Helping Trials to Help European Health Care

Sometime this autumn the European Union will announce details of the €600 million ($900 million) funding it is going to put into health care research in 2009, under the grandly titled program, "Optimizing the Delivery of Health Care to European Citizens." Much of the money will be available for assisting clinical trials—on condition that the candidates for funding match the very precise specifications that the EU sets out.

Based on the almost-final text of the program, it is possible to give interested readers the chance to get ahead of the field in preparing their applications, because many of the areas designated for support involve clinical trials. The inclusion of clinical research is expected in many of the broad themes the EU has chosen for the program. One of these themes, translating research for human health, aims at increasing knowledge of biological processes and mechanisms involved in normal health and in specific disease situations so as to transpose it into clinical applications including disease control and treatment, and to ensure that clinical data (including epidemiological) guide further research.

Peter O'Donnell

A main focus

The EU's broad-ranging overall objectives include, it says, improving the health of European citizens, boosting the competitiveness and innovative capacity of European health-related industries and businesses, and addressing global health issues, including emerging epidemics. The emphasis of the program is on the translation of basic discoveries into clinical applications and the development and validation of new therapies, and "clinical research will continue to be a main focus."

For clinical trials, the EU contribution will be limited mainly to Phases I and II, with further studies covered only exceptionally—such as in adapting off-patent medicines to the specific needs of pediatric populations, where consideration may be given to studies including up to Phase IV clinical trials. And, says the introduction to the program, all projects conducting clinical research must take account in their research protocols, methodologies, and analysis of results of possible differences between women, men, children, and the elderly.

Large-scale funding will be made available for many projects. One concerns optimization of current therapeutic approaches to schizophrenia. "The project should focus on the pathophysiology and treatment of schizophrenia, and has to include a preclinical (e.g., neurophysiology, pharmacology, functional imaging) and clinical component (clinical trials). A strong translational approach with a view of developing new or optimizing existing therapeutic tools is essential," says the EU.

Another, in translational vaccine research for poverty-related diseases—notably HIV/AIDS, malaria, and TB—will support early human testing of promising vaccine candidates. "The vaccine candidates must already have been selected through vigorous preclinical testing and must have demonstrated efficacy in recognized animal models. Projects will support Phases I and IIa clinical trial activities with a view to preparing the most successful candidates for later development."

Explicitly, activities related to the preparation of human clinical trials, including GMP production, formal preclinical toxicology, and protocol writing may be included in the projects. A related project will focus on the clinical development of promising anti-HIV microbicides, including studies on new and improved tools for in vitro research and for testing toxicity and efficacy in preclinical as well as in human studies.

Heart failure

"Academic, investigator-driven multicenter Phase III clinical studies to provide new evidence—not yet addressed by ongoing and/or previous trials—for new strategic decisions in the management of heart failure," will be rewarded with support too. To qualify, projects must address validation of new therapies or strategies, or address identification of the most effective ones among those already available but not well exploited. The study population should address gender balance and may include subjects with different degrees of functional impairment.

Another grant is available in the same therapeutic area for elucidating the genetic and environmental components that contribute to cardiac arrhythmias, the relative importance of each of these factors, and interactions between them. "Achieving this aim should be ensured by a multidisciplinary approach bringing together basic research studies with clinical investigation, and the involvement of industry."

Research into potentially new and reemerging epidemics is to be backed as well. The focus will be on confronting emerging pathogens with pandemic potential, including zoonoses (such as SARS and highly pathogenic influenza). Funding is available for the full value chain of health research: from innovative basic research to early stage clinical trials of new prevention, diagnostic, and therapeutic measures and all the way through to the implementation research supporting effective public health responses.

Identification and development of vaccine candidates for neglected bacterial infections is another area scheduled for support. Projects should give priority to pathogens causing trachoma, leprosy, and/or Buruli ulcer. Essential preclinical testing in vitro and in vivo should be an intrinsic part of the project, and bringing existing lead candidates to Phase I clinical trials is also covered by the funding.

