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CMAJ • JANUARY 6, 2009 • 180(1)© 2009 Canadian Medical Association or its licensors

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This overview of thelandscape of Canadianclinical trials, alongwith a historical primer

(page 23), is the first ina series of articles CMAJ

will present this year on the state ofclinical trials in Canada and abroad.Many believe the system is in disarraybecause of spiralling costs and con-flicting requirements. Among the is-sues that will be explored in upcom-ing articles are costs, recruitment,registration, ethical oversight, pa-tient safety, reporting and the pushfor reforms.

Industry, government and acade-mia will have to collaborate ifCanada is to maintain or increase

its share of clinical trials in the highlycompetitive global market, speakerstold the fifth annual Clinical Trials inCanada conference.

“We think there is a crisis of clinicaltrials leaving Canada and there is fearthat once they are gone they will be hardto get back,” said Ronald Heslegrave,chair of the ethics board at the UniversityHealth Network in Toronto, Ontario.

Compounding the problem is thedifficulty in recruiting physicians tohelp run trials. “Few doctors in their30s and 40s are interested in clinicaltrials or want to be trialists,” said Dr.Mary Bell, head of the rheumatologydivision at the Sunnybrook Health Sci-ences Centres in Toronto.

“We need to think about succession.We need to be more organized abouttraining for subinvestigators,” whilesome current investigators need retrain-ing, she told the conference, held Oct.21 and 22 in Toronto.

Canada has experienced an increase inthe number of phase I trials — a reflec-tion of a Health Canada move to shortenthe time to review these trials and a sig-nificant increase in spending worldwideat the phase I trial level. But the numbersof phase II and III trials have levelled ordeclined in the past few years (Fig. 1).

“My sense is it would be a successjust to maintain the current level of re-search and development,” commentedPierre Gervais, president of Q&T Re-search in Sherbrooke, Quebec.

Pharmaceutical companies are themain sponsors of clinical trials inCanada. In 2007, spending on clinicaltrials (close to $600 million) accounted

for 78% of the companies’ applied re-search expenditures.

The vast majority (88.7%) of thecompanies’ research and developmentspending was in Ontario and Quebec, ac-cording to the Patented Medicines PricesReview Board’s 2007 annual report.

Pharmaceutical companies are in-creasingly outsourcing the running of

Clinical trials: the muddled Canadian landscape

This artwork, entitled “God,” fetched £188 500 (about Can$353 670) for artist DamienHirst at auction. Medicine and drugs are recurring themes in this British artist’s work.

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CMAJ • JANUARY 6, 2009 • 180(1)© 2009 Canadian Medical Association or its licensors

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clinical trials to contract research organizations, which organize trialsboth in the community and withinhospitals.

Most phase I trials, however, areconducted by specialized contract re-search organizations, said Brett Wil-son, an associate director of clinicalsite monitoring for Bristol-MyersSquibb Canada.

Fifteen to 20 years ago “Canadawas the new kid” in clinical trials, butwith 4.1% of clinical trial sites, Canadanow ranks fourth in the world, after theUnited States (48.7%), Germany(5.7%) and France (4.3%), he said, cit-ing data from a recent article on theglobalization of clinical trials (NatureReviews Drug Discov 2008;[7]:13-4).

But the frontrunners are being chal-lenged by the rapid expansion of ca-pacity in countries such as Russia, Ar-gentina, India, Hungary and China.

Canada’s clinical trials future willdepend on cultivating the expertise torun smaller, more sophisticated trials,speakers from academic centres ar-gued. “Trials looking at small effectsand requiring large numbers of pa-tients will not be done in Canada. …The focus will be targeted drugs pro-ducing bigger effects in smaller popu-lations,” said Robert Phillips, deputydirector of the Ontario Institute forCancer Research.

Doctors and hospital-based re-searchers were urged to take a morebusiness-like approach. “Investigatorsdon’t think of themselves as businesspeople. … But they are in business.They are not practising medicine whenthey are doing a trial,” said MargaretKerr, a Toronto lawyer who specializesin contract work.

The meeting, organized by the pri-vate-sector group Insight Information, adivision of Incisive Media, was at-tended by about 85 people, includingthe speakers and representatives fromcontract research organizations, brand-name pharmaceutical companies andgovernment, as well as academic re-searchers and contract lawyers. It’s notoften that such a diverse group meets,several participants noted.

Some of the many challenges facingthe clinical trial industry identified atthe meeting include:

the task because the province couldprovide no information, Viel told theconference.

Meanwhile, little is known aboutwhere the organizations operate, be-cause many are involved with runningtrials offshore. “Canadian companieshave created thousands of jobs inter-nationally.”

Gervais said that government rep-resentatives have no idea about howmuch research is done in the privatesector, “there is no structure to wel-come more,” and governments seemto deem the sector too small to war-rant tracking.

Meanwhile, the academic clinicaltrial sector suffers from a similar lackof cooperation and information, speak-ers told the conference. Many Canadianhospitals and research institutions areaiming to improve their capacity to runclinical trials, and academic researchersare establishing and strengthening clini-cal trial specialty groups involvingmultiple sites.

But cooperation among hospitals “isthe exception rather than the rule,” saidPhillips. Clinical trials are “grafted ontoother hospital practices,” he said, not-ing that when he offered to help designmodel systems for clinical trials, hospi-tals “were so burdened with patientcare” that they couldn’t spare the timeto work with him.

