Clinical trials are an important area of health research. Clinical trials can test new drugs, devices or procedures or they may be testing existing therapeutic goods in a different manner for either the treatment of a different disease or condition or in a new combination with other therapies.
In Australia all therapeutic goods must be registered on the Australian Register of Therapeutic Goods (ARTG). If you are trialling a good that is not on the ARTG then your trial is subject to the Therapeutic Goods Act 1989 (Cth).
Before initialising a clinical trial, issues of trial design, resourcing, ethics review, regulatory oversight, institutional policies, research governance and many other issues must be considered. It is a legal requirement to obtain ethics approval prior to commencing a clinical trial in Australia and Human Research Ethics Committees (HRECs) are legally required to monitor the clinical trials they have approved. In submitting your ethics application, the following issues should be considered:
Clinical trial design
- What is the exact question this clinical trial is intended to answer?
- What is the primary outcome variable? Is this readily measured?
- Is it a direct measure of outcome or do you intend to rely on surrogate endpoints?
- Are these outcomes those specified by guidance documents as the preferred measures for the outcome of interest? (This of particular relevance if you intend the trial to be part of a marketing submission; see European Union Guidelines adopted in Australia).
- Is the trial design appropriate?
- Are participant numbers or event numbers sufficient to give adequate statistical power to detect a difference in treatments should one exist, or demonstrate non-inferiority (i.e. can the trial answer the proposed research question or will the data be equivocal)? (This aspect of design is often overlooked, but represents a genuine ethical consideration undertaken by HRECs and needs professional statistical consideration).
- Have you considered the ongoing treatment of trial participants should they respond to the unapproved medical product under investigation? Building in a trial extension provision into the original protocol design not only fulfils good clinical practice 'GCP' requirements but also can allow such treatment to continue without having to put together another trial proposal after the initial trial ceases. Of course, this is not the only way to provide ongoing treatment post-trial, but is a point to consider in the planning process.
Participant and staff numbers and resources
- Can your trial obtain an adequate number of participants?
- Should the trial be extended to additional sites to ensure recruitment? (Dealing with this early on reduces the likelihood of additional CTN applications being required later on. It also works towards adequate recruitment to satisfy statistical requirements.)
- Do you have adequate resourcing, facilities and oversight of the protocol?
Research principles and guidelines
Clinical trials must be designed so that they comply with the principles set out in the following guidelines:
- National statement on ethical conduct in human research 2007 — updated 2009 (National Health and Medical Research Council)
- Australian code for the responsible conduct of research (developed jointly by the National Health and Medical Research Council, the Australian Research Council and Universities Australia)
- If the therapeutic good has not been included on the ARTG then it is subject to Therapeutic Goods Act 1989 (Cth)
- Other state or federal legislation as relevant.
- Researchers are also subject to professional codes of conduct, such as the Australian Medical Association or the Australian Psychological Association even when they are conducting research.
Clinical trials of medicines and medical devices also must comply with
- Note for guidance on good clinical practice (CMP/ICH/135/95) (Therapeutic Goods Administration)
Clinical trials of medical devices must also comply with
- ISO 14155:2011 Medical devices — Clinical investigation of medical devices for human subjects: Good clinical practice (ISO)
Researchers must consult these guidelines when preparing their clinical trial submission.
Good clinical practice (GCP) in Australia
Researchers must design their clinical trial to ensure that it meets the requirements of GCP in addition to the National Statement and other relevant guidelines.
The principles of GCP have their origin in the World Medical Association's Declaration of Helsinki. The Declaration of Helsinki was responsive to the revelations of the Nuremberg trials conducted after World War II, and its drafters sought to ensure that human subjects involved in clinical research would, in future, have their rights, safety and well-being placed above all other considerations in clinical research.
The Declaration of Helsinki was used as a basis for the development of guidance for the conduct of clinical trials by the International Conference on Harmonisation (ICH). Originally developed for commercially sponsored late phase drug trials, this guidance has become known as the "Good Clinical Practice" (GCP) guidelines, even though the guidelines apply to clinical research rather than clinical practice.
