European Regulator-HTA Rapprochement Not Quite There

Oh wouldn't it be nice if regulators and cost-effectiveness bodies could align their demands a little more helpfully? What a boon such hand-holding would be for controlling the costs of drug development, while still supporting innovation and recognizing value.

Still, there remains little substance as to how such a partnership could be effectively achieved, as was clear from this year's meeting of The Organisation for Professionals in Regulatory Affairs in Rome, Italy, on Oct. 13-14.

Despite the logic of closer HTA/regulatory harmonization -- the timelines are so close anyway, and patient access is impossible unless both sets of demands are met – regulators and price-sensitive HTAs remain uneasy bedfellows.

Indeed, back in Sept. 2009, EMA's then-director Thomas Lönngren expressed an almost ethical concern that the two sides were getting too close, as if one risked undermining the other. Since then, there's a more widespread agreement that things need to change, but certain executives, such as Aginus Kallis, head of the Dutch medicines agency, are still skeptical as to whether a closer relationship could ever work.

The fact that HTAs are now requiring even earlier-stage data further increases the value of (and need for) a coordinated regulatory/HTA approach. But according to Mats Mårfält, Senior Director, European Regulatory Affairs at AstraZeneca, progress in a Swedish pilot study designed to promote such coordination has been disappointing.

The idea was for Sweden's medicines agency (Läkemedelsverket) and its HTA body (TLV) to progress step-wise from single, to parallel and finally to joint scientific advice. Mårfält’s assessment was that the result was cacophony, as each stakeholder – including the manufacturer – sought only to blow its own horn. The regulator and HTA were reluctant to disagree and even discuss in from of the applicant; there was no attempt to align views at all. Far from building relationships, this looked more like playground squabbles.

And sadly, Anders Blanck, current head of the Swedish pharmaceutical industry association, later confirmed that there had been no further advance since this embarrassing, early stage.

If the relatively progressive Swedes can't do it, what hope for regulatory-HTA rapprochement across the rest of Europe's nations, let alone the whole region? Not much, it seems.

But maybe that doesn't matter, suggested Andrea Rappagliosi, Vice President European Government Affairs, GSK. Sure, HTA is a hurdle (albeit one that we know won't go away), and the lack of coordination with regulators is a pain. But it's Europe's patchwork of pricing and reimbursement systems – some tied up inextricably with HTA and even approval, others not – that are the real problem for market access.

So let HTA and authorization bodies continue to remain apart, provided they enjoy "robust two-way communication" in order to avoid overlap and duplication (which, judging from the Swedish experience, may be a stretch). Just speed up pricing and reimbursement – something that's being attempted, via proposed amendments to the European Transparency Directive. And here progress is being made, according to Rappagliosi, but as always the wheels of the EU legislative process move slowly -- Faraz Kermani

image by flickrer wolfsoul used under creative commons

Sex, Payers & Product Development

OK – the title is a bit of a come-on, I’ll admit. Still, there’s a certain logic to it, if you’ll just bear with me.

To start with the sex part: I read in The Atlantic that men are doing a great job of making themselves irrelevant while women, economically speaking, are fast making up for lost time.

One big problem for the guys, says Hannah Rosin, the author of The End of Men: they aren’t willing to retrain when they have to.

Maybe she’s right; maybe women are more willing to learn new stuff. But it seems to me both sexes fail on that front. And particularly in that little niche of presumed intellectual flexibility, venture capital and the broader start-up world.

Like the broader economy, the health-care business is undergoing a vast economic disruption. And as the giant pharmas and device companies and insurers twist this way and that to figure out just how they’re going to continue to make money in an outcomes-focused economy, start-ups and their VC supporters are among the tiny creatures getting shmushed.

One has to be sympathetic given just how much work a start-up has to do. God knows the clinical and regulatory worlds are complicated enough to exhaust any mere mortal’s brain – and expensive enough to exhaust most wallets, too. Particularly because Big Pharma is asking for later-stage data before they’re willing to pony up significant purchase and licensing fees for a piece of one of those start-ups.

