A YEAR ago, news headlines made chilling reading for clinical researchers around the world. Six previously healthy young men were fighting for their lives at north London’s Northwick Park hospital after volunteering to take part in a phase I clinical trial of TGN1412, a drug targeted at leukaemia and chronic inflammatory conditions. Although all six pulled through, one was left disabled, and they all face years of uncertainty about the long-term effects.

“It was a huge shock,” recalls Leslie Curwen, a clinical research associate with Cancer Research UK. “It has made everyone in the industry very aware of what can happen, and reinforced the idea that safety is always our highest priority.”

Clinical research was already highly regulated and had an excellent safety record, but the increasing number of biological rather than chemical drugs entering trials had started to bring new challenges. “The checks and balances are in place but we need to make sure we are more prepared for the unpredictable,” says Eric Hurden, head of clinical operations at Cancer Research UK’s drug development office.

In future, “first in man” phase I trials of molecules that are deemed to be high risk will be handled even more carefully. The UK government’s Expert Scientific Group on Phase I Clinical Trials, convened in response to the TeGenero case, recommended more rigorous reviews of such drugs before human trials are authorised, as well as more conservative criteria for determining the initial dose.

“In future, ‘first in man’ trials will be handled even more carefully”

The group also recommended that only one patient should receive the drug at a time, that investigators should plan in advance how they will treat possible adverse reactions, with emergency facilities on standby, and that there should be a national inspection and accreditation system for centres carrying out such high-risk studies.

Despite an initial flurry of enquiries, the case has led to a fall in the number of volunteers coming forward to take part in phase I trials over the past year. But “we do find the volunteers, and the studies are still going ahead”, says Charlotte Taylor, from the contract clinical research company Quintiles.

Traditionally, healthy phase I volunteers have been mainly students and gap-year travellers. Because an increasing number of studies require follow-up over several months, however, the industry now needs to find ways to recruit from less transient groups, says Taylor.

Those healthy volunteers account for only a small proportion of people who take part in clinical trials, however. Most participants are patients suffering from the target disease, who are testing drugs that have already been through phase I. There are no signs that such patients have been put off these trials, explains Carol Aliyar, UK director of clinical research at Quintiles.

The TeGenero incident certainly raised the public profile of clinical research. But behind the glare of such publicity, the reality of everyday life as one of the UK’s thousands of clinical researchers is miles away from such controversy. For them, a typical week might involve two or three days on the road, visiting trial sites to check that investigators are sticking to the trial protocol and that patient recruitment is on target. Communicating with busy doctors, nurses and pharmacists has to become a finely tuned skill.

“Everyday life for clinical researchers is miles away from controversy”

Time in the office is spent completing the paperwork from visits, writing up progress reports and helping to set up new trials. Senior researchers can move over into project management, and may eventually find themselves running international trials with thousands of patients.

Life is dominated by two acronyms: GCP (good clinical practice) and SOP (standard operating procedure). Since any failure to comply with these could mean the results of a trial being declared invalid, researchers need a very good grasp of the regulations, which were tightened up further in 2004 by the European Clinical Trials Directive. “The regulations are definitely getting stricter, but they are necessary given the nature of what we do,” says Curwen. For clinical researchers this inevitably means more paperwork, with extra forms to fill in and new information to gather.

A second and more frustrating layer of bureaucracy for British researchers comes from dealing with the National Health Service. In 2004, fears that increasing red tape, coupled with competition from Asia and Eastern Europe, would drive research away from British shores led to the creation of the UK Clinical Research Collaboration. The CRC brought together the NHS, industry and academic sector research, with the aim of encouraging clinical research in the UK.

So have the subsequent initiatives produced any results so far? “It’s early days,” comments Aliyar, “but in some areas we have already seen a difference. For example, the Model Clinical Trial Agreement (a standard contract for sites participating in trials) is now accepted almost universally in the UK, and that has helped.”

There is also more transparency about just how much a trial costs. In the past, sponsors often ended up paying indirectly for routine aspects of patient care that were outside the trial. This no longer happens, and, as a result, UK trials are more competitive than they were five years ago, says Aliyar.

Cancer Research UK’s Hurden is cautious, however. “These initiatives will have a positive effect in the end, but we need to define exactly how they are going to work. We need to make sure the money is there.” Cash-strapped NHS trusts may divert money that is supposed to be ring-fenced for research, he says.

And each trust still wants to modify the standard contract used in trials. “If you have 10 sites you still need 10 agreements, but that is true globally. The UK is no worse than anywhere else,” adds Hurden.

Ask the Swiss what they see as their most important resources, and the response will likely be: “the mountains and our brains”. Skiers and scientists alike would agree that this is a country with much to boast about both.

You do not need to look far to discover why researchers view this tiny, landlocked country with such enthusiasm. For a country with a population the size of London, it punches well above its weight. Switzerland’s R&D spending sits at 2.7 per cent of its GDP – roughly the same as the US figure and second only to Scandinavia in Europe. Switzerland also has an impressive number of indigenous world-class companies. For example, Novartis and Roche are the world’s seventh and tenth-largest pharmaceutical companies respectively. So how has it achieved its success?

