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Landscape of cancer clinical trials in Australia: using trial registries to guide future research

Rachel F Dear, Alexandra L Barratt, Kevin McGeechan, Lisa Askie, John Simes and Martin H N Tattersall
Med J Aust 2011; 194 (8): 387-391.
Abstract

Objective: To quantify and describe current cancer clinical trial activity in Australia and help guide future trials research using trial registries.

Design and setting: Data from cancer trials recruiting in Australia at 31 March 2009 were extracted from the Australian New Zealand Clinical Trials Registry and ClinicalTrials.gov. A regression model was used to identify factors associated with industry sponsorship.

Main outcome measures: The proportion of cancer trials compared with estimated burden of disease for each cancer.

Results: There were 368 interventional cancer trials open to recruitment. The most-researched cancer was breast cancer, accounting for 17% of trials. Only 7% of trials were in lung cancer, yet lung cancer is responsible for the greatest burden of disease. Industry was the primary sponsor in 43% of trials. Drug treatments were tested in most trials (69%). Trials were more likely to be industry sponsored if they tested systemic rather than local treatments (OR, 16.71; 95% CI, 4.70–59.43), included patients with advanced rather than early disease (OR, 3.76; 95% CI, 1.78–7.94) and used random rather than non-random allocation (OR, 1.78; 95% CI, 1.06–3.00).

Conclusion: There is variation in the number of trials according to cancer site, with some cancers being underrepresented relative to their burden of disease. Industry sponsorship is more likely for trials that investigate systemic therapy, recruit patients with advanced disease and are randomised.

Clinical trial registries provide a comprehensive record of all trials commenced (with the aim of preventing publication bias). However, they may serve additional purposes. For example, data could be extracted and analysed to provide an overview of the amount and nature of current trial activity. This might enable researchers and funding agencies to explore whether certain types of cancer or types of trials are being disproportionately supported, and to identify gaps in research to guide new funding initiatives.

Furthermore, clinical trial registries are well placed to provide representative information about trial sponsorship and funding sources. A United Kingdom study1 found that support for randomised trials from non-industry sources in the UK had fallen, suggesting that an increasing proportion of trials were funded by industry, raising concerns about the desirability of this trend and whether policy changes should address it. In the United States, funding from industry sources (pharmaceutical, biotechnology and medical device firms) increased each year from 2003 to 2008.2 The concern is that studies suggest industry-funded trials tend to draw pro-industry conclusions.3

The largest trial registry, ClinicalTrials.gov (CT.gov),4 was established in the US in 2000.5 There is also a large European registry,6 and smaller local registries are being established in several countries. The Australian New Zealand Clinical Trials Registry (ANZCTR),7 a World Health Organization primary registry, was created in 2005, and 3668 trials were registered to the end of 2009.

Our aim was to explore whether we could use the data from the ANZCTR and CT.gov to quantify, describe and analyse current clinical trial activity in Australia. Cancer trials were chosen as the focus of this paper because we wanted to explore the implications for cancer-related research in Australia. Specifically, we aimed to explore whether trial activity reflected cancer burden of disease and might be associated with different sponsorship sources.

Methods

Data were extracted from the ANZCTR and CT.gov for trials that fulfilled three criteria: cancer, interventional trials, and recruiting in Australia at 31 March 2009. Original data were retained wherever possible; however, some data items were collected differently by each registry and were recoded for consistency (details of recoding are provided at http://sydney.edu.au/science/psychology/cemped/research.shtml#patientcommunication).

The cancer types used in our report have been standardised to those used by the Australian Institute of Health and Welfare and refer to the primary site of the cancer.8

We used the WHO definition of primary sponsor: “The individual, organization, group or other legal entity which takes responsibility for initiating, managing and/or financing a study.”9 Primary sponsors’ responsibilities include initiating and managing a study, appropriate conduct and reporting, and obtaining ethics approval to commence a study. We categorised primary sponsor as industry (pharmaceutical and device companies) or non-industry (universities, collaborative groups, charities and government organisations). The primary sponsor of a trial may or may not be its main funder. The main funder is defined as the “major source(s) of monetary or infrastructure support for the trial”,9 such as a funding agency, foundation, company, hospital or university.