And yet the further a start-up goes down the development path, the more it’s making reimbursement choices – even if it doesn’t recognize it’s doing so. Because just as Big Pharma is learning: the data gathered in clinical trials is not necessarily the data payers want.

Ask Lilly after their huge Phase III Effient trial. Or Merck (or perhaps more appropriately, Schering-Plough) for both Saphris and Bridion. Or Bristol-Myers Squibb and AstraZeneca for Onglyza. All of those drugs passed muster with regulators (in Bridion’s case, European regulators) but payers have simply turned up their noses.

The inattention to payer-focused endpoints is not just a pharmaceutical problem. My bet is that discovery-intensive diagnostic companies like Genomic Health, CardioDx, and XDx would have seen success far earlier had they accelerated their efforts to jibe clinical and reimbursement endpoints.

Managed care increasingly wants to see drugs developed and proven for patients that can’t be served by generics – where PBMs, at least, make most of their money.

(And with PBMs staring out at the very visible end of the big series of patent expirations – which has been almost as lucrative for them as it’s been disastrous for Pharma – they’re trying to figure out innovative ways of using generics in place of proprietary drugs. Medco’s trial comparing Effient just to the 70% of people who respond well to Plavix is a case in point: Medco is looking forward to the genericization in 2012 of Plavix and didn’t want doctors switching willy-nilly to Effient, which had proven modest superiority to Plavix, at least in part because it was comparing itself to a population in which 30% of patients didn’t fully metabolize Plavix). I’m also curious to see how Medco uses its developing pharmacogenomic understanding of warfarin dosing and response as Boehringer Ingelheim’s Pradaxa and the Xa inhibitors that follow it come to market. But I digress.)

Those development decisions need to be made early – and making them requires an understanding of both what managed care wants and how it works. Certainly it’s possible to come to market having proven a drug, as pharmas by and large are wont to do, basically comparable in a broad population to an existing brand. But then gaining market share with such a product, which is to say displacing the Tier 2 player, will require heavy rebating. And then companies should be asking: could they have spent less on a smaller trial showing dramatic benefit for an underserved targeted population, doubled or tripled the price to reflect the value, and ended up with a higher NPV?

In this new world -- our world today – physicians have been demoted from key decision-maker to stakeholder while payers have gone from stakeholder to key decision-maker.

The implications for start-up financing and exits are significant. Because they’ve got the money, and because they see that regulatory risk continues to rise, Big Pharma is requiring more than mere clinical proof-of-concept for the products they in-license or buy from start-ups. But because Big Pharma is also getting the message about payers (increasingly hard to ignore it after having been hit over the head with the formulary problems of their most important launches over the last two years) they also are beginning to ask for proof of reimbursability. They know that gathering that pharmacoeonomic data after approval, and waiting for insurers to make their own judgments, eats away at the economics of the product – which lowers its value.

Start-ups still by and large don’t spend a lot of time worrying about what payers might want from a clinical trial. Understandably. Their managers and investors have spent their professional lives learning how to prove discovery and clinical value to pharmas, and developing an extensive network of scientific and medical contacts to help them do so. Now they have to learn a brand new language, understand the dynamics of a new business, and develop a new set of contacts?

Oh, there’s plenty of lip service paid to the importance of payers. All the VCs and start-up execs I talk with tell me they know their products have to prove value to payers. And yet when I probe just a teeny bit deeper, virtually none of them know anything about how formularies work, which formularies matter, which non-traditional endpoints (both clinical and non-clinical) matter most to the most influential payers. Or seem to be doing much to figure it out. As one VC admitted to me: he knows five people to call when it comes to assessing a Phase II diabetes drug – but nobody when it comes to judging the criteria likely to win that same drug Tier 2 status or the implications if it gets Tier 3 but with no restrictions on its use…or Tier 3 with step-edits, prior authorization, and quantity limits.

