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Two United States institutions wield enormous power over healthcare in the US and around the world. The US Food and Drug Administration has the authority to approve, supervise and withdraw drugs, medical devices and food across the world’s single largest market, while the National Institutes of Health, with an annual $30bn scientific research budget, is the envy of its global peers. With the growing pace of scientific discovery, the globalisation of the pharmaceutical industry and a more science-friendly administration in Washington, the two organisations are building their domestic power and broadening their international focus.
Margaret Hamburg had scarcely begun her work as commissioner of the US Food and Drug -Administration over the summer when she travelled to meet her counterparts at the European Medicines Agency in London.
The trip symbolised a strengthening appetite for international cooperation between the FDA and the EMEA, at a time when the globalisation of medical products has highlighted continuing regulatory differences and made the demands for co-operation greater than ever before.
It also reflected a fresh sense of self-confidence and willingness to communicate externally at the US agency, after several years of unstable leadership and internal demoralisation in the face of criticism from politicians, lawyers, companies and medical researchers alike.
“Over the past eight years, there was only a true, confirmed commissioner for three and a half years,” says Kenneth Kaitlin, director of the Center for the Study of Drug Development at Tufts University in Boston. “That was very little time for someone to serve as the face of the agency and articulate its views to the public and Congress. It was open season for the critics.”
Now, with new leadership in place and a more supportive political environment with Democrats in the White House and Congress, as well as fresh funding, attention is again turning to addressing gaps between the US and EU systems, whether measured in the style, speed or results of their scrutiny. The conse-quences are important for patients and companies alike in two of the world’s most important healthcare markets.
In the second half of the 20th century, the FDA often distinguished itself by scrupulous use of science to make measured, cautious judgments. The persistent concerns of its employee Francis Kelsey meant thalidomide – a medicine sold over the counter for morning sickness in Europe – was never approved in the US, in spite of corporate pressure.
Kelsey was awarded a presidential medal for her efforts, which ensured American children were spared the fate of thousands of those born in Europe with stunted arms and legs, and many other physical problems. Legislation was rapidly altered to ensure tougher standards were imposed on both continents for future medicine approval.
Yet in the decades that followed, some saw a downside to the FDA’s caution. It led to criticism of a “drug lag”, with the US often slower to approve medicines than Europe’s then disparate national approval systems. The pharmaceutical industry pushed for greater clarity and rapidity in decisions.
During the 1990s, with the introduction of industry user payments for regulatory submissions (a practice also applied at the newly formed EMEA), the criticism of excessive caution faded. New incentives for accelerated review were also introduced to encourage drug companies to develop “orphan” drugs for rare diseases.
However, the renewed enthusiasm came under fresh attack in late 2004, after Merck voluntarily withdrew its painkiller Vioxx after fears it could increase heart attacks. That sparked an explosive debate about whether the FDA should have been more sceptical and cautious in its scrutiny, and pushed the agency back on the defensive.
Peter Pitts, a commentator and former FDA official, says: “In the late Bush era, all applications were given a ‘complete response’,” the agency’s letter -deferring a decision as it seeks more information. “When the political heat was on, there was greater reluctance to make a judgment that was not clear cut. Career staff were scared of their own shadow, and would not take decisions.”
For example, only this autumn did the FDA approve GlaxoSmithKline’s Cervarix, a vaccine to prevent cervical cancer – the first time in more than half a century that it had approved a novel “adjuvant”, an additive designed to boost the human immune response.
It has yet to authorise any flu vaccines with new adjuvants, although the EMEA has approved such products for years, and despite the public health gains of using the additives as a way to spread scarce supplies of vaccine more broadly.
Andrew Baum, pharmaceutical analyst at Morgan Stanley in London, says: “The EMEA goes at a good, steady pace, like a mountain goat. The FDA is like a bipolar rabbit, sometimes in a stupor and at other times bolting forwards very fast. Now we are starting to see the -science take precedence over the politics again.”
Yet such transatlantic comparisons are fraught with difficulty. Vioxx was approved by regulators in both regions, for instance, but it was subsequently marketed much more aggressively by Merck in the US. That resulted in more widespread use among patients who, along with relatives, responded aggressively in a more litigious culture by suing as side effects emerged.
