No More NICE by 2013?

Any drug developer who showed up at the Royal Society of Medicine in London this morning could have been forgiven for thinking Christmas has come early. By 2013, nice probably won't be doing cost-effectiveness analyses of individual drugs anymore, according to Lord Howe, Parliamentary Under Secretary of State in the Department of Health.

Speaking at the joint ABPI/BIA conference entitled "Our Vision for a New Decade" (where a few other worthy initiatives were announced), Howe declared that those highly visible, and controversial, opinions delivered by NICE on whether a particular new medicine should be reimbursed by the UK National Health Service "will probably be somewhat redundant" in a few years' time.

Don't get too excited: it's not that cost-effectiveness assessments are going away. It's just that, according to Howe's plan, by then the UK will have a spanking new value-based pricing system which will see a drug's value assessed and quantified during pricing discussions. That system will replace the current PPRS (Pharmaceutical Price Regulation Scheme, which caps companies' profits rather than drug prices directly) which expires at the end of 2013.

According to Howe, the new set-up will see "the price of a drug reflecting everybody's agreed perspective on the value it provides". We were unable to establish exactly who 'everybody' is, and how they might 'agree' on such a matter. But despite scant details, it appears that companies may in future discuss value with pricing authorities directly rather than have nice--usually post hoc--impose its judgment on a drug's cost-effectiveness.

So it's not quite Christmas. But it seems the industry associations have done a good job lobbying for greater influence in pricing and value decisions, and for nice's teeth to be blunted somewhat. (Perhaps the writing was on the wall in 2009 after Sir Ian Kennedy published his report on NICE's methodologies.) Plus a system wherein value is discussed at the same time as pricing is, arguably, simpler, and "anything that's simpler is better," says Roch Doliveux, CEO of UCB and a significant investor in the UK (largely courtesy of the 2004 Celltech acquisition).

No-one will admit outright that nice is about to take a back-seat in cost-effectiveness decisions. Universities and Science Minister David Willetts was quick to refute that there will be a "lesser" role for NICE, saying instead it would be a "changing role". A more "advisory" role. NICE will move away from single technology assessments (drug assessments) towards setting quality standards more broadly for public health and for care within the NHS, including in social care.

Here's the Department of Health's summary of where NICE will fit in:

"We respect the expert independence of NICE, and believe that it must be allowed to continue to issue guidance free from political interference. However, we believe that there are fundamental failings within the wider system for drug pricing and access. We are determined to address this and are clear that nice plays a vital advisory role."

Vital its advisory role in establishing a new drug pricing system may be, but a NICE focused on setting quality standards for public health will certainly be less controversial than in its existing form. And less powerful. Today, a NICE decision can--and quite often does--shatter a drug's commercial prospects in the UK. That power looks uncertain post-2013.

NICE Snubs Novo With Draft Lira Guidance

You'd think that even nice would have welcomed with open arms a new, effective treatment option for the UK's nearly 3 million diabetic patients--particularly one that not only lowers blood sugar, but also causes weight loss.

Nah. NICE is playing hardball (again). Its draft recommendation for Novo Nordisk's GLP-1 analog liraglutide (Victoza), although not nearly so damning as last week's preliminary guidance around Sprycel and Tasigna, suggests that the drug be used only in limited circumstances by the National Health Service. 'Limited' means a) as part of triple therapy regimens only (that is, for patients already on metformin and a sulfonylurea, or metformin and a thiazolidinedione, where the above combos aren't quite doing the trick), b) among patients with a body mass index equal to or higher than 35kg/m2 (that's high) and c) only at the lower, 1.2mg daily dose.

Ok, so patients that aren't quite so obese as 35kg/m2 could also qualify for the drug, "if it is considered that the drug's use could help to achieve levels of weight loss that could be beneficial in treating other conditions caused by being obese", the nice press release concedes.

But a quick read of the full appraisal consultation document reveals that even among those tightly-defined patient groups, drug treatment should only be maintained if the individual loses at least 3% of body weight after six months (that's not far off the threshold for an actual weight-loss drug) and sees a reduction in blood sugar levels of at least 1 percentage point.

It seems, at first glance, to be a case of "damned if you do, damned if you don't" for Novo. After all, weight loss is supposed to be a nice side-effect of the diabetes drug--one that could lead to lower incidence of co-morbitidies--yet it's apparently being used to limit its reimbursement.

Although NICE concedes that liraglutide "may have some advantages over insulin...in particular its effect on weight," it appears to rule out the higher dose point blank, and is asking for further analyses on the cost-effectiveness of liraglutide on patients with a lower BMI, which it says were not presented.

nice was also unsatisfied with the extent of the data comparing liraglutide in triple therapy with other combinations of oral drugs, including for instance DPP-4 inhibitors, and felt that the LEAD-1 trial comparing liraglutide to rosiglitazone used an insufficiently high dose of the glitazone.