The lack of obvious resources has forced the country to focus on high-value speciality products that it could sell to the rest of the world. It’s a strategy that helped turn it into one of Europe’s richest countries.

Switzerland’s three flagship science-based industries – pharmaceuticals, biotechnology and speciality chemicals – have benefited from this astute approach. And the second-tier concerns are also strong, from crop protection and materials science to mechanical and electrical engineering and communications technology.

Beyond borders

Switzerland may guard its political and cultural independence fiercely, but its scientific sector has a strongly international flavour. Companies and academic institutions actively work to bring in expertise from all over the world.

In recent years, the Swiss government has made boosting international collaboration a key part of its science strategy. For example, Swiss scientists can compete for funding from the European Union’s Framework programmes for research, even though Switzerland is not an EU member. What’s more, work and residency restrictions have been relaxed for EU citizens in Switzerland, and from May 2007, there will be no limit on the number of EU workers allowed into the country.

It is in Swiss universities that a willingness to welcome researchers from outside its borders is most evident. A fifth of students and a third of academic staff are foreigners. In the leading scientific research institutes the figures are even higher: Basel’s Friedrich Miescher Institute, for instance, counts almost 40 nationalities among its 90 PhD students and 75 postdocs.

Swiss institutions work hard to attract and retain high-calibre researchers. The main science funding body, the Swiss National Science Foundation (SNF), funds assistant professor posts for selected researchers of any nationality starting an academic career. In addition, over 7000 researchers receive project-based funding each year. The Federal Institutes of Technology in Zurich (ETHZ) and in Lausanne (EPFL) are bolstering these efforts with tenure tracking. Assistant professors in the scheme are offered a tenured professorship within six years, subject to a performance evaluation.

Academic salaries are some of the best in Europe. Experienced postdocs earn up to 100,000 Swiss francs (£44,000) per year, while a full professor could earn as much as SFr270,000. This above-average level of pay, combined with the quality of the science and standard of living, means researchers rate Switzerland highly. For example, the Friedrich Miescher Institute has recently been voted the best place to work for postdocs outside the US in a survey by The ��è����Ƶ magazine.

Crack the system

Pharmaceutical companies worldwide are keeping an eye on the emerging field of systems biology because of its potential for finding safer, more effective drugs. Systems biologists aim to gain a big-picture view of complex biological systems by studying interactions between components such as genes, proteins and signalling molecules. Modelling these systems could help us understand how a drug will act.

So it should come as no surprise that Switzerland – with its strengths in life sciences and computing – is at the forefront. Two of Switzerland’s biggest pharmaceutical firms, Roche and Novartis, along with the universities of Basel and Zurich and ETHZ, are backing a new network to coordinate Swiss research and teaching in the field. The network joins four “nodes”, with another two in the pipeline. A key node will be the new Centre for Biosystems at Basel, due to open in June 2006 with at least 15 professorships. It is hoped that more universities will join to create a world-class European research hub to rival America’s.

Bio benefits

You may not see it until you look closer at the figures, but Switzerland is a world-beater in biotech. If you measure success by number of companies, the country falls short – it has only around half the tally of Germany or the UK. But look at the money coming in, and you’ll see that Switzerland’s biotech industry is second only to that of the US, and accounts for a massive 40 per cent of European revenues in this area. Switzerland also employs more people in the sector than might be expected, with 1 in 3 of the biotechnology jobs in Europe.

Its top ranking is largely thanks to Serono, the largest biotech company in Europe and third largest in the world, after US giants Amgen and Genentech. The country’s excellent science base, well-organised technology transfer and the proximity of big pharma companies are key to its biotech success, according to Ernst & Young.

Other big players include Actelion and Basilea Pharmaceutica, both based in or near Basel. Arpida and Addex Pharmaceuticals are among the rising stars. Several large US biotech companies also have Swiss outposts. Behind the seven publicly traded companies are 20 medium-sized biotechs employing 50 to 100 people, and 100 or so smaller companies.

Biotechnology companies are found in four main clusters (see Map). The largest grouping, around Basel, forms part of BioValley, a biotech cluster covering adjoining areas of Switzerland, France and Germany. Smaller clusters are located around Zurich in the north and Geneva and Lausanne in the west.

Smashing stuff

Switzerland is world capital of particle physics – a position it will cement in 2007 with the opening of the world’s most powerful particle accelerator. The Large Hadron Collider is a global collaboration sited near the Geneva headquarters of CERN (the European Organisation for Nuclear Research).

It will accelerate beams of protons in a 27-kilometre ring, then smash them together in an effort to spot hitherto undetected particles. High on the wish list will be the Higgs Boson, thought to play a key role in endowing other particles with mass.

In the coming months, CERN scientists and engineers will begin making their final tests on the massive instruments used to detect the particles, before closing off the caverns in which they are housed ready for next year.

Funding remains the number 1 hurdle for British biotechnology firms. Getting the cash to move promising science into commercial development is now harder than ever.