From my conversations with them, most VCs and senior start-up executives still haven’t met more than a few medical directors from payers, let alone pharmacy directors (whose variable comp often depends on how well they manage the formulary budgets, which itself depends on how well they negotiate what goes onto the formularies in the first place).

I’ve also heard that while a deep understanding of payers might be important for companies developing me-too products, it’s unnecessary for those coming out with breakthroughs. Payers will have to pay for them. And that’s probably true. But the definitions of breakthroughs are getting tighter (my guess is that Effient would have been a breakthrough had it come out in 2005). And in any event, breakthroughs are rarer than hens’ teeth. Particularly breakthroughs that remain breakthroughs long enough to capture the full value of their development (the first-generation protease inhibitors against Hep C will certainly be breakthroughs when they arrive next year – but not after the next-gen protease inhibitors or the nucleoside polymerase inhibitors arrive in the definitely foreseeable future).

I’m not saying that any of this is easy. Or will guarantee results. Like regulators, payers can change their minds later (“I might have told you back then to prove such-and-such, but now, in order to pay for this, I want you to prove something else.”) But unlike regulators, there is no single reimbursement reviewer – a payer willing to pay for a cost-effective drug or device should attract additional business. And just as I don’t think it’s sensible to dismiss the regulators’ development advice just because they might change their minds later, I’d argue it’s probably not sensible to ignore – or forgo soliciting – payers’ advice because their requirements might change down the road.

Certainly, proving reimbursability makes everything more expensive (trial sites will have to gather more data, case-report forms will grow longer and more complex, and on and on and on). I don’t doubt that fewer companies will get started.

But there are a whole host of start-ups going now. And if we don’t want all that investment thrown away, then it’s time for the boys to go back to school. And any of the girls who want to play with them.

Roger Longman, a founder of Windhover and later head of the pharma group at its acquirer, Elsevier Business Intelligence, is CEO of Real Endpoints LLC, a new company focused on helping payers and drug and device companies create greater value from new and existing products in an outcomes-focused health-care economy.

image from flickr user truthout.org used under a creative commons license

NICE Death Reports Exaggerated, Says Dillon

"Reports of the institution's death have been greatly exaggerated," declared NICE chief executive Andrew Dillon at the FT Pharmaceutical and Biotechnology Conference in London today. Of course, it's clear from the cost-watchdog's latest spate of assessments that NICE is still going strong today.

Dillon's invocation of Twain refers to the fate of NICE post-2013, when a new value-based pricing system in the UK will necessarily change the institute's role. Lord Howe, Parliamentary Under Secretary of State in the Department of Health, recently declared that NICE's decisions on whether a new medicine should be reimbursed by the National Health Service will be "somewhat redundant". That's what prompted the death reports.

Ok, so they weren't really death reports, they were "NICE will soon have significantly less sharp teeth" reports.

And we stand by them (ours, anyway). No-one (not even Dillon) knows precisely what NICE's role will be in the UK's new value-based vision of health care provision, since the government's consultation report isn't out yet. (It's due before year-end, though, so watch this space).

Still, "what I do know is that NICE will continue to assess clinical and cost-effectiveness of new pharmaceuticals," Dillon explained. "But it seems we won't be asked to formally recommend, in the terms we have used to date, how a new drug should be used" (in other words, whether it is reimbursed or not).

So NICE's cost-effectiveness assessments of individual drugs, while still likely to happen, won't lead to stark 'yes' or 'no' recommendations. Instead, "we will articulate the outcome of our assessment in a way that makes clear the optimal use of the product," Dillon explained.

NICE will still express the output of its assessment in terms of cost-per-QALY (quality-adjusted life year), or in terms of a cost-per-QALY range, Dillon clarified to your blogger later. "But we will not be asked to say whether this cost-per-QALY is acceptable or not, as we do now."

