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Australian clinical trial handbook
Guidance on conducting clinical trials in Australia using 'unapproved' therapeutic goods
Responsibilities under the CTN and CTX schemes
Clinical trials are conducted by researchers as part of a broad group of stakeholders with varying responsibilities under the therapeutic goods legislation. These include trial sponsors, HRECs, approving authorities (institution in which the trial is being conducted), investigators and TGA. The key responsibilities for each of these stakeholder groups in the context of the CTN and CTX schemes are described below. There are other responsibilities for each stakeholder that are outside of TGA requirements. The Australian Clinical Trials website provides further information on other requirements.
Role of trial sponsors
All clinical trials conducted in Australia must have a trial sponsor that is an Australian entity (an overseas company cannot be the sponsor of a trial in Australia). Sponsors of trials under the CTN or CTX schemes may include individuals, companies, institutions, or organisations. Within the context of this handbook, we recognise two distinct definitions for the term 'sponsor':
- sponsor in relation to therapeutic goods: as defined in Section 3 of the Therapeutic Goods Act 1989
- sponsor in relation to clinical trials: as defined in the Guideline for Good Clinical Practice for medicines or biologicals or in ISO 14155 for medical devices
The trial sponsor is responsible for the initiation, management and financing (or arranging the financing) of the trial and carries the medico-legal responsibility associated with its conduct. The Australian trial sponsor is also the entity that is responsible for submitting a CTN or CTX to us.
Trial sponsors and the therapeutic goods legislation
The therapeutic goods legislation, as referenced in Legislative and regulatory provisions for the CTN and CTX schemes, specifies responsibilities of the trial sponsor under the CTN and CTX schemes. The trial sponsor takes the overall responsibility for trials conducted under the CTN and CTX schemes.
Trial sponsors should be aware of their responsibilities under the therapeutic goods legislation. Under the CTN scheme, the approval of the goods for use in the trial must be given by the sponsor (if the sponsor is conducting the trial), or by the body or organisation conducting the trial for the sponsor, having regard to the advice of the ethics committee responsible for monitoring the conduct of the trial. The sponsor must not receive advice from the ethics committee that is inconsistent with the continuation of the trial.
Under the CTN and CTX schemes the use of therapeutic goods in the trial must be in accordance with the Guideline for Good Clinical Practice, the National Statement and the protocol approved by the HREC responsible for monitoring the conduct of the trial.
The trial sponsor must also comply with the requirements of any other Commonwealth and/or state and territory legislation in relation to clinical trials and the supply of therapeutic goods.
The requirement to conduct a trial in accordance with GCP and all other regulatory requirements does not depend on whether the trial sponsor is a commercial company or a non-commercial institution or organisation (for example, a hospital or university). Where an investigator initiates and organises a trial without the involvement of an institution, he or she will take on the role of the trial sponsor and will then be responsible for the extensive GCP and regulatory requirements associated with both the management and conduct of the trial.
Where another party, such as a pharmaceutical or biotechnology company, provides investigational product (or other support) for an investigator-led CTN or CTX trial, the provision of that support does not oblige the company to take the role of trial sponsor.
Trial sponsor oversight of delegated functions
The Guideline for Good Clinical Practice and ISO 14155 allows a trial sponsor to delegate any or all of the sponsor's trial-related duties and functions, including safety reporting, to a third party such as a contract research organisation. However, the ultimate responsibility for the quality and integrity of the clinical trial data resides with the trial sponsor. The trial sponsor retains overall responsibility for all delegated functions in accordance with the Guideline for Good Clinical Practice and ISO 14155. This also applies when a non-commercial trial sponsor delegates duties; for example, to the coordinating principal investigator or trial coordinating centre.
The contracts and agreements between trial sponsors and third parties must ensure all roles and responsibilities are clearly defined. The approving HREC retains discretion to review and approve proposed delegations of trial sponsor functions.
Where sponsor functions are delegated to third parties, the trial sponsor should maintain appropriate oversight of those functions.
Reporting a change or transfer of trial sponsor
The transfer or change of trial sponsorship requires the submission of a new CTN or CTX form by the new trial sponsor for each of the clinical trials involved. This will ensure that the exemption or approval to supply the 'unapproved' therapeutic goods remains valid.
We recommend that the clinical trial start date reflects the date the new trial sponsor assumes responsibility for the clinical trial(s). Generally we have no objection to clinical trials continuing while all the necessary endorsements are obtained provided the original sponsor is able to fulfil their obligations until the new sponsor assumes responsibility.
