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Australasian Human Research Ethics Consultancy Services Pty Ltd (AHRECS)

Advances in Medicine often require innovation in ethical thinking too0

 

Nik Zeps and Tanya Symons
AHRECS Consultant

Breakthroughs in medicine often highlight the existing limitations of the frameworks established to manage the ethical responsibilities arising in healthcare. The contraceptive pill, organ transplantation, assisted reproductive technology, gene therapy and more recently gene editing are notable examples that have stimulated major debates and, in several instances, prompted changes to not only ethical guidelines but also legislation. However, there are also more subtle ethical issues that arise from doing established activities in a different context or scale. Think of so-called Big Data applied to health care or to uses of machine-based learning which promise to revolutionize practice but are really just larger scale applications of business as usual using more sophisticated technology than before. One result of these two developments is the amassing of personal data online which coupled with improvements in reidentification techniques present challenges to how we manage the privacy of individuals.  These have prompted amendments in regulation that facilitate the use of personal data whilst also strengthening protections for individuals (link to GDPR).

Less well known, are changes in the way we evaluate existing healthcare practices to ensure they are truly safe, effective and economical.  One such example is the increasing focus on Comparative Effectiveness Research (CER). These studies compare two or more existing practices that are in widespread use and have been found safe and efficacious. CER is an extension of audit/QI practices in that it uses clinical trial methodology and the power of randomisation to remove the biases inherent in the observed outcomes in a population of non-randomised patients receiving a particular health service. These studies generally include large numbers of patients (sometimes several thousand) so that they can detect differences between the interventions that, while relatively small, can nonetheless be clinically meaningful at a population level.

There is an over-riding ethical need to do this work constantly within what can be termed a ‘learning healthcare system’ 1.  Conceptually this means that every single instance that a person interacts with the health system should be captured in a manner in which it can be evaluated to make sure that optimal care is provided. Both patients and health system leaders expect this to be happening and yet in truth, the lack of standardisation in data capture, storage and interoperability means that few do this efficiently and effectively as part of routine healthcare activity. Moreover, existing research ethics frameworks impede the integration of healthcare and research by failing to recognise the differences between studies that involve standard care treatments from studies testing novel interventions with unknown safety profiles.  One example is the requirement to apply to comparative effectiveness studies informed consent processes that differ so greatly from routine consent to treatment they are impossible to integrate into routine clinical workflows.

In a recent paper, (Symons et al 2) we have considered whether approaches that utilise modified consent pathways for CER are permissible from an ethical and regulatory perspective. In an accompanying editorial 3Dr Evan Kharasch challenges the readers of the journal to consider how the existing ethical and legal frameworks can be complied with for trials where the risk of harm is small. There is a perception that as soon as a study employs randomisation it becomes more than low risk when this may not, in fact, be true. It is also important to consider the ethical issues that arise when this type of ‘public good’ trial is simply not done because using consent processes suitable for interventional trials of unapproved therapeutics makes them impracticable. If indeed a particular treatment is less effective or causes more harm and we continue to use it because we consider that currently required ethics processes render them impracticable, then those processes have led to potentially unethical outcomes.

To achieve the best healthcare outcomes, greater sophistication of thought is needed at the ethics committee level. It also seems obvious that greater engagement with consumers is a necessary and relevant pathway to designing and conducting trials that deliver on expectations. The Australian Clinical Trials Alliance (ACTA) together with the Trials Clinical Trials: Impact & Quality (CT:IQ) have developed a consumer involvement and engagement toolkit that serves this purpose [1]. By working more closely together and encouraging more flexible and contemporary approaches to research ethics compliance, we can achieve the ideal of encouraging and supporting clinicians and health services to undertake continuous improvements to health services using the best methodologies to achieve this for the benefit of the community they serve.

References

1          Faden, R. R. et al. An ethics framework for a learning health care system: a departure from traditional research ethics and clinical ethics. Hastings Cent Rep Spec No, S16-27, doi:10.1002/hast.134 (2013).

2          Symons, T. J., Zeps, N., Myles, P. S., Morris, J. M. & Sessler, D. I. International Policy Frameworks for Consent in Minimal-risk Pragmatic Trials. Anesthesiology 132, 44-54, doi:10.1097/ALN.0000000000003020 (2020).

3          Kharasch, E. D. Innovation in Clinical Research Regulation. Anesthesiology 132, 1-4, doi:10.1097/ALN.0000000000003026 (2020).

