“Informed Consent” to edit embryos: what consent?

Richard Milne and Anna Middleton from the Society and Ethics Research group provide a commentary on informed consent and its relation to gene editing in human embryos, in the context of recent activities in this area. Anna was an invited speaker at the 2nd International Summit on Human Genome Editing in Hong Kong.

Anna Middleton and Jennifer Doudna, inventor of CRISP-Cas9. Dr Doudna moderated the panel discussion Anna participated on.
Anna Middleton and Jennifer Doudna, inventor of CRISP-Cas9. Dr Doudna moderated the panel discussion Anna participated on.

Overview
At the Second International Summit on Human Genome Editing in Hong Kong 27-29 November 2018, Chinese scientist Jiankui He announced he had successfully edited two embryos, resulting in the birth of the first genetically edited humans. The reaction to the announcement was widely critical of its breach of international ethical standards, and raised questions about the ability of the scientific community to self-regulate. In this commentary, we focus in more detail on what has been revealed about the conduct of the study and consider the responsibilities of researchers and the scientific community to ensure this form of research is subject to scrutiny.

In his presentation to the 2018 Summit, Mr He declared that participants had given informed consent to have their embryos edited – he gave a public description of the consent process and stated that the informed consent form had been reviewed by four people before delivery by himself and his staff to the families (2). He also confirmed that the paperwork had been gone through ‘line by line’ to ensure participant understanding.

A still captured by Anna of He Jiankui, the controversial scientist behind the first live births to result from edited embryos.
A still captured by Anna of He Jiankui, the controversial scientist behind the first live births to result from edited embryos.

The principle of informed consent has long been a central element of research ethics, aimed at protecting individuals’ autonomy and right to self-determination, and preventing deception and coercion (3,4). The consent document for this embryo editing study had fundamental flaws. Informed consent is not in itself an “ethical panacea”(14), and good paperwork does not in itself ensure that research is “ethical”(15). Whether it is possible to obtain truly informed consent is debated, with concerns ranging from whether participants understand consent documents for complex research programmes, to recognising that decisions to take part in research are shaped by the expectations, hopes and pressures that both research participants and researchers bring into consent discussions. Nevertheless, the goal of obtaining participants’ informed consent remains a fundamental part of the work of research. In the case of the embryo editing experiment, it seems that this process was deeply flawed. The experiment failed to ensure clarity about core features of the research – its aims and the procedures research subjects were expected to undergo, the associated risks and protect the right to withdrawal.

We base our discussion on the consent form published on He’s research at the time of the 2018 Summit. We assume that this is indeed the one used in the experiment, presumably with the mothers, and referenced by He at the Summit on 28th November 2018 (2).

Explaining the purpose and process of research

The consent document was not clear about the goal of research. The study was introduced to participants as “an AIDS vaccine development project”, and later described it as “the HIV Development Research Project”. The accompanying application for ethics review further suggests that the edited CCR5 mutation will confer resistance not only to HIV, but to smallpox and cholera, but these are not mentioned in the consent form.

The consent forms were dense and difficult to understand. Scholars have repeatedly highlighted the critical importance of consent forms being clear and assessed for readability before use (8). The technical content of the paperwork and low global public familiarity with genomics (6) makes it possible that the provided information would be incomprehensible to many research participants (7). For example, the section on “why [are we] conducting this research?” responds: “gene editing of the CCR5 gene in the embryo would knock out the CCR5 gene. It would help these CCR5 gene editing [sic] babies to obtain the genotype of the Northern European to naturally immunize against HIV-1 virus”. Although only a guide, standard readability scores suggest that the consent form is only likely to be understandable to those with at least degree level education.

Informed Consent” to edit embryos: what consent
“Informed Consent” to edit embryos: what consent? (Image): Embryo slide

How clear were the risks?

As has recently been highlighted, the risks of gene editing remain unclear. The consent document highlights the risks, but again in a way that is unlikely to be meaningful: “The primary risk of gene editing (DNA-targeted CRISPR-Cas9 endonuclease) is the off-target effects of generating extra DNA mutations at sites other than the intended target. This is due to that (sic) the technique can cause nonspecific cleavage, resulting in mutations in non-targeted genomic sites.” However, there is no mention of the potential consequences of these off-target effects, nor whether they are reversible. Instead, the consent is more concerned with establishing liability: “Therefore, this project team is not responsible for the risk of off-target which is beyond the risk consequences of the existing medical science and technology.”

How feasible was withdrawal?

It is not clear how feasible it was for participants to withdraw from the He study. Participants should always be free to rescind their consent and withdraw from research. The consent document set out two situations in which participants may choose to cease involvement. If this occurred prior to embryo implantation, the “contract is terminated”. The second relates to withdrawal between implantation of the embryo and 28 days after birth. In these cases, a research subject becomes liable to “pay back all the costs that the project team has paid for you”. These costs are itemised, totalling 280,000 RMB (compared with an average cost of 20,000 to 30,000 RMB per IVF cycle in China (10)). If participants fail to pay within 10 days, a fine of 100,000 RMB is issued. These terms for withdrawal are clearly contradicted by international standards for research ethics which codify the right of research participants to withdraw “without reprisal” (11), and “at any time, without penalty” (12,13).

