Clinical trials regulation — how Canada compares

When a 48-year-old man with no history of cardiac problems suffers 2 heart attacks and dies during a testing of a new drug, it is axiomatic that concerns will resurface about the safety of clinical trials.

To clear his debts, Peter Munro, a healthy and athletic father of 3, had volunteered for a phase 1 trial of RhuDex, a new drug being developed by the German pharmaceutical company MediGene to treat rheumatoid arthritis. If the resident of Edinburgh, Scotland, had completed the trial, he would have been paid £2000 (about $4019). Instead, the bodybuilder is 6 feet under, his death is under investigation by the United Kingdom's Medicine and Healthcare Products Regulatory Agency, and his family is seeking legal redress and the closure of the Charles River Clinic in Tranent, near Edinburgh.

His death raised the spectre of the infamous phase 1 drug trial that 2 years earlier had sent 6 healthy men into survival watch in intensive care due to multiple organ failure that occurred during the testing of the immunomodulatory drug candidate TGN 1412, which was being developed by the now-bankrupt German biotech firm TeGenero and was being tested at London's Northwick Park Hospital. A 24-year-old was left without toes, while a 26-year-old man was dubbed “The Elephant Man” after his head swelled to nearly double its original size.

The reaction was swift. An ensuing inquiry revealed gaps in the UK's system for overseeing clinical trials and by 2007, the frequency of trial inspections was significantly increased.

It also put the international spotlight back on clinical trial regulation and inspection. Hard worldwide numbers about clinical trial participation are all but nonexistent, although it's estimated about 3.5 million Americans are enrolled annually. Canadian cancer groups have estimated that 7000–10 000 Canadians are enrolled in cancer trials, but neither Health Canada nor the Canadian Institutes of Health Research have data on participants, many of whom are recruited by family physicians.

As a result of clinical trials mishaps, the UK and United States have been moving quickly to reform their oversight regimes. Canada, by contrast, has not sought change with any measure of alacrity. Health Canada has been reviewing its clinical trials regulatory framework for nigh on 2 years and has conducted stakeholder consultations. But nothing in the way of a report or new proposals for restructuring the system have yet surfaced.

In general, regulators in Canada, the US and the UK use inspections as their principal means of oversight of clinical trials but recent history demonstrates that the approach has limitations, largely because of resource constraints.

In the US, for example, Inspector General Daniel Levinson reported in September 2007 that the US Food and Drug Administration (FDA) had little clue about the number of clinical trials being conducted, audited fewer than 1% of those and typically inspected after the tests were completed. With a scant 200 inspectors overseeing an estimated 350 000 sites, they almost never followed up inspections to determine if corrective action was taken and in 68% of all inspections, downgraded their findings. Levinson concluded that the FDA lacked the necessary “comprehensive management and reporting systems,” to meet objectives.

Meanwhile, the TGN 1412 debacle, which ultimately led to revisions in British guidelines for clinical trials and tightening of regulations surrounding phase 1 studies, “certainly woke people up to the fact that the system was not working,” says Dr. Michael Goodyear, an oncologist at Dalhousie University in Halifax, Nova Scotia.

Although Canada has thus far been spared such disasters, events in the UK should raise alarms here, Goodyear adds. “It could have happened here just as easily. There was nothing specifically about the UK that was lax.”

Moreover, there's an increased likelihood, given the growth of clinical trials in the country. And given that Health Canada doesn't maintain a clinical trial registry, data about the number of trials is somewhat imprecise.

Health Canada reports show that the total number of phase 1 clinical trial applications rose to 1118 from 714 in Canada between 2002 and 2007, while the overall total (including phase 2 and 3 trials, the number of which have been in a steady-state or a decline) rose to 1724 in 2007 from 1287 in 2002.

In short, almost all of the clinical trials growth has been at the phase 1 level, reaffirming the widely held notion that phase 1 trial units are sprouting up like mushrooms across the nation. This is largely due to changes in 2001 that shortened the standard Health Canada review for phase I trials in healthy volunteers to 7 from 60 days. The government widely advertised its new, shorter approval times, along with its low tax rates for companies involved in research and development, in a bid to attract companies sponsoring clinical trials. Health Canada officials even got the word out by attending meetings and writing articles.

The upshot has been that CenterWatch, a private firm in Boston, Massachusetts which gathers data on the industry, says Canada now ranks second in the world in terms of its number of clinical trial sites, following the US, but ahead of Germany, France and the UK.

Oversight, though, is hardly following the same growth curve.

Over the past few years, Health Canada has ramped up its inspection activities “at least to the equivalent of the FDA's,” says spokesperson Agnes Klein, director of the department's Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics. That may well be true, although the limited data available suggests that the level of inspection still falls well below a target of 2% of trials.