It's impossible to cover all the various permutations and combinations in diabetes therapy, however--and Novo did submit data from six trials in over 4000 patients. All except one of the trials showed that the drug reduced HbA1c levels significantly better than comparators, which included rosiglitazone (Avandia), sitagliptin (Januvia, the DPP-4 inhibitor), insulin glargine (Lantus), placebo, and Lilly/Amylin's exenatide (Byetta, the only other GLP-1 out there). The exception: the LEAD-2 trial, comparing liraglutide with glimepiride (Amaryl), which showed up liraglutide's weight advantage although no significant difference in blood sugar lowering.

Perhaps nice's conclusion isn't such a surprise, though, considering the fate of Byetta in the UK (which you can read about in nice's Type 2 diabetes guideline document). In brief, Byetta's "not recommended for routine use in Type II diabetes", with the same six-month benefit hurdles as described above, deemed as "expensive" and "not cost-effective for an unselected population as compared to commencing human insulin therapy."

As such, Novo's VP Europe, Viggo Birch, admitted that "given what they [NICE] have done for exenatide, this is what you'd expect in the first round." Still, "I'm not happy with it," he continued. "We have a much better product [than exenatide] and much better data." Novo's looking for reimbursement as second-line therapy, "at least for important patient subgroups," and a relaxation of the BMI-based restriction, since this, Birch claims, "isn't fair; it was plucked out of the sky."

There's a crack in the door, though. NICE will hold another meeting on March 18, allowing Novo and others time to comment and submit further data supporting wider use of the drug. And in its full diabetes document, nice does acknowledge, with regard to Byetta, some uncertainty as to whether GLP-1s would be deemed cost-effective if the [health economic] model "fully reflected the negative quality of life issues of insulin, including fear of hypoglycaemia, and the costs of support and patient education for modern intensity of insulin dose titration" and added that the "more obese require much higher insulin doses, such that insulin costs alone can easily exceed those of exenatide."

Still, reading between the lines, we suspect this preliminary appraisal for Victoza is a call not just for more analysis, but also for a cost-sharing scheme of some description to help smooth the drug's passage past the cost-effectiveness watchdog.

That's not likely, according to Birch. "It [a cost-share scheme] is not really on the radar for this product right now." Perhaps with reason: after all, Victoza's hardly the most expensive drug to cross nice's desk--the low dose costs GBP 954 per year, compared to tens of thousands of pounds for some cancer treatments.

But given the growing prevalence of diabetes, "nice is probably wary of giving free rein to something that [may become] so huge" comments one analyst.

The question is whether its hard-ball stance on Victoza ideally balances the concern over escalating drug costs, with that of the escalating costs of the disease itself (plus consequences), estimated to eat up about 10% of the health care budget.

image by flikrer Roland used under a creative commons license

"No!" says NICE, to Sprycel, Tasigna

The UK cost-effectiveness watchdog NICE today delivered a resounding "no" to the use on the National Health Service of Bristol's dasatinib (Sprycel) and Novartis' nilotinib (Tasigna) in chronic myeloid leukemia patients intolerant to imatinib (Glivec).

"The evidence available to support [the clinical effectiveness] of dasatinib and nilotinib was very poor," declared Professor Peter Littlejohns, clinical and public health director at NICE. "The drugs' cost is also very high," he added, in a press release announcing the latest draft guidance.

Sprycel costs about £30,477 per year, and nilotinib about £31,711, according to appraisal documents on NICE's website. And the drugs are taken for several years, with no evidence-based 'cut-off' point currently in use.

It doesn't even look as if the drugs came close, in other words. And Bristol and Novartis can't even consider one of the loopholes now available to companies, the end-of-life guidance issued in late-2008, which permits a somewhat higher cost-per-QALY (quality-adjusted life year) than usual for drugs that extend life in niche yet terminal diseases. (This, you will recall, is what allowed Celgene's multiple myeloma drug Revlimid to slip past the agency.)

The available evidence on the drugs' extension of life--typically required to be of at least three months--"is too weak", declares the NICE PR in yet another blow to the products' manufacturers. That the drugs, both second-generation tyrosine kinase inhibitors, offer such an extension, documents declare, "is plausible, but definitely not proven."

But at the end of this rather damning announcement came an olive branch. "It would be heartening to hear that pharmaceutical company manufacturers are prepared to share some of the very high cost of these drugs with the NHS," suggested Littlejohns.

Now if that isn't a call for a cost-share (or should we say 'patient-access') scheme, then I don't know what is. Recall that such schemes have allowed NICE to green-light a good handful of expensive drugs that likely would not have otherwise made the cut--including most recently UCB's RA drug certolizumab (Cimzia). (Interestingly, although Celgene also put forward such a plan for Revlimid, this wasn't what tipped the decision in its favor.)

