08-09-2008 - Making veterinary medicines available in Europe
Making veterinary medicines available in EuropeObtaining authorisations for new medicines in Europe can be a bureaucratic nightmare, especially when seeking approval across several countries. In 1995, the European Medicines Agency (EMEA) was formed with the aim of reducing red tape and helping drug manufacturers cope with the differing regulations of the (now 27) EU member states. Grainger Laffan talked to Dr David Mackay, head of the veterinary medicines and inspections unit of the EMEA, at his office in Canary Wharf in London, where this practising veterinary surgeon turned researcher, turned government agency executive, has headed the unit for the past two years and is seeking new ways to streamline the authorisation process.
DR Mackay qualified from the Royal Veterinary College and practised in the south of England before moving into research, working on exotic viral diseases in livestock. Most of his research career was spent with the Institute for Animal Health at its Pirbright laboratory. He also spent time at the Veterinary Medicines Directorate (VMD), where he became director of licensing. He moved to the EMEA in February 2006.
He explains that the EMEA is a coordinating body that relies on the competent authorities in member states to provide individual assessments of new medicines. Dr Mackay's team assists licence applicants to meet the requirements for an EU-wide authorisation by the European Commission so they can license a product for marketing throughout the EU.
'European licensing is quite a complicated area. There are a number of different ways that a product can be authorised. A manufacturer can go to a national competent authority like the VMD in the UK and obtain a national authorisation. But if you want an EU-wide authorisation then you come to us and we coordinate an assessment by all 27 member states and the European Commission then issues an authorisation. And that is then valid throughout all the member states. The scientific expertise for that is coordinated through our Committee for Veterinary Medicinal Products (CVMP).'
The committee is made up of representatives from all the EU member states, as well as from Iceland and Norway. Up to an extra five members are chosen from experts nominated by member states or the EMEA.
The EMEA has coordinated the authorisation of 78 veterinary medicinal products since it started 13 years ago, although four of these are no longer valid. Of the 78 products, 37 are vaccines and 41 are pharmaceuticals. Seventeen of the vaccines are for food-producing species, 13 are for companion animals, six are for horses and the remaining one is a rabies vaccine for several species. Of the pharmaceuticals, eight are for food-producing species, 27 are for companion animals and six are for both.
The agency handles more pharmaceutical products for companion animals than for food-producing species because of the increased cost and 'time to market' involved in demonstrating consumer safety for products aimed at animals intended to enter the food chain.
Dr Mackay expects that his unit will see around 17 applications for veterinary products in 2008.
He says the best part of his job is 'seeing Europe come together' and proving that the EU 'really can work': 'There is often a lot of bad press about Europe, but I think what we can do here, very easily, is assemble the best possible expertise that there is available within the Community.'
His unit is responsible for the authorisation of veterinary medicines at European level but it also has a dialogue with non-EU countries, and his team is often involved in mutual recognition or collaborative agreements: 'With areas like the USA and the Food and Drug Administration, we can bring together the best available expertise within Europe and, I think, globally to look at these issues on medicines.
'The veterinary medicines industry needs as much incentive as possible,' he says. 'The veterinary industry faces big challenges because if you compare us to the human industry we are about the size of one blockbuster human product. And yet all of the companies have to go through the full regulatory procedure for every product.
'So anything we can do to harmonise requirements at a European level, and then subsequently a global level, I think is the most interesting and challenging thing we can do.'
Comparing licensing in the human and veterinary fields, Dr Mackay says, 'We face a constant challenge to have our voice heard and say the veterinary industry is unique, and therefore legislation and requirements should reflect the needs of the veterinary industry and not be just a mirror reflection of what is done on the human side. Our industry is very fragmented. The human side has no concept of species because they don't need it. And for those two reasons, sometimes a different approach is needed.
'A good example, I think, is that we are facing quite a lot of challenges at the moment in terms of European licensing of generic products - where the initial period of data protection has expired and copy products are allowed - and that is because the generic model is based on the human model of following the innovative product. But, because of the issues of different species, and also because the veterinary market is more fragmented and the veterinary profession is quite different in different countries, much more so than on the human side, there are challenges in fitting the human generic model on to the veterinary model.'
Dr Mackay's team also provides the secretariat for the Coordination Group for Mutual Recognition and Decentralised Procedures. This group eases the process of achieving authorisation in a selected group of member states once an initial authorisation has been achieved: 'So if you go to the UK and you get your fish vaccine licensed, the only other countries you are likely to be interested in are possibly France, Norway, and Ireland maybe, but you wouldn't want to go to the others. So then you go through mutual recognition and it is coordinated through this group to ease the flow to those countries. So then you end up with the same authorisation in four or five countries but you haven't got it in all 27, and you don't have to worry about Maltese translations or packaging in Maltese.'
He says the EMEA only plays a coordinating role in this procedure unless there are disagreements between national competent authorities, in which case the CVMP steps in to arbitrate.
'I think the things that haven't worked so well, and where we are still challenged, is particularly generics and referrals [where disagreements are settled by the CVMP]. What is happening is that the change in legislation is forcing through a more level playing field, and the consequence of that is that it's leading to an increase to the number of referrals at the moment.
'Previously, if there was a disagreement, there was an option for one or other member states, or the manufacturer, to withdraw and effectively walk away from that problem, so they never got ironed out. But now what happens is there is compulsory arbitration. That means more work for us but it does mean that precedent is now being set. And it is starting to work. So now when member states come up against the same problem, they know there is no point arguing because the example has been set.'
An area where the EMEA's veterinary group has been very active in the past few years is in streamlining the authorisation process for vaccines against diseases classed as emergency conditions.