The sponsor relinquishing sponsorship may notify the TGA that the exemption is no longer required by submitting a completion advice to us.
Trial sponsor responsibility of trial management and monitoring
The responsibilities of the trial sponsor are extensive; however, this handbook does not describe all sponsor responsibilities as they are clearly described in Section 5 of the Guideline for Good Clinical Practice and throughout ISO 14155. Instead, this section provides detail on the overarching responsibility of the trial sponsor for monitoring and managing their trials; particularly the responsibilities for safety reporting to us. Trial sponsors should ensure that a trial is appropriately monitored for compliance with GCP.
The quality of information generated when clinical trials are conducted impacts on the future care of the Australian population. Before initiating a trial, the trial sponsor should ensure that quality management systems are in place and that these systems are robust enough to fulfil all GCP and regulatory requirements, including relevant state and territory legislation. For example, when designing a trial, the Guideline for Good Clinical Practice requires trial sponsors to use a multi-disciplinary team of qualified individuals (for example, biostatisticians, clinical pharmacologists, and physicians) as appropriate, throughout all stages of the trial process, from designing the protocol and case report forms to analysing and preparing interim and final clinical trial reports.
When planning a clinical trial, trial sponsors should have processes in place to ensure the risks associated with its conduct are identified and assessed so that adequate trial monitoring and management plans can be developed to mitigate risk that may adversely impact on trial quality or participant safety.
We recognise that clinical trials under the CTN or CTX schemes vary greatly in terms of the risks posed to participants when compared to normal clinical care. The NHMRC guidance on Risk-based Management and Monitoring of Clinical Trials Involving Therapeutic Goods provides further information on the implementation of risk based management and monitoring plans.
Conducting ongoing safety evaluation and safety reporting
The Guideline for Good Clinical Practice and ISO 14155 places the responsibility for the ongoing safety evaluation of the investigational product used in a clinical trial, with the trial sponsor.
To ensure there is appropriate safety oversight, trial sponsors should generally use an independent committee or independent individuals. A Data Safety Monitoring Board (DSMB) may be convened based on the potential risks and benefits to participants associated with the trial and the trial design. The NHMRC guidance on Data Safety Monitoring Boards (DSMBs) provides advice on the use of DSMBs and also describes other safety monitoring structures that may be utilised when a DSMB is not warranted.
See Safety reporting to TGA for CTN and CTX trials for information on how trial sponsors should notify us of safety reports for CTN and CTX trials.
Record keeping obligations
The trial sponsor's record keeping obligations are outlined in section 5.5 of the Guideline for Good Clinical Practice (with our annotations for local context) and section 7.4 of ISO 14155.
There may be longer (or indefinite) retention periods for certain trials (for example, trials involving children and trials involving gene therapy). State and territory and institutional requirements may also specify longer retention periods.
Registration of trial
The National Statement obligates researchers to ensure that their trials are registered in a publicly accessible database before recruitment of the first participant. The International Committee of Medical Journal Editors (ICMJE) has a policy requiring trial registration prior to publication. The Australian Clinical Trials website describes some of the reasons why trial registration is important and provides a link to appropriate registries.
The Australian Code for the Responsible Conduct of Research states, 'researchers have a responsibility to their colleagues and the wider community to disseminate a full account of their research as broadly as possible'. The Code also describes responsibilities in relation to the dissemination of research findings.
Notifying trial sites
While a number of sites may be involved in trial related activities, the need to notify each site to us on the CTN and CTX forms is a separate matter. The trial sponsor should consult the approving HREC to determine which sites to notify to us.
However, the essential documents relating to a trial are expected to describe in detail where each trial related activity will be taking place. These documents as well as any relevant legal arrangements between a trial sponsor and service provider should be made available to us if required.
Role of Human Research Ethics Committees (HRECs)
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We have adopted a risk-based approach to the governance of clinical trials in Australia, a concept that is supported by the Organisation for Economic Cooperation and Development (OECD) in their Recommendation on the Governance of Clinical Trials (pdf,7.63Mb. We recognise that Australian HRECs have the mission and competence to oversee clinical trials under such a framework. As a result, HRECs play a central role in reviewing clinical trials that are subject to the therapeutic goods legislation.
The National Statement requires that all clinical trials must be reviewed by a HREC. The responsibilities, composition, function, operations, procedural and record keeping requirements for HRECs in Australia are set out in the National Statement. Therefore, Section 3 of the Guideline for Good Clinical Practice is not applicable to clinical trials in Australia. If requirements specified in the National Statement appear to differ from those specified in the Guideline for Good Clinical Practice, the TGA recommends compliance with the National Statement. HRECs also need to be aware of relevant state and territory laws pertaining to clinical trials and the supply of therapeutic goods. HRECs have a high level of independence and are responsible for establishing their own processes for receiving and reviewing research proposals.
