European Change Is Still in the Air

You need more than the normal number of fingers to be able to count on one hand the number of changes in the air for Europe, its pharmaceutical industry, and the clinical trials sector. The European Union is on the brink of major political and constitutional changes that will affect everything from democratic rights to drug research. The EU is also laboring its waynot without difficultythrough a major rewrite of its specific legislation on pharmaceuticals, touching everything from data protection to adverse reaction reporting, and from registration procedures to regulatory competition. Now the clinical trials sector is between a rock and a hard place, trying to plan upcoming trials without knowing precisely how the new clinical trials directive will be implemented across key issues ranging from informed consent to the role of investigators.

Rewriting Europes future
At the macro-political level, the EU is being pushed by twin challenges into a profound review of its future. The most obvious pressure is the impending expansion of the EU into Eastern Europe and the Mediterranean, which will increase its membership from the current 15 countries to nearly 30, and which demands a streamlining of the EUs cumbersome decision-making procedures. To perceive just how big a challenge this is, you need only to reflect on how slow and tangled the discussions on changes to Europes pharmaceutical legislation are at present, and then to extrapolate that complexity into a Europe with nearly twice as many competing voices when EU ministers come together to make decisions. The average time for an EU legislative proposal to be adopted and come into force over recent years has been around three years. There is every risk that, without some speeding up of the process, a larger EU could take six rather than three years to agree on a rule such as the new clinical trials directive.

Equally important, however, is the more complex debate about what this larger Europe will be, what its fundamental aims should be, and how its different institutionsthe Parliament, the Commission, the Council of Ministers, and so onshould interact. This is largely driven by a growing recognition that, among most of its 300 million citizens, the EU is not a popular organization. It is seen as bureaucratic and remote, and even as irrelevantas is demonstrated by the plummeting voter turnout in the periodic polls for the European Parliament (around 30% of the population at the last election), or the recent rejections by popular referendum of the Euro in Denmark and of the new EU Treaty in Ireland.

So, in a bid to engage Europes citizens in fixing its objectives, a yearlong debate on Europes future has just got underway. Among recent contributions to this diffuse debate, one of the observations most relevant for the pharmaceutical sector came in early March from the leading French socialist Martine Aubry (the daughter of Jacques Delors, the European Commissions most effective president ever, whose energetic term of office spanning the 1980s and 1990s is remembered with affection by most Euro-enthusiastsbut a redoubtable figure in her own right). She told a special conference of the European Socialist Party, convened specifically to debate the partys position on the debate on Europes future, that the EU should aim to promote European research, so that Europe will not fall victim to the monopoly of U.S. drug multinationals.

Rewriting Europes drug rules
There will be plenty more of that over the coming year, as the EU prepares itself for a new rewriting of its basic Treaty and a new definition of its destiny.

But closer to home, the coming year will also see the debate open up on the EUs attempt to rewrite its drug rulesa rewrite ostensibly aimed at speeding new medicines to patients. Already the European Commissions proposals have run into heavy opposition from the drug industry and from some of the biggest EU member states. Topping the list of problems is a plan to limit industry choice on how drug companies put their drugs on the market. The Commissions proposals envisage obliging drug firms to submit every application for authorization for a new product through the EUs so-called centralized procedure, operated by the European Medicines Agency in London. This would eliminate the current choice open to firms to use the alternative national authorization channels first, and then to enter the market in other member states on the basis of the mutual recognition procedure. It would also cramp the style of leading national drug agencies. The UK and the northern European countries have already started to openly criticize the plan.

Industry is also anxious about proposed new requirements for compulsory product launch within three years, on pain of losing the authorization. It objects to the limitation to a single trademark for new products. It is apprehensive over possibilities that differences in member states assessments of products already on the market under national authorization procedures might automatically lead to an EU-level arbitration procedureand the risk of a product suffering changes to (or even losing) its authorization in one member state because of objections in another member state.

Filling in the clinical trials gaps
But at present, the drug industry in Europe is most concerned about the way the new EU clinical trials directive will operate. The directive, adopted in 2001, is due to come into force at the national level across the 15 member states in May 2004. But before then all the details of its implementation have to be defined via guidance from the European Commission. Since November 2001, member state experts have been discussing a series of drafts from the Commission, but the earliest date for this consultation to be widened to the industry is currently June 2002implying still further delay before it is finalized and published. Industry has already repeatedly complained that it is being excluded from the process, and is now fearful that the guidance may not only be inappropriate, but may also come too late.

Some of the key areas for which the guidance is needed include:

Applications. The issues include the content and format of companies applications to ethics committees to run a clinical trialand discussion continues on the respective roles of the committee and national authorities, on assessments of the suitability of the investigator and the facilities, on how a positive opinion might be reversed, and on the timing of an applicants response. Definitions are also needed for who can apply, in what languages, with what documentation, with what information to trial subjects, with what provision for declarations of the end of a trial, and with what date for its end.

GCP rules. The issues include tying down which Good Clinical Practice rules are to be followed, including the legal status of the guidance, differences in respect of commercial and noncommercial GCP, updating of the ICH rules on GCP, and whether and how the EU guidance can be updated through annexes. Decisions are also needed on whether and how to permit the conduct of placebo-controlled trials, how to deal with borderline studies and products, observational studies, noninterventional studies, and who will be designated the responsible contact person.