Analysis

We described trials in terms of: cancer type, intervention tested, sponsorship and funding source, phase and design (randomised versus non-randomised), characteristics of enrolled subjects, trial registry (the ANZCTR or CT.gov) and location of recruitment (Australia only or Australia and overseas). For each cancer, we obtained data on disability-adjusted life-years (DALYs) for 2003.10 DALYs are the sum of the years of life lost due to premature mortality in the population and the equivalent “healthy” years lost due to disability for incident cases. We tested whether the number of clinical trials for each cancer was proportional to the number of DALYs for that cancer using the χ2 goodness-of-fit test. The following cancer types with small numbers of trials were grouped together for this analysis: prostate and testis; head and neck, eye and thyroid; pancreas, liver and gallbladder; and cervix and uterus. The cancer types of all/multiple, other, other haematological, mesothelioma and unknown primary sites were not included in this analysis as DALY information was not available.

Bivariate analyses (χ2 test and logistic regression) were used to test whether the following prespecified variables were associated with primary sponsorship by industry: cancer type, intervention, allocation to intervention, and cancer extent. Their independent association was analysed by multivariable logistic regression.

SAS, version 9.2 (SAS Institute Inc, Cary, NC, USA) was used for statistical data analysis.

Results

We identified 368 cancer trials that were recruiting in Australia at 31 March 2009. Of these, 131 trials (36%) were registered with the ANZCTR and 237 trials (64%) were registered with CT.gov. Fifty-seven per cent were randomised controlled trials.

Cancer type

Most trials were in breast cancer, followed by lymphoma and leukaemia, lung cancer, colorectal cancer, brain cancer and melanoma (Box 1). Breast cancer trials anticipated recruiting the largest number of patients: 74 247 patients (38%) out of an expected total sample size of 195 982 for all trials combined.

Many of the cancers with higher burdens of disease (measured by DALYs) were underrepresented (Box 1 and Box 2). This was most notable for lung, colorectal, prostate and pancreatic cancers. Conversely, leukaemia and lymphoma were overrepresented relative to their DALYs. There was a significant difference between the observed number of trials in each cancer type and the number of trials expected based on DALYs (χ2 = 154.7; P = 0.001). We found a similar pattern for the anticipated sample size relative to DALYs (http://sydney.edu.au/science/psychology/cemped/research.shtml#patientcommunication).

Primary sponsor and funding source

Industry sources were the primary sponsor in 43% of trials (Box 3). There was strong evidence of a difference in the primary sponsor between the cancer types (χ2 = 26.7; P = 0.005). Of 368 trials, there were 337 (92%) with the same funding source and primary sponsor. Industry funded 98% of industry-sponsored trials and 13% of non-industry-sponsored trials.

Most drug trials were sponsored or funded by industry (56% and 64%, respectively). For all other interventions analysed, non-industry was the main source of sponsorship (Box 4) and funding.

Bivariate analysis showed a relationship between primary sponsorship by industry and cancer group (P = 0.001), intervention type (P < 0.001) and cancer extent (P < 0.001) (Box 5).

In the multivariate analysis, the significant factors were intervention type (P < 0.001), cancer extent (P = 0.001) and allocation to intervention (P = 0.030) (Box 5). Trials of systemic interventions were more likely than local therapies to be sponsored by industry (OR, 16.71; 95% CI, 4.70–59.43). Trials that included patients with advanced disease were more likely to be sponsored by industry than trials that included patients with early disease (OR, 3.76; 95% CI, 1.78–7.94), and randomised controlled trials had higher odds than non-randomised trials of being sponsored by industry (OR, 1.78; 95% CI, 1.06–3.00).

Intervention

Drug treatments were the most commonly tested intervention (69%), followed by biological treatments, behavioural interventions, radiation, chemoradiation, surgery and diagnosis (Box 6). The least common interventions tested included prevention, early detection and lifestyle (1% each).

Cervical cancer, melanoma and uterine cancer were the only cancer types for which drug treatment was not the main intervention.

Most trials investigating drugs, biological agents and radiation were registered with CT.gov and were open for recruitment internationally. In contrast, most trials investigating behaviour, lifestyle, diagnosis, early detection and prevention were registered with the ANZCTR and recruiting only in Australia (Box 6).

Results describing trials according to cancer extent, age restrictions and phase of trials can be found at http://sydney.edu.au/science/psychology/cemped/research.shtml#patientcommunication.

Location of recruitment and place of registration

Most trials (60%) were recruiting both in Australia and overseas, while 40% of trials were recruiting only in Australia. In cancers of the gallbladder (100%), oesophagus (83%), cervix (80%), colorectum (67%), head and neck (58%) and breast (54%), there was a higher proportion of trials recruiting only in Australia compared with other cancer types. Of 222 trials open to recruitment both in Australia and overseas, 84% were registered with CT.gov.

