A critical document governing clinical trials in Australia, the National Statement on Ethical Conduct in Human Research (National Statement), has been updated for the first time in 5 years. The new 2023 National Statement commences on 1 January 2024.
A number of significant changes have been made in the National Statement 2023, including:
- fully revising the guidance on risk and benefits from a three-level risk model to a continuum-based model with two broad categories and
- multiple updates to the guidance on research governance and ethics review.
Clinical trials continue to expand in Australia, with over 18 000 trials recruiting 8.7 million participants in Australia. [1] The National Statement is the foundational guide in the ethics approval process for those clinical trials in Australia—outlining the ethical principles and standards to which drug and device developers, researchers, ethics committees, and institutions must adhere when planning, conducting, and reviewing their clinical trials.
Stakeholders in research & development in life sciences should familiarise themselves now with these updates, which will affect study design, ethics approval procedures and risk assessment for future clinical trials of medicines and devices.
The changing landscape of clinical trials in Australia, Anna Lene Seidler, Melina L Willson, Mason Aberoumand, Jonathan G Williams, Kylie E Hunter, Angie Barba, R John Simes and Angela Webster, Medical Journal of Australia, 14 August 2023.
Clinical trials in Australia
Clinical trials play a crucial role in advancing the Australian health sector by driving medical innovation, ensuring patient safety, and improving healthcare outcomes. These trials provide a structured and controlled environment for testing new medical interventions, such as drugs, medical devices, and treatment protocols, before they are introduced into mainstream medical practice.
The economic investment in Australian trials is substantial, with an estimated $1.4 billion of public and private funding committed in 2019” - Medical Journal of Australia [2]
The Australian Government actively encourages clinical trials in Australia, including through the Research & Development Tax Incentive for industry. [3] Clinical trials are a cornerstone of the Australian health industry, providing not only medical insights but also substantial economic opportunities. By conducting trials for new medical interventions, Australia attracts international pharmaceutical and biotech companies to invest in research and development activities within the country.
What is the National Statement?
The National Statement sets out the criteria by which Human Research Ethics Committees (HRECs) authorise, monitor, and review clinical trials. For the majority of clinical trials in Australia, HREC assessment is the key approval process for commencement of a clinical trial in Australia. [4]
HRECs review research proposals for research and clinical trials that involve human participants (or data relating to individuals) to ensure that they are ethically acceptable. Before a clinical trial can begin, the sponsor (usually the organisation or company conducting the trial) must submit a comprehensive research proposal to an accredited HREC. The proposal includes details about the trial's objectives, methods, participant recruitment, informed consent process, potential risks and benefits, and more.
When researchers submit a clinical trial proposal to an HREC for review, the committee evaluates the proposal based on the ethics principles outlined in the National Statement. The committee’s role is to assess whether the trial's design, methods, and protocols align with these principles. The HREC's responsibilities don't end with approval. It continues to monitor the trial's progress to ensure ongoing ethics compliance. If any changes to the trial are proposed after approval, these changes may need to be reviewed and approved by the HREC before implementation.
The need for ethics review of research involving human participants was recognised in the 1960s and continues to be seen by the Federal Government as a pre-requisite to any Federal funding of medical research.
The National Statement has regularly been updated since 1999. In fact, the NHMRC has already flagged further review and public consultation on Section 4 of the National Statement that provides guidelines on the ethical considerations specific to certain participants, such as pregnant women, children, and Aboriginal and Torres Strait Islander Peoples.
Changes to the National Statement’s position on risk
Introduction of a new continuum-based risk model
The current three-level risk model (negligible risk, low risk, and greater than low risk) has now been replaced with a continuum-based model from lower risk to higher risk: [5]
As above.
Why conduct a clinical trial in Australia?, Commonwealth Department of Aged Care
In Australia, most clinical trials are subject to notification to the Therapeutic Goods Administration (TGA) under the Clinical Trial Notification (CTN) scheme. This scheme allows sponsors to begin a trial once they have notified the TGA, provided that the trial meets certain criteria and the relevant HREC approval has been obtained. For some high-risk trials, particularly those involving new investigational medicinal products, sponsors must submit a Clinical Trial Application (CTA) to the TGA for further evaluation and approval. The TGA reviews the application to ensure that the trial is based on sound scientific principles and that participant safety is adequately addressed.