Bye-bye the controversial £30,000 cost-per-QALY threshold for determining whether a drug will get reimbursement, in other words (although NICE tends to deny that such a cut-off exists anyway). That's the crux of it. That's the trigger for the death reports.

Instead, Dillon continued, "someone else" will decide whether that cost-per-QALY is acceptable or not, "since the drug price will be driven by someone else in the system," he continues, pointing to the UK's forthcoming value-based pricing set-up. Details of who or what that someone else is, and how they decide whether and how a new drug should be used, remain to be agreed. Formal discussions between industry and the department of health are due to begin next year.

ABPI director general Richard Barker is confident that these talks "won't be too protracted", and speaks positively about a "collaborative approach" where industry has a real say.

It seems unlikely, though, that it will be NICE which takes into account in its assessments the broader factors – including societal impact, treatment support & carer costs – which are to be included in the UK government's vision of value-based pricing and a health care system defined by "value-based pathways", as the catch-phrase appears to be.

Instead NICE will probably do broadly what it did before – and will do so in an equally transparently and consultative fashion, emphasized Dillon – but that this will be just one ingredient that's put into a bigger, as-yet-to-be-defined 'value-based' machine that will determine product usage. "I don't know for sure, though," qualified Dillon (although he did add that there are few if any concrete measures used, to date, to quantify the broader societal benefits of a particular drug…).

More important to Dillon right now is ensuring that his empire does remain a key influence on health care provision. "I want NICE to provide a point of reference on how an intervention should be used," he says."This is very important, and I expect will be expressed in the government's consultation document."

Being a 'point of reference' is somewhat different to being a key decider, as NICE is now.

So from industry's perspective, things probably look good, as far as NICE is concerned. Barker says he doesn't really care at what point these broader, less easily quantifiable elements are blended into decisions on drug usage – whether it happens within the NICE process or afterward. "We're not hung up on what institution does it." As long as it's in there, making it less likely that his members' innovative drugs are tripped up at the starting line.

OK then, NICE isn't dying. In fact it's taking on a broader remit; from 2012 NICE will look at social care, too, as well as maintaining and developing role in promoting optimal public health via general treatment guidelines. "This is a real opportunity for NICE to re-invent itself," and to make sure health care provision is value-focused and outcomes-focused, and to ensure it adequately encompasses social care, too, insists Dillon.

A NICE with a broader remit is a NICE that's spread thinner, though, with less weight in specific areas – like single drug reimbursement assessments.

The End of Free Drug Pricing in Germany?

According to local press, Germany's health minister Philipp Roesler is about to open fire against the branded drug industry with a proposal to break the sector's so-called 'price monopoly' and force them to negotiate lower prices directly with insurers.

Until now, Germany has been one of Europe's last bastions of "free" upfront drug pricing. Sure, the hurdles come afterwards, but both there and in the UK drug firms have--until now--been allowed to set more or less the price they like for new drugs.

"Focus" magazine reported on Saturday that Roesler would impose upon the branded sector fixed price ceilings for their products, should they not come to an agreement with the insurers. Either way, he's gunning for annual health care cost savings of €2 billion.

Direct price negotiations between insurers and drug firms have been legal since 2007. Unsurprisingly though, few if any branded companies have engaged in price-centric dealmaking (or indeed any dealmaking). Most prefer instead to focus on providing other benefits such as supporting compliance.

Meanwhile, as we reported in-depth last year in IN VIVO, the country's largest insurers have already squeezed out over €500 million in savings from the generics sector through inviting best-deal bids for two-year 'preferred supplier' contracts. That trend looks set to continue as firms compete for the next round of contracts.


This is also very likely what's prompting Roesler to try twist the branded sector's arm into likewise negotiating more competitive deals with insurers. We can't imagine that Christopher Hermann, chief negotiator and deputy CEO at the country's largest insurer, will have much to complain about. Frustrated up until now by the branded sector's reluctance to negotiate on price, he nevertheless appeared to see this coming when, back in early 2009, he told us: "I expect contracts around on-patent drugs to become more numerous, as in the next months and years there will be more contracts between health insurance funds and independent doctors' associations in Germany."

