Accrual to Phase III Trials in Europe Speeding Up

DALLAS—European clinical investigators in lymphoma have learned from the US how to plan successful Phase III trials, to the point where they are now surpassing researchers in this country in the number of patients accrued and the speed of enrollment. In a presentation here at the Southwest Oncology Group Annual Fall Meeting, Richard I. Fisher, MD, the cooperative group's Deputy Group Chair and Lymphoma Committee Chair, said that the story of Phase III testing today is really how the United States taught lessons to the world, lessons potentially eclipsing this country's ability to conduct certain studies. Up until the 1990s, “we were the only game in town,” and studies establishing standards of care in lymphoma were all conducted in North America, Dr. Fisher said in a presentation here at SWOG's Annual Fall meeting. A review of more recent and ongoing studies, however, shows that the rate of patient enrollment in French and German Phase III studies is accelerating, said Dr. Fisher, who is also Director of the James P. Wilmot Cancer Center and Professor of Medicine at the University of Rochester Medical Center. Thoughts from Dr. Bertrand Coiffier Dr. Fisher said he has asked noted French oncologist Dr. Bertrand Coiffier to explain why European trials of lymphoid malignancies have faster and larger recruitment. Dr. Fisher said that according to Dr. Coiffier, Europeans have a greater feeling of necessity to prove themselves. These studies are especially fulfilling for the smaller centers, he said. “Very importantly, although they are leading us in accrual, Europeans still look to the American literature as the place to publish their most important data, and it is easier to have a paper accepted in the US journals as a Phase III study,” Dr. Fisher said, again citing Dr. Coiffier.Figure: Richard I. Fisher, MD, SWOG's Deputy Group Chair and Lymphoma Committee Chair, said that the story of Phase III testing today is really how the US taught lessons to the world, lessons now potentially eclipsing this country's ability to conduct certain studies.American centers conduct more Phase II studies because they are easier to implement, to complete and to publish, Dr. Coiffier says. And Dr. Fisher quoted Dr. Coiffier as saying he believes US physicians have fewer problems getting Phase II studies accepted in US journals than Europeans do. The French physician also says American university centers compete to run and publish Phase II studies, while publishing a randomized Phase III study with a long follow-up is not as gratifying. And Dr. Coiffier, Professor and Head of the Department of Hematology in Hospices Civils de Lyon and a founding member of the cooperative Groupe d'Etude des Lymphomes de l'Adulte (GELA), believes pharmaceutical companies in the US find that Phase II studies are easier to design and implement, that results are rapidly published, and that physicians use the new drug even if its real toxicity and efficacy are not proven. Dr. Fisher agreed with Dr. Coiffier, saying, “this is one of the major differences between the US and Europe, where off-label use of drugs approved for an indication is very restricted to that indication.” Paradigm is Money Dr. Fisher said that from his perspective, one problem with accrual to US Phase III trials is the paradigm here that time is money. “Two thousand dollars a case does not cover the cost of conducting trials,” Dr. Fisher said. “Randomization increases physician and staff time, and where time is money in our practice systems this is a problem.” Informed-Consent Documents Dr. Fisher also pointed a finger at US informed-consent documents. “They are too long and too complicated to be useful for anyone in the world,” he said. “The informed-consent form in France is two pages long, significantly different from the legal documents we struggle with, some of which I have trouble understanding.” Patient attitudes in the US are different from those in Europe, Dr. Fisher said. “US patients have definite opinions about their preferred therapy, and don't simply follow the physician's suggestions,” Dr. Fisher said. “In some European countries there is more faith in ‘whatever the doctor wants I will do.’” And he agreed with Dr. Coiffier about off-label use of approved drugs. “In Canada, the use of rituximab was limited in large-cell lymphoma almost entirely to clinical trials until the label indication was done, because it simply wasn't paid for,” Dr. Fisher said. Dr. Fisher concluded with a quizzical remark, that one reason fewer US lymphoma investigators participate in Phase III clinical trials is that lymphomas are interesting to treat. “Everybody likes to do it, everybody has an opinion, and those opinions are all equally valid in everyone's own mind,” Dr. Fisher said. “So there is much less ability of the American leadership to say ‘we're going to change this in this small way,’ as opposed to the typical reaction of physicians in other countries such as Germany, for example.” European Perspective A European-trained oncologist now in the US concurred with Dr. Fisher that European Phase III testing has been gaining ground over the past decade. Fred R. Hirsch, MD, PhD, Professor of Medicine and Pathology at the University of Colorado Cancer Center, who is originally from Norway, trained in Denmark and held a position there as Chief Physician in the Department of Oncology of National University Hospital in Copenhagen. “We always looked to the United States as the master, where medical oncology was established,” Dr. Hirsch said, in a comment from the audience after Dr. Fisher spoke. He said European oncologists saw US cooperative groups conducting large clinical trials and decided that that's what they should be doing. And they are, he said, now that medical oncology is more recognized in Europe and an infrastructure for clinical trials has been built, especially through efforts of the European Organization for Research and Treatment of Cancer.Figure: Fred R. Hirsch, MD, PhD, who trained in Denmark and held a position there as Chief Physician in the Department of Oncology of National University Hospital in Copenhagen, said that European oncologists saw US cooperative groups conducting large clinical trials and decided that that's what they should be doing. “But the main difference between the US and Europe is the difference in the health care systems,” he said. “Most European countries have socialized health care, which makes it much easier to perform clinical trials and develop infrastructure, because government sets the rules.”“But the main difference between the US and Europe is the difference in the health care systems,” Dr. Hirsch said. “Most European countries have socialized health care, which makes it much easier to perform clinical trials and to develop infrastructure, because government sets the rules.” Socialized medicine also makes patient accrual easier in that patients are typically assigned to a specific hospital, and doctor shopping is unknown. Patients also will be seen by a specialist first in an academic setting, rather than after seeing several specialists in private practice. And socialized insurance makes it far easier to obtain historical data on patients and to keep track of them for follow-up. In an interview later, Dr. Hirsch recommended that US cooperative groups work more closely with community oncologists when designing protocols together in order to enroll more patients in academic studies.

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