Lab Business Magazine Article:

"The Lost Decade"


Canada's decline in clinical trials means profits for developing countries.

By: Julia Teeluck



With Canada already one of the least popular places in the world to conduct clinical trials, Canadian labs face significant challenges to bring future trial work home. Canada faces competition from developed economies and developing countries, where the costs of conducting trials is lower, finding patients to volunteer for drug testing is easier, and regulation is simpler.

Lowly ranked
Canada’s ranking as a place to conduct clinical trials has dropped steadily over the last five years. Between 2006 and 2010, the number of clinical trials and trial sites in Canada dropped approximately 30 per cent, with clinical trial applications for non-generic drugs decreasing to 596 from 777.

This flight of research from Canada sparked industry, academia and government to gather in Ottawa in September 2011 for the first Canadian Clinical Trial Summit. There, industry and policy-makers discussed Canada’s downward trend and worked on an action plan to improve Canada’s competitiveness.

The issue of Canada’s weakened competitiveness is not a new one. According to an article in the January 2009 Canadian Medical Association Journal, many people involved in clinical trials believed that cost and conflicting requirements were among the causes for the Canadian system’s disarray. In the article, Ronald Heselgrave, chair of the ethics board at the University Health Network, said there is the fear that once clinical trials leave Canada they will be difficult to get back. This fear may be the new reality. Clinical trials continue to decline, and there is little incentive
for companies to come to Canada except for a history of excellence in research. “What we’re talking about is a lost decade,” says Jack Corman, President, and Institutional Review Board Services. “So now we’re trying to play catch up.”

Corman says that how Canada proceeds depends on what government wants to accomplish—to rearrange the furniture or to make fundamental change to the clinical trial system in Canada. “Talk is cheap, and it’s not cheap talk. There are millions that have been spent—and I deliberately do not use the term invested—on governments constructing schemes to bring more research [to Canada], to harmonize or centralize ethics reviews in a government run system, and they’ve backfired every time. So maybe this time it’ll work, but I’m not counting on it based on the past record,” says Corman.

Expensive research
Canada is now the most expensive country in the world in which to perform a clinical trial. Although cost is only one of the many factors a company takes into consideration when choosing a clinical trial location, the price to do research in Canada is almost double that of Spain and the United Kingdom. In comparing the per-patient cost for the same trials, Canada is nearly twice as costly as France and Germany.

Patient recruitment adds to the expense of conducting clinical trials in Canada. Canada has a sparse population and marketing needed to reach these patients is not as plentiful or as sophisticated as in other countries. Researchers who can’t recruit a large sample won’t always get superior data from the trial.

“The name of the game in clinical trials is getting the data,” says Normand Laberge, Vice President, Regulatory and Scientific Affairs at Rx&D. If a country is slow and inefficient at getting results, why then, asks Laberge, would a company take the risk to invest there? “Canada went down significantly to the profit of other countries,” says Laberge.

Laberge explains that other countries are beating Canada on these simple administrative elements. “[Other countries] start up faster so they can recruit patients longer. Trials will start at the same time around the world, but if we spend three months or six months doing ethical reviews while the other countries are recruiting, at the end of the trial we will have recruited only half of the patients we were supposed to recruit, while the other countries recruited maybe 140 per cent. And that’s the case of Spain. They recruit 120 per cent, and they’re half our cost,” says Laberge.

Laberge also notes that bureaucracy at the start of a clinical trial contributes to a loss in performance. Currently, for example, if a trial has 20 sites in Canada, the sponsor company must sign 20 contracts with a representative (a manager or contract negotiator) from each site. Laberge believes the contract should be standardized. The same goes for ethical reviews. “The other thing is if we’re going to 12 different sites in Canada, why do 12 different ethical reviews? There’s no reason,” says Laberge.

Laurel Evans, Associate Director, Research Ethics, Office of Research Services University of British Columbia, addressed the issue of complicated administrative systems at the 2011 annual Clinical Trials in Canada conference. She says the Canadian Association of Ethics Review Boards views the standard developed by the Canadian General Standards Board as far too detailed.

If a country is slow and inefficient at getting results, why then would a company take the risk to invest there?

“We also have difficulties with the standard because from our perspective it’s partly standard operating procedure, and it’s far too detailed in many instances which constrain the flexibility of our research ethics boards,” says Evans. She says that while guidelines and rules are useful, research ethics boards must make decisions in relation to a specific project site and investigator. “They need to have certain flexibility around what they’re doing in that respect,” says Evans.

Corman advocates harmonized standards across Canada’s many jurisdictions. He also says researchers need a verification system for ethics committees in Canada. There is no federal or national inspection system for ethic reviews. Health Canada does not have the authority to inspect research ethics boards nor is there a Canadian accreditation body for research ethics boards. It is the sponsor’s responsibility to ensure a clinical trial is conducted according to the regulations and good clinical practice. “To my knowledge, we are the only country in the Western world that does not have some kind of an oversight system, verification system for ethics committees. I think that’s a huge hole that needs to be fixed, but harmonization alone without a standard doesn’t cut it,” says Corman.

