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It had all been going so well. The path EU legislation must navigate is notoriously complex. Consultations, proposals, amendments – input from MEPs and compromises between national governments – the road is long and winding.

But for the EU’s directive on how animals are used in medical research, this lengthy process appeared to have produced a compromise which governments agreed would raise standards of animal welfare, reduce red tape by harmonising rules across Europe, and promote the 3Rs.

Scientists, some of whom initially worried that the new rules would make research more difficult, had their say during the consultation period and broadly accepted the final outcome. Yes, there will always be some who hope for less regulation – just as others will be disappointed that the law could not go further – but EU policy is a world of compromise and this directive looked to have struck a reasonable balance after a robust debate.

So you might have expected that the final step in the journey – turning the EU directive into national law – would be the least complex. Not so!

All 27 Member States should have had laws, regulations, and administrative provisions in place by November 2012 so that these could be in force by the beginning of this year.

At last count, most governments were behind schedule and struggling to meet the deadline. Perhaps this is because not all costs could have been anticipated at adoption of the directive and only now has everyone realised some additional bureaucratic and financial burdens that stem from the way countries interpret the provisions.

While local political and economic crises might be dominating the agenda in several Member States, the directive has been coming down the tracks for some time, so its transposition ought to be a fairly routine technical matter.

Never-ending story

The painstaking process of agreeing on a final EU text has been concluded; the debate is over – or at least it should be…

Let’s look at Italy as an example. Efforts to transpose the directive into Italian law have been complicated by amendments proposed by Italian politicians. Scientists in Italy have already raised concerns about this, warning that medical research in Italy could be jeopardised if the country fails to implement European law.

Italy, which has endured its share of controversies over animal research in recent months, could even be hit with fines for non-compliance with a law its government signed up to.

Are national parliaments set to re-fight the battles that were fought before the directive was agreed?

And, in light of our Shall It Stay or Shall it Go debate, is this the latest signal that animal research is no longer welcome in Europe? If so, what would this mean for European patients and for animal welfare standards?

We want to hear from you

Some 3.8 million procedures were carried out on animals including dogs, cats, mice and monkeys last year, according to press reports.

The numbers are less important than the trend. The total figure is the highest since 1981.

[Here’s one for Europhiles: If you want a sense of how long ago that was, 1981 was the year when Roy Jenkins handed over the Presidency of the European Commission to Gaston Thorn; Greece joined the European Communities; and Bucks Fizz won the Eurovision Song Contest for the UK!]

The report was published by the UK Home Office and was met with some disappointment among animal welfare proponents. This comes after years of political commitments to reduce the number of animals used in research, refine experiments which rely on animals and, ultimately, replace animal models with viable alternatives (the 3Rs).

In light of the latest numbers from the UK, it might be tempting to claim that the ‘3Rs’ commitment is no more than a fig-leaf; an empty PR promise not reflected in the daily reality of research labs. Or maybe there are simply more research projects than before?

Digging into the data

On closer inspection of that 3.8 million headline figure, it emerges that some animals were operated on more than once so we are talking about 3.8 million procedures rather than 3.8 million animals. Large numbers nonetheless but details are important.

There’s also a matter of definition. The genetic modification of animals – which is done so that an animal carries certain genes or has particular symptoms that are to be studied – is classed as a ‘procedure’. The same is true of taking a blood sample.

In fact, the number of procedures classed as ‘significant’ was just 5% of the total.

Given the particular sensitivities about the use of primates, it’s also worth asking what animals were involved.

71% of the animals used in the UK in 2011 were mice; 15% were fish; 7% were rats and 4% were birds. 235 procedures were carried out on cats, although all of that work was aimed at improving nutrition and health in cats.

Meanwhile, there was a dramatic decrease – by 75% – in the number of new world monkeys used in research.

Inspiring progress

For all of that, the headlines generated by the report, coming as they do at a time when governments are converting the new EU directive into national law, should add extra impetus to the drive towards applying the 3Rs.