Eighty per cent of the trials open to recruitment only in Australia had a non-industry primary sponsor and 62% were non-industry funded. In contrast, the majority of trials open to recruitment in Australia and overseas had an industry primary sponsor (58%, 129/222) and an industry funder (also 58%, 129/222).

Comparison with cancer trials internationally

We conducted a search of the WHO International Clinical Trial Registry Platform (ICTRP) for cancer trials recruiting at 31 March 2009.11 We found a similar proportion of trials were recruiting for each cancer type as in our analysis (see http://sydney.edu.au/science/psychology/cemped/research.shtml#patientcommunication), suggesting that our data are representative of cancer clinical trials internationally.

Discussion

Our report uses clinical trial registry data to describe Australia’s cancer trial activity. The development of publicly accessible, online, searchable registries has made this possible. We found that the number of trials for each cancer type did not always match the burden of disease caused by that cancer, thereby identifying gaps in cancer trials research. Four of the five cancers that result in the greatest burden of disease had relatively few clinical trials (lung, colorectal, prostate and pancreatic cancers). It is possible they are underrepresented because, until recently, there have been relatively few interventions worth testing for these cancers. Repeating this analysis in a few years may reveal that the distribution of cancer types being studied in clinical trials changes due to the increasing investigation of targeted therapies.

In contrast, there were more trials relative to burden of disease for breast, brain, kidney and haematological malignancies and sarcoma. The highest proportion of registered, open-to-recruitment, interventional trials were in breast cancer. Breast cancer was also notable because it anticipated recruiting a very large number of patients relative to its burden of disease. Our findings are consistent with reports comparing the number of trials with cancer incidence and mortality data.12

Trials in breast cancer differed in important ways. For all cancer types except breast cancer, most trials included people with advanced disease, whereas most breast cancer trials included women with early-stage disease. A large proportion of breast cancer trials were investigating non-drug interventions — all prevention trials, two-thirds of lifestyle trials and almost 30% of behavioural trials. Relatively, a higher proportion of breast cancer trials were non-industry sponsored and funded. These features might be a consequence of consumer influence on the research agenda. For example, the US National Breast Cancer Coalition, set up in 1991, has been instrumental in increasing federal funding for breast cancer research in the US.13

Drug and biological treatments were the most common interventions tested. The least common interventions investigated were cancer prevention, early detection and lifestyle trials. Non-drug interventions should be an important consideration for future cancer clinical trials.

There was strong evidence that intervention type, cancer extent and allocation to intervention were related to sponsorship by industry after allowing for cancer type. It was surprising that cancer type was not significantly associated with industry sponsorship; type of treatment rather than type of cancer was more strongly associated with industry sponsorship.

The number of trials and their associated sample sizes are easily derived measures of the resources allocated to a particular cancer. A more comprehensive enumeration of the resources involved in each trial may provide different results.

Our study might not include all interventional trials open for recruitment in Australia. Unlike in the US (where trial registration of drugs and devices is legally required, except for Phase 1 trials14), it is not a legal requirement to register clinical trials in Australia, although policies to increase registration rates have been implemented. In 2007, the revised National statement on ethical conduct in human research, which governs the conduct of human research ethics committees in Australia, recommended that clinical trials be registered before enrolment of the first patient.15 As in other countries, we anticipate the majority of large, Phase 3 trials recruiting in Australia would be registered because proof of registration is increasingly required by institutional ethics committees. In addition, the Australian code for the responsible conduct of research states that “Researchers must register clinical trials with a recognised register to promote access to information about all clinical trials”.16 These policies have added to international initiatives, including the International Committee of Medical Journal Editors requirement for prospective trial registration17 and the Declaration of Helsinki, which includes trial registration as a core ethical principle.18 Unfortunately, the number of unregistered trials currently in progress in Australia remains unknown and is not estimable. Despite this limitation, we have observed some very strong associations in our data, and there would have to be a large number of unregistered trials with very different features from those described here to substantially alter the pattern of our results.

A search of the ICTRP found that 98% of registered trials open to recruitment in Australia were registered with the ANZCTR and CT.gov.11 Given that only 2% were registered with the other trial registries, it is unlikely that the exclusion of these trials would have affected our results.

Our findings demonstrate the potential of registry data to identify gaps in current trial activity and to guide future trials research. Recent studies19,20 used CT.gov to describe cancer vaccine trials and ongoing clinical trials in non-small cell lung cancer but did not provide a national picture or a comprehensive analysis for cancer. Our description of the national clinical trial landscape in cancer is unique. This approach may provide a useful addition for setting future research priorities and provides a baseline against which to measure future trends.