His point: insurance funds' negotiating clout is increasing as they wield more and more influence over precisely what drugs doctors prescribe (even though they're not allowed to dictate what drugs are prescribed, as they are in the case of generics).


Lesser of Two Evils?


If Roesler's plan is put into action, drug firms are unlikely to be able to afford to resist, given the alternative: imposed price ceilings that could impact prices not only in Germany, Europe's largest market, but also more broadly across Europe given that Germany service as a reference price market in several other (fixed-price) countries. Negotiating with sick funds may offer industry a little squeeze-room, for instance to provide or fund supplementary services. Such agreements also exempt them from an assessment by IQWiG, Germany's cost-benefit watchdog.

Indeed, another element of Roesler's plan--due to be presented this Wednesday--will allegedly require drug firms to submit, in parallel with a new drug application, a benefit-assessment study of their product, showing which patients the product will serve and which comparator drugs, if any, are already available.

None of this is particularly surprising in today's era of government spending cuts and (continued) targeting of drug manufacturers to make their quick-wins. But whilst it tastes bitter, it may also be an (the last?) opportunity for firms to avoid government-imposed price cuts.

Indeed, Novo Nordisk's CEO Germany, Willi Schnorpfeil , told us in mid-2009 that he would like to see a de-regulated market in Germany with price negotiations between drug firms and payors permitted from day one, as soon as a drug is authorized. Such a system—replacing the current set-up of free up-front pricing with complex rebate solutions and, potentially, centrally determined cost-benefit assessments slapped on thereafter--would allow faster market access to be a negotiating factor, too, he argued.

image by flickrer finlaystewart used under a creative commons license

Celgene: Not So Lucky This Time

Back in early 2009, Celgene was looking rather pleased with the outcome from UK cost-effectiveness watchdog NICE of its multiple myeloma treatment Revlimid.

The drug had won a green light even though the company's "patient access scheme" (as NICE and companies like to refer to cost-sharing deals) really wasn't going to help the UK National Health Service coffers that much. Instead it was NICE's late-2008 end-of-life guidance--a relaxation of the strict cost-per-QALY (quality-adjusted life year) threshold that the agency usually uses to judge whether a drug should be reimbursed or not--that allowed the drug to be waved through.

Not so lucky this time, Celgene. NICE today announced that it would not be recommending myelodysplastic syndrome drug azacitidine (Vidaza) for reimbursement, despite a proposed patient access scheme (almost becoming obligatory for approval these days, it seems) and despite meeting the criteria to be considered under the less stringent end-of-life guidance rules.

Somewhat tantalizingly, Carole Longson, Health Technology Evaluation Center Director at NICE, acknowledged in a statement that the drug could "potentially prolong the life of people with these conditions by around nine months longer than standard treatment," and claimed it was "disappointed" not to be able to recommend it.

We suspect there are poker tactics involved here. If this isn't a call for the company to try harder on its cost-sharing proposals, then what is? Even with the patient-access and end-of-life rules, "the magnitude of additional weight that would need to be assigned to the original QALY for the cost-effectiveness of the drug to fall within the current threshold range would be too great," concluded Longson.

Celgene's already offering a 7% reduction on the drug's acquisition cost, estimated at about £45,000 per patient. But according to NICE's final appraisal determination document, even with this, the most plausible cost-per-QALY would be a whopping £63,000, over double the agency's unofficial threshold.

Unfortunately for Celgene, NICE determined that the cheapest comparator--best supportive care--was also the most appropriate, since it's what's given to the majority of UK patients. This only increased the relative cost of Vidaza; more so than it would have done, for instance, if compared with chemotherapy. What's more, opines Professor Rodney Taylor, deputy chair of the patient support group MDS UK, "they didn't cost [best supportive care] appropriately," underestimating, in his view, the cost of blood transfusions for example.