Recent reforms under national and state and territory programs to harmonise HREC processes and to minimise duplication of review of multicentre research projects has resulted in increased standardisation of process.
The NHMRC's National Approach to Single Ethical Review of Multi-Centre Research (National Approach) aims to enable the recognition of a single ethics and scientific review of multi-centre human research within or across Australian jurisdictions. A key component of the National Approach is the National Certification Scheme of Institutional Processes related to the Ethical Review of Multi-centre research (National Certification Scheme).
Under the National Certification Scheme, some institutions have had their ethical review processes assessed by the NHMRC against an agreed set of national criteria. This has allowed HRECs to demonstrate, through assessment, that they are following the relevant guidelines and legislation when reviewing trial protocols and have processes consistent with the expectations of the National Statement. A list of institutions with certified review processes is available on the NHMRC website.
NHMRC has also developed the Human Research Ethics Application (HREA) as a national ethics form. Trial sponsors and researchers should use the HREA unless advised otherwise.
HRECs and the therapeutic goods legislation
The therapeutic goods legislation sets out a number of requirements for HRECs under the CTN and CTX schemes (See Legislative and regulatory provisions for the CTN and CTX schemes for specific references to the legislation). Under the Act, an ethics committee means a committee:
- constituted and operating as an ethics committee in accordance with guidelines issued by the CEO of the National Health and Medical Research Council as in force from time to time; and
- which has notified its existence to the Australian Health Ethics Committee (AHEC) established under the National Health and Medical Research Council Act 1992
A list of HRECs registered with NHMRC can be found on the NHMRC website.
Under the CTN and CTX schemes, the use of the therapeutic goods in a clinical trial must be in accordance with the Guideline for Good Clinical Practice, the National Statement and the trial protocol approved by the HREC that has the function of monitoring the conduct of the trial (see The HRECs role in monitoring a clinical trial).
Therefore, HRECs are responsible for approval of the trial protocol under both the CTN and CTX schemes. The HREC and the institution are responsible for establishing what information should be provided in support of an application and how the application will be reviewed by the committee. The HREC should request any additional information that it believes is necessary to undertake review of the proposed research.
The HRECs' role in monitoring a clinical trial
The word 'monitoring' in this context is used to describe the continuing review and oversight of the trial by the HREC. For example, this may include receipt of progress reports, safety information, approval of protocol amendments, notifications of serious breaches of the protocol or good clinical practice and updated trial documentation.
As the trial progresses, the HREC is also responsible for monitoring the continued benefit-risk ratio of the trial; in particular, whether any safety reports they receive impact on the continued ethical acceptability of the trial.
For further information on the safety monitoring and reporting responsibilities of researchers, trial sponsors, HRECs and institutions see the NHMRC Guidance: Safety Monitoring and Reporting in Clinical Trials Involving Therapeutic Goods.
The trial sponsor's monitoring responsibilities are outlined in both the Guideline for Good Clinical Practice and ISO 14155 and discussed further under Role of trial sponsors.
Withdrawal of approval by a HREC
It is a condition of both the CTN and CTX schemes that the use of the therapeutic goods in a clinical trial must cease if the HREC informs the principal investigator that the use is inconsistent with the protocol or a condition of approval by the HREC.
In addition, one of the conditions under which therapeutic goods are supplied in a CTN trial is that the trial sponsor must not receive advice from the HREC that is inconsistent with continuing the trial.
The HREC may review its ethics approval at any time in the light of safety reports, progress reports, issues raised by media reports or any other information (for example, a report of serious breach) that raises serious safety concerns or concerns about the conduct of the trial.
If the HREC becomes aware of information that may significantly impact on the rights, safety or wellbeing of participants or the credibility of trial data, it may advise the trial sponsor, approving authority and principal investigator that it intends to withdraw ethical approval at one or more sites for which the HREC is responsible. If the trial sponsor is not able to allay these concerns, then the HREC may withdraw ethical approval. The HREC should advise the trial sponsor, principal investigator, and the relevant approving authorities of any decision to withdraw approval. We should also be notified of the decision to withdraw ethics approval for a trial conducted under the CTN or CTX schemes.
The National Statement outlines the circumstances when research should be discontinued. The NHMRC has also published guidance on the Reporting of Serious Breaches of Good Clinical Practice (GCP) or the Protocol for Trials Involving Therapeutic Goods which provides further information.