[1] https://involvementtoolkit.clinicaltrialsalliance.org.au/

This post may be cited as:

Zeps, N. (22 December 2019) Advances in Medicine often require innovation in ethical thinking too. Research Ethics Monthly. Retrieved from: https://ahrecs.com/human-research-ethics/advances-in-medicine-often-require-innovation-in-ethical-thinking-too-2

Inclusion of Culturally and Linguistically Diverse populations in Clinical Trials:0

 

Nik Zeps
AHRECS Consultant

Clinical trials have enormous value to society as they provide the most robust means of working out whether or not particular treatments used to improve the health of our population work or not. Governments have a stated objective to increase participation in clinical trials based upon a series of assumptions that extend beyond their utility as a means to derive the highest level of reliable evidence about the efficacy and safety of interventions. One of these is that those people who are included derive a tangible benefit from doing so. Whilst this may not be true in all cases, after all up to 50% of people may receive an inferior treatment by definition, there is the potential for people to derive individual benefit, and it is often stated that those involved in a trial receive a higher standard of care than those not included. Certainly, the additional testing and closer scrutiny of people on a trial may equate in some instances to better care, but this should not be seen as a major driver as it could be argued that equitable care should be available as a universal right. A less discussed benefit is the connectedness and satisfaction that people may derive from making a tangible contribution to society through participation in clinical research. Furthermore, there may be indeterminate peer group benefits even if an individual does not benefit.

In an Australian study Smith et al (1) found that CALD people whose preferred language was not-English (PLNE) had the lowest participation rates in clinical trials. Whilst CALD people whose preferred language was English (PLE) had greater levels of enrollment than the PLNE group, they were still underrepresented by population. This has been described across the world and is identified as a pressing concern (2).  Understanding why this is the case is important for a number of reasons. In multiculturally diverse countries like Australia, testing interventions where a significant proportion of the population are not included could result in evidence that is not applicable to those people. This spans across biological differences which may be relevant to drug efficacy or toxicity through to interventions such as screening that may fail to be useful in those populations. Where there is evidence that participation in a clinical trial may present specific advantages there is also the issue of injustice through exclusion of a particular group or groups of persons. Certainly, from an implementation perspective, not including a diverse group of participants and analyzing for cultural and behavioral acceptability may mean that even if an intervention has merit it fails to be taken up.

The reasons for non-inclusion are likely more complex than those of language barriers, although having protocols for clinical trials that specifically exclude people who don’t have higher levels of proficiency in English do not help. It would seem that the language barrier could be soluble through providing greater resources to enable translation services, particular in areas with a clear need for this. Certainly, multi-national trials already have PICFs in multiple languages and these could be readily deployed through use of innovative technologies including eConsent processes.[1] Funders of clinical trials could make it a requirement for such inclusivity and back it up through provision of specific funding for this in any grants they award. Legal means to enforce this, whilst possible, are unlikely to drive systemic change and could have the unintended consequence of making it harder to do any trials at all in an environment already subject to extreme financial pressures.

However, a major reason for low levels of participation in clinical trials may be attributed to equity of access to clinical services in the first place. It is hard to recruit people from the general population into clinical trials, but even harder if specific members of the population don’t come to the health service in the first place. There is relatively little research on this topic and it would seem logical to do this as a priority in parallel with examining why people fail to participate in clinical trials due to language barriers. Perhaps clinical trials are simply the canary alerting us to broader inequities that need greater research and investment. Research into solutions to these inequities is accordingly a priority and may solve clinical trial participation rates as a consequence.

References

  1. Smith A, Agar M, Delaney G, Descallar J, Dobell-Brown K, Grand M, et al. Lower trial participation by culturally and linguistically diverse (CALD) cancer patients is largely due to language barriers. Asia Pac J Clin Oncol. 2018;14(1):52-60.
  2. Clark LT, Watkins L, Pina IL, Elmer M, Akinboboye O, Gorham M, et al. Increasing Diversity in Clinical Trials: Overcoming Critical Barriers. Curr Probl Cardiol. 2019;44(5):148-72.

Nik Zeps participated in the CCV forum at the COSA ASM. A full report of the workshop and research by the CCV and MCCabe centre is forthcoming.

[1] https://ctiq.com.au/wp-content/uploads/eConsent-in-Clinical-Trials-compressed.pdf

This post may be cited as:

Zeps, N. (4 December 2019) Inclusion of Culturally and Linguistically Diverse populations in Clinical Trials. Research Ethics Monthly. Retrieved from: https://ahrecs.com/human-research-ethics/inclusion-of-culturally-and-linguistically-diverse-populations-in-clinical-trials

Research Ethics and the New Gene-editing Technology0

 

Nik Zeps, Consultant, AHRECS

Keywords: Ethical Review, International Guidelines, Gene editing technologies,

It has now been over six months since He Jiankuiand his team used the CRISPR/CAS9 gene editing technique to introduce a gene alteration in twin girls (STAT). The revelation that he had performed this audacious experiment shocked the world and left people asking how he had been permitted to do it. Dr He Jiankui is not a medical doctor but is qualified in biophysics and was one of the pioneers of the new gene editing technology in China having worked in the United States for five years where he undertook post-doctoral studies.

