© Oxford University Press 2006.
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European Move Affects Academic Trials Research
Imagine trying to conduct a clinical trial across several countries, each with its own set of rules. One country would require that all sponsors formally apply to a central ethics committee, whereas another would merely ask for a letter notifying their ethics committee of the trial. One country would respond within 3 weeks, another within 5. The inconsistencies among countries would delay the trial, create extra paperwork, and demand an army of professionals to navigate the legal and bureaucratic landscape.
That was the situation for anyone wishing to conduct multinational clinical trials within Europe before the European Union. In 2004, the European Union issued a clinical-trials directive to harmonize clinical trials research across its 25 member countries and better protect trial participants. Rather than fixing the problem, though, recent efforts have made things worse, according to some trial sponsors.
Several academic researchers, including those conducting cancer studies, have had to drop their work or scale it down considerably because they lacked the funds to comply with the new rules, which set up new financial and logistical hurdles. Most member countries implemented the directive with only the deep pockets of industry in mind, the scientists argue. Consequently, their clinical trial research is suffering while the problem isn't solved: There remain inconsistencies among countries.
"Everybody knows that this is a terrible problem," said Akseli Hemminki, M.D., Ph.D., group leader of the Cancer Gene Therapy group at the University of Helsinki.
The directive was intended to have the opposite effect—stimulating high-quality international clinical trial research by setting consistent standards. To that end, it addresses three major areas. First, anyone who wants to conduct a trial must apply for an investigational medicinal product dossier (IMPD)—a document similar to an investigational new-drug application issued by the U.S. Food and Drug Administration—from the country where the trial will take place. Each member country should establish a national ethics review committee. And all clinical trials and their resulting adverse events must be registered in an E.U.-wide database controlled by the European Medicines Agency.
In practice, however, some investigators say that academic researchers' needs have been overlooked. Pharmaceutical and biotechnology companies, which by their nature are multinational, are accustomed to filing new-drug applications and have the necessary expertise in place, said Patrick Squiban, M.D., chief medical officer at Innate Pharma in Marseille, France. But many countries did not previously require academics to do the same paperwork.
The new E.U. directive also applies other regulations to academics that were previously applied only to industry. They must, for example, ensure that any drug given to a patient meets industry-grade manufacturing standards, and only certified people can import drugs between countries.
"This is a big change for academics institutions," said Squiban. "Everything you have to implement to comply is, of course, more difficult in an academic institution. There will be a diminution of studies as a consequence of the directive."
Hemminki, for example, has felt the directive's squeeze first hand. He and his colleagues are involved in several international cancer clinical trials, including one of the angiogenesis inhibitor bevacizumab, and have found themselves buried in paperwork. To ensure patient safety, the directive requires each trial investigator report each side effect and its possible cause to all other investigators working on the same molecule, as well as their own ethics committee.
But the directive doesn't distinguish among adverse events caused by the disease, chemotherapy, or the investigational drug; researchers must report each event. In Hemminki's case, the lead investigator received 219 faxes—each two to 36 pages long—reporting adverse events. Many patients in the trial had advanced disease and were seriously ill, Hemminki said, so the illness itself made up the bulk of side-effect reports rather than telling researchers something about the drug.
Moreover, the adverse-event reports for the trial were discussed in 14 different sessions of an ethics committee in Finland. The back-and-forth questions, paperwork, expenses, and time involved are all just too much for an academic with limited funds to handle, Hemminki said.
Finnish researchers aren't the only academics feeling the pinch. "The financial and administrative burden is eroding recruitment to pediatric cancer trials," said Christopher Mitchell, M.D., Ph.D., a consultant pediatric oncologist at John Radcliffe Hospital in Oxford, England. Mitchell went through his own hair-tearing experience with the new directive.
Mitchell and his colleagues initiated a phase III clinical trial of a drug—pegylated asparaginase—to treat pediatric acute lymphocytic leukemia. The drug wasn't approved to treat children, although it is standard therapy for adult acute lymphocytic leukemia. As mandated by the directive, Mitchell applied to the Medicines and Healthcare products Regulatory Agency—the agency in the United Kingdom responsible for approving clinical trials—for IMPD authorization. The agency approved the trial but excluded females of childbearing age. That meant that teenage girls—a substantial part of the population that the drug was intended to treat—could not be included, Mitchell said.