The continued supply of the 'unapproved' therapeutic goods would be unlawful if a HREC suspends or withdraws ethics approval for a trial conducted under the CTN or CTX scheme
Circumstances that may lead to a HREC withdrawing its approval for a trial are most likely to be identified in the course of monitoring a trial. These may include:
- evidence of significant or repeated deviation from the trial protocol and that, as a result, the welfare and rights of participants are not or will not be protected
- evidence that allowing the trial to continue carries an unacceptable risk of death, serious illness or serious injury to trial participants
- evidence from progressive review of a comparative study shows that one treatment proves to be so much better or worse that to continue the trial would disadvantage one group of participants
- evidence that the conduct of the trial is in breach of Commonwealth, state or territory laws
Role of approving authorities
Approving authorities are public or private legal entities (institutions or organisations) where trials are conducted (i.e. trial sites).
For investigator-led trials, the institution that is the approving authority may also be the trial sponsor. In such cases the institution must ensure that its overarching quality management systems delineate its responsibilities as a trial sponsor from its responsibilities as a trial site.
Private clinics may be used as trial sites for clinical trial purposes and therefore take on the responsibilities of the approving authority. These sites must comply with good clinical practice and all other applicable clinical trial legislation and requirements.
Approving authorities conducting trials under the CTX and CTN schemes have specific responsibilities as outlined in the National Statement, Guideline for Good Clinical Practice and ISO 14155 and the Therapeutic Goods Act 1989.
Approving authorities and the therapeutic goods legislation
Under the CTN and CTX schemes, the approving authority gives the final authorisation for the conduct of the trial at the site following approval by the reviewing HREC (see Legislative and regulatory provisions for the CTN and CTX schemes for specific references to the legislation).
We do not have a role in the site assessment and authorisation processes, this is the responsibility of the approving authority. The NHMRC has provided further guidance on the Good Practice Process for Site Assessment and Authorisation Phases of Clinical Trial Research Governance (the Good Practice Process).
The Australian Code for the Responsible Conduct of Research, states that bodies responsible for research should, 'provide an appropriate research governance framework through which research is assessed for quality, safety, privacy, risk management, financial management and ethical acceptability'. These operations are generally overseen by a research office within the institution.
The research office's responsibilities are distinct from those of the HREC. The granting of ethical approval by a HREC does not oblige an approving authority to grant authorisation at their site as the site may not have the capacity or capability to complete the trial based on protocol requirements. As part of the process to confirm whether authorisation should be granted, the research office liaises with the site principal investigator and the trial sponsor to establish requirements to grant site authorisation.
Monitoring by the approving authority
The National Statement sets out obligations relevant to monitoring for institutions. Monitoring under the National Statement refers to the process of verifying that the conduct of research conforms to the approved proposal. Responsibility for ensuring that research is reliably monitored lies with the institution under which the research is conducted.
Approving authorities must be made aware of any issues that may impact on trial authorisation or institutional risk (for example, significant safety issues identified by the trial sponsor). The approving authority may withdraw authorisation if necessary. Such a withdrawal should be communicated to the HREC and to us.
Where a HREC has withdrawn ethical approval, the approving authority is obliged to ensure that the principal investigator promptly suspends the research. Arrangements should also be made to meet the needs of the participants in the clinical trial.
Role of principal investigators
The principal investigator is referenced in the therapeutic goods legislation relevant to the CTN and CTX schemes (see Legislative and regulatory provisions for the CTN and CTX schemes for specific references to the legislation).
Investigators are responsible for protecting the rights and safety of trial participants under their care. A full list of investigator responsibilities can be found in the Guideline for Good Clinical Practice or ISO 14155. The principal investigator is the person responsible, individually or as a leader of the research team at a site, for the conduct of a clinical trial at that site. As such, the principal investigator is responsible for adequately supervising his or her research team.
The principal investigator must conduct the clinical trial in accordance with the clinical trial protocol. Any significant departures that impact on the safety of participants or the reliability of trial data that occur at their site should be reported to the trial sponsor, HREC and approving authority, in line with NHMRC guidance on the Reporting of Serious Breaches of Good Clinical Practice (GCP) or the Protocol for Trials Involving Therapeutic Goods.
The principal investigator must ensure adequate medical cover is provided for the trial and ensure that all adverse events are reported in accordance with the trial protocol. The NHMRC Guidance: Safety monitoring and reporting in clinical trials involving therapeutic goods provides more information on the safety reporting responsibilities of investigators.
