EU Rolls Out New Medicines Initiative

By the time you read this, the European Union will have announced the formal start of its so-called Innovative Medicines Initiative—and the clinical trials support programs that go with it.

Peter O'Donnell

The initiative, backed by the European Union—with an initial grant of €122 million ($200 million)—and the European pharmaceutical industry, claims to support more efficient discovery and development of better medicines by removing research bottlenecks in the current drug development process. No new medicines will be developed as such. The focus will be on the delivery of new approaches and technologies and improved knowledge management of research results and data.

Under the broad title of improving the predictivity of efficacy evaluation, it is going to address improved understanding of disease mechanisms, predictive pharmacology, the identification and validation of biomarkers, patient recruitment, and benefit-risk assessment.

One of the projects to be supported in the first phase deals with the qualification of translational safety biomarkers. The rationale is that a lack of specific and sensitive mechanistic safety markers and their respective assays for human samples is regularly delaying drug development programs. In addition, the predictivity between nonclinical and early clinical studies of currently accepted markers is very poor, says the project outline.

As the initiative points out—and here, the voice of industry can be heard clearly—there is still no clear process on how to qualify new safety biomarkers for clinical regulatory decision making. Since no official process exists yet, cooperation is vital in the definition of a generic process and in testing several options before one could be accepted by all parties.

The project will focus on three target organs as examples of critical drug-induced pathologies (liver, kidney, and vascular). Based on previous discoveries and other preclinical qualification exercises, a subset of markers will be identified and their assays developed for human use if they are not yet available. The selection of the markers will be based on their potential or probable success of becoming a useful translational tool. This five-year project is promised assistance in personnel, equipment, and material worth €21 million from European pharmaceutical companies.

Another five-year project with industry backing worth €20 million will look at surrogate markers for vascular endpoints. It aims to find validated and scientifically justified biomarkers or surrogate endpoints for micro- and macrovascular hard endpoints in diabetes clinical research. Its starting point is that patients with type 1 or type 2 diabetes eventually tend to develop micro- and macrovascular compli-cations—retinopathy, nephropathy, neuropathy or atherosclerosis, with the associated risks of myocardial infarction or stroke. "The factors that contribute to these complications are not well understood," says the project outline. "There is a need to develop ways to reduce the size and timelines for evaluating therapeutic efficacy on the establishment/progression of micro and/or macrovascular complications."

It adds that the project will also attempt to respond to the lack of animal models that can predict the development of diabetic micro- or macrovascular disease, which remains a major issue in the development of novel therapies. The project will therefore also aim to develop and validate new in vitro or in silico tools to test novel therapies.

Neurodegenerative disorders are targeted in another five-year project with €7.5 million industry backing. Because of the notorious length and cost of clinical outcome studies in this field, the project will aim to accelerate the successful development of molecules. To do this, it says, it is essential to improve the predictive value of animal models, identify pharmaco-dynamic markers of drug response, and develop pharmacodynamic models that allow early prediction of efficacy and markers to aid in the stratification of the patient population. The project requires the integration of preclinical and clinical science to ensure translation of efficacy from bench to bedside and vice versa.

The project focuses on the development of translatable animal and human volunteer models predictive of clinical efficacy in patients in the areas of Alzheimer's disease, Parkinson's disease, and multiple sclerosis. One long-term objective will be to exploit similarities in these diseases to develop models that support clinical development across all three diseases.

Discovery, research, and development of new treatments for severe asthma is the subject of another project. In particular, the project says, there is a need for effective use and further development of diagnostic criteria for mechanistic and therapeutic trials. Without better understanding of disease etiology and pathogenesis, relevant preclinical and clinical models cannot be developed to enable translational research strategies.

The project aims to build an EU consortium focused on understanding severe asthma. This will set up a large, longitudinal patient cohort that will enable research to validate novel biomarkers and clinical measures and will serve as a vehicle for developing translational models. Industry support of €12.5 million is to be made available over five years.

Moans and groans

Meanwhile, industry rumblings continue over the deficiencies of the European Union's clinical trials directive. The European biotechnology industry association, EuropaBio, is continuing to demand a review of the much-maligned measure so that it actually improves harmonization of procedures to approve the conduct of clinical trials in Europe—thus making industry's life easier. So far, seven years after the directive's emergence and six months since the EU authorities agreed to listen to complaints about it, the procedures remain divergent across the 30 European countries that are supposed to have signed up to simplification.

Top of the list of EuropaBio's specific complaints is the lack of harmonization for applications for clinical trial authorizations, because national requirements on dossiers still vary from country to country. This leads to increased bureaucracy and to constant uncertainty, particularly when a trial is being conducted in two or more countries. Other persistent EuropaBio complaints include different interpretations of the definition of investigational medicinal products, varying requirements for safety reporting, and some countries' approach to good management practices.

"As a result, Europe is now regarded as a less attractive location to undertake clinical development. Indeed, some member companies have already decided not to conduct their clinical studies in the EU. If the current situation is not addressed and improved, it will be particularly damaging to the continued viability of the bioscience sector in the EU," says EuropaBio. The impact on smaller firms is significant since they lack resources to cope with the administrative burdens and consequent delays.

Quite distinct from the plans for the innovative medicines initiative, a different form of the EU-backed project is already underway that might serve to ease the objections in the clinical trials community to the directive. Under the EU's framework program for support of research of all kinds, a one-year project is aiming to measure and analyze the direct and indirect impact of the directive and related legislation in the EU. Its target is wide-ranging: the impact on all categories of clinical research and on all parties involved—commercial and noncommercial sponsors, ethics committees, and competent authorities. The project is being coordinated by the European Forum for Good Clinical Practice, and involves the European clinical research network (ECRIN), the European cancer research organization (EORTC), the Hospital Clinic of Barcelona, and the ethics committee of the Medical University of Vienna.

"This initiative fits with the need to adapt the current legislation and will help determine the most relevant pathways for improvement," says the project outline. It cites that although the directive's objective was harmonization of the EU regulatory environment for clinical research and improving the protection of participants, "this legislation only protects participants in clinical trials on medicinal products."

In addition, continues the project outline, the directive is indiscriminate in its effects. "It requires almost similar procedures for all types of clinical trials with medicinal products, from registration studies on innovative treatments to studies comparing treatment strategies using marketed drugs or applying minimally invasive procedures." As a result, it concludes "academic institutions and the industry, including smaller firms, face major difficulties in fulfilling their sponsor's responsibilities." It shares EuropaBio's view that the directive's transposition into divergent national legislation missed the harmonization goal and makes multinational trials difficult to perform.

Against this background, it is instructive to read the section dealing with implementation of the clinical trials directive in the just-published 2008 workplan for the European Medicines Agency. The agency says its objectives and main initiatives in this area are to support the implementation of the directive (and the linked good clinical practice directive that appeared in 2005), and the next phase of incorporating aspects of the new pediatric regulation into Europe's EudraCT database of clinical trials.

As theatre critics say about a show for which they predict a long life, "This one will run and run."

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