The EMEA appeared quicker and less cautious when approving rimonabant, Sanofi-Aventis’s weight-loss drug, in 2006. The FDA delayed approval, ultimately refusing it entirely on concerns it triggered suicidal feelings – leading the company to abandon the medicine entirely.
Thomas Lönngren, head of the EMEA, points out his agency’s swifter approval reflected Sanofi-Aventis’s decision to file the drug for European scrutiny long before it did so in the US. That meant a decision based on less data. Subsequent experience in patients indicated lower efficacy and more side effects than in the original clinical trial results. “It was about clinical trials versus reality,” he says.
More generally, he argues today “there are not so many differences in judgment” with the FDA. The US regulator has traditionally required different types of “end points” to measure efficacy of medicines, and sought comparison with placebos, where the EMEA has preferred an “active comparator” against the existing best drugs.
That is now changing, as the two regulators converge in many ways. The EMEA was slower to introduce incentives for orphan and paediatric drugs, but quicker to have a regime that scrutinises drugs destined for developing countries and introduce systems to assess biosimilars – generic biological drugs. That debate remains contentious in the US.
As both regulators discussed how they could work more closely with industry and academia to adapt to evolving science and make judgments more effectively, the US came up with its Critical Path collaboration for stream-lining drug approval earlier. The EU has since launched its Innovative Medicines Initiative, and some see that moving more quickly than the US programme.
Now Lönngren sees further convergence in standards, and co-operation that could lead to common application forms and identical requests for information, thus easing the burden and cost of conducting separate clinical trials in different markets.
Over the past five years, he can point to a confidentiality agreement between the two agencies that has helped their joint work and sharing of information. Pilot projects are under way on joint inspections to assess good manufacturing practice, good clinical practice and scrutiny of the producers of active -ingredients used in pharmaceuticals.
Josh Sharfstein, Hamburg’s deputy, says: “Our hope is that by having better scientific tools, we can make better judgments.”
Abroad, the FDA has now opened small offices in India and China, and continues to support a secondee with the EMEA in London. Yet in the coming months, much of the agency’s focus will be domestic – alongside new money and staffing, it has new responsibilities in food labelling and tobacco.
Pitts argues the agency still faces enormous challenges in updating its computer systems and adapting to an era of biological medicines.
As for international convergence, he adds it too has limits. “Different nations need different bodies to be held accountable,” he says.
The scientific world is benefiting from the National Institutes of Health’s recent windfall. By Clive Cookson
The US National Institutes of Health has long been the world’s great powerhouse of biomedical research, with a budget that far exceeds those of comparable agencies elsewhere.
For this year and next, that power has been supercharged, with the addition of $10.4bn from President Barack Obama’s Recovery Act economic stimulus package on top of the NIH’s $30bn-a-year regular budget. Compare that with the UK Medical Research Council, Britain’s counterpart to the NIH and one of the few other international research organisations with similar remit, which spent £700m ($1.16bn) on research in 2008-09.
Beyond the US, the NIH is an engine that drives global bioscience. It adopts an open attitude to the outside world and, like federal research agencies in other fields, funds scientists in many other countries.
Biology’s biggest research effort so far – the $3bn International Human Genome Project, which culminated in 2003 with the completion of a finished sequence of the 3bn chemical “letters” that make up our genetic code – was led by the NIH, under the direction of Francis -Collins. In July, Obama appointed him to manage the agency.
Distributing the stimulus money has been an organisational challenge. For the US fiscal year 2009, which ended on September 30, the agency awarded more than 12,000 Recovery Act grants worth $5bn, including 1,800 to researchers who had never before had an NIH grant.
The NIH had expected at most 5,000 applications for its flagship Recovery Act programme, the Challenge Grants. “We received more than 20,000,” says Dr Collins. “But the NIH scientific staff was exhilarated, not dismayed. They recruited 15,000 reviewers and instructed them to aim high in identifying the most innovative proposals. They counselled anxious applicants and, once the rigorous reviews were completed, NIH staff processed the awards in record time.”