Where an investigator initiates and organises a trial, he or she will take on the role of the trial sponsor and will then be responsible for the GCP and regulatory requirements associated with both the management and conduct of the trial.
Role of TGA
Requests for information
Under the Therapeutic Goods Act 1989, we can request certain information or documents, in writing, about therapeutic goods exempt under the CTN scheme or approved under the CTX scheme relating to:
- the supply of the goods
- the handling of the goods
- the monitoring of the supply of the goods
- the results of the supply of the goods
This can include documentation such as the investigator's brochure and protocol, further information about safety reports, clarification about the safety profile of a specific therapeutic good, or details of problems or complaints.
We can require the trial sponsor of the goods exempt under the CTN scheme or the person who is granted approval under the CTX scheme to provide this information or documents.
It is a criminal offence to fail to comply with a request for information or documents that is made under the legislation, or to knowingly provide false or misleading information or omit any matter without which the information is misleading. Civil penalties also apply for giving false or misleading information or documents. See Legislative and regulatory provisions for the CTN and CTX schemes for the relevant sections of the Therapeutic Goods Act 1989 relating to requests for information.
With respect to the CTX scheme, we can inspect clinical trial sites as described in regulation 12AC of the Therapeutic Goods Regulations 1990 and regulation 7.4 of the Therapeutic Goods (Medical Devices) Regulations 2002. We can also request the principal investigator to answer questions and produce any records or documents we request.
We can release information obtained in a response to a request for information to an authority of the Commonwealth, a state or a territory that has functions relating to therapeutic goods as well as medical boards.
When further action is required
We may ask further questions or raise concerns that may need to be addressed from the review of requested information or documents. Further action may be required if any issues of concern are identified. This may include liaison with trial sponsors, principal investigator(s), approving authorities or the approving HREC.
Therapeutic goods supplied under the CTN scheme are exempt from the requirement to be included in the ARTG, subject to conditions. If these conditions are not complied with then the goods are no longer exempt from inclusion in the ARTG and cannot be lawfully supplied. Offence provisions may also apply where a person does an act, or omits to do an act, that results in a breach of condition of a CTN exemption.
Under the CTN scheme, if we direct the trial not be conducted or become aware that to conduct or continue the trial would be contrary to the public interest then the goods used in the trial would no longer be exempt from inclusion in the ARTG. For example, this may be where it comes to our notice that allowing the trial to proceed or continue carries an unacceptable risk of death, serious illness or serious injury.
We can also revoke an approval of a clinical trial under the CTX scheme where the conditions of approval are not met. In addition to revoking approval, offence provisions may also apply where goods which are the subject of a CTX approval are not used in accordance with that approval or a statutory condition made under subsection 19(4A) of the Therapeutic Goods Act 1989.
Procedures following the revocation of approval under the CTX scheme or a breach of the conditions of the CTN scheme would be determined on a case-by-case basis based on the impact on participants and their ongoing safety. It is the trial sponsor's responsibility to notify the HREC of a change in CTN or CTX status; however, we may liaise with the HREC in certain circumstances in a confidential manner. For multicentre studies the trial sponsor will have the additional responsibility of notifying all sites. A lead HREC in a multicentre study will need to liaise with the sites and trial sponsor when determining which, if any, are affected and the actions they need to apply.
Criminal and civil penalties may apply where a therapeutic good is used in a clinical trial in circumstances where a CTN exemption or a CTX approval no longer applies to the supply of the therapeutic good.
A CTN exemption will automatically cease to apply to the supply of a therapeutic good in a clinical trial if a condition of the exemption is breached.
A CTX approval will cease to apply to the supply of a therapeutic good in a clinical trial if we revoke the approval. We may revoke approval if a trial sponsor breaches a condition of approval.
Offence provisions may apply where there is a breach of a condition of a CTN exemption or a CTX approval.
Release of information
Information provided to us concerning the use of 'unapproved' therapeutic goods in relation to clinical trials will be treated as confidential. For information about the release of this information, see TGA approach to disclosure of commercially confidential information.
We have powers under the Therapeutic Goods Act 1989 to release certain information about therapeutic goods in specified circumstances. One such circumstance is where release is necessary to ensure the safe use of particular therapeutic goods. Depending on the circumstances, there may be a need to release information to a HREC where release is necessary to ensure the safe use of therapeutic goods in a clinical trial.
Concerns or complaints about a clinical trial
The NHMRC has published guidance for consumers titled What to do if you have a concern about a clinical trial? A person or organisation may also report a perceived breach or questionable practice involving the use of an 'unapproved' therapeutic good in a clinical trial anonymously through our website or contact us for assistance.