One thoughtful response to the figures came from a group of scientists who took the opportunity to suggest that European funds should be tapped to fund investment in non-animal research. In fact a lot of research of this type has been funded without much genuine progress. So rather than focusing researchers on non animal research methods, wouldn’t it be better to invest in the development of more effective research tools that would bring clear 3R benefits?

Perhaps the EU’s Horizon 2020 research and innovation funding programme has the firepower and forward-looking mandate needed to support large projects of this kind.

Maintaining momentum

So while the total number of procedures on lab animals in the UK last year was up, there might be reason to hope that the momentum generated by the report will encourage timely transposition and implementation of the EU directive – and maybe even inspire policymakers to focus on and invest further in innovative research tools which could bring us faster to non animal alternatives.

During our two hours discussion, Professor Nouët touched on different aspects of the use of animals in scientific research, including alternatives and the 3Rs. We will be publishing parts of the interview over the coming weeks, however looking at your comments and questions over the past months, we thought the following topic was a good one to start with.

Professor Nouët, what does ‘alternative to animal testing’ mean exactly?

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A couple of months ago we had the privilege to go to Paris and interview Professor Jean-Claude Nouët, Honorary President and cofounder of the Ligue Francaise des Droits de l'Animal, éthique et science (LFDA).
During our two hours discussion, Professor Nouët touched on different aspects of the use of animals in scientific research, including alternatives and the 3Rs. We will be publishing parts of the interview over the coming weeks, however looking at your comments and questions over the past months, we thought the following topic was a good one to start with.

Professor Nouët, what does ‘alternative to animal testing’ mean exactly?
Path:

The new directive, Directive 2010/63, will come into effect at the beginning of 2013. Being new to this legislation, I wanted to get a better understanding of the impact it would have, particularly on lab animals. So I’ve tried to summarize key elements and the thinking behind the new policy.

Revising Directive 86/609
After being in use for 20 years, the 1986 directive no longer reflected all the scientific changes that have taken place, including today’s use of transgenic animals, more sophisticated science and more non-animal research methods (alternatives).  There was also no mention of appropriate care and handling of different types of animals or any enforcement of good practice.

From a research point of view, authorization of a research study varied greatly from country to country, ranging from 30 days to more than 200 days.

So in summary there was a need to adapt to new thinking and technology, to set European standards that would help to create a level playing field across Europe and enforce good management of animal care.

Key objective of Directive 2010/93
The new legislation ensures that animals are used according to certain standards, and only as a last resort only because there isn’t a viable alternative method. Researchers must always apply the 3Rs principles – the least possible distress and pain, the lowest numbers and sound justification that the animals are really necessary.

Target audience of the directive
This directive governs virtually every sector that uses animals for research and development of products such as chemical and pharmaceutical industries as well as those developing cosmetic and consumer goods. Not only does this legislation affect the researchers, it also gives legal direction to lab animal breeders and transporters of lab animals.

Key legislative changes
The biggest shift in the text appears to be the move from optional best practice, to mandatory procedures. Below are some of the key changes:

Improved legislation:

• Each research project must pass a project (ethical) review. The proposed research must prove that it’s scientifically justified, and the researcher has applied the 3Rs principle of reduction, refinement and replacement. Part of the review now includes a cost/benefit assessment; showing the benefit to the patient or consumer, versus the harm done to the animal.
• The authorization system is now mandatory however most member states had this system in place already.
• The text has become clearer about the use of alternatives where they are available.
• The use of non-human primates has been restricted to essential biomedical research only.
• Some animal welfare staff are now mentioned and the role of the veterinarian and the animal welfare officer have been strengthened. There is now a requirement to have an animal welfare body within the research organization, which provides ongoing advice about, among other things, the 3Rs principles, accommodation, care and welfare of the animals and review of procedures.

