FEATURE: Clinical trials on trial

Clinical trial activity in Australia is booming, reports Melissa Trudinger -- but can the system cope?

The high quality of research and clinical medicine in Australia, coupled with the relatively low cost has meant that Australia has garnered a reputation in recent years as a good location for clinical trials.

"Clinical trials are being undertaken more and more in Australia, both to help improve clinical practice in Australia, and also internationally," says Prof John Simes, director of the National Health and Medical Research Council's clinical trials centre, a research unit associated with the University of Sydney. "Australia is recognised as a place that does high-quality trials."

And Australia's deregulated system for the approval of clinical trials is considered to be a good model by local and international groups. "From our perspective, the system as it is works very well," says Prof Wayne Hooper, managing director of Queensland University clinical trials spin-off Q-Pharm.

According to the First Australian Clinical Trial Survey (FACTS), produced by medical communications group ProScribe earlier this year, around 600 clinical trials are performed in more than 2000 sites around Australia annually. The FACTS study is really the first benchmarking study of clinical trials in Australia, according to ProScribe CEO Karen Woolley, addressing the credibility gap surrounding Australia's clinical trials industry with a solid evidence base of data.

Among the findings of the FACTS study, which was supported by Medicines Australia and the Association of Regulatory and Clinical Scientists, were Australia's performance in meeting recruitment timelines and targets, its relative cost advantage, and its reputation in performing high-quality clinical trials. But the study reveals a few areas where improvement is needed -- the ethics submission and approval processes, as well as a need to raise the profile of Australia's ability to conduct ethical and efficient trials.

Currently, the Therapeutic Goods Administration (TGA) and the NHMRC, which oversees the Human Research Ethics Committees (HREC) responsible for approval of clinical trials, are conducting a review of Australia's clinical trials system, to see where improvements can be made to it. It's been around 10 years since the last review, which resulted in the deregulation of the approval process. Part of the impetus for the review is also the proposed plan to merge the TGA with its New Zealand counterpart to form a trans-Tasman agency for regulation of the pharmaceutical and medical industries.

The review should be completed at the end of this year, but stakeholders have already identified a number of issues that need to be addressed.

"Most of the system works very, very well, but there are occasional hiccups along the way," says George Mihaly, managing director of contract research organisation Kendle Australia.

The biggest such hiccup is the slow and often bureaucratic process required to get ethical approval to initiate a trial. Under the TGA's CTN system, trial proposals are submitted to hospitals' ethics committees, which review the protocols and if necessary, the scientific basis of the trial. Once ethical approval has been granted, the TGA is notified and the trial can commence. In the less commonly used CTX scheme, protocols are submitted to the TGA for evaluation prior to ethics approval -- a system more akin to the US FDA regulatory process.

Swamped

But the sheer number of trials now being performed in Australia, both by local biotechs and pharma companies and by international pharmas, in addition to the investigator-initiated trials, means that many ethics committees are swamped with clinical trial applications. And the increasing number of trials for novel therapeutics is also putting a strain on the system.

"Many ethics committees realise they lack the expertise to review novel therapeutics, especially in 'first time in humans' situations," says Hooper. This means that protocols have to go out to subcommittees for expert evaluation prior to the ethical approval, prolonging the time required to gain approval.

"The process for undertaking ethical review is important and should be done well, but it needs to be streamlined," says Simes. "The current model is unwieldy when it comes to large multi-centre trials, but we don't want to compromise on ethics."

Deborah Monk, the director of science and technology affairs for pharmaceutical industry body Medicines Australia, agrees. "Trials often run into delays because different ethics committees want to make different changes," she says. Part of the problem seems to be that each ethics committee has its own personality -- although the NHMRC's Australian Health Ethics Committee oversees individual committees, there are no overarching rules for the committees to follow. And every committee has its own application forms and procedures to follow, increasing the administrative load on trials organisers.

One of the recommendations that Medicines Australia has made to the TGA/NHMRC review of the clinical trials system, in fact, is to standardise the forms and procedures used by ethics committees to facilitate and streamline the process.

