has since successfully petitioned the House of Lords which will hear their appeal on March 7, Consent: Since many sibling bone marrow donors for young children will be strictly incompetent with regard to consent the decision making process must be approached with regard to their best interest. Where parents and clinicians agree that donation is the best course of action for the existing sibling the procedure tends to go ahead. In the case of dispute or uncertainty recourse may be had to interdisciplinary fora, ethics committees or the courts. Further information may be found in the document attached at Annex E. Opinions of ethics committees and advisory bodies 22. Since the HFEA s landmark policy decision in to permit PGD with HLA typing in November 2001, ethics committees of professional bodies, foreign regulators, and other national and international bioethics committees have delivered opinions and produced guidance on the use this technique. The HFEA s decision has also been subject to considerable discussion in learned periodicals.

7 23. Committee opinions: The majority of those committees that have addressed the subject have agreed with the HFEA that HLA typing combined with PGD for serious disease should be permitted, although many have disagreed with the HFEA s licensing criteria. Among these, there is considerable variation in the arguments that are found to be relevant and the weight given to these. Despite in many cases reaching similar conclusions, there is apparently no consensus among the committees about what the decisive arguments might be. 24. In particular, many bodies discuss whether preimplantation HLA typing should be restricted to cases in which embryos are at risk from the genetic disease affecting the existing child. 3 There is also some suggestion 4 that the technique should also be available where the intention is to use bone marrow from the resulting child and not merely cord blood. Additionally, some 5 feel that a decision of this sort should rest with the parents of the child concerned and not with regulators whilst others 6 would seek guidance from Parliament. 25. Academic articles: More thoroughly and consistently argued positions are found in the academic and professional journals. Arguments discussed include reproductive autonomy, procreative beneficence and the moral value of parental motivation, child welfare and the instrumentalisation of the child, and the slippery slope. 26. Further information may be found in the document attached at Annex F which also contains a digest of journal articles relating to the ethics of bone marrow donation. Research into opinion formation and public debate 27. In order to probe the way in which public opinion on this and related issues is formed and influenced, and to identify significant thresholds in public acceptance of new reproductive technologies, the HFEA commissioned a market research company, Opinion Leader Research, to conduct a series of workshops with members of the public. Six groups, each comprising 6-8 individuals (two groups having direct interest in either genetic disability or assisted conception) were convened to discuss the issues and to develop their opinions on the use of assisted reproductive technologies. The same individuals were then brought together for a three-hour evening workshop with invited experts to explore their views further. 3 For example, the Medical Ethics Committee of the BMA suggests there is no morally significant distinction between PGD/HLA and HLA typing alone and concludes that both should be available. On the other hand the International Bioethics Committee of UNESCO, the French National Ethics Committee for Life Sciences and Health and the Infertility Treatment Authority in Victoria, Australia, (which has recently produced guidance on the use of PGD/HLA) for various reasons consider it unacceptable to select an embryo on the basis of HLA type alone, whilst the Danish Council of Ethics considers it unethical for PGD to be used to obtain compatible tissue type at all. 4 See, for example, the Medical Ethics Committee of the BMA. 5 For example, the British Fertility Society. 6 Members of the HC S&T Committee, obiter.

8 28. Participants initial feelings were broadly in favour of the use of any technique which could save the life of a child, as long as the risks were well managed. Their primary considerations tended to be for the families involved (the affected child, donor, and parents) and their initial cautious approval tended to be confirmed by more sustained consideration of the issues. They were generally reassured by the views of the experts from whom they heard. Pre-family groups tended to be approach the issues more objectively and were slightly more sceptical than those with children, or with experience of infertility or disability. The majority of participants agreed that regulation was important but indicated a need for the benefits of technology to be more widely communicated and for decision makers to take into account both the views of experts in all relevant disciplines (medicine, psychology, ethics, etc.) and the subjective responses of the wider public. 29. Generally, participants did not consider it to be important whether the condition affecting the existing sibling was hereditary or not, although they thought the justifiability of the procedure would depend on the seriousness of the condition and should be addressed on a case-by-case basis. Many had greater reservations about the use of the procedure to produce a bone marrow donor, but these concerns tended to diminish in the light of more information about the procedure. 30. A brief presentation of topline findings from this research may be found in the document at Annex G and a summary report will be circulated to members on June 15. The full report will be available for the July Authority meeting. Developments 31. Anecdotally centres abroad are understood to have received applications for HLA typing where the existing child is not currently affected but is in remission, for example, from certain sorts of cancer. Obviously, in these cases, should the existing child relapse, there is likely to be insufficient time to go through the process of creating a tissue-matched sibling. However if one existed already, tissue that could be used in treatment would then be at hand if and when required. Whilst there are likely to be different arguments required to justify the preimplantation HLA testing in cases such as this, some 7 have argued that in such a situation the argument that the child is instrumentalised by being selected in this way is diminished since in this case the use of the child as a donor is merely conditional. 32. Further situations, many of which were considered in the EC Opinion, may be envisaged, such as where the intended tissue recipient is a parent, where non-regenerating organs (such as a kidney) would be required, or where the only suitable embryo will result in a child with a significant but less serious medical condition than the existing child. 7 e.g. Pennings, G., Saviour Siblings: using preimplantation genetic diagnosis for tissue typing, Elsevier International Congress Series 1266 (2004) (in press).

9 33. On the other hand, efforts in related areas of biomedical science, such as the management of disease, the use of combined cord or mismatched transplant tissue, the expansion of peripheral blood stem cell populations and therapeutic cloning to derive stem cell for treatments may, in time, provide viable alternatives to the use of tissue from matched siblings. Some relevant lines of research were considered at the Scientific & Clinical Advances Group in April. Conclusion 34. Members are asked: to consider whether risks associated with blastomere biopsy are relevant to the question of whether (1) PGD/HLA typing or (2) preimplantation HLA typing alone should be permitted (as distinct from the question of whether PGD should be permitted) and to consider the relevance of the distinction between (1) and (2); to consider whether there is any evidence of adverse psychological affects which is transferable and relevant to the question of whether (1) PGD/HLA typing or (2) preimplantation HLA typing alone should be permitted; to consider whether there are any additional arguments relating to the psychological effect of (1) PGD/HLA typing or (2) preimplantation HLA typing alone (as distinct from the effects of bone marrow donation in fortuitously matched siblings) that are relevant to the licensing of these techniques; to consider whether there is any evidence relating to the procedure of cord blood/ bone marrow donation which is relevant to the question of whether (1) PGD/HLA typing or (2) preimplantation HLA typing alone should be permitted where (A) the intention is to take only cord blood and (B) there is an expectation that bone marrow will be required, and to consider the relevance of the distinction between (A) and (B); to consider whether there are any legal issues relating to the procurement of (1) cord blood and (2) bone marrow that are relevant to the question of whether (1) PGD/HLA typing or (2) preimplantation HLA typing alone should be permitted; to consider whether there are any ethical arguments not already present in the revised Ethics Committee Opinion which are relevant to the question of whether (1) PGD/HLA typing or (2) preimplantation HLA typing alone should be permitted; to consider the preliminary findings of the public opinion formation research and to what extent these are relevant to the question of whether (1) PGD/HLA typing or (2) preimplantation HLA typing alone should be permitted;

10 in the light of these considerations, to identify the relevant considerations and to assess their force, and to make recommendations to the Authority regarding the ethical and legal aspects of PGD/HLA typing to assist the Authority with its review of policy in this area; to identify, in particular, significant ethical and legal developments since November 2001 relevant to the issue of preimplantation tissue typing, to be brought to the attention of the Authority. HFEA Executive (Policy) June 10, 2004