The GCP guideline details the requirements for trial documentation, protocol amendments, requirements such as indemnity, reporting lines for adverse events and provision of medical care for trial participants.
The Therapeutic Goods Administration(TGA) has adopted the European Union version of these guidelines in Australia. The TGA advice includes specific comments from the TGA relevant to the Australian context. Several other guideline documents provide additional helpful advice with respect to clinical trial issues. Of particular note is the Note for guidance on clinical safety data management: definitions and standards for expedited reporting, which describes the reporting processes for expedited reporting of adverse drug reactions in clinical trials.
The TGA has also adopted ISO 14155 Clinical Investigation of medical devices for human subjects – Good clinical practice. ISO 14155:2011 articulates standards for the design, conduct, recording and reporting of clinical investigations carried out in human participants to assess the safety or performance of medical devices for regulatory purposes.
The National Statement requires that, before granting approval to a clinical trial, a Human Research Ethics Committee (HREC) must be satisfied that the protocol conforms to:
- the National Statement
- the World Medical Association Declaration of Helsinki
- where relevant, the CPMP/ICH Note for Guidance on Good Clinical Practice (CPMP/ICH-135/95), the ISO 14155 Clinical Investigation of Medical Devices and the requirements of the TGA
- any requirements of relevant Commonwealth or state/territory laws.
Submitting to the HREC at Macquarie University
Information about the ethics application process is available at the HREC's Application Process page.
When submitting you clinical trial, the following documentation must be provided:
- Research ethics application form (this can be on the National Ethics Application Form (NEAF) or on the Macquarie University Research Ethics Application Form).
- Research protocol
- Participant Information and Consent Forms (PICFs) on Macquarie University letterhead
- If relevant, an Investigator's Brochure should be supplied
- Any other documents as relevant, such as patient cards, advertisements, specifications etc.
If you have any questions about the ethics application process, or would like to discuss your protocol further, please contact the Ethics Secretariat on +61 2 9850 4194 or email@example.com
If you are a sponsor conducting a trial at Macquarie University, please ensure that you provide a table listing the documents that you are submitting for HREC review. This will ensure the correct documents are listed on any approvals correspondence. Please ensure the table documents the name, version number and date of each document you are submitting for review.
Sometimes sponsors contact the HREC requesting the names and contact details of HRECs members. It is a policy of Macquarie University not to provide this information. The HRECs are constituted in accordance with the National Statement and information about the HREC composition (for GCP purposes) is available on the HREC's website and in the Terms of Reference.
Monitoring approved research
Once a clinical trial has received HREC and institutional approval, the trial must be monitored. The Macquarie University HRECs have an obligation to ensure that research participants are protected as much as possible and that any changes in the benefit/risk balance of the clinical trial are compatible with continued ethical approval. The National Statementdescribes the ultimate responsibilities for monitoring the conduct of approved research in ch 5.5 and describes specific responsibilities for clinical research in ss 3.3.19 – 3.3.22. The NHMRC's Position Statement: Monitoring and Reporting of Safety for Clinical Trials recognises that sponsors, institutions and HRECs all have responsibility in monitoring approved research and that these should work together to clarify the responsibilities of all parties in relation to reports of adverse events (AE), including serious adverse events (SAEs) and suspected unexpected serious adverse reactions (SUSARs), occurring in clinical trials for which institutions are responsible and the HRECs have reviewed and given ethical approval.
Institutions in Australia have a wide variety of models of fulfilling research governance and ethical review responsibilities. Institutions and HRECs should work together to establish that an adequate mechanism is in place to monitor the conduct of clinical trials at sites for which they have responsibility. Some mechanisms are described in section 5.5 of the National Statement.
The HREC has information on monitoring and managing approved research on its website.
Clinical Trials - Reporting Serious Adverse Events (SAEs)
The HREC's requirements for monitoring approved research and reporting adverse events are in the Terms of Reference.
The HREC's requirements for reporting protocol deviations/violations are in the Terms of Reference.
Data Safety and Monitoring Boards
More information coming
Guidelines for Monitoring
Ethics Office to post Guideline documents here.