So we understand NICE's call for companies to make an effort on the cost-share front--indeed, the agency's CEO Andrew Dillon has told us clearly that he'd prefer if manufacturers simply submitted such schemes up front rather than waiting for a rejection in order to fish one out.

But is Littlejohns implying that a cost-share proposal would simply eliminate all the problems that the appraisal committee identified in the submission, around trial data and design? These seemed considerable: no studies submitted assessed either drug against relevant comparator; trials were 'heterogenous in terms of design, population, implementation and analysis'.

We put this question to NICE. Their reply:

Although there is some evidence to suggest that dasatinib and nilotinib could be considered clinically effective in cases of chronic myeloid leukaemia (CML), the quality of that evidence was extremely poor. This, coupled with the very high cost of the drugs, meant that the independent appraisal committee could not recommend them as an appropriate use of NHS resources.

During the public consultation on the draft recommendations manufacturers will have the opportunity to propose a patient access scheme, to make it easier for the NHS to afford expensive new treatments. We would be happy to look at such a scheme.

The answer is still not entirely clear (to me anyway; and I'm pushing for further clarification). But it sure looks as if patient access schemes will trump poor data.

If that's true, we're not sure that will do anyone any good--the NHS (paying, if a reduced price, for drugs that aren't effective), companies (forced to submit access schemes above all else), or patients (potentially receiving an ineffective drug and, as a group, perhaps not getting something else as a result).

We hope, then, that we're wrong.

image by flikrer greenchartreuse used under a creative commons license

"We're Not Like NICE," Barks Germany's IQWiG

It's not as if the UK's cost-effectiveness watchdog NICE isn't used to a bit of bashing. Patient groups, spurned companies, disease foundations, the good 'ole British public have all had a go over the decade or so since this fourth hurdle came into being.

But NICE has stood up relatively well, we feel. Sure, it has U-turned on a few decisions, and has bowed to pressure for increased transparency. No bad thing. But overall its role and influence are growing, not shrinking. And its measure for assessing cost-effectiveness, the controversial QALY (quality-adjusted-life-year), remains central.

So nice isn't going to flinch at a dig from its German counterpart, IQWiG, which in October declared what it clearly views--perhaps justifiably, we're not judging--as a far superior method for evaluating cost-benefit. (So we're a bit slow to react, but the English translation has only just been made available.) Note that IQWiG has only since 2007 been allowed to take cost into account at all--this is the outcome of a two-year study.

Basically, IQWiG's new method doesn't impose a uniform upper cost threshold across all diseases, akin to NICE's £30,000-per QALY guideline limit. "We compare the relation between cost and benefit for each individual disease," says the PR, using existing treatment prices in that area as benchmarks. Indeed, "such a [NICE-style, uniform upper] threshold "would not be in keeping with the German Social Code Book," the release continues. (But should cancer or heart disease sufferers have a right to more expensive treatment than, say, diabetes patients....?)

Then the socio-cultural philosophy kicks in: "Peter Sawicki [IQWiG's Director, unlikely to be appointed for another term next year] is convinced that the utilitarian mindset which underpins the British approach would not be accepted in Germany," pipes the release. Sawicki is then quoted as saying: "This benefit maximization ethic leads, for example, to cancer patients not receiving the expensive drug Avastin, because the costs are seen as too high in relation to extending life. On the other hand, despite doubts surrounding their additional benefit, diabetes patients are prescribed insulin analogs because the higher costs seem reasonable in the face of the supposed increase in the quality of life. In Germany, this would be seen as unfair."

Talk about mobilizing the anti-NICE troops. (Regarding insulin: in Germany rapid-acting analogs must be priced no higher than human insulins because of these 'doubts' over additional benefit; never mind speed-of-onset or convenience.)

IQWiG, it seems, is cosying up instead to the Australians. Its approach is to outline a maximum reimbursable price for products, taking into account additional benefit relative to other therapies within the same TA, and performing budget impact analyses not just on overall health care spend, but also taking into account other costs, such as social insurance and productivity losses resulting from sick leave. (Another subject that came under recent scrutiny at NICE.) "There are clear parallels with Australia, the country with the longest experience in matters concerning health economic evaluation," the PR goes on.

And another kick at the QALY: "While our British colleagues work more or less exclusively with QALYs.....after 15 years' experience, the Australian Pharmaceutical Benefits Advisory Committee (the Aussie version of nice) has warned that there is a high price to pay for carrying out general therapeutic comparisons using QALYs. The utility weightings required for this are often based on many ambiguous assumptions."