"There needs to be some degree of centralisation, and systems to avoid duplication without compromising the underlying ethical principles," says Simes.

Kiwi complication

But the idea of centralising aspects of the approval process is a thorny issue. Monk says that Medicines Australia doesn't want to see a two-step process becoming the norm, as it will slow things down. They have recommended to the TGA that the CTN system be retained, as it has been largely responsible for increasing Australia's clinical trials capabilities. And they are worried that a trans-Tasman regulatory agency will implement a system similar to New Zealand's Scott system, which requires every application to go through the Scott committee prior to ethics approval.

Medicines Australia is carefully watching the 'shared scientific assessment scheme' currently being pilot tested by the NSW government, which aims to perform a single scientific review for all multi-centre clinical trials in the state. But in the end, says Monk, it's a trade-off. "Although we want speed, we don't want poor decisions," she says.

At the heart of the issue is the need for more resources to support ethics committees and clinical trials processes. Monk says most ethics committees in Australia are under-resourced, significantly contributing to delays. And Medicines Australia is not the only one to say it.

"Probably one of the biggest issues is ensuring that the level of support and resources from the hospital is sufficient to allow trials to move forward in a timely manner," says Kendle's Mihaly. "I get less concerned about the due process bureaucratic steps than I do about adequate resourcing at the institution to get things done in time."

The potential implication is that longer times are needed to get approval and carry out the trial, and this translates into a higher burn rate, which particularly affects Australia's emerging and very cash-conscious biotechnology sector.

But the delays also affect Australia's ability to compete for trials participation in the global market and contribute significantly to international studies. Asia and Eastern Europe are getting better at doing clinical trials, which means Australia has to be much more competitive to attract and increase investment in clinical trials, Monk says.

"To me, one of the main problems is that Australia has to become aware that it is just an affiliate to the big countries," says Stefan Krug, head of clinical research at Aventis in Australia.

A looming problem for Australia is clinical trials insurance, another victim of the problems in the insurance and indemnification industry in Australia and other countries.

"The number of underwriters available to Australian biotech companies [for insuring trials] is limited," says Mihaly. "And some ethics committees require levels of insurance and financial liquidity to meet any needs."

According to Simes, insurance costs are usually built into trials funded by pharmaceutical companies, but problems can arise for investigator-sponsored trials.

"It is becoming an issue that highly valuable studies are not being done because of insurance problems," he says. "But insurance is something that will have to be tackled at a national level."

Getting on the register

Another facet of the TGA/NHMRC review is an evaluation of the need to put together a clinical trials register in the Australia. But there are mixed views on whether a register is needed in Australia, and its use.

"Something I have been a champion of for 17 years now is the need for a national register of trials," says the NHMRC's John Simes. "We've been registering some studies in the cancer and neonatal area, but we're not adequately funded."

Simes is a member of the advisory group for Current Controlled Trials (www.controlled-trials.com), a UK-based organisation that has set up an international registry of clinical trials (the metaRegister of Controlled Trials), as well as a system to allocate unique identifying numbers to each registered trial (the International Standard Randomised Controlled Trial Number scheme). The USA has a register of clinical trials (clinicaltrials.gov) which lists some 8800 trials, mainly in the US and Canada, but also in other countries. And there are other registers for specific disease groups and conditions.

A mechanism already exists to capture the required information for a clinical trials register, as the TGA is notified one way or another about every clinical trial conducted in Australia. But questions still remain.

"We're willing to consider it if someone can explain why they want it," says Medicine Australia's Deborah Monk. "There's a need to demonstrate the current unmet need, what information would go on the register, what kind of trials would be included and who would be responsible for it."

And there is concern that pharmaceutical companies might be reluctant to list trials on the register, particularly early phase trials of new drugs. But Simes says these kinds of issues can be addressed by building in mechanisms to protect the trial sponsor where required.

For his part, Aventis' Stefan Krug is in favour of a register. "If you really would like to get information on what's going on in the market, it would be better to get it from a register than through rumours," he says. "The key question is, what is the main purpose of the register? Is it for patients and doctors so they can find out about trials? If yes, that's good. It's better to be a reliable source."