Taking it elsewhere
There has been rapid growth of clinical trials in Latin America and Eastern Europe. The reason for outsourcing is complex. Many companies choose to conduct their trials down south or offshore where costs are low, the population is plenty, and the laws are “streamlined.” One of the reasons companies leave Canada, according to Corman, is that the quality of research is improving in developing countries. “Often the quality of the data is as good, if not better than in the West,” says Corman.

While the data may be comparable, the level of regulation is not. A 2001 report from the Human Health Department, the U.S. government agency responsible for health care in America, noted that the pharmaceutical industry, national regulatory agencies, the National Bioethics Advisory Commission, and the World Health Organization, all had concerns over foreign review boards and a lack of experience and poor monitoring practices in some clinical trials. Although these concerns are well documented, the number of clinical trials to Latin America has continued to grow.

The U.S. Federal Drug Administration does not require sponsors of foreign-based research to conduct research under an Investigational New Drug application, and does not require foreign investigators to sign an attestation that they will protect their human subjects. According to a 2010 report by the inspector general of the Department of Human Health Services, which outlines the challenges the FDA has in monitoring and inspecting foreign trial sites, sponsors are increasingly conducting early-phase clinical trials at foreign sites without Investigational New Drug applications. The applications are not required for trials conducted outside of the United States, but are required for those conducted within the United States. The application informs the FDA about the protocol of the clinical trial, about the qualifications of the staff conducting the trial, and assures the FDA that the subjects involved in the trial will be protected and that the subjects will not be exposed to any “unreasonable risk.”

Language barriers and a lack of intellectual property protection may present a problem for research organizations that choose to do research in developing countries. Many Latin American countries, such as Argentina, Venezuela, Brazil and Mexico, are on the United States Trade Representative Special 301 Report’s Priority Watch List. The report is an annual review of the global state of intellectual property rights protection and enforcement.

Despite these concerns, Corman says a country’s ability to recruit large numbers of subjects quickly into clinical trials is an important factor for research sponsors. Corman tells the story of a top Canadian recruiter who was able to recruit 150 patients for a trial. The sponsor was very pleased at these results. At a later meeting, the top Canadian recruiter spoke with a person who had participated in a research site in Taiwan. The researcher had recruited 1,500 patients in one week for the Taiwan trial. More than 23 million Taiwanese live on the 36 thousand-square kilometer island compared to the 34 million Canadians spread over nearly 10 million square kilometres.

What’s happening here
When it comes to health care in Canada, patient care steals the agenda. Clinical trials, an important part of patient care, are a secondary concern. This divided mentality shouldn’t exist, Laberge says. If Canada wants to improve patient care, then attention needs to shift to clinical trials. Countries that conduct clinical trials benefit from the knowledge transfer, the key to any innovation policy in this country. “If the trials aren’t done here in Canada, when the medicine is going to be approved, we will have no knowledge base on how to appropriately use it,” says Laberge.

Canada has a reputation for excellence in research and continues to attract clinical trials, in spite of low patient recruitment and high costs. For example, in October 2011, Health Canada approved Cytonet, a biotechnology company based in Germany and the United States, to extend a phase three trial, currently being conducted in the United States, into Canada. The SELICA III trial will evaluate the safety and efficacy of liver cell therapy in children with urea cycle disorders, a genetic disorder of the liver that can lead to brain and nerve damage. The Alberta Children’s Hospital in Calgary and the Hospital for Sick Kids in Toronto will participate in the trial.

Cytonet’s decision to extend to Canada was based on its existing relationship with Dr. Aneal Khan at the Alberta Children’s Hospital, who said he would be able to secure patients for the trial. “The Canadian scientist that we were working with had also contacted us and said that they had the capability to recruit the patients—we’re dealing with an extremely rare disease and I think that’s one of the things you have to keep in mind,” says Rodney Monroy, Senior Director, North American Clinical Operation at Cytonet. “We’re looking at genetic defects in a certain set of children, and [Khan] said that he often sees children with this type of defect. And so he contacted us and they’re currently getting ready to pass through their review ethics boards, so the clinical site’s ready,” says Monroy.

Dr. Khan explains there is a need for innovative treatments for urea disorder and bringing the trial to Canada would allow those families whose children suffer from this disease an alternative therapy. “We’re hoping this technology can change this number around,” says Dr. Khan.

The future of trials in Canada
Glenn Brimacombe, President and CEO of the Association of Canadian Academic Healthcare Organizations, says he hopes the action plan, which is in development by the association, will be available by the end of 2011. It will include suggestions made by participants at the Clinical Trial Summit in Ottawa and will serve as a road map for government, industry and academia to address the barriers to clinical trials that are causing Canada to fail. While Canada retains a reputation for excellence in research, there remains competition from developing countries that can offer access to more human subjects.

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