Investigator initiated clinical trials are critical to the advancement of cancer care in Australia. Cooperative clinical trials groups in Australia and New Zealand contribute greatly to independent investigator initiated research across a wide spectrum of cancer types and interventions. Achievements of the groups and their contributions to improvement in cancer care over the past 40 years are highlighted. Future challenges in the field of clinical trials are discussed with particular regard to cooperative clinical trials groups.
The advantages of conducting clinical trials are widely recognised.1 The information gained from well conducted trials can be readily incorporated into clinical practice, and used to inform policy.
Investigator-initiated trials, often co-ordinated by a cooperative clinical trials group (CCTG), have played a critical role in establishing the efficacy and safety of a wide range of interventions in the treatment of cancer, including a variety of issues in surgery, chemotherapy agents and radiation therapy, as well as in establishing the role of psychological, supportive care and palliative interventions. Trials are also critical in establishing the benefit or otherwise of primary or secondary screening and preventative approaches, although the majority of CCTGs tend to be less involved in these approaches. The results of these investigator-initiated trials then inform subsequent clinical practice.
Australasia is recognised as a region that conducts clinical trials of both high quality and importance across a range of cancer types and clinical scenarios. Over the last 40 years, the growth of clinical trials groups in Australia has paralleled the recognition of the importance of conducting clinical research both locally and internationally. While individual patients may or may not receive a personal benefit from the intervention under investigation (for example when patients are randomised to the control arm of a two-armed phase 3 study), there is evidence that outcomes are in general improved for clinical trial participants, perhaps because of the rigour that trial processes impose on treatment options.1 Leading cancer agencies invariably recommend participation in clinical trials as an important part of care for patients and not just confined to situations in which the optimal course of treatment is not known. Even in the absence of measurable benefits to individual patients, participants in clinical trials also contribute to advancing knowledge and increasing treatment options for the future.2
The desire to improve outcomes for patients and carers is the common goal of all clinicians involved in the management of patients with cancer, but it was the realisation that we could all achieve a lot more by working together that led to the formation of the CCTGs. The majority of groups formed out of informal collaborations and developed more formalised structures with time. The willingness of investigators to share their knowledge and experiences has led to the depth and breadth of experience in clinical trials today. The importance of clinical trials to the health system as a whole is widely acknowledged within the academic community,3 even if policy on the funding of trials has been slow to follow.
The importance of investigator-initiated trials in influencing practice is also recognised. A recent study in the New England Journal of Medicine found that results of investigator initiated trials were more trusted by physicians than those that were industry sponsored.4 The degree of independence required of investigator initiated studies, and the requirement that the question under study be recognised as significant by a substantial proportion of peers, are valued characteristics of cooperative group trials. Additionally, investigator-initiated trials conducted by CCTGs represent the only available avenue for determining the place in therapy of many drugs, devices and technologies where there is no commercial imperative to evaluate them.
Cooperative trial groups are aptly named – the success of these groups relies on the enthusiasm and collaboration of members in diverse roles. Substantial voluntary contributions of time, energy and expertise from members of collaborative trials networks are required to see a trial through from initial concept to presentation of results, a process which can take many years.
From the oldest CCTG (Australasian Leukaemia and Lymphoma Group) to the youngest (Primary Care Collaborative Cancer Clinical Trials Group), all the groups formed around a nidus of committed clinicians and researchers, who shared the common goal of improving outcomes for patients with cancer. The results of these years of hard work has been a body of evidence that has contributed to improvements not just in the survival of patients involved as well as those not involved in these studies, but in many other aspects of care for patients across a variety of tumour types and stages. The cancer CCTGs are listed in table 1.