Applications to national authorities. Issues include which documents must be submitted for evaluation, how closely they correspond to the headings under the clinical trials directive, whether there should be a limitation on the number of pages, how documentary requirements should correspond to successive phases of trials, how to provide for health volunteer trials, and the format for applications.

Pharmacovigilance. Issues include the role of the member states and the EMEA in recording events and in evaluation, how to handle reports from non-EU countries, how to handle duplicate reports, arrangements for alerts, overall analysis, dialogue on safety concerns, electronic access, and line listing for short trials.

Databases. The issues include the respective roles of the EMEA and the member states, whether databases should be separate or linked, what the user requirements will be, what amount of information they should carry, the extent to which the information should be available to the ethics committee, how to assure quality control, how to handle modification of data, what elements should be searchable, and what arrangements to make for noncommercial trials and for trials that do not start.

Other issues are still unresolved. Ethics committees must be composed of health-care professionals in the EU directive, but under ICH guidance the criterion is scientifically qualifiedleaving open the decision on who assesses what science means. There are unanswered questions on whether incapacitated adults may be included, on who should carry responsibility for indemnity and compensation, and on whether the assessment of the risk-benefit justification should be conducted by the ethics committee or the national authority. And should ethics committees have a role in trial monitoring and inspection? It is also still unclear what constitutes the significant or substantial changes that should trigger formal amendments to protocols. Other areas of uncertainty include rules for investigational medicinal products, inspection documentation and procedures and qualifications of inspectors, and safety reporting.

Arielle North, of the European Commissions pharmaceuticals unit, has added a further complexitythere is a distinction, she pointed out recently, between a detailed guideline (involving member states in a legal procedure under the EUs so-called comitology procedure, which operates via standing committees) and detailed guidance (which is discussed directly with member states without a formal committee procedure). This may seem like esoteric theologybut Brussels decision-making processes are full of these quirky complications about who can do what to whom and how often. The consequence tends to be more delay and more confusion.

Industry wants the system to be as efficient as possibleso, for instance, it says the documentation required by ethics committees and national authorities should be short and, as far as possible, the same, allowing companies to generate (and update) a single document that meets both needs. It says the GCP requirements should be covered by an enunciation of principles and a reference to existing ICH guidance. Informed consent requirements should be dealt with under the ICH GCP guidance, possibly with additional recommendations where necessary for special populations, but with no need for further or new guidance. And, it says, new pharmacovigilance requirements for clinical trials (currently being drafted by Germany on behalf of the Commission) should be in line with existing ICH and CIOMS principles and should limit annual reporting requirements to the substance itself, rather than imposing reporting requirements in respect of each country or protocol. Impending guidelines on manufacture and import requirements must, says industry, provide one standard in all member states and address the what and the why of controls, but leave the detail of how to the manufacturer.

According to Barry Arnold, MB, FRCA, FFPM, of AstraZeneca, a binding clinical trials directive is needed to ease the process for industry, because member states have been slow to implement many of the standardized procedures that have already been agreed at international level. The ICH guideline on expedited reporting of test results was implemented by only five of the 15 EU member states (France, Finland, Italy, Sweden, and the UK), despite the fact that it is already in force in the United States and Japan. Austria, Belgium, Denmark, Germany, Greece, Ireland, Luxembourg, The Netherlands, Portugal, and Spain are still operating on the basis of local legislation, with different rules and timelines.

Some of these member states have refused to budge, because they had not themselves signed on to the guideline and did not accept that the Commissions signature on the ICH document was a sufficient base for them to act in line. But this impedes companies conduct of their clinical trials, alleged Dr. Arnold. The best safety data is collated data, so a standardized approach is desirable, and the clinical trials directive can help us and help improve public health, he said. Similarly, he pointed out, member states requirements on periodic reporting of investigational products continue to vary widely.

Meanwhile, there is anecdotal evidence that The Netherlands and Sweden are slowing down the start-up of trials. Local ethics committees are delaying central committee decisions, according to Guy Belcher of Takeda. But North says the Commission has already been obliged to back down from its original proposals to legislate on the type of committee that member states should put in place, and now it has no power to get involved at the local level. We cant intervene at member state level on how they organize their ethics committees, she admitted. Moira Daniels of AstraZeneca says she sees real problems in enforcement of timelines on the handling of submissions if member state authorities are not vigilantas she points out, individual companies will hardly want to be taking legal action themselves against local ethics committees.

Despite industry complaints, the Commission refuses to bring forward its planned consultation with the industry on all these important details. It is necessary for the Commission to obtain consensus on at least a core document among member states before opening the process up to consultation with the industry, says North. Otherwise it will become unmanageable. And so far, member states have been showing reluctance to abandon their own procedures for trial authorizationonly in recent weeks has a breakthrough occurred in moving towards acceptance of a single harmonized application format to be used in all member states. Until this point, there had been a real risk that companies would have to submit a single cover sheet with additional separate annexes for each member state in which they wanted to run the trial.

Daniels says industry is worried by the delay in agreement on the guidance for implementation of the directive. Companies are already setting up timetables for trials to start in 2004, but they are handicapped because they still do not have the information on how the EU rules will be operating at that time.

We can meet the requirements, Daniels said, but we need to know. And while companies could, if necessary, put more resources into their clinical trials departments to deal with additional regulation, it had not been expected that the new directive would make compliance more complicated. We shouldnt have to increase the bureaucracy, she said.

Change may still be in the airbut in some areas it is taking too long to turn into clear rules for the industry to work by.