Staying on course

In all walks of life, at some point or other people will be required to perform a balancing act. A young mother might have to juggle between advancing her career and meeting the demands of parenthood. A middle-aged fitness fanatic may have to tread very carefully between successfully keeping in trim and bringing on a heart attack by overdoing it. I once met a physical education teacher who found himself in a quandary. He explained that his natural urge was to make his sessions as competitive as possible to motivate his best students to become the sports stars of the future. However, the latest politically correct initiative from the Education Ministry said he had to introduce a non-competitive, inclusive element to his lessons to cater for the less able of his students. Whatever your vocation, balance is crucial.

Some would argue that it has been an incongruous start to the 21st century for pharmacovigilance. Less than two years in and the withdrawal of Bayer's anticholesterol drug, Baycol, had people questioning the procedures already in place to assess the safety of medicines. By the time Merck had withdrawn its COX-2 inhibitor, Vioxx, from the worldwide market in autumn 2004, they weren't so much questioning the process as fervently condemning it. The regulatory authorities soon found themselves between a rock and a hard place. On the one hand, patient groups were screaming out for faster access to new drugs to alleviate their particular conditions; on the other, health campaigners were pointing to cases such as Vioxx and Baycol as permanent reminders of the dangers of putting powerful medicines onto the market without a full assessment of their safety profile.

Addressing serious unmet needs
The aim of new European pharmaceutical legislation (Regulation 726/2004), which at the time of writing was on the brink of becoming effective, is to increase the availability and speed of access of new medicines to the market, while at the same time ensuring that the basic criteria of safety, quality and effectiveness are met.

One particular initiative within this wave of legislation is the move to allow pharmaceutical companies to apply for a Conditional Marketing Authorisation (CMA) from the European Medicines Agency before all relevant clinical trials data are available. In short, companies will be able to have the EU approval of drugs `fast-tracked' so long as they can prove that the products address serious unmet medical needs safely.

It is over this sensitive issue that health ministers find themselves being pulled in opposite directions about medicines policy. This time the see-saw lurches precariously between the (some would say conflicting) interests of raising European pharmaceutical industry competitiveness and serving the interests of public health.

There are three broad categories that define which products can benefit from a CMA: those that treat, prevent or diagnose diseases that are chronic, seriously debilitating or life-threatening, orphan medical products, and medicines for use in emergency situations or in response to public health threats duly recognised by the World Health Organisation. While nobody would deny that drugs correctly classified in any of these categories should be assessed as quickly as possible so that patients can benefit, some critics fear the scales have tipped too heavily on the side of the industry.

One of the most scathing critics of the new CMA regulation has been the French medical journal, La revue Prescrire, which is published by the Association Mieux Prescrire (Association for Better Prescribing). In a position statement, the journal announced that it was 'deeply opposed' to the project, saying that 'the underlying aim of the text is not to help patients but rather to facilitate market access for inadequately assessed drugs'.

So what has got so many people's backs up? Some healthcare professionals are concerned that the field of application is simply too large. They argue that while it is acceptable to consider orphan drugs and those used in emergency situations, such as pandemics and bioterrorism, for CMA approval, the first category is far too wide-ranging. Others argue that the broad nature of the field of application is simply immaterial when the whole regulation is inherently ill thought through.

I don't like this regulation at all, it's simply a reflection of how close the European Commission is to the industry, says Joe Collier, professor of medicines policy at St Georges, University of London. The problem is that because pharmacovigilance in Europe is so poor, it is unacceptable to introduce a CMA system.

If the authorities could promise that the existing pharmaco-vigilance system could be improved then it might be valuable, but as things stand, it's not on.

He argues that a fast track procedure for drugs deemed to be in the interests of public health is, in fact, a system designed simply to favour the pharma industry rather than protect the welfare of European citizens.

The quid pro quo is that companies will bring these drugs out and the regulators will watch very closely, he continues. Unfortunately, we have no guarantee that drugs will be monitored closely enough so bringing them out quicker doesn't work. On past history, it's a bad idea - in order to fast track the approval process, you need to keep a very close eye on developments, but in reality the pharmaco-vigilance system has not shown itself to be capable of that.