In the end, the NIH could only fund roughly 3 per cent of the Challenge Grant applications. The overwhelming -response from scientists illustrates “the pent-up demand that had been building over five years of flat budgets”, Dr Collins told the magazine Science in a recent interview.
In fact, total NIH spending during the last five years of the Bush administration rose from $27bn in 2003 to $29.3bn in 2008, though that amounted to a cut of almost 20 per cent in terms of buying power, according to Dr Collins, because of the cost inflation in biomedical research.
Of course the problem with a one-off gush of money is what happens after the flow is turned down again. Clearly the Recovery Act funds will not relieve much of the pent-up demand from US medical researchers. Many scientists who went to the trouble of preparing -Challenge Grant proposals and did not win funding will rework their applications and submit them again for regular funding next year, when less money will be available.“
There is much discussion about the NIH falling off a cliff,” Dr Collins conceded in another interview, with the New England Journal of Medicine. “Scientific research is not a 100-yard dash; it is a marathon. Two years is way too short to take a cool idea and develop it to some sort of end point … The feast-or-famine scenario has to be the worst possible thing for medical research.”
So, Dr Collins is already making the case with the White House for giving the NIH the biggest possible budget in 2011 after the economic stimulus funding has run out. “Of all the arguments for increasing the NIH budget, the one I come back to and that most people resonate with is scientific opportunity,” he says. “There are unique opportunities to understand the fundamentals about how life works and how disease occurs.”
However, he told Science, “there’s going to be a lot of people making the case for why their particular part of the government is a uniquely wonderful investment. At the same time, we have an economy that continues to struggle; we have a deficit that has now grown to something like $9,000bn. The scientific community should not in any way imagine this is going to be easy.”
The fact that NIH grants are hard to obtain, even for established US scientists, means the economic stimulus funding has brought no rush of biomedical researchers from abroad. Jürgen Mlynek, president of Helmholtz Association, the German public research organisation, says the brain drain of the 1990s from Europe to the US had reversed during the Bush administration – and not resumed under Obama.
The latter’s nomination of Dr Collins as NIH director at the age of 59 came as no surprise. He was the best-known figure in the organisation, having served from 1993-2008 as head of the National Human Genome Research Institute (NHGRI) – one of 27 individual institutes and centres that make up the NIH. (Roughly 10 per cent of the NIH budget goes to “intramural” research in its own labs, while 83 per cent is for “extramural” research, mainly in universities.)
His scientific enthusiasm is personalised medicine – tailoring diagnosis and treatment to the patient’s genes – and his book The Language of Life: DNA and the Revolution in Personalised Medicine comes out next year.
Dr Collins is among a minority of senior scientists who have made a con-sistent and public proclamation of their Christian faith. His book The Language of God: A Scientist Presents Evidence for Belief spent many weeks on the New York Times bestseller list in 2006.
Although there was some discussion about whether Dr Collins’s religious views would influence his leadership of the NIH, he insisted they would not – and the US scientific community believes him. He has made clear his faith does not -extend to belief in creationism or “intelligent design”.
Nor, fortunately, does it lead him to reject research on -human embryonic stem cells. A new departure for the NIH this year is the ability to fund stem-cell research on a scale that was not possible under the Bush administration, which imposed severe restrictions on the work.
The NIH issued guidelines for a more liberal stem-cell policy in July and is now gearing up for an expanded programme to combine embryonic stem-cell research with work on “induced pluripotent stem cells” – made directly from adult cells without involving an actual embryo.
Although it is too soon for NIH-funded stem-cell research to have produced much in the way of results, on October 28 the agency was able to announce success from a project at Stanford University. Researchers there discovered how to transform human embryonic stem cells into germ cells,
the precursors to sperm and eggs. The advance, published in the journal Nature, will allow researchers to observe human germ cells – previously inaccessible to science – in laboratory dishes, which could be important for studying infertility.It should not be too long before the NIH becomes a global powerhouse in stem-cell research, as it already is in so many other fields of biomedical science.