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Profound delays in the approvals process for clinical trials mean doctors face months of form-filling and administrative checks that make it impossible to run crucial tests in good time, said Jeremy Farrar, in his first major interview as director of the Wellcome Trust.
Farrar, a world expert on infectious diseases at Oxford University, has taken over from Sir Mark Walport, who left the medical charity to become the government's chief science adviser.
Farrar's warning is backed by other senior figures including Sir Michael Rawlins, president of the Royal Society of Medicine, and Prof Peter Openshaw, who advised the government during the pandemic flu outbreak in 2009.
Farrar said the unwieldy system puts public health at risk, particularly when pandemic flu and other infectious diseases strike, because doctors have no idea which interventions work.
"The systems we have got in place are not fit for purpose when the situation is moving quickly," said Farrar. "We have nothing that enables us to respond in real time."
The Department of Health on Monday approved proposals from the Health Research Authority to streamline clinical trials, but some leading experts argue that far more work is needed within the NHS to fast-track trials in an emergency.
An emerging infection such as bird flu, Sars or pandemic influenza could spread across Britain and burn itself out within the space of eight weeks.
But doctors hoping to test drugs or other interventions in patients can face delays of more than a year before they can recruit a single case.
The delays mean that doctors have almost no hope of learning which treatments might save lives during an outbreak because patients will have recovered or died before a trial can start.
Farrar said the system needed a radical overhaul so emergency trials could launch within 24 hours of an epidemic emerging. "Getting this information early on is critical to inform what we do and how we treat patients. Without it we are completely in the dark," he said.
Pandemic influenza is considered the most serious civil emergency risk that Britain faces, but other infections, such as novel coronaviruses and the alarming rise of drug-resistant pathogens, are also a serious threat. Clinical trials need formal approval from the NHS and other bodies before doctors can recruit patients, but the process is held up at almost every stage. Researchers must apply for grants, submit study protocols and patient consent forms, gain ethical approval, find hospitals with the right facilities, equipment, supplies, staff and patients, and then sign legal contracts with them all.
The process is necessarily thorough to protect patients and hospitals from litigation. Trials can go spectacularly wrong, as happened in 2006 when six young men were nearly killed by an experimental drug in a trial at Northwick Park hospital in north London.
The 2002 Sars pandemic killed 774 people and infected more than 8,000. Had the virus not been contained it could have killed far more. The reason the death toll was not higher was that patients were most infectious when they were most sick, so isolating the ill stopped the virus spreading.
"There is no doubt we were very lucky with Sars," said Farrar. "But nobody knows where it has gone and we don't have a vaccine. If it were to come back tomorrow and I got infected, the doctor treating me wouldn't have a clue which drug, if any, to give me."
Without hard evidence, the government's preparedness rests on educated guesses. The Department of Health spent £424m stockpiling Tamiflu (oseltamivir) for a flu pandemic. But the lack of trials in sick patients means doctors disagree on how well the drug works.
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© Chris Radburn/PAThe DoH spent £424m stockpiling Tamiflu for a flu pandemic but the lack of trials in sick patients means doctors disagree on how well the drug works.
Sir Michael Rawlins, president of the Royal Society of Medicine, who chaired the report, said progress was disappointing. "It's going in the right direction, but it's painfully slow," he said.
The Health Research Authority was set up in response to the AMS report and charged with streamlining approval times. It has already cut delays that held up ethical approval. One change was to hold weekly meetings of ethical committees to consider and approve trials submitted in the days beforehand, and a system for convening ethical committees virtually when a trial is urgent. One trial to look at the effect of a vaccine in pandemic influenza received ethical approval in two days.
But the major delays are not with ethical approval, but sign-off from the NHS centres that host trials. It is here that the HRA proposals aim to make their greatest impact. Instead of individual NHS hospitals duplicating each other's work by independently reviewing, querying and finally approving a trial, the HRA will act as a central authority, giving a single sign-off for all participating hospitals.
Relieved of that workload, hospitals can focus on the practicalities, such as obtaining trial drugs and making sure patients are enrolled. If the health department agrees to the plans, a simple trial could be approved within 25 days.
"We will give researchers a lot more confidence that the NHS can respond if the HRA is doing the greater part of the approving," said Janet Wisely, chief executive of the HRA.
She said that ultimately, they should be able to approve emergency trials within 24 hours. "If you are intending to treat someone in a 24-hour timeframe then research should match that. It's a challenge, but it's what we should aim for," she said.
Farrar wants more trials pre-approved so that doctors can start emergency tests in patients the moment an outbreak is identified. "We need generic protocols which have been pre-approved by ethics committees and institutions at a national level. All the information, from what samples to take to the forms we'd record patient data on, would be openly available. Then, in an emergency, a group that has worked on the top three or four interventions can start enrolling patients within 24 hours," he said. "There are groups trying to address this, but it's nowhere near there yet."
Lessons from 2009
Bureaucracy and delays ruined plans for a drug trial during the global flu pandemic in 2009, which killed an estimated 200,000 people around the world. Peter Openshaw, director of the centre for respiratory infection at Imperial College's National Heart and Lung Institute in London, hoped to launch a trial that May, a month after the virus emerged. But it took eight months to enrol the first patient. By then the first wave of the pandemic had passed and the second was waning. Most patients were recruited the following year.
"The projections were that this was going to be a single-wave pandemic, that it would all be over in six months. If that had been the case, we wouldn't have recruited a single case," Openshaw told the Guardian. "It is absolutely crucial that we do better next time."
Openshaw's study hit the buffers from the start. The grant took several weeks to win. Imperial College then refused to commit staff until the money had cleared its account. A doctor who had a "research passport" that should have allowed him access to patients in different London hospitals was held up because each hospital required different occupational health checks. Openshaw needed a legal agreement with all 11 hospitals involved in the trial, but each hospital's legal department requested its own changes to the contract, and some even demanded separate contracts with all the other hospitals involved. It took months to sign the agreements.
The delay was exacerbated by lawyers putting the work on hold for their summer holidays. "We were feverishly trying to get the study ready, but from a legal point of view, it was just another bit of work that stopped for the summer," Openshaw said.
Openshaw's 2009 flu trial hoped to reveal why some people who caught the pandemic strain became seriously ill and died, while others had a far milder infection. The strain turned out to be less dangerous than many had feared, but that was down to luck, said Farrar. "With that pandemic it didn't particularly matter in the sense that it didn't kill us all. But you can imagine a different epidemic where getting information early on is going to be absolutely crucial," he said.
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