EU Regulation: Help From a Guiding Hand

Advances in technology drive advances in regulation—but often not fast enough for the fastest movers. The consequence, in the field of clinical trials, is that sponsors with innovative approaches are sometimes obliged to operate without clarity or certainty about what rules apply.

Peter O'Donnell

As a matter of routine, the European Union therefore tries to help out with updates wherever it can. It has just, for instance, provided guidance on what the 2001 clinical trials rules mean for studies that involve a medical device.

Its answer makes a distinction according to the role of the device. If it can be regarded as a single integral product, combining a device and a medicine product, and the study concerns the medicine, then the 2001 rules apply. At its simplest, the guidance indicates this would be the case of a prefilled syringe, which would be regarded as an integral delivery product. Similarly, combined advanced therapy medicinal products as defined under the EU's 2007 rules would also be covered. In addition, an interventional study would be a clinical trial, and would thus fall under the 2001 regulatory framework. But if the object of the study is the device, then the clinical trials rules do not apply.

If the object of the study is a medicinal product and medical devices are used during the trial (as is frequently the case, sometimes with the medical devices supplied directly by the sponsor), the clinical trials rules apply to the medicine, and the medical devices have to comply with the EU rules for placing on the market and putting into service of medical devices.

If the study is comparing a medicine against a device for the same indication (for example, a comparison of a warming medicinal product applied topically with a warming medical device applied on the skin), the 2001 rules apply to the part of the study assessing the medicine, but not to the device.

Update

The guidance comes in the latest update, published on March 18, to a document that perhaps deserves wider attention than it receives: the European Commission's "Questions and Answers," which is part of Eudralex, the EU's compendium of legislation on pharmaceuticals. The Q&A guidance is an annex to Volume 10 of Eudralex—the chapter dealing with clinical trials.

This latest version of the Q&A is the eighth to date. The content is regularly discussed within the commission's ad hoc group for the development of implementing guidelines for the 2001 rules, which is chaired by the commission and includes representatives of all EU member states. It makes clear, in a standard disclaimer for all EU guidance, that "the views expressed in this questions and answers document are not legally binding. Ultimately, only the European Court of Justice can give an authoritative interpretation of community law." But it provides some helpful indications of some of the basics and some of the complications in the everyday decisions about trial design and execution.

The questions range from the broad (e.g., "What is a 'clinical trial?'" or "How is 'sponsor' defined?"), to the highly specific (e.g., "A study might involve the administration of a medicinal product, while the object of the investigation is not the administered medicinal product, but exclusively the physiology of the body. Are these studies 'clinical trials?'" or "Can the dates of the annual safety reports be aligned with other periodic reporting requirements?"). They also extend to the procedural (e.g., "After the receipt of the opinion of the Ethics Committee, is the applicant allowed to appeal against the opinion?" or "If a site does not start the trial, but was listed on the application form when the trial got authorization, what should the sponsor do?").

Women and clinical trials

March was remarkable not only for the update to the guidance on EU rules for clinical trials. It was also the month that marked the 100th anniversary of International Women's Day, and the European and Developing Countries Clinical Trials Partnership (EDCTP) celebrated this anniversary by honoring the contribution of women, in all capacities, in the fight against HIV/AIDS, tuberculosis, and malaria.

This worthy partnership, on which this column has commented in the past, aims to accelerate the development of new or improved drugs, vaccines, and microbicides against HIV/AIDS, malaria, and tuberculosis. It was created in 2003 as a European response to the global health crisis caused by these three main poverty-related diseases, and now brings between 14 European Union member states plus Norway and Switzerland together with 47 sub-Saharan African countries.

Many projects funded by EDCTP are of immediate relevance to the struggle for equal opportunities for women and to the improvement of the health of women and children. Women play crucial roles in all EDCTP activities as policy makers, scientific project managers, research scientists, healthcare professionals, field workers, patients, and healthy volunteers.

This year's observance of International Women's Day focused on equal access to education, training, and science and technology, and EDCTP highlighted some of the scientific and medical work of women in the projects it funds. In total, 43 out of 160 EDCTP-funded projects are led by female scientists as project coordinators: this total comprises 15 integrated clinical trial projects, seven career development and senior fellowship projects, five directly funded PhD and MSc training awards, nine projects to establish or enhance the capacity to conduct medical research in conformity to professional ethical standards, one project furthering collaboration in regional networks of excellence, and six networking grants. EDCTP says that gender balance is one of the concerns in evaluating applications for the funding of projects, and projects often provide for extensive professional training for women healthcare workers.

EDCTP studies

One of the EDCTP studies—Kesho Bora, which means "a better future" in Swahili—offers new hope for preventing HIV infection and death among infants in low-resource settings where many mothers with the virus breastfeed. From June 2005 to August 2008, 882 women were enrolled, 824 of whom gave birth to 805 live born infants. The results show that providing a combination of a triple antiretroviral combination to pregnant and breastfeeding mothers is a safe and effective way to reduce HIV transmission to infants. The findings have influenced the revised World Health Organization guidelines on prevention of mother-to-child transmission of HIV and infant feeding.

Another project, led by Professor Clara Menéndez, aims at developing new clinical interventions to fight malaria by the evaluation of different antimalarial drug alternatives as intermittent preventive treatment in pregnancy in the context of insecticide treated nets. It will compare the safety and efficacy of the currently recommended drug with those of mefloquine. The study includes HIV-infected pregnant women to provide a better understanding of the interactions between antimalarial and HIV treatments. Another EDCTP project aims to optimize the existing dose and regimen of intermittent preventive treatment in pregnant women with sulfadoxine-pyrimethamine.

And an EDCTP-funded project lead by Kishor Mandaliya, MD, is sampling a variety of study populations in four African settings in a bid to refine both clinical and laboratory methods and findings in search of more reliable safety biomarkers for the development of microbiocides for intra-vaginal application to prevent infection with HIV and possibly other sexually transmitted infections. Recent research with anti-retroviral based microbiocides has shown promise in offering women protection against HIV, but, as EDCTP points out, there is still a need to increase knowledge on reliable biomarkers during Phase I and II trials.

EU medicines research funding

Also in March, and closer to home, the European Union announced that eight new research projects worth ᣞ172 million would be launched over the coming weeks under the so-called Innovative Medicines Initiative. The focus will be on cancer, rheumatoid arthritis, infectious disorders, and e-health.

One of the projects, known as BTCure, will focus on development of curative treatments for early intervention against rheumatoid arthritis. The aim is to develop an understanding of the early process in arthritis subsets that will allow precise and eventually curative treatments to be used before irreversible destruction and loss of joint function and mobility have occurred in patients. Another, known as PREDECT, is developing new models for novel treatments of breast, prostate, and lung cancer. It says it will permit the emergence of faithful models for target validation and beyond, as a response to the poor predictability of drug efficacy in traditional preclinical discovery methods, particularly for target validation. It will focus on complex but transferable next generation in vitro and in vivo models for breast, prostate, and lung cancers.

Innovative Medicines Initiative (IMI) claims that the first wave of its projects, now up and running for around a year, are already providing tangible benefits, ranging from the biggest database ever compiled on schizophrenia to an international consensus statement on the classification of patients with severe asthma and international agreement on the strategy to be followed to qualify biomarkers for drug safety in clinical trials. Further upcoming IMI projects, likely to be launched in 2012, will cover the development of treatments for autism, tuberculosis, and diabetes, and the safety of drugs and vaccines.

Altogether—in terms of medicines, at least—not a bad month.

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