To list all the achievements of the CCTGs (see Table 1) in advancing cancer care is outside the scope of this article. However, some notable achievements by include:
Australasian Gastro-Intestinal Trials Group (AGITG) – has led or collaborated on practice changing trials, furthering understanding of the relationship between treatment and biology in gastrointestinal cancers. Notably, the CO.17 trial, conducted in collaboration with the Canadian NCIC CTG, established the benefit to patients with K-ras wild type metastatic colorectal cancer treated with cetuximab, following failure of other therapies.5
Australasian Leukaemia and Lymphoma Group (ALLG) – the ALLG has conducted several practice changing trials, including AMLM2 which established the role of etoposide in AML.6 More recently the ALLG has established the National Leukaemia and Lymphoma Tissue Bank, in conjuction with the Leukaemia Foundation which will provide a platform for improved healthcare outcomes through translational research.
Australasian Lung cancer Trials Group (ALTG) – has established highly productive international collaborations resulting in large scale randomised trials of novel targeted agents with the Canadian NCIC Clinical Trials Group (BR-26 and BR-29),7,8 and with the Dutch NVALT group (thalidomide in mesothelioma and nitroglycerin in non-small cell lung cancer).9,10
Australian and New Zealand Breast Cancer Trials Group (ANZBCTG) – has developed or collaborated on many randomised phase III trials, that have led to significant advances in the management of both early and late stage breast cancers. One example is the ANZ 0101/BIG 1-01 HERA trial,11 which investigated adjuvant trastuzumab. This led to the registration and pharmaceutical benefit scheme funding of this therapy for Australian women with early breast cancer in October 2006 and Pharmac funding in New Zealand in 2008, and led to other new international trials for HER2 positive early breast cancer.
Australian and New Zealand Children’s Haematology/Oncology Group (ANZCHOG) – has developed a national paediatric cancer clinical trials registry that is available online,12 for the use of health professionals, as well as patients and their families. This registry lists all trials available in Australia, including international trials and the institutions at which they are available.
Australia New Zealand Gynecological Oncology Group (ANZGOG) – in collaboration with GINECO, the Calypso phase III trial defined a new standard of care for women with platinum sensitive recurrent ovarian cancer; carboplatin and liposomal doxorubicin was more effective and better tolerated than the combination of carboplatin and taxol. ANZGOG/National Health and Medical Research Council (NHMRC) CTC served as statistical centre for this international trial.13
Australia and New Zealand Melanoma Trials Group (ANZMTG) – led the first international randomised phase III trial demonstrating a benefit from adjuvant radiotherapy for patients at high risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma.14
Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP) – lead ANZ participation in an international trial of adjuvant therapy with targeted therapy (sorafenib) to improve cure rates in renal cell carcinoma,15 and developed a substudy determining patients’ preferences.
Australasian Sarcoma Study Group (ASSG) – creation of a national database of sarcoma patients with several projects planned that will provide valuable information to inform current and future research in sarcomas.
Cooperative Trials Group for Neuro-Oncology (COGNO) – has completed a national multicentre trial of bevacizumab in recurrent glioblastoma, the largest conducted to date in this population.16
Primary Care Collaborative Cancer Clinical Trials Group (PC4) – rapid growth since establishment in 2009 with 16 concepts currently under development and 35 trials supported since inception. Establishment of a joint Community Advisory Group with Psycho-oncology Co-operative Research Group (PoCoG).
Palliative Care Clinical Studies Collaborative (PaCCSC) – successful completion of two phase III randomised control trials examining the role of ketamine in treating cancer related pain,17 and octreotide in malignant bowel obstruction.18
Psycho-oncology Co-operative Research Group (PoCoG) – development and initiation of a phase III trial of an intervention for Fear of Cancer Recurrence funded by NHMRC,19 following three successful pilot studies (2009-2011). Development of a searchable database of measures relevant to psycho-oncology, standard operating procedures for psycho-oncology studies and a range of resources to support researchers in this area. Development of a quality of life office to support all trial groups in incorporating quality of life questions and measures into their studies.
Trans-Tasman Radiation Oncology Group (TROG) – the TROG 96.01 trial showed that the chances of cancer returning in the prostate could be reduced by approximately 60% using a course of hormone therapy prior to radiotherapy.20 The study also showed that the treatment with hormone therapy substantially reduced the chances of cancer appearing in other parts of the body, which could otherwise prove fatal. TROG 96.01 was Australia and New Zealand’s largest cancer trial when it completed recruitment of over 800 men with inoperable prostate cancer in February 2000. Long-term follow-up of these men is continuing.