The conventional business model has been to persuade investors to back fledgling firms based on unproven science. Now many industry watchers are asking whether this model needs to change. Seed funding is in short supply, and venture capitalists, who traditionally bankrolled companies after the seed funding ran out, have become reluctant to risk their money without some data to show the firm’s product could work. This trend means that the gap between the haves and have-nots is set to grow.

But new strategies are emerging that should help keep the funding coming in. One is to bring in experienced business managers to guide products from academic labs through the early stages of development. These managers provide reassurance to investors by being sufficiently detached to pull the plug on all but the best prospects.

Investor caution also means later-stage biotechs are finding it harder to float on the stock markets. As a result, selling out to a larger company is set to become a more popular option in 2006. With big pharmaceutical companies currently cash-rich but product-poor, good science will attract buyers.

Traditional funding can still come up with the goods, however. This May saw one of the largest European venture capital investments of recent years, when Oxford-based Oxagen raised £31.6 million to fund development of drugs for asthma and other inflammatory conditions. Nevertheless, companies know they need alternatives to survive.

A new strength

The government has thrown its weight behind efforts to make the UK a leader in bioprocessing – the methods used to manufacture biopharmaceuticals and vaccines.

Historically the UK has had a strong record in this area. Lack of strategic coordination has threatened to allow this early lead to slip away, but this year a raft of initiatives were announced to boost the sector.

The latest of these is the Bioprocessing Research Industry Club (BRIC), which has allocated £10 million over five years to bioprocessing research that benefits industry. The bulk of the cash is coming from government-funded research councils, with industry contributing £1 million.

Meanwhile, construction workers in Speke, near Liverpool, are putting the finishing touches to the National Biomanufacturing Centre, which is financed by £34 million of public money.

The centre will fill a crucial gap when it opens in January 2006. Small companies with limited funds often struggle to make enough of their drug to enable proof-of-concept trials, especially as all clinical trial material must now have quality certification. The centre will provide these facilities and will also offer specialist drug development expertise. “We have people with real-life experience of taking biotechnology drugs right through development to regulatory approval,” says Derek Ellison, the centre’s business development director. Ellison earned his stripes at Medeva, one of the UK’s leading biotechnology companies before it was acquired by another UK firm Celltech in 1999. Cash-strapped biotechs can apply for grants of up to £68,000 to use the facility.

Britain on trial

A rising tide of paperwork demanded by regulators has led to a fall in the number of clinical trials being conducted in the UK. “You can get trials up and running in the US in the time it takes to begin patient recruitment in the UK,” says Aisling Burnand, chief executive of the BioIndustry Association. “We need to improve the system.” The main bottleneck is local NHS Trusts’ R&D offices, which have to approve every trial conducted on their patch. Industry wants more coordination between the trusts to avoid duplication and delays.

The flow of R&D investment out of Europe and into the US is a continuing concern. But it is not entirely one-way traffic. In September, the US biotech giant Genzyme unveiled an R&D centre in Cambridge, its first outside the US, and also announced an expansion of its UK manufacturing activities. And the US pharma and biotech major Wyeth has said it intends to make a significant investment in medical research at UK universities.

There had been fears that extra regulatory requirements contained in the European Union’s Clinical Trials Directive would decimate clinical research when it was implemented in 2004. Public sector research is having problems because of the extra layers of bureaucracy it has brought, but so far the biotech industry is managing to live with the directive, Burnand says.

The UK also has a unique clinical trials resource that offers a bright prospect for the future: the NHS patient database. Unlocking its research potential is a key aim of the UK Clinical Research Collaboration, a partnership formed in 2004 between industry, government, public-sector research funders and the NHS. Industry will need to cut through the red tape first.

White heat

High oil prices this year have sparked renewed interest in industrial biotechnology, otherwise known as “white” biotech, which uses enhanced microorganisms to transform renewable feedstocks into products such as detergents, biofuels, bioplastics and speciality chemicals. Other white biotech products include enzymes and biocatalysts for producing textiles, paper and leather. Some observers believe biotechnology’s greatest long-term impact may be industrial rather than medical, or “red”, biotech. Consultants McKinsey & Company predict that biotechnology could be used in up to 20 per cent of chemical production worldwide by 2010.

With little cash available for white biotech start-ups, the large chemical companies have so far been its main advocates. But there are signs that this may change, with Axiom Venture Capital setting up Europe’s first specialist white biotech venture capital fund. The UK is among the handful of European countries that is well organised to take advantage of this fledgling sector.

White biotech R&D will get a major boost from The University of Manchester’s £25 million Centre of Excellence in Biocatalysis, Biotransformations and Biocatalytic Manufacture (otherwise known as CoEBio3), due to open in late 2006. Housing around 120 researchers, the facility will take bench-scale processes and ramp them up to commercial levels, so companies can make substantial amounts of their products, says CoEBio3’s director, Stan Roberts. “The centre is unique, with no equivalent set-up in the US or mainland Europe. For once we are in the lead position.”