The report that accompanied the announcement of the birth of the twin girls outlined how He and his colleagues had sought out couples where the father was HIV-positive but the mother was not. The purpose of their work was to alter a gene known to confer resistance to HIV infection, CCR5, so that the children would be naturally resistant to possible infection. The public response worldwide was one of outrage and fierce opposition from all quarters. His fellow scientists and doctors denounced his actions as immoral and unethical and he was fired by the Southern University of Science and Technology in Shenzhen, China.

Chinese authorities immediately placed a prohibition on any such activities and research (human embryonic gene editing that leads to the birth of babies) and claims were made that he and his team had acted against the law. The People’s Republic of China does have guidelines that forbid any research that involves human reproductive cloning; however, they do permit therapeutic cloning using embryonic stem cells where the aim is to cure or prevent illness. This is similar to the United Kingdom and several other European countries, but this is not legal in Australia. The key question here is whether such research is restricted to generating embryo stem cell lines or whether it permits the creation of embryos that can be implanted and grown to a full-term delivery.

There remain many unanswered questions from this case. He claims that he had ethics approval but the responsible committee denies they had any involvement. Clearly the clinic that recruited the potential parents (several signed up) also knew of the work and endorsed it. All of those working on the project presumably knew what the aim of their work was and yet still conducted it willingly. It is also important to note here that in this highly controversial case the world does not have any independent confirmation that any gene editing actually happened or that the twin girls have the CCR5 alteration. However, prominent scientists who were present at the announcement appear to believe the claims and some of the details in the report itself appear to reflect the reality of his claim.

In response to international outrage, a group of prominent scientists have called for an international moratorium. This would be similar to the 1975 Asilomar conference on recombinant gene technology. In 2015 UNESCO called for a moratorium on genome editing of the human germline at least until the ‘safety and effectiveness of procedures remain unproven’. Both calls envision the possibility that prohibitions may be lifted if the evidence for safety and effectiveness can be met in contrast to those that wish for a permanent outright ban. The general prohibition on research involving human embryos, such as is the case in Australia, prevents anyone doing research that might demonstrate that such work is safe and effective though, effectively shutting the door. In the United States there is only a prohibition for federal funding of such research so private enterprise could easily step in. Moratoria are notoriously difficult to monitor or enforce and the lure of making money or gaining fame from the research may prove to be too powerful. He might reflect that he has achieved notoriety rather than fame as a hero but reports generally paint him as ambitious and naïve, conveniently ignoring the guidelines or ethical issues rather than being actually evil in intent. After all, the intention was to augment human capacity, even though that has led to claims of ‘taking a step down the road’ of human eugenics by prominent bioethicists such as Arthur Caplan.

One of the key messages coming out of the debate is that self-regulation by scientists remains open to abuse. On the other hand, scientists argue that attempts to limit their work with increased scrutiny may be disproportionate and have a negative effect on research that may ultimately lead to improvements in human health. This is the ‘rotten apple’ argument and to some extent it is fair to be sympathetic toward it as there are good examples of how increased regulation does not necessarily improve patient or community safety. However, there is more to this debate than just regulation of laboratory activities and the issues related to what it is to be human and the consequences of manipulation that extends into augmentation or spurious characteristic selection such as eye colour or enhanced sport performance are real.

The World Health Organisation (WHO) has called for international guidelines https://www.who.int/ethics/topics/human-genome-editing/en/to be developed and deployed by members states, forming a working party to develop these in December 2018. However, these would only be guidelines that would then have to be adopted by member countries. Importantly, the WHO panel does not envisage a permanent prohibition of embryo gene editing but stated in a media release that ‘The Committee will explore how best to promote transparent and trustworthy practices and how to ensure appropriate assessments are performed prior to any relevant work being undertaken.’ This clearly indicates that the intention is to regulate rather than prohibit future work in this area.

In many respects this is not a new ethical issue as the technology to alter the human genome has been around for many years, just not so cheap and potentially efficient. In addition, there are other applications of CRISPR that do not involve use in embryos or require a hereditary component. Somatic cell treatments for diseases such as muscular dystrophy and Beta Thalassemia have the potential to alleviate human suffering and are distinct from embryonic gene editing. It is probable that restrictions on these activities could also occur unless legislation and guidelines are careful to avoid capturing areas that are unintended. One could argue that these treatments which are aimed at people after birth should be treated in the same way as other biological therapies.