National Statement 2023, Chapter 2.1.
Source: National Health and Medical Research Council, National Statement 2023, Chapter 2.1, p 12.
The National Statement 2023 makes it clear that research in which the risk for participants or others is greater than discomfort level and involves a risk of harm is not low risk research and should be considered higher risk. All higher risk research requires review by an HREC.
Amendments clarify that processes for reviewing research may differ according to the levels of risk
Recognising that risk in research exists on a continuum, the National Statement 2023 says that institutions may choose to:
- differentiate between levels of lower risk or between levels of higher risk for review or monitoring purposes and
- develop review processes to accommodate these different levels of risk, while taking care to respect the principle of proportionate review.
Amendments clarify what is considered harm versus discomfort, burden, and inconvenience
The National Statement 2023 now recognises that harm can be experienced individually or collectively.
It also:
- makes some changes to the examples of potential harms:
- including anxiety-related psychological harm such as re-traumatisation and
- removing the explicit reference to cultural harm
- re-asserts that discomfort is considered less serious than harm and explains that discomfort can involve physical or psychological impacts, such as minor side-effects of medication, discomfort related to non-invasive examinations or tests (for example, measuring blood pressure), and mild anxiety associated with an interview
- explains that where a person’s reactions might exceed discomfort and become distress, this should be viewed as the potential for harm
- explains that some participants may be at higher risk of harm or discomfort arising from research and that this increased risk of harm or discomfort can express itself in different ways at different times and to different degrees and
- recognises that participation in research can also impose burdens or inconvenience (such as time given up and travel costs) on those involved in research but that these should not be considered a type of harm or discomfort and therefore should not be viewed as a risk. Nevertheless, the impact of any of these burdens or inconvenience on participants should be considered by researchers, institutions and HRECs and balanced against the potential benefits of the research.
Amendments clarify that the assessment of risk is a shared responsibility of institutions, review bodies, and researchers
The National Statement 2023 emphasises that researchers, institutions, and ethics review bodies are all engaged in the risk assessment process. It also reminds researchers, institutions, and ethics review bodies that the assessment of risk informs the determination of the appropriate level of review for a research project by the institution and reviewers’ judgments about whether risks are justified by potential benefits.
It also clarifies that:
- in assessing the risks of a research project, researchers, institutions and ethics review bodies should only consider the risks that may result from the research, as distinct from the risks participants would be exposed to if they were not participating in the research and
- that developing and promoting clear policies for the processes for assessment of risk and review of research are an institutional responsibility.
Changes to the National Statement’s position on research governance and ethics reviews
The new National Statement makes a number of changes in Section 5 regarding research governance and ethics reviews, the first of which is to align this section with the changes made in Chapter 2.1 on risk. For example, the new introductions to section 5 and Chapter 5.1 make it clear that developing and promoting clear policies for the processes for assessment of risk and review of research are an institutional responsibility.
The guidelines for ethics review exemptions have been updated
Some research may be eligible for exemption from ethics review. Previously, institutions could choose to treat as exempt from ethical review research that involved ‘negligible risk’ or involved the use of existing collections of data or records that contain only non-identifiable data about human beings. This has now been updated.
The new guidelines also make it clear that research that involves the use of data that includes personal information without consent cannot be granted an exemption from ethics review. [6]
The decision whether to grant an exemption is made by the institution responsible for the research, and when there is no institution providing oversight of the research, the decision needs to be made by an ethics review body.
