EMEA and FDA Team Up on GCP

By the time you read this, transatlantic cooperation on Good Clinical Practice will have passed a new milestone. As from September 1, 2009, the European Medicines Agency (EMEA) and the US Food and Drug Administration (FDA) will have launched their joint initiative to collaborate on international Good Clinical Practice (GCP) inspection activities. The two sides will share information on inspection planning, policy and outcomes, and on the conduct of collaborative inspections.

Peter O'Donnell

The justification for this innovation is that it will help protect clinical trial subjects in the face of increasingly globalized clinical research. As the EMEA says, in defense of the scheme, "in most cases" the same clinical trials are used to support marketing authorization applications in the European Union and new drug applications and biologics license applications in the United States.

The scheme has become possible because of confidentiality arrangements that have been established recently between the EU and the FDA. It will look at GCP-related information contained in applications for scientific advice, orphan medicines designation, pediatric investigational plans, and marketing authorization or postauthorization activities of significant public health interest.

Thomas Lönngren, the EMEA's executive director, speaks warmly of "the increasing collaboration" between his agency and the FDA. He sees this latest move as "an important step to the building of a global regulatory network for supervision of clinical trials."

In any case, limited inspection resources mean that "only a sample of sites and clinical studies can be inspected." So on a more empirical and local level, the cooperation should certainly save some time and energy, or, as Lönngren puts it: "By working together in a collaborative and synergistic manner, GCP inspection resources can be used more efficiently." Notably, the exchanges should make the selection of studies and sites "well informed."

The initiative has been started with an 18-month pilot phase, which will focus only on products regulated by the Center for Drug Evaluation and Research in the United States and by the EMEA for the centralized procedure. But over time what is envisaged is the periodic exchange of GCP-related information, collaborative inspections, and systematic mutual alerts on GCP-related legislation, regulatory guidance, and related documents.

The results expected by the authorities will be streamlined inspection planning, faster and more effective communication of inspection outcomes, alignment of inspection procedures, and, over time, a closer sharing of interpretation of GCP, allowing the two sides to "act together to benefit the clinical research process." The cooperation is, says the EMEA, designed to build mutual understanding of, and confidence in, the GCP inspection processes. Trial sponsors can help too, says the EMEA, by informing regulators in the United States and EU of a joint filing, which can be coordinated in both regions.

Anyone conducting a clinical trial who is curious to know more about how this is going to work can get real close to the action. The EMEA and FDA are inviting volunteers to participate in a collaborative inspection during the pilot phase. The opportunity is there to sign up "to engage in dialogue and planning of joint inspections involving applications that are anticipated to be submitted fairly simultaneously to both agencies within the next 12 months."

Information on spending

Getting improved information flows is also identified as a priority in the just released 2009 compendium of health data from the Organisation for Economic Cooperation and Development (OECD).

"The demand for health-related data is high," it remarks—adding that "one of the main obstacles limiting meaningful analysis of health care systems has always been, and still is, the lack of sufficient coverage and availability of health care statistics." As if to prove its point, the OECD offers a striking paucity of information on the pharmaceutical aspects of health care across its 40-plus member states. While noting a generalized increase in pharmaceutical spending to 17.1% on average in 2007, the latest year for which it provides data, its own summary provides figures on only a handful of the 27 EU countries.

In the Czech Republic, where pharmaceuticals accounted for 21.5% of total health spending, the increase is, says OECD, "one of the factors behind the rise in total health spending." A "strong rise" in pharmaceutical spending, to 31.2%, has had a similar effect in Hungary, which holds the dubious distinction of ranking first among OECD countries for spending on pharmaceuticals as a proportion of total health expenditure.

Pharmaceuticals accounted for 24.5% of total health spending in Poland, ranking it fourth among European countries for this proportion of spending on pharmaceuticals—coming also behind the Slovak Republic's 27.9% and Greece. In Portugal, the figure was 21.8% and in Spain 21%.

"The need for internationally comparable data is on the rise as national administrations seek to evaluate their health care systems against those of other countries," OECD remarks—with justice, given the increasing trend toward health technology assessment as a mechanism for limiting the access of new medicines to the market. But OECD admits that at present its statistical tool is still "in the process of development," and "its accuracy and the consistency of series...are to be refined."

There are few generalizations about pharmaceutical spending in Europe that can be drawn from the OECD data as they stand. One tentative inference—confirming the findings of other analyses—is that the north/south split in the EU not only persists, but that the high proportional spending on pharmaceuticals in the "Club Med" countries of southern Europe is largely mirrored in the EU's new member states from central and eastern Europe. Meanwhile, the more puritanical north is keeping spending on pharmaceuticals as a percentage of total health expenditure.

In Germany, pharmaceuticals accounted for 15.1%, while in Austria and Sweden the figure was only just above 13%, and in Denmark just 8.6%. Even here, however, the share of total health spending allocated to pharmaceuticals has nonetheless increased over the past decade.

Getting it right with lipids

The EU has decided it is time to update its current recommendations for the clinical development of lipid-lowering and blood pressure-lowering agents. At present, the EU accepts the possibility of drug registration for so-called biological indications, permitting demonstrations of efficacy through their effect on biological markers (LDL-cholesterol and blood pressure respectively). Now it wants to bring more clarity to this policy, to explicitly state where these principles would not be applicable, and where further data on the effect of these medicinal products on morbidity and mortality would be required before a marketing authorization is issued.

As a note from the EMEA remarked at the end of July, use of surrogate markers as proof of efficacy for drug approval has been a matter of debate. While use and validation of biomarkers in drug development is encouraged—they "may play a critical role in the early prediction of the effect of a drug in terms of both safety and efficacy," says EMEA—for drug approvals, complete information for a sound benefit-risk assessment may not be provided by the proof of efficacy of a surrogate.

So it is no longer content merely to ensure that product information highlights the limitation of the data on which an authorization has been granted, and that no suspicion on a detrimental effect on morbidity and mortality is found. These recommendations should be further detailed, it says, in order to allow applicants to anticipate in which situations outcome studies might be required before a marketing authorization is issued.

The plan is to revise guidance by specifying the type and level of detail of the clinical and nonclinical information expected for a proper evaluation of the safety profile of a new medicine, in relation to key organs and systems (notably cardiovascular, renal, and hepatic safety). Discussion will also cover how far the quantity and quality of information should reflect the mechanism of action of the medicine (such as whether there is known class toxicity, or if it is a new class of drugs).

What should emerge from all of this, by early next year, is a safety evaluation algorithm that will help establish the need for outcome studies and whether they will be required pre- or postauthorization. It should "provide guidance to industry when performing trials to develop lipid-lowering and antihypertensive drugs, and also provide a clear basis for the EU authorities when assessing data and providing advice on these types of drugs."

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