International Clinical Trials Symposium, 1999


Session 18: Novel approaches in the conduct and review of clinical trials

Chair: Eleanor McFadden, Eastern Cooperative Oncology Group, Boston, USA; Val Gebski, NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia


Amanda Milne, Barry Gray, Alan McCulloch, Bruce Neal* and Anthony Rodgers

Rob Herbert*, Chris Maher, Anne Moseley and Cathie Sherrington

D Hugo Stephenson* and Sinead Garrett

Julia Shelley

Guorang Hu, Ronald Walls*, Diana Bass and Ramon Bullock

Julie A Ely* and Geoff P Symonds


18.1

Internet-based clinical trial management systems

Amanda Milne, Barry Gray, Alan McCulloch, Bruce Neal* and Anthony Rodgers

Clinical Trials Research Unit, University of Auckland, Auckland, New Zealand

The development of the internet has provided substantial opportunities for the conduct of clinical trials, in particular for remote randomisation and data entry.

Possible advantages of internet-based systems include more rapid data processing, reduced costs, better quality data and greater opportunities for communication.

Commercial expansion of the internet has stimulated improved methods for secure data transmission that are being enhanced steadily. Also, certain security measures would not be possible with telephone or fax systems, such as password-controlled unblinding limited to prespecified locations.

There are, however, relatively few data available measuring any changes produced by switching to internet-based systems. The Clinical Trials Research Unit at the University of Auckland has developed an internet-based system for an international trial that provides an opportunity to collect such information. All data are provided on paper forms. Registration, randomisation and follow-up data may also be entered remotely at collaborating centres.

About one-third of patients were registered, and one-third of patients were randomised, using remote data entry.

This early experience suggests that internet-based systems are likely to complement rather than replace paper-based systems, at least in the short term. The reasons for this include the necessity for keeping paper source documentation, the patient–clinician barrier and lack of technical skills and hardware at centres. While the advantages of internet randomisation and data management are considerable, perhaps the greatest gains will be improved communication and information sharing concerning queries, study materials, newsletters, etc. The CTRU data services page is http://www.ctru.auckland.ac.nz/data_services.html.


18.2

PEDro: a Web-based database of quality-assessed randomised controlled trials in physiotherapy

Rob Herbert*, Chris Maher, Anne Moseley and Cathie Sherrington

School of Physiotherapy, University of Sydney; Rehabilitation Studies Unit, University of Sydney; and Bankstown–Lidcombe Hospital, Sydney, Australia

We are developing a Web-based resource to facilitate access to randomised controlled trials and systematic reviews of randomised controlled trials in physiotherapy.

A library of randomised clinical trials and systematic reviews relevant to physiotherapy was established by combining a database compiled by the Rehabilitation and Related Therapies Field of the Cochrane Collaboration and personal databases maintained by the authors and their colleagues. Additional trials have been identified by volunteers performing systematic searches of the literature using computerised databases and by scanning reference lists of identified trials.

The methodological quality of each trial on the database is assessed using the PEDro scale, a modification of the Delphi scale (Verhagen et al., 1998). The PEDro scale has been shown to have an acceptable level of inter-rater reliability.

We are currently undertaking further investigations of the properties of the PEDro scale. Trials are indexed so that they can be searched for by subdiscipline, problem treated, intervention and body part, as well as by author and free text in titles, abstracts and subject headings. The indexing system has been developed in consultation with members of the physiotherapy profession.

A web site has been established (http://ptwww.cchs.usyd.edu.au/pedro). It gives access to a powerful, easy-to-use search engine used to search the database. When complete, the database will be made freely available to the public via the Web.

Verhagen AP et al. Journal of Clinical Epidemiology 1998; 51: 1235–1241.


18.3

A reusable electronic data collection system for reducing the cost, error and time associated with clinical trials

D Hugo Stephenson* and Sinead Garrett

Health Research Solutions, Melbourne, Australia

Large clinical trials have implemented electronic data collection systems in order to minimise error and accelerate data analysis.

These electronic systems are often purpose built and are associated with considerable overhead in terms of new hardware, development time and cost, as well as the instability associated with new software. Importantly, when the software is not developed in-house it is often difficult and expensive to make small changes to fields or forms once the system is running.

To address these problems, the Case Report Form Suite (CRF-Suite) was developed to provide a low-cost, flexible and reusable platform for designing electronic data collection solutions. Just as Microsoft PowerPointTM facilitates the creation of slide shows without requiring a programmer, CRF-Suite can create and manage electronic CRFs.

The CRF-Suite was used to create an electronic data collection system for a commercial clinical trial involving over 300 data points, 12 visits and almost 100 participants. An electronic system was ready within one week using the CRF-Suite.

The trial, involving seven centres, now takes advantage of real-time error trapping during direct data entry, intelligent character recognition for reading hand-written forms from noncomputerised centres, data tracking and participant auditing. Principal investigators have access to a live view of their data.

The CRF-Suite has since been used to create other electronic data collection systems for commercial and academic clinical trials.

This technology represents a marked advancement by rendering fully featured electronic data collection systems more accessible to small and medium-sized clinical trials.


18.4

The design of a randomised trial of treatment following first-trimester spontaneous miscarriage

Julia Shelley

La Trobe University, Melbourne, Australia

Curettage has been standard care for women who experience a first-trimester spontaneous miscarriage for more than 50 years. Improvements in many aspects of medical care, such as antibiotics and ultrasound, the improved health status of women and the availability of synthetic prostaglandins suggest that other approaches to care after miscarriage may be effective and acceptable.