The criteria for the minimum membership of an HREC has been updated
Specifically, in addition to the existing requirements [7], the National Statement 2023 now requires:
- two people who bring a broader community or consumer perspective and who have no paid affiliation with the institution (previously the requirement was for ‘at least two lay people, one man and one woman, who have no affiliation with the institution and do not currently engage in medical, scientific, legal or academic work’)
- a person who performs a pastoral care role in a community including, but not limited to an Aboriginal and/or Torres Strait Islander elder or community leader, a chaplain or a minister of religion or other religious leader (changes in italics) and
- a qualified lawyer, who may or may not be currently practicing and, where possible, is not engaged to advise the institution on research-related or any other matters (changes in italics).
Further guidance on the membership of HRECs and ethics review bodies
National Statement 2023, section 5.1.16.
National Statement 2023, section 5.1.30, which required (a) a chairperson with suitable experience, including previous membership of an HREC, whose other responsibilities will not impair the HREC’s capacity to carry out its obligations under the National Statement, (b) a person with knowledge of, and current experience in, the professional care or treatment of people such as a nurse, counsellor, or allied health professional and (c) two people with current research experience that is relevant to research proposals to be considered at the meetings they attend.
On top of the minimum members an HREC is required to have, institutions may appoint additional members and these members may represent minimum membership categories (for example, an additional community member, lawyer or researcher) or have experience or expertise relevant to the work of the committee. [8]
National Statement 2023, section 5.1.33.
As before, institutions are encouraged to establish a pool of appointed HREC members to draw on as needed. [9]
National Statement 2023, section 5.1.34.
New guidelines have also been added on membership diversity and expertise.
For example, the guidelines now require HRECs and other ethics review bodies to ensure that, as far as practicable, the membership at each meeting has diversity, including gender diversity. [10]
Institutions that establish HRECs should also ensure that at least one third of those participating in each meeting are from outside of the institution. [11]
National Statement 2023, sections 5.1.36 and 5.1.37.
National Statement 2023, section 5.1.36.
The guidelines have also added further guidance on how institutions ensure that its ethics review bodies have access to the expertise needed to enable it to properly review research. [12] This may require going outside of the review body’s membership for review of individual research projects to seek assistance from individuals with:
- specialised scientific or scholarly expertise (including research methods)
- specialised technical expertise, such as statisticians or data security, storage and safety specialists
- expertise related to participant groups, including participant advocates and
- expertise related to research contexts, such as clinical or community care.
National Statement 2023, section 5.1.38.
The National Statement 2023 adds a new requirement that HRECs that review research concerning Aboriginal and Torres Strait Islander people or communities should appoint one or more members who have knowledge of research with Aboriginal and Torres Strait Islander Peoples or who are familiar with relevant cultural knowledge, if such a person has not already been appointed to the committee. [13]
National Statement 2023, section 5.1.39.
Finally, the National Statement 2023 now allows an HREC to delegate some of its responsibilities to its chairperson, one or more of its members, a sub-committee, or its administrative officers. However, it is clear that actions taken by these delegates are not equivalent to decisions by the HREC and some of these actions would need to be ratified by an HREC. [14]
National Statement 2023, sections 5.2.9 and 5.2.10.
Additional guidance on ethics review policy and processes
The National Statement 2023 states that institutions can establish their own processes for ethics review of research or use the review processes of another institution or external ethics review body. [15]
This also includes overseas review bodies. When institutions are considering accepting the outcome of another institution’s ethics review process, including a review conducted by an overseas review body, the Statement recommends they follow the updated guidelines in Chapter 5.5 that aim to minimise the duplication of ethics reviews. [16] These guidelines include the following changes of particular interest:
- Wherever more than one institution has a governance responsibility to ensure that ethics review of a human research project has taken place, each institution has the further responsibility to adopt a review or authorisation process that minimises any unnecessary duplication of ethics review. [17]
- Institutions that will serve as individual sites for a multi-centre research project should make every effort to avoid multiple ethics reviews of the same research project, other than specialised review that may be required. [18]
- Institutions should determine the criteria that must be satisfied for them to accept an ethics review conducted by an entity external to the institution, including overseas review bodies. [19]
- To facilitate the efficient ethics review of research, researchers must inform any reviewing body of:
- all sites at which the research will be conducted
- any information on local site circumstances that is relevant to the ethics review
- any other body that will be considering ethical issues related to the research and
- any previous decisions to approve, re-consider or deny approval of the research by another review body in Australia or elsewhere. [20]
- Researchers who wish to submit evidence of ethics approval by an external ethics review body in support of single ethics review should be aware of existing national or international programs, protocols, policies, standards, and guidance that may be relevant to the institutional decision to accept the review. [21]
Other changes
The NHMRC has also:
- made a structural revision to the National Statement by separating the responsibilities of HRECs and other ethics review bodies, which are now contained in Chapter 5.2, and the responsibilities of researchers, which are now contained in Chapter 5.3 and
- made it clear that the failure to comply with the requirements of the National Statement may result in the HREC being removed from the list of HRECs registered with NHMRC.
