One Step Closer to the Fourth Hurdle

February 16 was Mardi Gras—that last great feast before the long period of privation imposed by the tradition that gave rise to the celebration. Mardi Gras 2010 may well be remembered in future years in Europe as the day that the "fourth hurdle" to drug registration came a significant step closer—the harbinger of a long period of potential privation for everyone developing new medicines.

Peter O'Donnell

While others across Europe were celebrating Mardi Gras with extravagant drinking and eating, and in fancy dress balls and carnival parades, more serious-minded people in London and Copenhagen were announcing a new joint attempt to check out whether new drugs merited authorization. They are to work together, they said, in improving the evaluation of whether new drugs are needed, rather than just on the three conventional and well-established criteria of the intrinsic quality, safety, and efficacy of the product.

The apparently anodyne announcement of a new collaboration from the European Medicines Agency and the European network for Health Technology Assessment (EUnetHTA) does not, of course, mention any "fourth hurdle." It merely states that the two organizations have held "the first of a series of workshops" in which they will be "considering how the European Public Assessment Report (EPAR) could make a better contribution to the assessment of relative effectiveness by health technology assessment bodies in the EU member states."

But for many people developing medicines, health technology assessment is no more than polite code for a fourth hurdle. In other words, no matter how hard you try to make your product safe, efficacious, and of quality, you may not quality for authorization—or for reimbursement status—if you have not also demonstrated that you are better than other products already on the market.

The challenges in this concept have been widely publicized by many drug developers—ranging from the impossibility of demonstrating the full scope of a product's value at the time of authorization, through to the impossibility of knowing precisely what will be on the market (and how good it is compared to your product) by the time you get to seeking authorization. As research departments and company finance offers have frequently lamented, there is a profound discouragement to innovation when every new product runs the risk of flat rejection by regulators at the last minute, because of some unforeseeable arrival of another, arguably superior, therapy just before you seek authorization.

As the European Federation of Pharmaceutical Industries and Associations has pointed out, getting medicines to market quicker is a question not only of speeding up regulatory approval and reimbursement processes for new medicines, it is also necessary to "ensure that health technology assessments do not become a 'fourth hurdle' to the market." The specter of arbitrary rejections of authorization and reimbursement applications on spurious grounds haunts the industry, which harbors suspicions that some member states just want to use it as a respectable smokescreen for cutting their drug bills.

This is why the announcement has sent a chill through many a Mardi Gras procession, and flattened the spirits at numerous pancake parties.

Response to a recommendation

As the two regulatory bodies put it, in cold clear terms suitable for February, "Relative effectiveness assessments are increasingly used in the European member states to help policy makers to identify the most valuable medicines." The new collaboration is the response, they explain, to a recommendation "to improve the availability and best use of data relevant to relative effectiveness assessment." That recommendation came, they add, from the Pharmaceutical Forum, which many remember as an unhappy amalgam of politicians, drug firms, doctors, patients, and insurance funds that labored away earnestly between 2005 and 2008 to square that old circle of keeping drug costs down while keeping industry revenues up. It drew its final strained breath back in 2008, but its vague and contradictory conclusions are still, evidently, informing pharmaceutical policy formation and implementation.

In concrete terms, EMA and EUnetHTA are going to be focusing, they say, on the European Public Assessment Reports (EPARs), which the agency publishes for every medicine authorized through the EU's centralized procedure. EPARs reflect the scientific conclusions reached by the agency's Committee for Medicinal Products for Human Use at the end of the evaluation process, although commercially confidential information is deleted from them.

Specifically, EMA and EUnetHTA will be "considering how the information on the assessment of the risks and the benefits of a medicine contained in the EPARs can best be used in the assessment of the relative effectiveness of new medicines carried out by health technology assessment bodies in the member states."

The agency says the task meets one of its own newly established goals of making it easier for everyone to access EPAR information, which has led among other things to the use of revised assessment report templates, and to the search for new ways to improve the transparency of the scientific assessment. That is all very commendable, but making information available is not necessarily the same thing as giving such a ringing endorsement to what is still the very much emerging science of HTA. Nor will it bring much comfort to drug developers fearing for the worst that the two organizations "also agreed to explore other areas of possible collaboration or exchange of information in the future."

The birth of EUnetHTA

EUnetHTA, like the recommendation to explore relative drug effectiveness, sprang from the Pharmaceutical Forum. It was formed by a group of 35 organizations throughout Europe, led by the Danish Center for HTA in Copenhagen, and its first manifestation was as the EUnetHTA Project, which ran from 2006 to 2008. This coordinated the efforts of 29 European countries, including 25 EU member states, in evaluating health technology in Europe. The objective was to connect national or regional HTA agencies, research institutions, and health ministries so they could exchange information effectively and give support to policy decisions by the member states. During these first three years of its existence, EUnetHTA built up an organizational framework and created communication tools so that HTA results could be circulated among member states to provide policy advice.

In November 2008, EUnetHTA took on a new project, transforming the network into a more permanent collaboration. This so-called collaboration project is designed to promote good practice in HTA methods and processes, and in 2009 it joined forces with other partners across Europe, including the European Commission, the Council of Europe, the World Health Organization, and numerous public health institutes in the member states. In this latest guise, it has obtained funding to explore relative effectiveness assessment of pharmaceuticals through to 2012 as a joint action with its new partners.

HTA is not going to go away. The European agenda for implementing it goes back earlier still. In 2004, the European Commission and Council of Ministers targeted HTA as "a political priority," recognizing "...an urgent need for establishing a sustainable European network on HTA." Those earlier political aspirations are coming close to practical realization. So everyone who is at risk of suffering from ill-judged assessments—and that includes everyone involved in drug development—is going to have to take even more seriously the debate about how effectiveness can be accurately established, and explain even more thoroughly the limits of prediction and predictability. Otherwise, HTA is going to turn into a "fourth hurdle"—and that is going to spoil a lot of Mardi Gras celebrations for years to come.

Maltese cross

The old joke about "how do you make a Maltese cross?" is likely to get some mileage over the coming weeks, as the new European Commissioner for Health grapples with his new role. John Dalli, until recently the health minister of the EU's smallest member state, won endorsement from the European Parliament in early February, and took up office on February 11. Unlike previous health commissioners, Dalli will enjoy sweeping new powers over pharmaceutical policy too. A reshuffle of portfolios in the European Commission has put him in charge of the European Medicines Agency in London, the European Center for Disease Control in Stockholm, and the pharmaceuticals unit of the European Commission in Brussels.

The implications of this reshuffle are far-reaching. No longer will the pharmaceutical industry be able to rely on the backing of a strong European Industry Commissioner to argue its case for it when faced with demands to bring down its prices or direct its research into socially acceptable avenues. Calls of this sort have routinely come in the past from Health Commissioners and their staff, and have been countered in the past (more or less effectively) by Industry Commissioners and their staff. Now the traffic could be all one way. So even if the Maltese does not get cross, there will be plenty of people cross with him.

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