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Europe is debating the process by which drugs receive marketing authorization. As ever, the debating table features the EU, the pharmaceutical industry and the usual suspects among the European lobbies. The crux of the matter? Should comparative efficacy play a role in marketing authorizations?
Of all the battles that the European pharmaceutical industry has been fighting since the European Union (EU) started to regulate medicines, the fight it has done best with is keeping at bay the fourth hurdle, or "the need clause" as the concept of comparative efficacy is quaintly known. When the first EU pharmaceutical rules appeared in 1965, the drug industry, by a combination of good luck and good judgement, managed to limit the criteria for authorization decisions to just the three hurdles of quality, safety and efficacy. The concept of comparative efficacy, the performance of one medicine against others or the need for another medicine, was not included. Since then, despite innumerable attempts to change the rules, the industry has managed to keep the three hurdles set in stone, with no additions - so far. This could be about to change, for two compelling reasons.
One reason is that the European Parliament has been keeping up the pressure for such a change. After 2 years of debate, the Parliament's environment committee decided that the ongoing review of EU pharmaceutical rules should come close to breaking the mould. During its discussions regarding the changes to EU drug authorization rules, there were repeated calls from many Euro MPs requiring new medicines to prove they were better than others to win marketing authorization. The reasoning was invariably the same - too many products appear with no real advantage, resulting in higher costs for health services. If, the argument ran, new medicines were allowed into the market place only when they demonstrated added therapeutic value, there would be fewer me-toos, drug firms would have more incentive to conduct breakthrough research and public money for medicines would be better spent.
This view was hotly contested by the drug industry, which has always argued that it is impossible to prove a new medicine's full merits at the time the marketing authorization application is made - often a product's value only emerges when it is in wide-scale clinical use. A premature judgement regarding "comparative efficacy" would inevitably be ill-founded and could result in potentially useful products being kept off the market forever, the industry argued.
It was also rejected by the European Commission (which proposes new EU rules) and by the European Council (the member state ministers that take decisions on EU rules). In fact, member states already frequently employ the relative efficacy principle in national pricing and reimbursement policies - in compiling their positive and negative lists or other categorizations. Pricing and reimbursement decisions are, however, separate from authorization decisions. EU law has little to say about pricing and reimbursement, where member states are more or less free to make up their own rules. But on authorization decisions, it is EU law - including respect for the criteria agreed at EU level - that governs how member states must behave.
The European Commission (EC) said it could accept a reference in the new version of the EU rules to the principle of comparative efficacy, but only as a tool that member states may use in their decisions concerning pricing and reimbursement: "It is important to also emphasize that this evaluation should not be considered as a necessary criterion for the application or for the authorization of medicinal products. In effect, only the criteria of the quality, safety and efficacy of the particular medicinal product should be used in the evaluation of medicinal products," the EC insisted.
The Council also acknowledged that member states have developed comparative efficacy evaluations of medicinal products aimed at positioning a new medicine in relation to others in the same therapeutic class. In fact the Council itself, in a resolution back in June 2000, emphasized the importance in such circumstances of identifying medicinal products that presented an added therapeutic value. But, like the EC, the Council was adamant: "This evaluation should not be conducted in the context of the marketing authorization, for which it is agreed that the fundamental criteria should be retained."
In the face of this rooted opposition, the committee eventually chose not to go quite so far in its demands as some of its more radical members had been urging. In the early stages of discussions, the committee had proposed that "in the interest of public health, it is necessary that authorization decisions under the centralized procedure be taken on the basis of the objective scientific criteria of quality, safety and efficacy, and added therapeutic value." But in its final formal view, delivered in November (2003), the committee limited itself to a more prudent course. Instead of seeking directly to bring the fourth hurdle into the authorization decisions, it enthusiastically embraced the work being done in the field at member state level.
The committee urged that the European Agency for the Evaluation of Medicinal Products (EMEA) should collect any available information on methods used by member state authorities "to determine the added therapeutic value that any new medicinal product provides …" and "to promote scientific exchange and avert potential conflict, the agency shall draw up discussion papers that compare these approaches and formulate open questions."
"The scientific discussion regarding the concept of 'therapeutic added value' is complex but very important for long-term developments of national budgets for medicinal expenses," it said. "The agency should, therefore, not only collect data but rather play an active role in facilitating the debate."
And it pumped up to giant-size a provision on creating a medicines database. The EC and Council had merely foreseen a database accessible to the general public and provided information in an appropriate and comprehensible manner. But the committee said the database should be maintained independently from pharmaceutical companies and "should enable a comparison to be made between various medicinal products in terms of efficacy, adverse reactions and contra-indications on the basis of the information already authorized for the package leaflet."