As some expected, the European pharmaceutical industry is in full support of the proposed CMA scheme. European Federation of Pharmaceutical Industry Associations (EFPIA) spokesman, Christophe de Callatay, says the organisation welcomes the approach taken by the Commission in its draft regulation.

We reject criticisms or allegations that this new system would basically facilitate market access for drugs which have not been sufficiently assessed, he states. The objective is clearly to help patients and not to put their health at risk. No R&D-based pharma company would actually accept to run the risk of being granted a CMA if the product had not been sufficiently evaluated.

ENFORCING CONDITIONs
According to the European biotechnology industry association, Emerging Biopharmaceutical Enterprises (EBE), the CMA proposal is a beneficial system that has been introduced to further improve the existing EU assessment and approval situation and will be an important addition to the EU's legal framework that only allows safe, efficacious and high quality medicines to reach the European patients.

Caroline Ruggieri, acting executive manager at EBE, believes that the quality of drug assessments under the CMA system will not be inferior to those of `normal' products.

This new system aims to allow - in certain circumstances - earlier access to treatment for the target population in question, she notes. While the CHMP (Committee for Medicinal Products for Human Use) will have a certain degree of discretion, we do not believe that they would waiver from their long held and cornerstone principles of rigorous assessment of quality, safety and efficacy data.

She adds that the CMA will not be available for every type of product, but only for those where there is a strong reason for allowing early market access.

There is some debate as to how much the European Medicines Agency will be able to enforce the conditions mentioned in the draft regulation. La revue Prescrire points out that describing this new type of marketing authorisation as `conditional' is a slight misnomer, considering the fact that many marketing authorisations granted through the European centralised procedure are already subject to conditions. It is not unusual for the CHMP to grant a favourable opinion on a product on the stipulation that the relevant company conducts further clinical trials, or completes ongoing trials, or conducts post-marketing pharmacovigilance studies of the first patients to receive the drug.

However, according to Collier, these are conditions that are rarely met: Companies often don't fulfil the conditions that are set down - basically they don't do what they are supposed to do and manage to get away with it because European laws aren't strong enough.

Ruggieri at EBE points out that while many products are already approved with post-marketing commitments, such as the so-called `phase IV' trials, the thing that differentiates the CMA is that it gives the authorities the opportunity to revoke it every year if they choose not to renew it.

Under current `exceptional circumstances' provisions, the risk-benefit assessment is carried out every year, and the authorities can remind an applicant about their commitments, or push for a better definition of the indication in question, but the MA remains valid for five years, she explains. The authorities have no real handle to revoke the licence. Under the new [CMA] system, the evaluation is done each year and the MA automatically lapses, unless re-granted. The system is actually more rigorous.

The draft regulation places the emphasis on companies themselves to apply for a CMA, something which EFPIA supports. De Callatay says that this initiative should also be accompanied by scientific dialogue with industry to consider the acceptability of surrogate end-points in general, since an important use of the procedure will be in the situation where `presumed positive risk benefit balance' comes from studies using surrogate end-points, which are then verified by later clinical trials.

At the time of publication, the draft regulation was at something of a hiatus although there are signs that it could see some progress in the near future. It needs to be stressed that there are several steps that need to be taken before the CMA system can be actualised. The first of these steps is the entry into force of Regulation 726/2004, which was due to happen on November 20, 2005. But following that, the draft regulation on CMAs needs to be adopted.

It has been out for consultation but still has not been finalised, and even when it is, Article 11 stipulates that the European Medicines Agency (EMEA) will have to draw up draft guidelines for the application process, which in turn must go through the consultation process.

EMEA spokeswoman, Monika Benstetter, says that as long as the finalised regulation on CMAs requires the agency to produce these guidelines (as the draft regulation has) then it will do so.

As things stand, the regulation is still in its infancy. It seems almost ironic that legislation designed to make life-saving medicines swiftly available to EU patients has yet to circumnavigate the slow-grinding European consultation and approval process.

It is a bit too early to criticise a process that is still very much a `work in progress', says Ruggieri. We would encourage all stakeholders to be part of this process, and get involved in the process of developing the system.

The Author
Gareth Carpenter is assistant editor of Pharmaceutical Marketing Europe