Cancers causing the greatest burden of disease in Australia are underrepresented in recruiting trials, revealing gaps in current research activity. Industry sponsorship is associated with supporting randomised controlled trials of systemic therapies that include patients with advanced cancer but not with cancer type. Our analysis raises concerns about the direction of the research agenda and may be useful when designing and funding future cancer clinical trials. Clinical trial registries are a largely untapped resource to describe the clinical trial research landscape and guide future trial activity.

1 Cancer types ranked by number of clinical trials, burden of disease (as DALYs) and total target sample size

Trials


DALYs


Sample size


Cancer type

No.

Rank

No.

Rank

No.

Rank


Breast

62

1

60 654

3

74 247

1

Lymphoma

31

2

22 263

6

7923

8

Leukaemia

31

2

19 956

8

14 183

3

All/multiple*

31

2

na

na

9060

6

Lung

24

5

88 904

1

16 062

2

Colorectal

21

6

63 605

2

8636

7

Brain

21

6

19 792

9

4792

11

Melanoma

17

8

20 236

7

12 044

5

Kidney

15

9

12 487

13

5933

10

Myeloma

15

9

8925

16

3311

13

Sarcoma

15

9

5879

17

6423

9

Prostate

14

12

36 547

4

12 175

4

Head and neck

12

13

17 215

10

1428

19

Ovary

9

14

11 994

14

4076

12

Other haematological

7

15

na

na

940

22

Oesophagus

6

16

14 163

12

670

25

Other

6

16

na

na

1400

18

Pancreas

5

18

22 680

5

1658

16

Stomach

5

18

15 218

11

2430

15

Cervix

5

18

5231

18

1600

17

Liver

3

21

4716

19

2650

14

Uterus

3

21

4663

20

1320

20

Bladder

2

23

10 077

15

990

21

Eye

2

23

952

22

690

24

Testis

2

23

862

23

326

26

Mesothelioma

2

23

na

na

870

23

Gallbladder

1

27

3549

21

45

28

Thyroid

1

27

762

24

100

27

Unknown primary

0

29

na

na

0

29

Total

368

471 330

195 982


DALYs = disability-adjusted life-years.
na = not available: the all/multiple, other, other haematological, mesothelioma and unknown primary sites were not reported in the source from which DALYs were obtained.
* All/multiple category included because Phase 1 trials and trials investigating behavioural interventions may include patients with any type of cancer.
Bone marrow transplant, myelodysplastic syndromes, haemaglobinopathies.
Non-melanoma skin cancer, bone, adrenocortical.

2 Number of cancer trials, by disability-adjusted life-years

3 Industry-sponsored trials, by cancer type*

Cancer type

No. of trials

No. of industry-sponsored trials


Haematological

84

36 (43%)

Breast

62

20 (32%)

All/various

40

17 (43%)

Urogenital

33

20 (61%)

Lung

26

20 (77%)

Colorectal

21

10 (48%)

Neurological

21

5 (24%)

Upper gastrointestinal

20

7 (35%)

Gynaecological

17

5 (29%)

Melanoma

17

9 (53%)

Sarcoma

15

7 (47%)

Head and neck

12

3 (25%)

Total

368

159 (43%)


* χ2 = 26.7; P = 0.005 for test of equal proportions across cancer type groups. Cancer type groups: all various = all/multiple, other, eye and thyroid; upper gastrointestinal = oesophagus, stomach, pancreas and liver; gynaecological = cervix, uterus and ovary; haematological = lymphoma, leukaemia, multiple myeloma and other haematological; lung = lung and mesothelioma; urogenital = kidney, bladder, prostate and testis.

4 Primary sponsorship of intervention types used in cancer clinical trials

Intervention type

No. of trials

No. of industry-sponsored trials


Treatment: drugs

253

141 (56%)

Treatment: biological

31

12 (39%)

Behaviour

22

0

Treatment: radiation

18

2 (11%)

Treatment: chemoradiation

14

Treatment: surgery

9

Diagnosis

8

Prevention

4

Early detection

3

Lifestyle

3

Treatment: other*

3

Total

368

159 (43%)


* Acupuncture, nasopharyngeal humidification and enteral nutrition.

