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Patients fared worse than expected, but scheme continues

* Experts say drug firms were main beneficiaries

By Kate Kelland

LONDON, June 4 (Reuters) - A scheme enabling multiple sclerosis patients to get expensive drugs paid for by Britain's state-funded National Health System has been a "costly failure", health experts and economists said on Friday.

In a series of commentaries in The Lancet, health economists said the scheme had wasted an estimated 50 million pounds ($74 mln) a year since its 2002 launch and should now be abandoned.

The drugs included in the scheme were Biogen Inc's (BIIB.O), Avonex, Bayer's (BAYGn.DE) Betaseron, and Merck KGaA's (MRCG.DE) Rebif, as well as Copaxone from Israel's Teva Pharmaceuticals (TEVA.TA).

"The scheme was a success for the drug companies, who sold at close to full price to the NHS," said James Raftery, a professor of health technology assessment at Southampton University. "For the NHS, however, the scheme can be judged only a costly failure."

Raftery said an assessment of the scheme in 2009 by its scientific advisory group, which included the drug firms, found that patients fared worse on the drugs than had been expected, suggesting the medicines were not cost effective. Yet the panel decided to continue with the project.

The risk sharing scheme was set up by the government in 2002 to make disease-modifying multiple sclerosis drugs available on the NHS after the country's health costs watchdog, the National Institute of Health and Clinical Excellence (NICE), ruled that they were not cost effective.

Under the terms of the scheme, the government agreed to pay for the drugs on the NHS while research was carried out to assess their long-term cost effectiveness. The agreement was that the NHS would then gradually stop paying for the drugs if patients did not appear to be benefiting.

In 2009, seven years after the scheme was set up, the first analysis of the data published in the British Medical Journal showed that patient outcomes were worse than predicted, but the scheme's scientific advisory group said it was too soon to reduce prices without further analysis.

Christopher McCabe, a professor of health economics at the University of Leeds, said in a separate analysis that the decision to delay a price review was not justified.

"It is difficult to see how they can justify such an expensive divergence from the scheme rules," he wrote.

Both experts, whose commentaries were also backed by several colleagues, questioned the independence of the advisory group, which included patients, doctors and drug firms.

McCabe added that if a proper assessment had been done after the first two years of the scheme, the NHS could have already saved around 250 million pounds ($369 million).

But Alastair Compston a professor of neurology at Cambridge University, who helped set up the scheme, argued that although it had not been run entirely properly or adequately governed, it had helped patients.

"Regardless of the scheme's outcome, it has advanced the situation for people with multiple sclerosis," he wrote. "Now that the principles of when and who to treat are better understood, more effective treatments can be developed." (Editing by David Cowell)

The first report on the scheme was published in late 2009, with details of patients’ outcomes for 2005-7.3 Disease progression was not only worse than predicted by the model used by NICE,1 it was worse than that in the untreated control group. The primary outcome—the difference between actual and expected benefit as a percentage of expected benefit—was 113%, well above the 20% tolerance for price changes (any value above 0 indicates that benefit is less than expected). The report stated "the outcomes so far obtained in the pre-specified primary analysis suggest a lack of delay in disease progression."3


Other aspects of the scheme must also be questioned. Firstly, designed to confirm cost effectiveness, it seems to have been unprepared for the possibility that the drugs would be ineffective, something noted in 2003.14 The use of historical controls was an inherent part of the scheme, which was accepted and refined by the scientific advisory committee in 2002. The decision to pursue "alternative sources of data of progression in untreated patients"3 at this stage is extraordinary. Secondly, the design of the scheme around the Sheffield cost effectiveness model used by NICE has proved difficult. Several assumptions in the model did not hold in the scheme. One was that those patients whose disease progressed would discontinue taking the drugs—many did not. Another assumption, necessitated by the way the historical control data were reported, was that treatment could at best only slow the decline in patients’ disability scores. In the scheme, 38% of patients had improved scores at one year. However, the limitations of the extended disability status scales as a measure of disability were noted around the start of the scheme.14

None of these problems constitute compelling reasons for disregarding the terms of the scheme, which specified using the two year results to set the price. The fact that the prices would have had to be cut to zero (given outcomes were less than those of the controls) is hardly a reason for not proceeding. If patients are to continue to receive drugs through the scheme, big price cuts seem necessary.

The scheme was a success for the drug companies, who sold at close to full price to the NHS. It has also been a success for the companies making natalizumab (Biogen Idec and Elan International), which would not have been recommended by NICE in the absence of the scheme.

For the NHS, however, the scheme can be judged only "a costly failure"11 as suggested by the House of Commons Health Committee which has been raising concerns about the Scheme for several years. The biggest losers are the other NHS patients who would otherwise have benefited from the money spent on the scheme.