The other reason is probably even more disturbing for the pharmaceutical industry because it comes from member state level (and if anyone has any doubts about the relative power of the EU and its member states, they need only reflect on how the UK and Spain acted on Iraq, despite EU rules on consultation on foreign affairs; or on how France and Germany have flatly refused to observe the EU rules on keeping public deficits in check; or on how - despite the supposed consensus on the need to update the EU treaty - the summit for sealing the deal in early December  collapsed in acrimonious disarray, with Spain and Poland moving firmly in the opposite direction to France and Germany).
Pressure for a fourth hurdle has come from member states in the past, of course. Countries with little in the way of a domestic innovative drug industry tend to be dismissive of arguments regarding industrial imperatives or the nature of research. They want the cheapest drugs possible, because it keeps down their drug bill. And if they could limit the number of drugs on the market by demanding demonstrations of added therapeutic value at the time a marketing application is sought, they would be all the happier.
But from member states with a more business-friendly attitude (and a more powerful or effective national drug industry activity to be more friendly to), the attitude to the fourth hurdle has been, until now, very similar to the line taken by industry. And among these pro-industry countries, the UK has probably been the most conspicuous and consistent defender of the three initial criteria - and the most adamant in rejecting any fourth hurdle or need clause.
But right at the end of 2003, from the very heart of the UK, up popped a public argument that came close to demanding a need clause. Not just from one of the "usual suspects" among the health activists or environmental lobbies. It came from the eminent and highly influential King's Fund - a think tank which is a sharp observer of the UK health care scene with a big reputation for common sense.
"Getting the Right Medicines?" as the report is entitled, claims to be "putting public interests at the heart of health-related research." It professes that in the UK, the pharmaceutical industry has been the active driver in its relationship with government and has remained "largely free to provide products that it considers likely to be profitable." The government has tended to be a passive purchaser, "rarely proactive and only in limited instances making clear requirements for specific outputs," states the report.
This has made the relationship an economic success (with UK pharmaceutical exports at more than Â£9 billion in 2001, generating a record trade surplus of approximately Â£2.9 billion), but "there are two significant problems," the King's Fund warns. Because it is focussed on new medicinal drugs, the relationship neglects some other research areas that may be potentially beneficial for promoting people's health, such as alternative therapies; research designed to protect and promote health currently attracts far fewer resources than research focussed on searching for new pharmaceuticals, claims the report.
In addition, the relationship does not fully consider the needs of some major groups, including children and older people, alleges the report. Government reforms designed to empower patients and the public in the governance and delivery of health care have not yet been extended to pharmaceuticals research, it says.
As a result, the partnership "is not sufficiently focussed on achieving better health for the UK population" and a reshaping of the framework is needed if users of the health care system are to get a better deal. The "independence" of the whole drug development process must be guaranteed, with more public oversight, it says.
The underlying assumption in all of this is that the drug industry is subverting, with the connivance of government, some democratic exercise of rights of access to health care. The report doesn't call, as such, for a fourth hurdle, but all arguments are focussed on what it depicts as the essentially autocratic and self-serving manner in which the drug industry does more or less what it damned well likes - including, notably, researching products for which there is not necessarily demonstrable need, and neglecting areas where, in public estimation, there is greater need.
The trend underlying this chain of argument is that a brake needs to be put on the industry's freedom of action. The report calls for the formation of a UK task force to "include the views of all those who may be poorly served by the existing arrangements … primarily, the general public, who are current and/or future users of health care … (and clinicians and public health experts) who may challenge the focus of research programmes on new treatment as opposed to the effective application of existing interventions, or highlight bias towards commercially viable interventions compared with other approaches." It proclaims as one of its key objectives "promoting greater public and patient involvement in health and health care issues - as a route to greater ownership of health and health issues at individual and community level, and to more responsive and inclusive services." This will be served by "helping to develop an effective health system - with a greater focus on health outcomes, not simply on service delivery."
There should be systematic evaluation of neglected areas of R&D where there is potential high benefit, whether in the development of new drugs or therapies or in areas such as post-licensing clinical trials. And the public sector should become "a better purchaser" by developing the role of product assessment upstream of reimbursement decisions, "ensuring that the earlier stages in the therapy development process produce the data it needs."
All good democratic stuff, of course. But its starting point is similar to those who would impose a "comparative efficacy" in authorization decisions: it is tantamount to a claim of superior knowledge - something, in fact, akin to omniscience - by the general public and all experts other than those in the pharmaceutical industry.
Once ideas of this sort take root firmly in member states that have until now been ready to accept a degree of serendipity in the way private industry runs its research, it will not be long before new hurdles appear along the path of drug development. Each expert group, or spokesperson for the general interest, will attempt to impose his or her own favourite hurdle on the area he or she feels is insufficiently regulated. And one of the first areas that is likely to find itself fully hurdled will be the criteria on which authorization decisions are made.