New legislation:

• Member states must perform a certain number of inspections per year, some of which are unannounced.
• There are new detailed standards on caging and housing.
• The 3Rs principles are now very clearly referenced throughout the legislation, which removes any ambiguity.
• To increase transparency, research application must now include a non-technical summary outlining the process and objective of research project in layman’s terms. If the application is approved this lay summary will be published on the Internet.

All up, the legislation is much stronger than before and includes penalties for non-compliance.

Next steps
Right now all 27 member states are in the process of translating the new directive for national implementation on 1 January 2013. Over the coming months Animal Testing Perspectives will be following the activity at national level to see how the legislation is being adopted.

Related content

Finding the right balance between animal welfare & human welfare

How did we arrive at the 3 Rs: Replacement, Reduction, Refinement?

What’s in a name? Animal research vs testing vs experimentation

Testing chemicals that are used in the pharmaceutical, agrochemical and consumer-products industries to establish the likelihood of their causing cancer (carcinogenicity testing) still requires a great deal of animal experimentation, with up to 800 rodents used for each substance and around 12,500 laboratory animals used annually in the UK.

Finding alternatives to animal tests for assessing cancer risks to humans that are faster, more efficient and which benefit animal welfare is an urgently important issue, as the current carcinogenicity studies are time consuming and expensive and are of limited practical use in large-scale chemical evaluation programmes such as REACH, the European Union regulation concerning the Registration, Evaluation, Authorisation and restriction of Chemicals. In addition, the 3Rs (‘Replacement’, ‘Reduction’ and ‘Refinement’ of animal research) focus on an area of biological research where there is a real need to advance one or more of these legislation criteria concerning animal testing and research. NC3RS are confident that their grants to Professors Newbold and Jenkins will deliver tests that will benefit both animals and the industries in which they are used across the EU and Europe.

In particular, rodent cell-based in vitro tests for detecting a chemical’s potential to damage DNA and/or cause mutations (genotoxicity assays) are already used in regulatory carcinogenicity testing strategies, but are felt to be limited as stand-alone tests, due to their high rate of misleading positives (where chemicals that do not damage DNA in vivo are wrongly classified as potential carcinogens), which then require animal experiments for clarification. For more information concerning the awards, click here.

Advances in science will present some people with new dilemmas. What if new research methods mean more primate-based studies but using fewer animals overall?

The latest trends in biopharmaceuticals will make it possible to develop fragments of antibodies – some of which can be used as new therapies – without using as many mice or rats as would have been required in the past.

The early stages of research can be done using large volumes of cell samples and with the help of computer modelling, so we essentially skip the animal-intensive phase of early research where large numbers of potential therapies would previously have been tested on rodents.

Now we are moving into an era where we will find ourselves with a smaller number of candidates – let’s call them ‘could be’ therapies – which are ready for the next stage.

However, these antibodies are so highly specific to primates, the group to which we as humans belong, that testing in rodents is less likely to be succesful. Trying out new biological therapies in humans is a non-runner: some will not work; others could have serious side effects. The upshot is more primate research.

If we carry out studies using, for example, dozens more monkeys but it means thousands of fewer mice are needed, will this be more or less controversial?

Refining research methods

All of this brings me to the question of how we define progress in animal testing. In Europe, the focus has been squarely on the 3Rs – reduction, refinement and replacement.

There is, in my view, a particular emphasis on replacement. But rather than look exclusively at the absolute number of animals involved, we should consider the methods being used and the quality of science being produced.

‘Refinement’ is in danger of becoming the forgotten ‘R’. The total number of animals being used in Europe has been more or less constant in recent years but investment in science has increased and the output has also risen.

So research activity has actually increased without a major leap in the use of animals. To me, this is progress, but if you look only at the total number of animals used in research, it looks like we’re going nowhere fast.

Transgenic and humanised animals

Other developments in animal research – like the ability to breed transgenic animals in order to design highly specific experiments – have also had an impact on the quality of science. We have also been able to create mice that accept an exchange of their mouse blood with human blood, thereby creating an animal that is able to be infected with parasites that only infect human beings.