"This despite the fact that the drug is not known to cause birth defects and that we have used the parent compound, nonpegylated asparaginase, for years," he said. The restriction took a great deal of paperwork to correct.
Prior to the directive, academic-sponsored clinical trials in the United Kingdom required approval only from ethics review boards. The Medicines and Healthcare products Regulatory Agency was not involved in clinical trial authorization. Some researchers speculate that the agency is inadequately prepared to manage the extra duty of approving clinical trials.
Still others are finding it difficult to finance the increased workload. Max Watson, M.D., a consultant oncologist at Belfast City Hospital, shut down a trial to investigate melatonin's role in helping cancer patients sustain weight. The documentation required to file for an IMPD was too expensive to produce, Watson lamented. And he was not able to lure financial support from the pharmaceutical industry, presumably because there is no money to be earned from melatonin, he said.
Cancer Hit Hardest
Of course, any new legislation creates more bureaucracy to police it. But the academic grousing in this case is backed by statistics.
Last year, The European Organization for Research and Treatment of Cancer (EORTC), the largest independent cancer research network in Europe, reported that the number of new cancer trials fell from 19 in 2004 to seven in 2005—a 63% drop. At the same time, trial costs increased 85%, and insurance costs more than doubled.
In Finland, the numbers show the same trend. One ethics committee in Helsinki reported a 42% overall decrease in approved oncology drug trials, from 120 in 2002 to 70 in 2005, and a 75% drop in academic sponsored oncology trials since 2002, from 20 to 5.
Academic-sponsored research is especially important in oncology, said Francois Meunier, Ph.D., director general of EORTC, because therapies often consist of multiple treatment arms. Academics typically study combinations of drugs, surgery, and radiotherapy. Such studies don't aim to register and market a new drug but rather seek to improve overall treatment.
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"No drug company is going to sponsor a surgical clinical trial," said Meunier.
Indeed, clinicians deserve much of the credit for developing sentinel node biopsy and breast-conserving surgery, two important adjuncts to breast cancer detection and treatment.
If cancer has been hit hard by the new rules, European researchers are particularly vulnerable. Although there is enough funding for basic research, money for clinical trial research is lacking. That reflects cultural attitudes, said Meunier. "In Europe there is still this misperception that clinical research should be done by the pharmaceutical industry. Government agencies generally don't fund clinical trial research."
The E.U. directive's additional requirements further tax academics' already minuscule budgets.
"Cancer patients should be worried," said Hemminki. "If clinical and translational research is thwarted, the newest or most effective therapies may not become available."
Fixing The Problem
Aware of the problems academics are having, the European Commission (EC) has assembled a committee to monitor how member states implement the clinical trials directive, since inconsistency among countries has been one of the biggest problems. Although the directive instructs countries to implement specific changes, it allows for individual interpretation to respect each country's sovereignty. But that freedom has come at a cost: It has undermined the directive's goal of unifying the application process.
Germany, for example, has not established a national ethics review committee. Neither has Italy. Both countries continue to have regional ethics boards. Researchers must apply to each local jurisdiction where a proposed trial will take place, so the paperwork load remains the same. Ethics review committees may ask for different types of documentation and data. And although some countries have included special provisions to streamline academic sponsored trials, others have not.
The different rules have also affected industry. Most clinical trials are multinational to recruit enough patients. "Unfortunately you still have specific requests for more information depending on the country [when filing an IMPD]," Squiban said. It would have been better if the European Union had created a central agency like the European Agency for the Evaluation of Medical Products, which approves drug marketing for the entire European Union, he suggested, because the process of applying to each country is cumbersome.
Although creating a centralized agency isn't likely to happen soon, the EC committee is presently investigating these country-to-country differences in implementing the directive, said the EC's Birka Lehmann, Ph.D. Indeed, several academics including Meunier have been filing their complaints with the EC in hopes that it will come up with a solution to what some academics view as a crisis. By the end of this year, the EC will evaluate the situation and decide on possible further action, Lehmann said.
And despite scientists' frustration, the directive does have positive aspects. "It brings pan-European legislation that in the long term will not only improve patient safety," Squiban said, "but also improve the quality of our data."
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