Celgene plans to appeal the decision, and will argue that the drug fits not only the end-of-life criteria, but also qualifies for various innovation criteria agreed by NICE with the Department of Health designed to increase access to highly novel medicines serving small patient populations. (Read this for more on the review of NICE that led to these proposals). The company is not at this point considering a more aggressive patient-access scheme.

This is the latest in a series of tough decisions emanating from NICE recently; another was its somewhat restrictive policy on second-line anti-TNF use in rheumatoid arthritis patients. These suggest that we were wrong to propose, in the light of the various loopholes that have appeared over the last year or so, that NICE was going soft. The teeth are still there, and sharp, it seems.

image by flickrer greenchartreuse 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

Pfizer Deceives, While GSK Shines

Pfizer has apparently held back clinical trial data for its anti-depressant reboxetine (known in Germany as Edronax) from IQWiG, Germany's drug-benefit assessment agency, leading the agency to declare "no proof of benefit" in its preliminary report.

The report was commissioned by Germany's Federal Joint Committee, which uses such information to determine which drugs should be reimbursed.

In holding back data from at least 9 studies of reboxetine (Edronax), which has been tested in at least 16 trials, according to IQWiG, Pfizer's committing "deception through concealment," according to Peter Sawicki, the agency's director, which he describes as a "non-trivial offence."

A Pfizer spokesman was quoted in German daily Die Welt as saying "we made sufficient data available to IQWiG". Whatever the truth--and why else would Pfizer hold back various published and un-published data, we ask, unless it was un-flattering?--it's certainly ruffled IQWiG's feathers.

The Agency issued a separate press release about Pfizer's misdeeds, alongside its announcement of the preliminary report on anti-depressants. In it, it talks about "publication bias" being "one of the most important and dangerous sources of error in medicine." Quite right too. And why is Pfizer's behavior just asking for trouble in this particular case? Because "other researchers have already shown that the effect of several [anti-depressant] agents has always been exaggerated in the published literature--up to 70%."

IQWiG has concluded that a 2005 agreement with one of the country's pharma associations whereby manufacturers voluntarily disclose clinical trial information, published and unpublished, is no longer reliable. It' s calling on an EU-wide legal obligation to publish results--including retrospectively, as exists in the US.

Pfizer isn't the only perpetrator here. "Companies have repeatedly refused to provide the institute with study documents requirement for the benefit-assessment," the press release continues. In this latest preliminary report on anti-depressants, Essex Pharma was also pushed into the spotlight for possible trial concealment, with the result that its drug, mirtazapine, received a distinctly luke-warm assessment as well.

Only GlaxoSmithKline shone as an example of how things should be done. In the case of bupropion XL, the institute was given "access to the complete clinical study reports by the manufacturer." And, guess what, there was proof of benefit for this agent compared to placebo in acute therapy and no indications of harm. (It wasn't a good as venlaxafine XR, mind you.)

These aren't big drugs, they aren't new drugs. But Pfizer isn't doing itself or the sector's reputation any good in holding back data. It should probably at least pretend to take IQWiG a bit more seriously, given the agency's role as a health-technology assessor in Europe's largest market.

All the more so since Pfizer has been stung in Germany before--like when it refused to accept authorities' decision to group Lipitor (known there as Sortis) into a broader 'jumbo-group' pegged at a similar price to other statins. The drug's share fell to below 3%, prompting Pfizer to return with a rebate deal.

And on the subject of rebate deals: we'll have some more posts on those shortly. For now, let's just say that they've become widespread since German payors have been allowed to negotiate directly with pharmacos. And the signs are that some companies now realize they have no choice but to get even more creative in building relationships with payors. So buck up, Pfizer.

image by flikrer Aelle used under a creative commons license