• A lack of basic information aboutthe clinical trial landscape in Canadaand a lack of cooperation among thevarious parties

• The increased complexity of docu-mentation required for clinical trials,lack of standardization in contractsand among research ethics boards,as well as other bureaucratic and ad-ministration complications

• The public’s lack of confidence inpharmaceutical companies and diffi-culties recruiting patients for trials(with the exception of trials for can-cer drugs)

• Clinical trials that are unnecessarilycomplex and/or uninteresting to re-searchers, and the time and cost pres-sures resulting from drug firm finan-cial realities. Although pharmaceutical compa-

nies have increasingly outsourced theclinical trial business to contract re-search organizations, (these privatesector organizations now run moreclinical trials than universities or hos-pitals), the sector is “fragmented anddiversified,” said Carl Viel, presidentof PÔLE, an agency established topromote economic development in theQuébec City metropolitan area.

Indeed, when PÔLE set out to mapthe presence and activities of contractresearch organizations in the QuébecCity area, it had to hire a student for

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Figure 1: Canadian clinical trials, according to a Centerwatch analysis of HealthCanada’s Therapeutics Directorate annual reports.

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And within hospitals, individual sitegroups are “often autonomous empireswith little oversight,” Phillips added.When his institute established a data-base (www.ontariocancertrials.ca) ofclinical trials “we thought it was for pa-tients, but nurses use it to find outabout trials in their own hospitals.”

The current system typically worksfor well-known senior clinician scien-tists, who are sought out to conducttrials, but it can be hard for young sci-entists to get a foot in the door, headded.

Meanwhile, variations in contractlanguage and in the requirements ofresearch ethics boards pose problemsfor both hospitals and research insti-tutes, speakers told the conference.The push to standardize contracts andto harmonize research ethics boardapproval standards is making slowprogress.

The University of Toronto systemhas developed a template contract, andSt. Michael’s Hospital often settles oncontract language with the sponsoringpharmaceutical company, said MichelleMoldofsky, a policy and legal adviserwith the hospital’s office of researchadministration.

But contract research organizationsare “adding another party to the mix”and they “very rarely” agree on thesponsor’s template, she said.

For Canada-wide trials, organizersmust cope with differing provincial pri-vacy legislation, and the increase in thenumber of foreign-sponsored trials isaccompanied by language, cultural andlegal challenges, she said.

“With the globalization of research,we have to reach through layers andlayers of people,” added Kerr. “Weneed a Batphone to the commissioner.”

Foreign sponsors have also hadsome difficulty with the fact that Cana-dian physicians are not site employeesbut rather independent contractors,which affects the insurance provisionsof contracts, the lawyer said.

For the Canadian subsidiaries of in-ternational pharmaceutical companies,difficulties can arise when trials are setby global colleagues so that sub-sidiaries are limited in their ability toinfluence contracts or protocols, severalspeakers said.

On the other hand, Pierre Geoffroy, asenior director with sanofi pasteur, sug-gested public confidence may have beenundermined because advances in phar-macovigilance and post-market surveil-lance of drugs are leading to publicityabout “post-market misadventures” thatmay have gone unidentified in the past.

To attract more doctors to clinicaltrials, the administrative burden onthem must be lifted, said Wilson.

But part of the difficulty in recruit-ing physicians lies in the trials them-selves, argued Muhammad Mamdani,director of the Applied Health Re-search Centre at the Li Ka ShingKnowledge Institute in Toronto. “Ican’t tell you the number of industrytrials which are of no interest to doc-tors,” he said.

Mamdani said the unnecessarycomplexity of trials is another stum-bling block.

Heslegrave concurs. “At the REB[research ethic board] level, we see in-creasingly complex studies that try todo too much, that have one primaryand lots of secondary objectives, andare not powered enough, so questionsarise if these are even valid studies.”

For Canada to “survive and pros-per” with clinical trials, there must bemore early cooperation on study de-sign between academics and the phar-maceutical companies sponsoring thetrials, and multicentre trials must beeasier to initiate, said Phillips. “Com-panies can’t just come to a CRO [con-tract research organization] and say,‘here it is, do it’.”

In the future, clinical trials shouldanswer not just whether or not a drugworks for a specific population, butwhy, Phillips added. “Drugs should bebased on science, not serendipity. Thegoal will be to design drugs targetedto patients and we need to recognizethis change.”

If contract research organizationswant to be involved in high-impactclinical trials, they will have to buildlinks with the academics, Phillips latersaid in an interview. “Everyone is grop-ing with how to come to a mechanismto bring teams together.” — Ann Silversides, CMAJ

DOI:10.1503/cmaj.081897

Kerr said another stumbling block forsome sponsors is the University ofToronto’s requirement that clinical trialsites report any adverse events sufferedby patients to both Health Canada andthe research ethics boards of other sitesinvolved in a multisite trial.

Those adverse events may be be-coming more common because of timepressures, suggested Janice Parente,president of ethica Clinical ResearchInc. of Montreal, Quebec. Drugs arebeing withdrawn from the market be-cause “the research was not done prop-erly. … Maybe we need to relax thetime,” she said. “We are making hugemistakes that affect humans.”

Heslegrave said that in protocol viola-tions involving patients — for example,a pregnancy test not being undertaken ona trial participant — the excuse typicallyoffered is that “there is no time.”

Only 1%–3% of the eligible Cana-dian population participates in clinicaltrials, Wilson said. Speakers blamedthe difficulty in recruiting patients (ex-cept for cancer patients) on widespreadpublicity about drug withdrawals, aswell as a shift in the public’s perceptionof drug companies — from discoverersof new medications to commodityproviders.

This change in perception is likelyfuelled by widespread direct-to-consumer advertising of prescriptiondrugs (illegal in Canada but familiar toCanadians through United States televi-sion and magazines), said MurrayJensen, director of clinical and scien-tific affairs for ethica.

It is estimated that only 1%–3% ofCanadians participate in clinical trials.

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