In fact, in fiscal year 2006/07, according to a Health Canada presentation at the 4th annual Clinical Trials in Canada conference in April 2008, the department's 39 “Qualified Investigators” managed to inspect 40 trial sites, or about 1% of sites with ongoing trials. (The number of inspected Canadian sites is actually somewhat higher as the figure doesn't include Health Canada investigations in response to a complaint; FDA inspections of FDA approved trials in Canada and US National Institutes of Health inspections of trials they fund here. According to CenterWatch, 128 international inspections took place in Canada between 1980 and 2006. About 60% of FDA inspections in Canada between 2002 and 2006 resulted in a requirement for voluntary action by the sponsor).

Although similar to the level achieved in the US, Health Canada spokesperson Paul Spendlove says the inspectorate's objective is to conduct approximately 80 inspections per year.

The UK's 60 inspectors managed inspections of 96 trial sites in 2006, about one quarter of which resulted in a critical finding. If a response to such a finding is inadequate, it can lead to a re-inspection or referral to the agency's inspection action group but press officer Jennifer Kyne says the agency has only very rarely exercised its authority to stop a trial.

Canadian regulators have proved no more eager to intervene.

Health Canada has been known to stop trials in midstream twice since 2001, when new clinical trial regulations were adopted. Prior to that, trial oversight was primarily the purview of the local research ethics board that had approved the protocol.

Klein says that in the most recent case in which her office stopped a trial, “we discovered a couple of instances of potentially unwarranted risk taking in 1 instance with 1 investigator, and we actually have requested that he suspend studies until he satisfies us with what he does and how he does things.” Departmental spokesperson Stéphane Shank says privacy and confidentiality issues preclude disclosure of further information about the trial.

Another known suspension involved a drug being tested in Germany and Canada. Dr. Siddika Mithani, then-head of Health Canada's clinical trials program, halted that trial after learning of the death of a healthy volunteer in a parallel German trial. During a talk at Dalhousie University in 2003, Mithani, who now directs Health Canada's veterinary drugs directorate, said that she informed the sponsoring firm “not on my watch. You're not doing that trial in Canada.”

Dr. Robert Peterson, who was head of Health Canada's therapeutics products directorate at the time, says he knew of several similar situations involving trials in Canada that were stopped when sponsors were reprimanded by another country. “If the regulator in the other country said, ‚Wait a minute, we've got a problem; we're going to suspend your licence', I can tell you that would terminate a clinical trial here pretty quickly.”

According to Health Canada's Paul Spendlove, the department “has not changed its processes in any way,” since the period referred to by Mithani and Peterson. But the department issued only one “Not Satisfactory” letter to clinical trial applicants between 2004 and 2007, as compared with 5 in 1999, 2 in 2000, 7 in 2001, 4 in 2002 and 4 in 2003.

Klein says Health Canada's inspection processes “parallel” those of the UK and US but the Canadian inspectorate is smaller than its counterparts; its inspections are fewer and it severely lags in issuing reports (sidebar, page 636). Dr. Stuart Macleod, a drug safety expert at the University of British Columbia, is concerned that Health Canada doesn't have sufficient personnel “to do what they're trying to do.”

Peterson, who left Health Canada in 2005, says the trials inspectorate was “resourced adequately” at that time but he worries that staff levels have not since kept pace with need.

The department also lacks what many would call basic data. Although it is working on a process for registration of clinical trials, this effort has lagged and there is now no trial registry, or even a registry of research ethics boards in Canada.

The latter is a real shame, says Goodyear, former chair of Dalhousie's research ethics board. “We have no way of finding out how many REBs there are in Canada and who they are and where they are,” he says, adding that the problem is particularly acute in British Columbia, Quebec and Ontario, where private ethics boards often oversee clinical trials.

Canada also lags in any form of oversight of trials conducted outside its borders on products whose manufacturers are expected to seek regulatory approval from Health Canada. Departmental spokesperson Alistair Sinclair stated in an e-mail that for trials with sites in “India, China or other countries,” the department relies on “international guidelines for the conduct of clinical trials” and monitoring by “sponsors and other regulatory agencies.”

The migration of clinical trials to Eastern Europe, Latin America, India and China has been inexorable in recent years as the pharmaceutical and biotechnology industry move to take advantage of lower costs, larger populations of potential research subjects and less restrictive regulations. But it's come at the cost of spate of drug trial horror stories, prompting the World Medical Association to move to update its cornerstone guidelines on ethical trial conduct (CMAJ 2008;178[2]:138).

The FDA, meanwhile, has moved to expand its capacity to conduct inspections in the developing world, promising to establish satellite offices in China, India and South America (CMAJ 2008;179[2]:131). Inspectors based overseas will mostly oversee manufacturing facilities, but they may also be in a position to monitor clinical trials.

For its part, the federal government seems focused on promoting Canada as a trials site and stemming the flow of trials to the developing world. At the Biotechnology Industry Organization's international meeting in San Diego in June, Industry Canada distributed literature promoting the nation as a competitive candidate for commercial clinical trials due to its low institutional overhead costs, thriving contract research industry and streamlined regulatory process. “Canadian trial sites,” states one of those brochures, “are regularly monitored by Health Canada, the US FDA and industry sponsors.”