'If there is a new incursion of one of these major diseases of livestock, then the EU legislation would allow a member state to use a product without an authorisation if it wished, but the responsibility rests then solely with that member state. But obviously the most desirable situation, particularly with a disease that easily transmits across member states, is to have a central authorisation so wherever that disease spreads, the same product can be used and there is no question about whether you can vaccinate up to this border, but it hasn't got a licence beyond there, so then it has got to stop.
'So central authorisation has a lot of attractions, but the problem is that up until 2007 there weren't any authorisations for any of those major epizootic diseases. There were a few national authorisations, but in many cases the manufacturers knew if there was an outbreak the chief veterinary officers would come to them and say they wanted the product whether it was authorised or not. It's not a good situation and I think the ideal is that the products have been assessed.
'We face a constant challenge to have our voice heard and say the veterinary industry is unique, and therefore legislation and requirements should reflect the needs of the veterinary industry and not be just a mirror reflection of what is done on the human side'
'So, in terms of avian influenza, our CVMP looked at that in advance and said that to get an exceptional authorisation - in other words an emergency one - these are the minimum requirements that you need to meet. As you can imagine, some of the requirements like duration of immunity, stability, even some of the tests that are required can take quite a long time to do. Therefore, if you want to license quickly you have to reach a compromise and say we will license the product on this minimum package to show it is safe to the animals, consumers and the environment and that enough evidence of its efficacy has been produced, with a commitment to ongoing studies.
'So we were able then to license vaccines against avian influenza in 90 days. That happened in spring of 2007. The normal minimum period was 210 days with various stops for provision of more information.'
Dr Mackay is hoping that this first test case will pave the way for more such streamlined emergency authorisations in the future. And he says the agency is adopting a similar approach for bluetongue.
The average cost of an authorisation is 78,000 but fee waivers or reductions can also be used by the agency to facilitate fast emergency authorisations.
'What we are trying to do is look at being more strategic - to be proactive rather than reactive and looking more long-term at the problem of these major diseases,' he says. 'The main three are avian influenza, bluetongue and foot-and-mouth disease. We've recognised that the legislation has to change to make it more fitting for this type of vaccine where there are multiple serotypes and multiple strains within serotypes. You could, just like that, get a completely new strain come in and therefore you need to be able to change your authorisation.
'At the moment, for each avian influenza it is a separate authorisation and that becomes very, very cumber-some, both for ourselves and for manufacturers. So we are looking at this multi strain concept where effectively you have one authorisation but you may have separate antigens or combinations of antigens. There are proposals going through the Commission at the moment to amend the legislation to work with that concept, to allow a multistrain dossier.'
Dr Mackay doesn't foresee any major problems for the proposals, but warns that even though member states have given their agreement to changes, they will still take 'a couple of years' to be realised.
He feels that the agency's work in streamlining authorisations for emergency disease situations is one of its major contributions to the UK's Animal Health and Welfare Strategy: 'If the animal health strategy is saying we are going to use more vaccination, we have to play our part by saying okay, we will make it easier to authorise products for when they are needed.'
Another area that Dr Mackay and his team are working on is to improve the transfer of maximum residue limit (MRL) data across species. The introduction of MRL requirements caused many products to be withdrawn from the market in the late 1990s, and the cost of doing studies to meet MRL requirements acts as a disincentive to bringing new products to the market.
'We are aware that the industry needs as much incentive as possible to bring products on to the market, particularly the small fragmented markets,' he says. 'And so the EMEA has introduced a number of measures in terms of extrapolating MRLs. In other words, if you have got an MRL set for cattle, then provided you can provide some data, you can extrapolate that data to other species and you can have that product used in, say, sheep. You don't have to start all over again from scratch to get that product to sheep. The data requirements for extrapolation from cattle to sheep have been considerably reduced.'
The agency has also been working on establishing the minimum data requirements for authorising new minor use, minor species products: 'If you have got what is only a minor indication for a major species, so it is a disease which is not widespread but there is an animal health need for it, then what the CVMP has looked at is what the minimum data requirements are so that manufacturers can bring products on to the market for conditions which otherwise would not be financially viable because the indication is just too small.
'Copper deficiency is a good example. It's limited to the West Country and some areas in Europe, and the cost of bringing a completely new product out for copper deficiency would be very great. Similarly, if you look at products for pheasants, the CVMP has again looked for the minimum data requirements for a minor use, minor species to bring the product out.
'And also what it has done is give out free scientific advice. So, a manufacturer can come to us with an issue and ask what clinical trials would be needed to get an authorisation. They can come before going before a national competent authority, and can ask the CVMP for scientific advice. And in the case of products for minor use, minor species, that advice is free.
'If you say to me "What is one of the biggest issues facing veterinary medicines in Europe?", I would say availability'
'If you say to me "What is one of the biggest issues facing veterinary medicines in Europe?", I would say availability. Therefore, anything we and the national competent authorities can do [to improve availability], I see as one of the most important things we do. There is not much point us being here if there aren't the products that vets need out in the market.'
The final issue the agency is currently tackling is antimicrobial resistance: 'That's a very high priority for the CVMP, and for the European network as a whole. And I think the pressures are building up in terms of antimicrobial resistance.
'What has been formed is a task force on antimicrobial resistance, which is specifically looking at the impact on human health of the use of antimicrobials in veterinary medicines... the pressures are building and if the veterinary world is not seen to put its own house in order, then I think that the pressures will build for others to do it.
'What we need to make sure of in the veterinary world is that the risk management measures that get put in place are science-based. And if we are not careful then there is a lot of pressure that will say antimicrobial resistance on the human side is due to misuse on the veterinary side without looking at the science properly.
'We have to make sure that the science is really looked at and any measures that are put into veterinary use are based on the science of that veterinary use and veterinary context and not the preconceptions they have on the human side.'