Several assumptions in the model did not hold in the scheme. One was that those patients whose disease progressed would discontinue taking the drugs—many did not.

zap wrote:oh, man am I glad I never bought into the fear-based drug pushing when I was diagnosed!

....Thus the only outcome measure that remained was relapse frequency—and this was unambiguously reduced in patients undergoing treatment in the risk sharing scheme. However, total relapse numbers do not predict the time to disability or death. Although relapse frequency in the first two years after onset has some association with long term outcome,8 participants in the pivotal trials of interferon and glatiramer acetate had disease durations of several years.1 3

Long term data

Although the drugs have been licensed for 20 years, we still have no clear evidence on long term outcome. This is because the FDA failed to tie approval of interferon to mandatory follow-up for hard outcomes in the original trial patients, as had been suggested, and did not enforce its requirement for validation of the original surrogates.9 The agency, beset by aggressive criticism from Congress, shifted the onus for gauging effectiveness onto practising physicians. Many US and EU physicians failed to perceive the added responsibility. A Cochrane review had conceded very short term efficacy only. 10 Evidence from more recent long term studies is not definitive and ascertainment is suboptimal.11 12 13

The sobering interim findings from the risk sharing scheme spotlight important broad issues about the importance of determining efficacy in chronic diseases, in particular, the methods required to do this. The scheme also emphasises the "fragility" of adopting surrogate outcomes of impact. Shortcuts are wanted and needed, but measures with face validity and formal validation remain essential.

None of the proffered reasons for delaying the price review withstand critical assessment. So why does the scientific advisory group consider a price review to be premature.4 The answer may lie in the governance arrangements of the scheme. The manufacturers, patient groups, clinicians, and the Department of Health are represented on the scientific advisory group. All these bodies have a vested interest in maintaining the status quo. The budget holders, who pay for these drugs, with responsibility for the health of populations served by the NHS, are not represented on the scientific advisory group, and as a result there is no countervailing influence on the group’s decision making. To be truly independent, the scientific advisory group should resemble the data monitoring committee of a clinical trial. Without such independence, hard decisions, such as recommending a price reduction or closure of the scheme, are unlikely to be made.

The delay in the publication of these results is a further cause for concern. Depending when the majority of patients started treatment, the first analysis has reported between two and five years after the data became available. The annual drug cost of the scheme is reported to be around £50m.8 If an assessment had been completed after the first two years, the NHS could have saved up to £250m already. Why has it taken this long? Again, the answer may lie in the governance arrangements. Day to day management of the scheme is the responsibility of the Multiple Sclerosis Trust, which campaigned for funding of these treatments and appealed against the NICE recommendation that these treatments were not cost effective. 9 There is a tension between its historical position as a proponent of the value of these treatments and its current responsibility to deliver analyses that could lead to their withdrawal from NHS practice. Good governance requires that those charged with delivering these schemes are demonstrably free of such conflicts.9

The National Institute for Health and Clinical Excellence decided in 2001 not to sanction beta interferon - or another MS drug, glatiramer acetate - for use on the NHS, ruling they did not represent value for money.

However, after a sustained campaign by the pharmaceutical companies, charities and patients, the government came up with an alternative approach known as the Risk Sharing Scheme.

Under its terms, the government committed around £500 million to providing the MS drugs over a ten year period while scientists studied their long-term effectiveness.

If the study reveals the drugs are not as effective as the pharmaceutical companies say, they will have to drop the price of their products to the NHS.

The original contract to evaluate the progress of the thousands of MS patients on the scheme was given to the Sheffield team.

However, sources have told the BBC that the contract was re-tendered last year following a dispute over the university's right to publish independently on their findings.

Sir Iain Chalmers, editor of the James Lind Library, which reviews scientific research, is uneasy about the decision.

He said: "I think it's a totally unreasonable expectation, that information which may be important to patients and prescribers should potentially be suppressed because a company does not find it in its interests to see it made public.

One of the pharmaceutical companies involved in the scheme has denied that any of the research will be suppressed, even though each company in the risk sharing scheme has the right to decide if any research involving their own drugs should be published.

Pete Smith, managing director of Biogen Idec in the UK and Ireland, said: "It may look like a veto but it really isn't a veto.

"We are very confident that our drug is going to demonstrate its value here in the UK and to those patients who are in need of care and we are quite frankly looking forward to those results being published at the completion of this study."

progression was faster in the patients who had the drugs than in untreated patients

patientx wrote: Many, especially well-informed members of thisisms have chosen not not take one of the CRABs based on their own trade-off assessment - the lack of efficacy vs. the side effects and/or costs I completely understand and agree with this decision. We need much better than the 30% relapse reduction. But we already knew this.

I don't understand why this British study is shocking everyone.

AMcG wrote:Not shocking?