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Australian clinical trial handbook
Guidance on conducting clinical trials in Australia using 'unapproved' therapeutic goods
Clinical trial phases and stages
Clinical trials of medicines and biologicals typically proceed through 'phases' of development whereas clinical trials of medical devices are more appropriately represented by 'stages'. The tables below provide a summary and comparison of the phases and stages of clinical trials involving the use of therapeutic goods. The table uses the objectives of the trial as the framework to assist trial sponsors to determine the phase or stage of the trial. The table should be considered as a guide only and is not intended to be exhaustive.
We acknowledge that clinical development pathways are becoming less rigid with respect to phase and that seamless adaptive trial designs and other cross-phase studies exist (for example, Phase Ib-II and Phase IIb-III). Therefore, there may not be clear delineation between individual phases and stages. The basis for conducting clinical trials sequentially is that the results of prior studies should influence the plan of later studies. However, the table below does not imply a fixed order of studies since the typical sequence may not be appropriate or necessary for the development of certain therapeutic goods.
Phase 0 has been introduced to assist in eliminating ineffective products early in the development process and is not considered to replace formal Phase I safety and tolerance studies.
Summary of clinical trial phases for medicines and biologicals
|Phase||Indicative number of participants||Objectives|
|Phase 0: Human pharmacology (micro-dosing)||
Involves dosing a limited number of humans with a limited range of doses for a limited period of time
Gather preliminary data on pharmacokinetics and bioavailability to determine if the drug behaves as expected from preclinical studies 'Micro-dosing' studies
|Phase I: Human pharmacology||
May involve the first administration to humans, usually to small numbers of healthy volunteers or to patients
Safety and tolerance
Define or describe pharmacokinetics and pharmacodynamics
Explore drug metabolism and drug interactions
Identify preferred routes of administration
Phase Ia: Single ascending dose
Phase Ib: Multiple ascending dose
|Phase II: Therapeutic exploratory||
May be undertaken in a larger group of human patients (several hundred)
Efficacy and safety
Demonstrate clinical efficacy or biological activity through pilot studies
Explore therapeutic dose range
Determine optimum therapeutic dose and regimen (with efficacy as primary endpoint)
Resolve uncertainties regarding the design and conduct of subsequent trials
|Phase III: Therapeutic confirmatory||
Usually involve a large group of patients (from several hundred to several thousand)
Safety, efficacy or effectiveness
Determine the therapeutic effect in patient populations for which the drug is eventually intended
Provide a definitive assessment of risk-benefit balance (to support drug registration or change in clinical practice)
Increase patient exposure and support marketing claims or publication
|Phase IV: Therapeutic use||1000's||
Post marketing surveillance or resolution of treatment uncertainties
Monitor safety in real world populations
To refine knowledge of the risk-benefit balance, detect rare or long-term adverse effects, drug interactions
Pharmacoeconomics to gather data in support of the use
Comparative effectiveness and community based research (sometimes described as Phase V trials)
Trial combinations with existing products
Summary of clinical trial stages for medical devices
|Stage||Indicative number of participants||Objectives|
Usually involves a small group of human patients
Exploratory investigations to determine preliminary safety and performance information to plan design modifications or provide support for a future pivotal study.
(Includes first in human and feasibility studies or proof of concept)
|Pre-market pivotal||100's||Confirmatory investigations to evaluate performance and safety for a specified intended use to satisfy pre-market regulatory requirements|
Confirmatory investigations to establish performance and safety, for example, in broader populations
Observational investigations or surveillance to gain better understanding of device safety, long-term outcomes, health economics
The phases and stages of clinical trials summarised in the tables above are described extensively in other documents; however, in relation to the safety of Australian participants, early phase trials; particularly first in human trials pose the greatest risk. The following section provides additional considerations for early phase trials and also links to further information.
Early phase trials
Early phase trials are no longer defined as traditional Phase I trials. Early phase trials can be broadly defined as non-therapeutic, exploratory trials in human participants who may be healthy volunteers or have a specific disease.
