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Jun 13, 2012

EC Eyes Summer Overhaul for Clinical Trial Rules to Improve Drug Development

Commission is moving from a directive to a regulation so guidelines will be implemented into law immediately across members.

EC Eyes Summer Overhaul for Clinical Trial Rules to Improve Drug Development

Suggestions to improve clinical trial policies in the EU include offering a single-submission option, allowing for multiple sponsors, and removing insurance requirements for low-risk trials. [© senoldo - Fotolia.com]

  • The EC envisioned creating a single harmonized framework for clinical drug research across the continent when it created the Clinical Trials Directive (CTD) nearly a decade ago. But CTD, which took effect in 2004, has instead worsened many of the problems it was designed to address.

    By 2010, most biopharma companies, medical groups, and even many European politicos agreed that the time had come to revise CTD, an effort more than a year under way. Progress toward that goal is expected to occur by this summer, when the EC submits a draft revised CTD to the European Parliament for review.

    Perhaps the most significant change for CTD will be its legal form. The EC’s Health and Consumers Directorate-General, also known by its French acronym DG Sanco, has disclosed that the revised CTD will not be a directive, which would have allowed individualized country-by-country implementation across Europe. Instead, the revised clinical trial standards will be a regulation, which doesn’t have to be implemented into national law yet enjoys the force of law immediately for all EU countries.

    That should resolve one of the three main criticisms about CTD; i.e., that different countries have implemented the directive differently. The current CTD doesn’t allow simultaneous submission of clinical trial applications to all member states involved nor enables member states to work together to assess or follow up on such requests, two provisions that have inflated administrative costs. In addition to lack of harmonization among EU members, the Directive has been faulted for being extremely bureaucratic to navigate.

    To be fair, Europe was set to lose some clinical activity over the past decade as biopharma grew in China and the rest of Asia, aided by much lower labor costs and less red tape. But CTD has cost the continent additional clinical trial activity beyond what has been lost to Asia.

    “Other countries outside Europe are increasing their activity in the field of clinical trials because they are less bureaucratic,” Kirsten Steinhausen, M.D., science officer in the biomedical sciences unit of European Science Foundation (ESF), pointed out to GEN. “This makes it dangerous for Europe if they don’t adapt their regulations.”

  • Suggestions Made

    ESF and its European Medical Research Councils (EMRC) have offered their own prescriptions for changing CTD. In 2009, EMRC concluded that investigator-driven clinical trials needed streamlining of authorization procedures as well as improved training, more funding, appropriate numbers of patients, and adoption of a risk-based approach.

    Streamlining, EMRC said, entailed actions ranging from identical documentation and a single database across Europe to a one-stop-shop for multination trials and allowance for multiple sponsors. Few agencies or organizations want the liability and other burdens associated with trials of investigational medical products.

    In a position paper released this January, ESF and EMRC spelled out some national-level challenges of conducting clinical trials in Europe. They cited differences in authorization procedures, insurance requirements, compliance, interpretation of good clinical practices, reporting of adverse events, and definitions of sponsor responsibilities.

    While sponsors have both responsibility and liability for clinical trials in the U.S., the ESF-EMRC paper noted, CTD regulates only a sponsor’s responsibility, not its liability, in running trials. That leaves all participants in trials vulnerable to lawsuits if something goes wrong. That in turn raises legal costs.

    DG Sanco also issued some guidelines through a “concept paper” putting forth a single-submission option, sparing trial sponsors from resubmitting previously sent information. The directorate laid out three options for how to give member EU nations a say: separate assessments, likely to water down the harmonization sought by drug developers and medical groups; a single assessment, which the paper cautioned may give short shrift to national and local concerns; and a compromise requirement combining a single application with a coordinated assessment procedure, giving member states a chance, but not a requirement, to weigh in. One scenario envisions funneling national input through a “lead” member state.

    The concept paper also sought comment on proposed changes to CTD that include a multisponsor option giving each sponsor responsibility for a specific task within trials; removal of insurance/indemnification requirements for trials deemed to be low-risk to cut insurance costs; and creating an “auxiliary medicinal products” designation allowing for less onerous regulation of drugs beyond the subject of a clinical trial.

  • Impact of Current CTD

    DG Sanco acknowledged that CTD was a factor in the declining number of European clinical trials. The number of clinical trials performed in the EU fell nearly 17% between 2007 and 2010, sinking from 5,028 to 4,193. The number of clinical trial applications in the EU during most of the period slipped almost 13% from 9,948 in 2007 to 8,672 two years later (a 2010 figure was unavailable). Interestingly, clinical trial declines were evident across all four phases. Phase I trials skidded 8.4% from 1,510 in 2007 to 1,383 in 2010. Declines were 22% in Phase II, Phase III, and Phase IV, where the number went from 904 to 707.

    That decline is less evident when you look only at clinical trials involving only EU member states, which account for 25% of EU clinical trials. For example, the number of two-nation trials jumped from 229 in 2007 to 364 the next year, then dipped to 238 in 2009, which was still 4% above two years earlier. Trials involving most EU members saw increases, though totals were very small: the number of 19-nation trials, for example, jumped from one in ’07 to five the following two years.

    Declines in trials are evident in the U.K. In 2006, Cancer Research UK (CRUK) carried out a study into CTD’s impact on the costs and conduct of noncommercial U.K. cancer trials. The study concluded CTD had doubled the cost of running clinical trials in the U.K. and delayed the start of trials, Layla Theiner, CRUK’s European public affairs manager, told GEN.

    “The lack of central guidance, the lack of clarity over how to interpret the guidance notes, and the unnecessary increase in paperwork are all of major concern to our researchers,” Theiner added. “And the trial units were unable to open trials in non-U.K. centers because of the different interpretation of the CTD by member states.” Peter Johnson, CRUK’s chief clinician, offered a stark picture of CTD’s impact, telling the Daily Telegraph in February that the U.K.’s share of trials worldwide dropped from 6% to 2% since the directive was introduced.

    Johnson blamed CTD for drug companies pulling jobs out of Britain. Last year AstraZeneca closed a research campus near Loughborough while Pfizer began a two-year shutdown of its Sandwich R&D center. But that’s just as likely due to patent expirations of blockbusters; Eli Lilly launched a new neuroscience research site at its Erl Wood R&D campus in Surrey, while GlaxoSmithKline and University of Nottingham will establish a drug development sustainable chemistry lab in the country.

    Job fluctuations have many explanations, so they are harder to blame on CTD than reduced clinical trial activity. Participants in planned clinical trials within the EU fell by 26%, from 535,481 in 2007 to 396,784 in 2010. When multinational trials including at least one EU site are counted, the patient count fell 15% from about 1.02 million in 2007 to 866,155 in 2010.

    So CTD should be overhauled. But any proposals to do so should be accompanied by solid projections of how much the new rules will save in time and money, since industry and medical groups have identified both as being wasted by the status quo. The more substantial the savings, when balanced by safety and quality concerns, the better the odds of at least some clinical trial activity returning to the continent. However, there is no guarantee that an overhauled CTD will beat a path to Europe’s proverbial door, at least not as long as the biopharma industry continues to look to China and other emerging nations for future growth.


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