We have designed a randomised trial to evaluate three methods of care for first-trimester spontaneous miscarriage: standard surgical care (curettage), medical care (vaginal administration of the synthetic prostaglandin misoprostol) and expectant care (watchful waiting).

The multicentre trial, the Victorian Miscarriage Treatment Study (VICMIST), is now in progress. Unusual features of VICMIST include:

  • the evaluation of ‘lower-tech’ approaches in comparison to standard care, in particular a nonintervention ‘watchful waiting’ approach (expectant care)
  • the contracting of a medical locum service to run a 24-hour randomisation and enrolment service for the trial
  • the inclusion of a cohort group (n=1200) in parallel with the trial (n=840) to examine outcomes that may be affected by randomised allocation to treatment group
  • the breadth of the outcomes being evaluated, which include women’s physical and emotional recovery and their satisfaction with and preferences regarding care in addition to safety and effectiveness
  • the integration of a cost-effectiveness study into the trial
  • the use of qualitative as well as quantitative methods to evaluate outcomes.

This paper will expand on the rationale for including each of these features in VICMIST.


18.5

The utilisation of traditional Chinese medicine BIMIN capsules in management of perennial allergic rhinitis: a randomised, double-blind, placebo-controlled clinical trial

Guorang Hu, Ronald Walls*, Diana Bass and Ramon Bullock

Department of Immunology, Concord Hospital; Department of Medicine, University of Sydney, Sydney, Australia

Allergic rhinitis is a common disorder throughout the world, with a prevalence of 40% in Australia. Safe and effective pharmaceutical agents are available to control the symptoms, but they have no cumulative benefits, and they do not cure the condition.

There is increasing interest among the general population to seek other approaches to therapy which do not involve the regular taking of medicinal drugs. Herbal therapies have been used in allergic rhinitis but none have been shown in controlled scientific clinical trials to be effective.

We set out to conduct a trial of a Chinese herbal formulation, BIMIN, for the treatment of perennial allergic rhinitis, in a randomised, double-blind, placebo-controlled, parallel-group clinical trial.

Subjects with perennial allergic rhinitis were recruited from the general population by advertisement in the local newspaper. The diagnosis was established by history and physical examination, and they were shown to have sensitisation to house dust mite by skin-prick testing. Patients with concomitant diseases were excluded. Females of childbearing age were required to take precautions against pregnancy. The study was approved by the institutional human ethics committees.

A total of 58 patients were randomised to receive either herbal medication (n=26) or placebo (n=32) in doses of five capsules twice a day for 12 weeks. Twenty-one subjects in the treatment group and 29 in the placebo group completed the trial. The five in the treatment group and the three in the placebo group who dropped out did not differ in their characteristics from the rest of the group. Groups were well-matched in age, sex and severity of disease.

The trial outcomes were evaluated by four different assessments, which showed significant improvement in the herbal treatment group compared with the placebo group:

1. physician’s overall assessment: the total effective rates were 85.7% vs 62.7% (P=0.036)

2. visual analogue scores: highly significant improvement in all five symptoms (P<0.000 to P=0.013) and less extra medication (P<0.001)

3. quality-of-life questionnaires (global improvement in 29 questions: P=0.048)

4. daily symptom assessment scores: sneezing was significantly improved (P=0.003). For other symptoms (except nasal congestion), there was a consistent trend over time in favour of the herbal treatment.

A pilot study using GC mass spectrometry showed that there are no known antihistamine substances or ephedrine in the herbal extract.

We conclude that a Chinese herbal formulation, BIMIN, is effective in treatment of perennial allergic rhinitis. This is the first herbal medication to have been shown to be effective in a randomised double-blind, placebo-controlled, parallel-group clinical trial in allergic rhinitis. Its mode of action is unknown but is presently being investigated.


18.6

Conducting gene therapy clinical trials: paving a new path in clinical research

Julie A Ely1* and Geoff P Symonds2

1Janssen-Cilag Pty Ltd, Sydney, 2Johnson & Johnson Research Pty Ltd, Sydney, Australia

The relatively recent development of gene therapeutics presents new challenges in the conduct of appropriate clinical research to test this novel approach.

Gene therapy typically uses one of two methods for the introduction of the therapeutic gene. The first is an ex vivo method in which target cells are removed from the patient, the therapeutic gene inserted into the cells in a laboratory setting and the gene-modified cells then returned to the patient. Alternately, the therapeutic gene may be directly injected into the patient (in vivo) and delivered to the target cells using a viral vector or other chemical means.

Regulatory approval to conduct such trials requires the development and use of appropriate laboratory facilities certified to good manufacturing practices and good laboratory practice standards to ensure the purity, activity, identity and safety of the gene-therapeutic and the gene-modified cells.

Highly skilled laboratory staff are needed to conduct the production and testing procedures for the gene-modified cell products, and extensive documentation is required for the quality control and quality assurance of the final product. In addition, coordination of the production of gene-modified cells and patient treatment is necessary during the clinical trial. Gene therapeutics is still in the early phase of clinical development and therefore complex and specialised safety testing is required, both for the gene-modified final cell product and the patients themselves.

Our experiences developing gene therapy clinical trials, both in Australia and the United States, will be used to highlight some of the unique aspects of conducting clinical trials in this novel therapeutic area.


12 November 1999