Most of the drug industry would agree with Sawicki on this one. Shame, then, that IQWiG's bark is so much louder than its bite. Unlike NICE, whose yes/no decision determines whether a drug will be commercially successful in the UK, IQWiG has no such power. It can only make recommendations--if requested to--as to the relative benefit of a drug and, from now on, as to a maximum reimbursable price. Health insurers can either follow those recommendations, or not.

And in contrast to most other countries, where health technology assessment agencies are gaining sharper teeth, IQWiG's likely going the other way: most expect the newly-elected government to appoint a more pharma-friendly chief, effectively putting the agency in industry's pocket. But that's a whole other blog post.

image by flikrer stereonaut used under a creative commons license

No Cure, No Pay

For most other consumer goods, you’d expect to get your money back if the product didn’t work. Not so for drugs, where many treatments don’t work in at least a significant minority of patients—but payors and governments can’t claim a refund.

That may be about to change. Today Johnson & Johnson’s Janssen-Cilag subsidiary offered to pay back the UK’s National Health Service if their blood cancer drug Velcade fails to help improve patients’ condition.

It’s not a done deal—the Department of Health will now consider the proposal. And there are still plenty of creases to iron out, such as what levels of improvement the drug would need to show in order to trigger payment. But the proposal has the backing of the UK’s cost-effectiveness body, the National Institute of Clinical Excellence, which means it’s likely to be accepted in some form or another.

Janssen isn’t doing this just to look good: for them, this scheme is the only way it will see any reimbursement for the £25,000-per-cycle drug, which NICE initially deemed too expensive to be cost-effective. This risk-sharing agreement is part of Janssen’s appeal against that decision, and the trend will probably catch on as other firms seek to overturn negative reimbursement outcomes. Some are already talking to NICE about similar schemes.

And small wonder: no cure, no pay makes absolute sense. It renders the cost of treatment economically feasible for payors, and it may help manufacturers, too, by forcing them to identify patients that will respond best to their treatment, and to find ways to improve compliance if a drug does not appear to have the same effect in daily use as it does in controlled trials. That will facilitate more widespread reimbursement and sales.

So why hasn’t 'no cure, no pay' caught on? It’s not as if Janssen is the first mover here. Novartis in 2004 tried it with hypertension treatment Diovan, to try to boost flagging sales in the US; the company claims it worked. In 2005, Bayer did the same with erectile dysfunction drug Levitra in Denmark, offering patients a refund if they were not satisfied. There are plenty of other even earlier examples, according to a paper in the British Medical Journal by Claus Møldrup, Associate Professor in the Department of Social Pharmacy at the Danish University of Pharmaceutical Science in Copenhagen. (See Box.) No cure, no pay hasn't caught on because it hasn't had to: traditional marketing techniques have worked fine.

Until now, that is. From here on, we'll see more money-back guarantees, and we’ll also see other schemes linking price to performance. GSK in September 2006 announced that it had persuaded two European governments to allow the price of pharmaceuticals to vary, in either direction, according to real-life data that emerge on the drug's effectiveness. (See February's IN VIVO article for a discussion of this and other price-discounting schemes underway in the UK.)


So governments and payors had better get cracking and set up their systems to receive funds, rather than simply pay them out—this was just one of the challenges that helped snuff out the Danish no-cure, no pay arrangements.

In the latest Velcade proposal, the NHS will be refunded in the form of a credit note from Janssen, according to the BBC. It’s not quite your money back, then—but at least you can try a new product for free.


SOURCE: BMJ 2005;330:1262-1264 (28 May)

While You Were in the Cheap Seats

Go Phils!

IN VIVO Blog took in the Phillies-Giants game at Citizens Bank Park in Philly on Sunday. Hopefully our readers had better weather (though the game was excellent!). A few tidbits from the weekend ...

• It seems like Dr. John Buse's Congressional testimony on Wednesday will sure be interesting. The American Diabetes Association president-elect issued a statement on Friday (perhaps in an attempt to avoid mis-quotes), intended to be his only public communication until the testimony, that addresses the notion that GSK tried to silence his criticism of Avandia's risks in the past. NYT has the story, and Buse's statement.


• ASCO ... ASCO, ASCO. Have you heard, there's an oncology conference in Chicago? Lots of news from Pfizer, GSK, BMS and the rest. Covered well over at the WSJ's Health Blog.


• Wouldn't it be NICE? J&J has made the UK's National Institue for Clinical Excellence an offer it would be tough to refuse: the drugmaker will cover the cost of Velcade for patients who don't respond. The NIH would only pay when patients did well on the drug. Of course the details need to be ironed out. Full story at the FT. Hat tip Pharmalot.


• Insider at Pharmagossip highlights Big Pharma's latest new media problem: Youtube. He also directs us to this recent Simpsons excerpt: "Nappien activates your brain's napping centers, and attacks your body's awakegens."