Conclusions

Investigations are ongoing in China and the United States to establish who could and should have known about and acted to prevent He’s experiment. The lack of institutional and community oversight of the research provided the context in which the experiment became possible. These failings were compounded by the haphazard way in which the study was conducted, and the lack of any significant effort to obtain genuine free and informed consent from participants.

The history of biomedical and psychology research highlights the consequences of conducting research without appropriately consenting participants (or at all). High-profile cases of the past, from Henrietta Lacks to the Havasupai Indian study, are still prominent in how communities engage with research (3,16). The He case reminds us of the importance of treating informed consent as the foundation for transparency and partnership rather than an exchange of contractual paperwork, and of the continuing need for robust informed consent process to uphold participant dignity, protect the right of withdrawal, and promote considered decision-making – however technical the domain (17).

To achieve this, journals and scientific bodies need to play their role. The scientific world has inevitably been overwhelmed with interest and curiosity as to how the technique works, and what the long-term effects are. The data are a potential valuable source of evidence. However, the Declaration of Helsinki is clear that “reports of experimentation not in accordance with the principles laid down in this Declaration should not be accepted for publication” (11). Editorial policy has not always been equally firm (19). Given the decision to publish, the journal should demonstrate the steps they have taken to ensure that research was conducted in such a way as to protect the interests of participants, regardless of wider questions about the ethics of gene editing techniques themselves. Not to do so, involves abrogating the responsibilities associated with the gatekeeping role that journal editors and reviewers continue to play in science. It does little to encourage the “rigorous, responsible translational pathway” (1) set out in consensus statements on human genome editing and undermines the partnership between scientists and patients.

Key messages: 
1. The informed consent process for the gene editing experimentation was flawed

2. Participants may not have been able to understand of the experiment (no fault of their own, but the information provision was severely lacking)

3. Penalties for withdrawal violate research ethics principles

4. The ethical concerns associated with the study present challenges for the scientific community and journals – due to the inability to clearly demonstrate adherence to ethical principles that underpin research, Mr He’s study will never be published in a reputable journal and thus will miss out on being subject to scientific scrutiny.

References:

1. Statement from the Organizing Committee on Reported Human Embryo Genome Editing. Available at: http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=11282018b

2. He, J. Presentation to Second International Summit on Human Genome Editing. Second International Summit on Human Genome Editing 28th November 2018, Hong Kong Available at http://www.nationalacademies.org/gene-editing/2nd_summit/second_day/index.htm
3. Wolf, S. M., Clayton, E. W. & Lawrenz, F. The Past, Present, and Future of Informed Consent in Research and Translational Medicine. J. Law. Med. Ethics 46, 7–11 (2018).

4. Grady, C. Enduring and Emerging Challenges of Informed Consent. N. Engl. J. Med.372, 855–862 (2015).

5. Anon. Informed Consent document, version Female 3.0 (archived version 28/11/18) https://web.archive.org/web/20181126211842/http://www.sustc-genome.org.cn/source/pdf/Informed-consent-women-English.pdf
6. Middleton, A. Public Engagement about Genomics. Public Engagement Efforts. Second International Summit on Human Genome Editing 28th November 2018, Hong Kong Available at http://www.nationalacademies.org/hk/

7. Organisation for Economic Co-operation and Development (OECD). OECD skills outlook 2013: first results from the Survey of Adult Skills. (2013).
8. Niemiec, E., Vears, D. F., Borry, P. & Howard, H. C. Readability of informed consent forms for whole-exome and whole-genome sequencing. J. Community Genet.9, 143–151 (2018).
9. Hallowell, N. et al. Lay and Professional Understandings of Research and Clinical Activities in Cancer Genetics and Their Implications for Informed Consent. AJOB Prim. Res.1, 25–34 (2010).
10. Wahlberg, A. The birth and routinization of IVF in China. Reprod. Biomed. Soc. Online2, 97–107 (2016).
11. World Medical Association. World Medical Association Declaration of Helsinki. Ethical principles for medical research involving human subjects. Bull. World Health Organ.79, 373 (2001).
12. Council for International Organizations of Medical Sciences. International ethical guidelines for biomedical research involving human subjects. Bull. Med. Ethics 17 (2002).
13. International Conference On Harmonisation Of Technical Requirements For Registration Of Pharmaceuticals For Human Use. Guideline for Good Clinical Practice: ICH Harmonised Tripartite Guideline. (1996).
14. Corrigan, O. Empty ethics: the problem with informed consent. Sociol. Health Illn. 25, 768–792 (2003).
15. Burke, W., Beskow, L. M., Trinidad, S. B., Fullerton, S. M. & Brelsford, K. Informed Consent in Translational Genomics: Insufficient Without Trustworthy Governance. J. Law Med. Ethics J. Am. Soc. Law Med. Ethics 46, 79–86 (2018).
16. Beauchamp, T. L. Informed Consent: Its History, Meaning, and Present Challenges. Camb. Q. Healthc. Ethics 20, 515–523 (2011).
17. Annas, G. J. Informed Consent: Charade or Choice? J. Law Med. Ethics J. Am. Soc. Law Med. Ethics 45, 10–11 (2017).
18. Saegusa, A. South Korean researchers under fire for claims of human cloning. Nature 396, 713 (1998).
19. Sade, R. M. Publication of unethical research studies: the importance of informed consent. Ann. Thorac. Surg. 75, 325–328 (2003).

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