It is likely that a general prohibition of embryo manipulation for reproductive cloning will remain in most countries and some may now move to more specifically outlaw therapeutic cloning using gene editing. Many jurisdictions have looked at guidelines that prohibit this but there is little harmonization of these thus far. There is a great deal of work underway in many countries now to examine the issues and to establish appropriate pathways for regulation. AHRECS will monitor these activities and report on them as they arise.

This post may be cited as:

Zeps, N. (26  May 2019) Research Ethics and the New Gene-editing Technology. Research Ethics Monthly. Retrieved from: https://ahrecs.com/human-research-ethics/research-ethics-and-the-new-gene-editing-technology

A call for a national inquiry into the burden of research ethics and governance1

 

Adrian Barnett, Queensland University of Technology

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Do we need a national inquiry into the burden of research ethics and governance in health and medical research Australia? Many Australian researchers would cry “yes!” because they have repeatedly experienced application systems that are time-consuming and illogical.

I have never met a researcher who did not think that ethics and research integrity wasn’t vitally important, but many current application systems have more to do with risk aversion than the safety of patients or the public.

This risk aversion means that millions of dollars worth of Australian researchers’ time is being wasted on submitting the same forms to multiple ethical review committees. For example, getting approvals for our group’s low-risk survey of nurses in 50 hospitals cost an estimated $348,000 in staff time and delayed the study by six months (Barnett et al 2016).

Another Australian study of 60 nationwide hospitals spent an estimated $264,000 on approvals and the researchers’ experienced puzzling variations in submission requirements and decisions about the study’s level of risk (Clay-Williams et al 2018).

Another Australian study found that the time taken to complete the ethics and governance forms for a negligible risk study took eight times longer than the actual research (Rush et al 2018).

These are not isolated experiences and the current processes are driving researchers crazy. In our recent one-day meeting on improving research quality, we asked attendees to vote on the changes most needed to improve research and reduce research waste. The idea of a national inquiry into ethics and governance was voted fourth highest out of 21 policies (the full survey results are available here).

What should a national inquiry consider? The primary question should be: why can’t we have a national system? A national system that has standardised forms and is used by every state and territory health department. A national system that covers all types of research, not just clinical trials.

An inquiry into ethics processes could have been part of the Chubb inquiry (had Labor won the election) that promised a root-and-branch examination of Australia’s overall research framework and to “ensure that Australia maintains its international competitive advantage”. Other countries use simpler approval processes and we hamper our ability to conduct research by tying up researchers in wasteful knots of unnecessary paperwork.

A national inquiry should engage with the people doing the hard work of reviewing applications on ethics committees. These people should also welcome a streamlined system that cuts-out the requirement for them to review already reviewed applications, giving them more time to focus on important ethical considerations.

Researchers should also acknowledge that some delays and duplication are their own fault. A key problem is that ethics applications can be so badly written that committee members cannot judge the ethical implications of the study.

Australian researchers want a system that improves and facilities their research, not one that puts “virtually insurmountable and costly barriers in place” (Clay-Williams et al 2018). We want a “tailored and harmonised” system (Rush et al 2018).

Many researchers have been talking about the need for change for over a decade, but have seen only small improvements and plenty of backwards steps too. A national inquiry would cost time and money, but the potential long-term savings to researchers and the public from this important reform could be enormous.

Declaration of conflicts of interest: Adrian Barnett receives funding from the National Health and Medical Research Council.

References

  • Rush, A., Ling, R., Carpenter, J. E., Carter, C., Searles, A., & Byrne, J. A. (2018). Research governance review of a negligible-risk research project: Too much of a good thing? Research Ethics, 14(3), 1–12. https://doi.org/10.1177/1747016117739937
  • Clay-Williams, R., Taylor, N. & Braithwaite, J. (2018) Potential solutions to improve the governance of multicentre health services research. Med J Aust; 208 (4): doi: 10.5694/mja16.01268
  • Barnett, A. G., Campbell, M. J., Campbell, Shield, C., Farrington, A., Hall, L., Page, K., Gardner, A., Mitchell, B.G. & Graves, N. (2016) The high costs of getting ethical and site-specific approvals for multi-centre research. Research Integrity and Peer Review 1:16 https://doi.org/10.1186/s41073-016-0023-6

This post may be cited as:
Barnett, A. G. (22  May 2019) A call for a national inquiry into the burden of research ethics and governance. Research Ethics Monthly. Retrieved from: https://ahrecs.com/human-research-ethics/a-call-for-a-national-inquiry-into-the-burden-of-research-ethics-and-governance

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