Best clinical practice

Another broad theme, translating the results of clinical research outcome into clinical practice, will aim to identify the best clinical practice in order to understand decision making in clinical settings in primary and specialized care and to foster applications of evidence-based medicine and subject empowerment. The focus will be on the scientific benchmarking of strategies; investigating outcomes of different interventions; some aspects of pharmacovigilance evidence; specificities of the subject (such as genetic susceptibility, age, gender, and adherence); and cost benefits. Overall, this should advance the application of evidence-based medicine in Europe, says the introduction to the work program. "The improved use of clinical research findings in clinical diagnosis and treatment as well as subject self-management of disease should be demonstrated and the cooperation between researchers in Europe and other geographic regions enhanced to promote integration and excellence of European research in the area."

Within the theme of innovative therapeutic approaches and interventions, the focus for 2009 funding is regenerative medicine—enhanced by the recent adoption of the EU regulation on advanced therapy medicines. Three major collaborative project topics are envisaged, all aimed at translating promising therapeutic approaches from the preclinical to the clinical stage. Projects will be expected to include in-patient trials at some stage of their duration, paving the way toward therapeutic products. Proposals containing appropriate preliminary data will be able to proceed to in-patient trials earlier in the project. The essential feature of each project will be the identification of a potential therapy to move into the clinic, and surrounding this with necessary ancillary research.

In cell therapy for tissue and organs, proposals are invited on transplantation of cells for reconstruction and regeneration of diseased or injured tissue in systems that have potential for appropriate in-patient trials during the course of the project. Proposals with sufficient preliminary data to proceed to in-patient trials at an early stage of the project are preferred. Proposals involving in-patient trials at a later stage of the project will also be considered, provided they include a road map to the clinic containing predetermined milestones. To complement in-patient trials, supporting research—such as improving understanding of mechanisms, immunogenicity, methodology to demonstrate whether the treatments are having a direct effect, or testing refinements to the system—should be carried out.

From pipe dreams to pipelines

On a more prosaic note than these heady heights of new research, some useful advice has just appeared on the processing of products already in the EU authorization pipeline. The European Medicines Agency has issued a guide clearly setting out the time allowed for applicants to respond to questions and issues raised during the assessment of new marketing authorization applications in the centralized procedure. This has been a vexed question for years because of the intrinsic complexities of the procedure, and many executives responsible for development and registration will welcome a clear statement of the rules.

As is well-known, the legislation sets out a timetable of 210 days for the evaluation of centralized marketing authorization applications, from submission to opinion. But as is equally well known, confusion sometimes arises over how long applicants may take to respond to questions or issues raised during the assessment. The agency says it is aiming to give applicants enough time to respond, including to requests for additional data or for results from additional studies.

At the same time, it wants to avoid premature applications—which are then supplemented during the review period with substantial new data that should have been presented with the initial application. The note contains a firm reminder that, in general, no substantial data derived from new studies should be introduced as part of the responses to questions, unless specifically requested by the agency. What may be included quite legitimately is new analysis such as follow-up data from previously submitted studies.

What the agency is recommending is that before an application is submitted, the applicant should seek a presubmission meeting with agency experts, including a discussion of related ongoing studies—covering safety, when those studies will be available, and whether they are critical to the assessment. This will give the agency a sense of whether the application is premature or if it might benefit from the inclusion of data from ongoing studies prior to the application being submitted—although "it is of course recognized that it is up to the applicant to decide when to file and whether to accept the advice."

The procedure, as the agency sees it, should be as follows. The agency's committee on human medicines (the CHMP) produces a list of questions at day 120. The agency and its designated experts for the application—the rapporteur and corapporteur—should immediately meet the applicant to clarify the intent behind the questions and explain the concerns. Applicants need to be given sufficient time to respond, and the agency is suggesting a limit of three months, extensible by agreement for up to another three months. The clock then restarts on day 121. At day 180, the CHMP produces a joint assessment report with a list of outstanding issues to be addressed by the applicant.

There is a need for a more streamlined process from day 180 to the opinion being adopted, believes the agency. So the written response to this list should normally be delivered within one month and should contain only very limited new data derived from new studies. In exceptional circumstances, a one month extension in submission of the written responses may be granted if sufficient scientific justifications is presented. Applicants should also be ready to provide an oral explanation at this stage.

After that, it should be straight downhill to marketing authorization—but that is perhaps still in the realm of pipe dreams.

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.