According to the World Health Organisation (WHO), the largest single health threat to the population of the world today is antimicrobial resistance (AMR). How can it be countered and what options are open to government regulators, the medical profession and, especially, the pharmaceutical companies for the development of new antibiotics?
These issues were at the heart of a one-day workshop – ‘Best use of medicines legislation to bring new antibiotics to patients and combat the resistance problem’ – at the European Medicines Agency (EMA) in London in November 2013. Participants included regulators, medical bodies, pharmacists’ organisations, patient and healthcare professional groups, reimbursement bodies and the pharmaceutical industry. There was a strong attendance from the US, including representatives of the Food & Drug Administration (FDA), the Infectious Diseases Society of America, and Cubist Pharmaceuticals.
A post-antibiotic era is now a real possibility
‘Antibiotics are the most life-saving drugs invented but a post-antibiotic era is now a real possibility,’ warned Dr John Rex, Vice President for Clinical Infection at AstraZeneca. ‘A path to a diverse, sustainable pipeline must be found.’
The good news is that the meeting’s consensus was that the regulatory framework as it has evolved in the EU is now probably fit for purpose for companies wanting to develop new antibiotics for unmet needs. And this regulatory solidity would be strengthened if EU rules were more in line with those in America and other countries because, as one speaker said: ‘The last thing we want is industry using the inadequacy of the regulatory framework as an excuse for not developing the right drugs for the right patients for commission.’
An eagerly awaited contribution was that of Dr Hugo Hurts, of the Ministry of Health in the Netherlands, a country widely held to have gone further than any other in Europe in controlling and limiting the use of antibiotics in primary healthcare.
‘We do have a positive history in the use of antibiotic drugs on the human side and this is the result of better prescription and better use,’ he said. ‘Dutch physicians are prepared to take a careful look at when these drugs are useful and when they are not, and they are prepared to tell patients also when and when not.
‘It’s not a problem in the Netherlands and people are OK with the explanations. They won’t ask for antibiotics if there is no clear need for them. It may be our culture, but it’s a good thing that we have it and that we have a medical profession that has guidelines and sticks to them.
‘We could do better in some areas, in the prevention of infection in hospitals – not all hospitals operate on the level we should want – but we are able to ensure that the Dutch healthcare inspectorate makes it a priority to improve in this area, and this has happened. Now we should make a serious job of cutting out OTC antibiotic sales.’
As to whether the Dutch experience can be repeated in other countries, he said: ‘Things can change; things taken for granted aren’t so forever.’ Dr Hurts said that combating AMR will be a priority of the Dutch presidency of the EU in the first half of 2016. He suggested that health professionals should try to look beyond the pressures from research and the development of new products, the ‘push’ factors. ‘We can use our regulatory authority, our reimbursement machinery and perhaps even pricing decisions to stimulate the pull factor,’ he suggested.
Dr John Chave, Secretary General of the Pharmaceutical Group of the European Union (PGEU), representing European pharmacists, regretted that more countries were not like the Netherlands in this regard. The country stood out because ‘more than any other EU country it has very high levels of co-operation between primary care and health professionals, and in particular between physicians and pharmacists’. It also has a relatively strong and vigorous health care inspectorate.
The question was, he said: ‘How do we replicate some of the positive features of antibiotic stewardship, which has been quite successful in secondary care centres, into the primary care sector where, in Europe, in nearly all countries, pharmacists and physicians carry on their practice in “silos” and do not communicate adequately with each other?’
Over-the-counter sales of antibiotics are illegal in all 28 EU member states, yet in some countries the trade is allowed to continue at a high level
According to Dr Chave, the enforcement of rules is a big issue. Over-the-counter sales of antibiotics are illegal in all 28 EU member states, yet in some countries the trade is allowed to continue at a high level. He wondered why this was happening in some countries but not others.
Traditionally, and legally, the EU had little competence in the dispensing and prescribing area, he said. But it was not so much a question of existing rules and guidelines: ‘It’s a question of why more pharmacists who are doing this illegally aren’t caught doing it,’ he said.
‘Why, when you go to Greece and Romania and the south of Europe and perhaps the Baltic states, do you see this more than elsewhere?’ he asked.
There was some evidence that illegal dispensing was financially motivated, he suggested, ‘although more research is needed on behavioural and cultural issues’. There was also evidence that national awareness campaigns could affect illegal dispensing, he said, citing the success which followed a recent campaign in Spain. ‘If healthcare professionals are prepared to take the battle forward, then progress can be made,’ he said.
Imprudent prescribing is probably an under-researched area, said Dr Chave. ‘The causes are likely to be multi-factorial, including unrealistic patient expectations and delayed prescriptions where the doctor says if the condition doesn’t go away come back and I’ll prescribe antibiotics – in effect leaving the decision about antibiotics to the patient,’ he claimed.
Another factor is the relatively high cost of visits to doctors in some countries. In Ireland, people pay €50 for a GP visit and if the doctor says there is nothing to be done patients are reluctant to leave empty-handed.
Imprudent prescribing is probably an under-researched area
Dr Chave also blamed the willingness of patients to go to doctors with minor or self-limiting conditions, which was a problem right across Europe. A challenge for the future would be ‘to move some patients away from seeing physicians, from going into a prescribing area where they’re more likely to get an antibiotic prescription for a condition which doesn’t need one’. He endorsed a campaign by the health service in Ireland, which told people that colds and flu are caused by a virus and antibiotics do not work on viruses.
Dr Radu Botgros, of EMA, spoke on improving and harmonising the summary of product characteristics and conditions of use (SmPCs), explaining that the summary was ‘the basis of information for healthcare professionals on how to use that medicine, updated throughout the life cycle of the product’. Mainly for historical reasons there were, for older antibiotics, different SmPCs in different EU member states ‘and we think it important to look into harmonising the text so it is the same version for all healthcare professionals in the EU’. But harmonisation cannot and should not replace treatment guidelines and other methods of antiobiotics stewardship, he said.
Speaking for the European Centre for Disease Prevention and Control, Dr Anna-Pelagia Magiorakos said that AMR was a cross-cutting and multifaceted issue and could not be discussed only from the human side. It was important that there was full commitment from all involved. Dr Magiorakos said there were no antibiotics to treat many patients at present ‘and later on we may not have any antibiotics to treat certain patients who had bacterial resistance to everything’.
The European Commission spent a lot more on research into antimicrobial resistance than all the EU member states together
Professor Herman Goossens, of Antwerp University, Belgium, quoted a report by the Medical Research Council in the UK on AMR research which, according to preliminary data, had found that the European Commission had actually spent ‘a lot more on research into antimicrobial resistance than all the (EU) member states together’. The challenge now was to get the results to GPs and prescribing authorities.
But speaking for AstraZeneca, Dr Rex told the workshop that ‘if we want a diverse, vibrant project, we have to find ways to fund and incentivise industry’. The task is to minimise the use of all antibiotics, to provide new antibiotics on demand and ‘we want those antibiotics developed before the epidemic hits’. Companies could not be made to do the work – ‘we have to make them want to do this work’, he said.
To illustrate the risk/reward challenges to the industry, Dr Rex showed a 33-year financial projection showing the development of a new drug by a single company that involved spending of €450m in the first 13 years but delivered a return of about €2bn in the last 20 years. ‘That might look like a good place to be. But what about the present value of money?’ He said it was necessary to take off 10% for inflation, the risk of total failure, the discount factor, ‘and keep doing that’.