The Clinical Oncological Society of Australia (COSA) has provided valuable support for the CCTGs in a number of ways. Establishment of an Executive Officers Network was identified as important for the CCTGs; this network facilitates supportive relationships between groups, and acts a reference group for many common issues arising in the conduct of multi-site investigator initiated research. The opportunity to link to other CCTGs through this network allows groups to share information and knowledge on emerging issues in clinical trials, and learn from the collective experience of other groups in facing common challenges. COSA has also supported other initiatives, including commissioning an independent review of biobanking ‘Developing a nationally coordinated approach to biobanking for Cancer Trials in Australia 2010’ (by Deloittes), support for essential training in good clinical practice training via ARCS Australia, and access to programs of mutual relevance from the funding secured via the COSA’s successful NHMRC enabling grant. COSA has been instrumental to the CCTGs’ ability to confront and resolve many issues the groups face in the ever changing regulatory environment. Examples of this include establishing an umbrella clinical trials insurance policy, single CCTG clinical trial research agreements for sites and, representing a substantial reduction in administrative burden an costs to the groups.
While CCTGs have achieved much during the last 40 years, many challenges lie ahead if the groups are to continue to undertake relevant, timely and meaningful trials. As is often the case in research, time, money and other external factors are potential barriers to success, although particular aspects of these are of relevance to CCTGs in Australia.
Trial design and patient selection
The recognition that cancers arising in the same anatomical location are a heterogenous group of diseases with different biological identities, has implications not just for clinical practice but for trial design. The previous paradigm of large benefits from a single intervention in a disease based on tumour site is no longer feasible in many tumour types. As a result of improvements in outcomes for several tumour types, and with the subdivision of anatomic groups by tumour biology, it is increasingly difficult to demonstrate the smaller benefits seen in the previous generation of trials. Traditional trial designs often require both larger cohorts and longer trials, complicated by the decreasing available pool of patients when groups of cancers are subdivided along biological lines. Novel trial designs have been increasingly championed by some as a solution to these problems.21,22 However, the potential improvement in trial feasibility these designs offer, by decreasing the number of patients required for each trial, is offset by the potential difficulty in interpreting results, such that these may not be accepted by clinicians or regulatory authorities.
A similar challenge lies in the identification and incorporation of appropriate endpoints, including surrogate endpoints and patient reported outcomes. Overall survival has previously been accepted as the gold standard for phase III trials, but its relevance is being increasingly challenged, particularly in trials of first line therapies where multiple subsequent treatments exist. The use of surrogate endpoints has the potential to shorten trial duration, and accelerate the pace of resulting clinical decision making. However, the identification and incorporation of surrogate endpoints carries its own challenges, with such endpoints requiring validation that they are both significant and meaningful for the disease and setting under investigation.
Strategies for ensuring appropriate funding of investigator initiated trials
A substantial amount of resources, including both fiscal and human capital, are required in the months and years from concept to activation of a clinical trial. The current model of funding investigator initiated trials requires significant investment in the development of an idea prior to application to government or philanthropic bodies for funding. At present, the majority of the groups support these activities through infrastructure grants awarded by Cancer Australia, Cancer Institute NSW and others bodies for this purpose, often in conjunction with collaborating academic centres specialising in clinical trials (see table 1). These grants are typically cyclical in nature and in several cases are used to fund positions jointly with coordinating centres. The short to medium term nature of these grants (typically from three to five years) makes developing and retaining a skilled workforce without job permanency difficult.
Similar challenges lie in the current model of funding trials. The maximum funding terms for grants from NHMRC and Cancer Australia (and partners) are five and three years respectively. The annual process for grant review means a delay of between seven to nine months between submission and outcome of funding requests. The substantial amount of work required to determine feasibility and develop a well thought out concept, often incorporating translational, health, economic and patient reported outcomes, means that an idea for a clinical trial often takes months, if not years to evolve before a request for funding is even submitted. In order for clinical trials to keep pace with and lead clinical practice, more efficient models of funding are required.