For example, it was once feared that studying how the parasite which causes malaria affects humans would not be possible using animal models. However, humanised mice allow us to do things never thought possible. These mice allow us to test new drugs that are targeted to the very parasite that causes such havoc in humans in many parts of the world.

Good news? For me, the answer is yes as it opens the door to a deeper understanding of malaria.

Others dislike the idea of creating transgenic or mutant animals because they see it as unnatural. Indeed it is. But if it’s natural to die from a mosquito bite then most will agree that ‘unnatural’ interventions are morally acceptable – if not imperative.

A new era

My point is that science is moving towards an era which will force us to confront difficult questions.

• Will we accept more primate research if it reduces the use of large numbers of rodents?
• How should we view the huge growth in transgenic and other modified animals given the potential benefits for animals and humans?

Philosophical debates, like science, often presents us with complex equations; equations which perhaps cannot be solved by reliance on simplistic interpretations of the 3Rs.

We ought to focus on the quality of our animal science rather than zeroing in on the quantity alone.

The public is uneasy about animal testing yet research advocates shun the spotlight

Animal research has been back in the news again as controversy rages over major European laws which have been recently revamped by Brussels.

New EU rules on the use of animals in medical research are also due to be introduced across Europe in 2013 but anti-vivisectionist campaigners say the revised law was watered down by MEPs who were lobbied by pharma companies. For example, a clause that would have completely banned the use of primates was amended after industry and research organisations argued that this could jeopardise essential research into Alzeimer’s and Parkinson’s diseases

Critics claim that EU research agenda is driven by commercial interests and point to the composition of the European Partnership for Alternative Approaches to Animal Testing (EPAA) as a prime example. However in fairness the EPAA was set up to be a public-private partnership between the European Commission and industry to work together to find alternatives.

‘Tell me if this hurts’

The updated EU legislation on medical research classifies pain as “mild”, “moderate” and “severe” – a deeply subjective judgement made without the facility of asking the subject. How can anyone truly know the pain of another?

This definition matters. The decision to reuse an animal which has already been subjected to tests depends on whether scientists perceive that the animal in question has already endured “moderate to severe” distress.

The leeway given to researchers is, according to the European Coalition to End Animal Experiments (ECEAA), a compromise won by vested interests. The group says that even some of the tougher aspects of EU laws will count for little unless enforcement is improved at national level.

On top of that, they say academic and industry researchers have shared very little information with the public about how and why animals are used in research. Ironically, those claiming to stand for science are accused of stifling scientific debate.

The ‘3 Rs’

There was a time when animal research was barely questioned. There were no ethics committees, no legislation and no animal rights activists. But those days are long gone.

Today, several stakeholders subscribe to the notion that the use of animals should be reduced; that animal-based research should be replaced with alternative methods where possible; and that experiments should be refined to minimise harm.

These “3 Rs” have been a guiding principle for half a century, yet there are now more animals used in research than there were then.

The trouble is the degree to which stakeholders think each principle should apply: anti-vivisectionists would like animal testing “replaced”, while researchers have found it easier to “refine” their experiments that to phase out animal testing altogether.

In addition to research designed to understand the body or to develop new medicines, animals are used as a routine part of vaccination production to test the consistency of one batch of vaccine to the next.

The Eurogroup for Animals says around 12 million animals are used for research and testing every year in Europe. It believes there is enormous scope for “replacing or refining” many of these practices and, in some cases, discontinuing them altogether.

Public perceptions

Whatever about industry groups and activists, what does the rest of the public think?

A Eurobarometer opinion poll shows the public is divided on the use of animals in experiments – even if researchers claim their work will lead to benefits for human health. This is particularly stark when people are asked whether scientists should be allowed to experiment on larger animals like dogs and monkeys for the improvement of human health.

Only 44% of respondents agree while 37% disagree. In some countries, such as Finland, Slovenia, Luxembourg and France more than half of those surveyed opposed such experiments, according to the ECEAE.