Over recent years, the conduct of early phase trials has evolved. Increasingly, trial sponsors are submitting early phase trials to HRECs that combine a number of different study parts within an integrated trial protocol. Common activities and objectives of early phase clinical trials using integrated trial protocols (human pharmacology) are outlined in the table below.
|Initial studies||Follow-up Studies|
Similar activities and objectives may be applied to early phase trials for biologicals, with additional consideration of the potential risk posed by the biological to patients, medical personnel and the population as a result of the origin of the cells or tissue, the manufacturing process, or the route of administration. Additional aspects of integrated trial protocols may include:
- requirement for concomitant medication, for example immunosuppressive regimens, for effect
- monitoring of viability, proliferation or differentiation, migration and persistence
- specific potential toxicities (for example, immune responses, infections, malignant transformation)
There are several clinical and non-clinical guidelines that should be considered by HRECs, trial sponsors and manufacturers in the context of early phase trials including:
- Non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals (ICH M3 (R2)) (pdf,263kb)
- ICH guideline M3 (R2) - Questions and Answers (pdf,210kb
- EMEA/CHMP Guideline on human cell-based medicinal products (EMEA/CHMP/410869/2006) (pdf,205kb)
- EMA/CAT Reflection paper on stem cell-based medicinal products (EMA/CAT/571134/2009) (pdf,113kb)
- EMEA/CHMP Note for guidance on the quality, preclinical and clinical aspects of gene transfer medicinal products (CPMP/BWP/3088/99) (pdf,127kb)
As outlined above, first in human trials have the greatest element of uncertainty in relation to risk. Obtaining appropriate nonclinical data and properly considering this information is critical to safety. The European Union Guideline: Strategies to Identify and Mitigate Risks for First-In-Human Clinical Trials with Investigational Medicinal Products (pdf,228kb) includes recommendations that incorporate the findings from investigations following overseas clinical trial incidents to appropriately manage the risk posed. It also provides guidance on appropriate sentinel dosing.
There are four key recommendations that trial sponsors should consider when conducting early phase trials:
- Better identification of factors influencing risk
- mode of action (for example, targeting multiple pathways, having long lasting effects)
- nature of target (for example, 'down-stream' effects of target and 'off target' effects)
- relevance of animal species and models
- findings in non-clinical safety studies
- Careful dosing selection
- use of minimum anticipated biological effect level (MABEL) and pharmacologically active dose (PAD) and not just no observed adverse effect level (NOAEL)
- better justification of dose escalation
- maximum dose should take into account target saturation (for example, where the intended therapeutic effect is linked to enzyme inhibition, when complete inhibition is achieved)
- Better justification for and planning of integrated protocols
- scientifically justify overlap of SAD and MAD parts of the study
- ensure sufficient space between sub-studies
- Careful selection of participant group and development of other treatment precautions
- justify the decision to include healthy volunteers or patients
- ensure adequate time period between doses within cohorts and between cohorts
In response to the changing environment, some jurisdictions are developing frameworks for early phase clinical trials which includes the appointment of specialist early phase trial HRECs. The NHMRC has assessed and certified the ethics review processes of certain institutions under the National Certification Scheme. A list of HRECs with certified ethics review processes is available on the NHMRC website. We recommend, at a minimum, that first in human trials are reviewed by a HREC on this list with a certification category relevant to the phase of the trial.
Medical device stages
A new device is often subject to extensive preclinical testing through engineering analysis and testing, computational simulation, biocompatibility testing including immunogenicity and carcinogenicity testing and, in appropriate instances, animal testing. The invasive nature of many medical devices precludes initial testing in healthy volunteers, necessitating the use of animal model testing. Initial clinical testing of devices usually involves a pilot study in small groups of patients.
If the feasibility of the concept is proven, larger studies with well-designed trial protocols and a sound statistical basis are undertaken. Studies may also be carried out to confirm the performance and safety of changes in design or material of a device or to assess the device's performance against new clinical indications. The clinical safety and performance of many devices depends largely on the experience and training of the clinician using the device. These are important considerations when assessing a clinical trial application. Implantable devices also require special consideration. A surgical procedure in itself poses risk to a patient; and in the event of a device failure, a second surgical procedure may be required to remove a faulty experimental device.
We recommend that HRECs, trial sponsors and manufacturers utilise individuals with adequate expertise (such as clinical experience using similar devices) to assess and manage higher risk early stage trials to minimise any issues, including the risk of adverse events, as with early phase clinical trials with medicines. This includes the technical considerations for medical device design and preclinical evaluation.
The Essential Principles set out the requirements relating to the safety and performance characteristics of medical devices. When applying for inclusion in the ARTG, evidence from a clinical trial will be required to demonstrate that a manufacturer has validated the design of the device, and to provide objective evidence to substantiate compliance with some of the Essential Principles.