Another weakness of the current model is the requirement for individual trials to compete against each other, as well as against other models of research for a fixed pool of funding. The scale and complexity of trials, while representing real value to the community, means clinical trials of all phases are at risk of not being seen as competitive against basic research questions, which may carry shorter term goals for individual projects. Private or corporate philanthropy cannot be relied upon to make up the shortfall; few philanthropic organisations exist with sufficient resources or willingness to fund large scale trials with outcomes that may take many years to be realised. Strategies for funding clinical trials in addition to current funding models have been proposed: allocation of a proportion of the overall health care budget (0.5-1% phased in over several years);3 central allocation of funding for projects and infrastructure in a similar model to the National Institute of Health Research model in the UK;23 and evaluation of new drugs or new indications for existing drugs funded by the Pharmaceutical Benefits Scheme.24
Barriers to trial approval and initiation
Once funding has been obtained, the process for trial approval and initiation at sites can be long and burdened with seemingly unnecessary delays. Two cooperative groups in the US recently reported their experiences – Cancer And Leukemia Group-B and Eastern Cooperative Oncology Group – with an average time of 784 days and 808 days respectively from concept to trial initiation.25 Multi-centre ethics approval has demonstrated reductions in time to overall trial approval for national trials,26 and the rollout of the HOMER multi-state ethics approval process may reap further rewards as it is more widely adopted. However, not all states or sites have signed on and many, particularly private hospitals, are unlikely to do so. Even with a condensed process for ethics approval, the time required for governance approval in tertiary institutions with large trial units can range from four weeks to over six months in our experience. A recent publication examining regional experiences from the international phase III ALTTO trial described an average time from ethics committee approval to the first patient randomised of 172 days across the Asia Pacific region.27
Integration of clinical and basic research
Clinical trials and the resulting data sets represent a substantial resource with the potential to yield valuable information for current and future questions. In the era of translational research and personalised medicine however, the clinical data is most valuable when it is able to be linked with biospecimens. Similarly, a biobank that is not linked to high-quality clinical data – often confined to clinical trials – is a (bio) bank that pays no interest. How to best obtain, preserve and utilise the resources entrusted by clinical trial participants remains a challenge for researchers. Obtaining and storing biospecimens in physical or virtual biobanks is an ongoing challenge, as is the prioritisation of subsequent research on a finite amount of specimens. Researchers must also attempt to predict the direction of future research and obtain appropriate types and amounts of biospecimens for as yet unspecified research, without placing an unnecessary burden on participants.
As the complexity of trials increases, the need to provide site payments that reflect actual costs of conducting research grows in importance. While actual costs to individual sites are difficult to establish, models for determining workload for clinical trials based on complexity have been developed.28 Per patient payments for CCTG trials are frequently lower than commercial trials of the same phase; sites must often choose between commercial and investigator initiated trials in the same indication. For sites where only a few eligible patients are likely to be recruited, it may not be feasible to open a CCTG trial. Rural and regional sites are particularly vulnerable, more so since schemes that provided direct support for site staff and infrastructure targeted at the conduct of cooperative group trials have recently been withdrawn by Cancer Australia. Additional complexities are often encountered in attempting to conduct research in the private sector, which represents a growing proportion of cancer care. How to maintain equitable access to clinical trials for patients in the private sector, and in rural and remote areas remains a challenge that the CCTGs cannot address alone.
Considerable efforts by CCTGs and collaborating centres in Australia and New Zealand have resulted in significant gains in the understanding and treatment of patients with cancer over the past 40 years. Many challenges still exist if the CCTGs are to continue to successfully undertake the ‘ordinary miracle’ of completed clinical trials.29 Input is needed from government and policymakers to ensure the many roadblocks to successful research and improved health outcomes are removed or minimised. However, the collective enthusiasm, skills and experience of the CCTGs and their many members, as well as the collaborating academic institutions (trial centres), ensure that local trials are well placed to continue to deliver world class research and improved outcomes for patients and the health system.
The authors would like to thank the chairs and executive officers of the CCTGs who provided information for inclusion in this article.