Existing Applications for ethics review
- Applications that have already been submitted to an HREC prior to 1 January 2024 when the new National Statement takes effect that are under review or have not yet been reviewed can be considered under the current version of the National Statement.
What next?
All stakeholders in the research and development ecosystem should familiarise themselves with the amendments in time for commencement of 2023 National Statement next year. This includes making any necessary adjustments to policies, processes, or individualised application or project description templates in readiness for 1 January 2024. This is particularly important for current and future Medical Research Future Fund (MRFF) grant recipients as MRFF grant agreements require compliance with the National Statement.
Prior to the 1 January commencement date, the NHMRC will also be making minor changes to the Human Research Ethics Application.
Further updates are proposed to Section 4
Stakeholders should also consider NHMRC’s proposed changes to Section 4 of the National Statement, which covers the ethical considerations specific to certain groups of participants, such as pregnant women, children, and people with cognitive impairment, an intellectual disability, or a mental illness. The NHMRC have released drafts of an updated Section 4, a National Statement preamble, an updated purpose, scope and limits statement, and section 1, as well as explanatory materials. Submissions are being sought from all interested parties in relation to the proposed changes.
The closing date for submissions is 15 September 2023.
Summary of changes to the National Statement
National Statement 2023, section 5.1.8.
National Statement 2023, section 5.1.9. The guidelines on minimising the duplication of ethics review were previously contained in National Statement 2007 (Updated 20018), Chapter 5.3.
National Statement 2023, section 5.5.1.
National Statement 2023, section 5.5.2.
National Statement 2023, section 5.5.3.
National Statement 2023, section 5.5.6.
National Statement 2023, section 5.5.7.
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KEY CHANGE
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BRIEF OVERVIEW
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2023 REFERENCES
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A new continuum-based risk model |
The National Statement has moved away from a three-level risk model (negligible risk, low risk and greater than low risk), and it has been replaced with the continuum-based model (lower risk to higher risk). |
Chapter 2.1 |
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The assessment & review of risk |
The National Statement clarifies that processes for the assessment of risk and processes for review of research differ according to the levels of risk. Also makes it clear that assessment of risk is a shared responsibility of researchers, institutions and reviewers. |
Chapter 2.1 |
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What is considered harm? |
The National Statement now differentiates between ‘harm’ versus discomfort, burden, and inconvenience. |
Chapter 2.1 |
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Ethics review exemptions |
The expansion of eligibility for research that may be granted exemption from ethics review now aligns with the new risk model and is consistent with international standards. The Standards provide updated guidance in relation to granting an ethics review exemption. |
Sections 5.1.15 — 5.1.17 |
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The membership of HRECs & ethics review bodies |
The National Statement now provides new minimum requirements for HRECs, new options to add HREC members, updated diversity and expertise guidelines. |
Sections 5.1.33 — 5.1.39 |
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New option to delegate |
The National Statement now allows an HREC to delegate some of its responsibilities to its chairperson, members, a sub-committee, or its administrative officers. |
Sections 5.2.9 & 5.2.10 |
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Ethics review policy and process |
The National Statement 2023 provides that Institutions can establish their own processes for ethics review of research or use the review processes of another institution or external ethics review body, including an overseas review body. |
Section 5.1.8 & 5.1.9 |