Worth the ‘sacrifice’

Animal rights groups argue that despite the millions of animals killed in the name of, for example, cancer research, medical progress has been too slow to justify the suffering.

Most experiments will not lead to medical breakthroughs and are conducted to test how animals respond to drugs, stress, foods or chemicals. Often this work adds little to scientific knowledge but the animals are killed – or ‘sacrificed’, to use the industry jargon – anyway.

Part of the reason for this, say activists, is that the genetic and physiological differences between humans and mice are greater than once presumed. Cures that work in animal models sometimes fail – or are unsafe – in humans, and vice versa.

‘Trust us, we’re scientists’

So between accusations that industry groups are lobbying policymakers behind closed doors and claims that scientists are shy about sharing details of their work, it’s clear the public have been left out of the discussion.

Expecting the public to support the use of animals in research simply because most scientists say it’s necessary will no longer wash. There’s a lot of explaining to do…

So, it’s easy to find information that points the finger at industry and the biomedical community at large. Silence has been the preferred response so far, but its time the research community to step forward to help us understand what they are doing, for whom and why.

The EPAA is an independent platform which brings together the European Commission and industry groups to collaborate on implementing the 3 Rs Declaration. It has been running since 2005 and has done a lot to bring together people who don’t talk as much as they should – like companies and regulators, or scientists and EU officials.

Last year’s event put the focus on ‘reduction and refinement’ while this time around the spotlight is on Integrated Testing Strategies (ITS) in animal research.

ITS can be tricky to define but is essentially a way to connect animal research methods, non-animal testing techniques and computer-based modelling to advance the cause of our old friends, the 3Rs.

Last month the EPAA ran a workshop on ITS so the annual conference is a natural follow-on from that.

The discussion will look at how ITS can be applied in a way that delivers efficient science-based results while reducing the use of animals, but at the same time meeting the growing demands of authorities and legal risk assessors.

Given Europe’s current obsession with innovation and competitiveness, it will be interesting to see whether ITS can really be the silver bullet that delivers all the information scientists need without compromising on speed, cost, or product safety. Plus, given that we’re in Brussels, one wonders what the EU can do to promote the use of appropriate ITS?

Can public and private stakeholders work together on non-competitive projects that will ultimately benefit all, perhaps along the lines of the Innovation Medicines Initiative?

The conference programme looks busy so hopefully we’ll get some answers on 9 November. We’ll be attending with a video to capture feedback from the day.

In this second video, Neil goes into detail on what drove his decisions that shaped the final legislation; policy regarded by some as contradictory and by others as too pro-science.

However, Neil is made of sterner stuff and I respect his final comment in the video, “I wasn’t going to be dictated by just the popular view, I was actually going to take a view that I could stand up in [sic] my conscience and live with”.

I’d be interested to hear your views on our chat with Neil, particularly his comments on the 3Rs (Replacement, Reduction, Refinement) policy. He believes the 3Rs focuses science and industry on reducing and find alternatives to using animals in research, do you?

Related content
How did we arrive at the 3 Rs: Replacement, Reduction, Refinement?

Understanding Directive 2010/63: the new legislation governing the use of lab animals

Finding the right balance between animal welfare & human welfare

After six and a half years at UAR, Simon is moving on to a new sector and new job, but before leaving I caught up with him to hear first-hand about some of the key issues that he has been trying to improve.  Poor scientific communication was at the top of his list, which I wasn’t actually expecting from him, being a supporter of science.

Simon gives an open and frank view on where the scientific community went wrong, why this happened and some concrete actions that the scientific community can do to increase their transparency to the general public.

Just as a side note, Simon uses the word anti-vivisectionists, which is often used in the UK to describe animal rights campaigners.

Enjoy the video.

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Neil Parish MP: balancing science and ethics in a political environment

What’s driving the increase in animal research?

Finding the right balance between animal welfare & human welfare