5 Factors associated with industry primary sponsorship of cancer clinical trials

Bivariate analysis


Multivariate analysis


No. of trials

χ2

Odds ratio (95% CI)

P

χ2

Odds ratio (95% CI)

P


Cancer type*

Breast

62

24.2

1.00

0.001

18.8

0.064

Colorectal

21

1.91 (0.70–5.23)

2.04 (0.58–7.16)

Gynaecological

17

0.88 (0.27–2.82)

0.83 (0.20–3.55)

Haematological

84

1.58 (0.79–3.13)

0.69 (0.30–1.60)

Head and neck

12

0.70 (0.17–2.87)

0.90 (0.18–4.60)

Lung

26

7.00 (2.43–20.13)

4.58 (1.35–15.54)

Melanoma

17

2.36 (0.79–7.04)

2.10 (0.60–7.42)

Neurological

21

0.66 (0.21–2.04)

0.47 (0.13–1.68)

Sarcoma

15

1.84 (0.58–5.78)

0.95 (0.27–3.42)

Upper gastrointestinal

20

1.13 (0.39–3.27)

0.72 (0.22–2.40)

Urogenital

33

3.23 (1.34–7.77)

2.14 (0.75–6.12)

All/various

40

1.55 (0.68–3.53)

1.20 (0.44–3.23)

Intervention type

Local

44

68.1

1.00

< 0.001

31.2

< 0.001

Systemic

284

15.96 (4.83–52.73)

16.71 (4.70–59.43)

Other

40

1.11 (0.21–5.83)

0.56 (0.08–3.87)

Cancer extent

Early

74

27.5

1.00

< 0.001

13.7

1.00

0.001

Advanced

267

3.82 (2.09–6.98)

3.76 (1.78–7.94)

Not applicable

27

1.04 (0.36–3.00)

7.93 (1.56–40.18)

Allocation to intervention

Non-randomised trial

159

1.5

1.00

0.226

4.7

1.00

0.030

Randomised controlled trial

209

1.30 (0.85–1.97)

1.78 (1.06–3.00)


* Cancer type groups: all various = all/multiple, other, eye and thyroid; upper gastrointestinal = oesophagus, stomach, pancreas and liver; gynaecological = cervix, uterus and ovary; haematological = lymphoma, leukaemia, multiple myeloma and other haematological; lung = lung and mesothelioma; urogenital = kidney, bladder, prostate and testis.
Intervention categories: local = radiation, surgery, chemoradiation; systemic = drugs and biological; other = other, behaviour, lifestyle, diagnosis, early detection and prevention.
Advanced and haematological cancers.

6 Intervention types, by trial registry and recruitment location

No. of trials

CT.gov

ANZCTR

Australia only


Treatment: drugs

253 (69%)

187 (74%)

66 (26%)

71 (28%)

Treatment: biological

31 (8%)

20 (65%)

11 (35%)

15 (48%)

Behaviour

22 (6%)

2 (9%)

20 (91%)

21 (95%)

Treatment: radiation

18 (5%)

11 (61%)

7 (39%)

9 (50%)

Treatment: chemoradiation

14 (4%)

7 (50%)

7 (50%)

9 (64%)

Treatment: surgery

9 (2%)

4

5

2

Diagnosis

8 (2%)

2

6

8

Prevention

4 (1%)

1

3

3

Early detection

3 (1%)

0

3

3

Lifestyle

3 (1%)

1

2

3

Treatment: other*

3 (1%)

2

1

2

Total

368 (100%)

237 (64%)

131 (36%)

147 (40%)


ANZCTR = Australian New Zealand Clinical Trials Registry.
CT.gov = ClinicalTrials.gov.
* Acupuncture, nasopharyngeal humidification and enteral nutrition.

Provenance: 

Not commissioned, externally peer reviewed.

Received 
26 Aug 2010
accepted 
24 Jan 2011
Rachel F Dear, MB BS, FRACP, Medical Oncologist and PhD Candidate, Centre for Medical Psychology and Evidence-based Decision-making
Alexandra L Barratt, MB BS, MPH, PhD, Professor of Public Health, Sydney School of Public Health
Kevin McGeechan, BSc, MBiostatistics, Lecturer in Biostatistics, Sydney School of Public Health
Lisa Askie, PhD, MPH, Director of Systematic Reviews and Health Technology Assessment, NHMRC Clinical Trials Centre
John Simes, MD, FRACP, Director of the NHMRC Clinical Trials Centre
Martin H N Tattersall, MD, MSc, FRACP, Professor of Cancer Medicine, Discipline of Medicine
University of Sydney, Sydney, NSW.
Correspondence: 
Acknowledgements: 

This work was supported by the National Health and Medical Research Council (grant reference number 512380). We thank Sheena Arora for her assistance in recoding and merging data and Thuyen Vu of the ANZCTR for extracting data from the ANZCTR and CT.gov.

Competing interests: 

Lisa Askie and John Simes are Manager and Director, respectively, of the ANZCTR.

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