EMA Leadership: Mr. Rasi Goes to London

From out of the mists of confusion created by the European Medicines Agency’s initial ineptitude in seeking a new head – its first job advert in German was wrongly directed at physicists and not physicians – an apparent savior has charged: Guido Rasi, current Director General of the Italian medicines agency, AIFA. The reaction of delegates at the OTC-focused AESGP meeting in Rome (where this blogger is currently reporting for "The Tan Sheet") to his nomination as EMA's next Executive Director is one of relief. Rasi, it appears, is whiter than white.

Unlike some of his AIFA predecessors, perhaps. Rasi's appointment to the top position of AIFA in 2008 came after its previous head, Nello Martini, was removed after being charged with “culpable disaster” (he was indeed acquitted in 2010). Martini's alleged crime, as deemed by public prosecutors at the time, was to have delayed the updating of pharmaceutical packaging and labeling where in fact a brief rewording of the documentation would have been appropriate. At the time, this resulted in delays to access and greatly angered the pharmaceutical industry.

But worse still were the crimes of Duilio Poggiolini, another former head of the Italian committee for drug registration, a forerunner of AIFA, who was accused of amassing a fortune in the region of CHF15 billion ($18 billion). The story goes that when police lifted floorboards in his house, they found underneath millions of Liras worth of gold bullion. (Lira was the pre-Euro Italian currency, for those of you with shorter memories).

And so Rasi was brought in to balance the ship and restore credibility to the medicines authority. An academic and physician by profession – until his AIFA appointment, he held a series of high-profile posts at various research institutes in Rome – he was credited with speeding up the drug registration process and thereby patient access.

His outstanding qualities in the eyes of his Italian colleagues, in addition to his acknowledged management skills, are honesty and trustworthiness. (Rare qualities indeed in anyone anywhere near the top of any multinational organization, let alone one whose shortened name has "As" and "Fs" in it..) Pharma industry commentators have already claimed that these qualities are growing in importance at EMA, following its ticking off by the European Ombudsman in June last year for a lack of transparency, and the questionable departure of its last Executive Director, Thomas Lönngren, to join the European regulatory and market access business the NDA Group. This move was seen as raising conflict of interest issues by many in industry, political circles and public interest groups.

The European Commission may have found a man to set the EMA’s house in order, but also one who will toe the line. The word in pharma circles is that he can be told to do things, but that he will then do them his own way.

Rasi's relatively short experience within the regulatory world (he's been chief of AIFA only since 2008, though on the board since 2004) may be an advantage, say some, as he comes without the baggage of a long-serving regulator. AIFA isn't a high profile agency within Europe, either (Italy is rarely used as a reference member state for decentralized approvals, for example). It does have a strong leaning towards risk-sharing deals, however-- which may prove significant.

Mr Rasi will go before a hearing of the European Parliament's committee on environment, public health and food safety on July 13, and his nomination will have to be approved by Parliament as well.

-- Faraz Kermani

A Leaderless European Medicines Agency: Does it Matter?

Will it matter if Europe’s top medicines regulator, the European Medicines Agency (EMA), is without an Executive Director for the next six months or so?

A headless EMA is on the cards because of a translation mistake in a European Commission recruitment advertisement – the use of “Physiker” in German, meaning physicist, rather than the German word for physician.

This meant that the recruitment process, which started earlier this year, had to be repeated, and will not be finalized before Thomas Lonngren, the current Exec Director, bows out at the end of December.

The EMA is really only a co-ordinating center for the 27 national regulatory agencies in the EU, and it’s these agencies, and their employees, that do most of the actual work.

So, it is a totally different beast to a more politicized regulator like the U.S. FDA, where the top position is a political appointee and the agency itself makes the regulatory decisions.

And let’s face it, the FDA has been without a Commissioner in the recent past, and has not gone completely awry, so it should be relatively easy for EMA to do the same. EMA’s recently appointed Acting Executive Director, Andreas Pott should have no problem keeping everything ticking over, anyway; he has been EMA’s head of administration for 10 years.

Maybe there's more required than ticking over, though. Europe has a new Health Commissioner, John Dali, who is keen to make his mark, and there is draft EU legislation rumbling around on counterfeit drugs, patient information, pharmacovigilance and the like. All of this needs EMA's input.

Furthermore, the agency is halfway through deciding its work priorities for the next five years via its “roadmap for 2015”. And what would happen if the region had to confront another public health crisis, like the swine flu epidemic?

On the plus side, when the new (non-physicist?) Executive Director does show up, he or she will (hopefully) be well placed to reinvigorate the agency.

Despite new websites and rebranding initiatives (the infamous pestle-and-mortar logo) and a new, shortened acronym (EMEA is so passé), the agency and its Executive Director are still largely invisible to Europe’s general public.

What EMA really needs is an individual who is comfortable with having a high public profile, someone who is not only a highly skilled regulatory bureaucrat but who communicates effectively to the public, and becomes a publicly recognized figure.

Yes, the agency is excellent at putting “regulatory affairs” documents on its website, but is this what the public wants, or needs? As I write, the communication heading the “What’s New” category on the EMA website is titled: “Guidance on centrally authorised products requiring a notification of a change for update of annexes”. Not something that is likely to grip the attention of many of the EU’s population of half a billion souls.

Perhaps there is an opportunity here to move beyond considering national regulators for the post, and to consider academics, or even individuals with a more political background.

But one major regulatory stakeholder, the pharmaceutical industry, is sure to remain quiet during the recruitment process. Any indication that the industry backs or favours a particular candidate is not likely to enhance that candidate’s prospects. Expect nothing from the industry until the decision is made.

Potential candidates should hurry, however. The closing date for submitting applications is Nov. 24.

-- John Davis

image from flickr user sebr used under a creative commons license

Regulators and Cost Watchdogs Getting Too Close, says EMEA's Lonngren

The European regulatory agency, EMEA, and Europe's various cost-effectiveness watchdogs are brushing up a little too close for comfort, according to Thomas Lonngren, EMEA's executive director. "The decision points for approval [of a medicine] and its health technology assessment [in individual European countries] are getting very close," he observed during a media workshop in London yesterday.

That in itself isn't the problem--it's simply a reflection of governments' and payers' increasing rigor in testing new drugs' cost-effectiveness before they dish out too much money for them. The problem, Lonngren continued, is that some health technology assessment agencies (HTAs) give scientific advice, "and so do we. And we'll have a big problem in drug development if there's too much different scientific advice going around," particularly as it's increasingly given at about the same time in a drug's development path.

The UK's NICE and Sweden's HTA both provide advice to companies on what kind of clinical data they need to provide in order for a green light. At least for NICE, it's a relatively recent additional activity, providing some welcome on-the-side income. Speaking to The IN VIVO Blog back in December 2007, NICE CEO Andrew Dillon argued: “Regulators charge extra for early consultations with companies,” he says, “so why not us? It’s what everyone wants.”

Now sure, companies want to know what kind of data they need to secure both an approval in the first place, and reimbursement. One's no good without the other. But "we need some agreement [with HTAs] so that industry doesn't find itself doing one development program for EMEA, and another 27 for the various member-state HTAs," Lonngren told The IN VIVO Blog.

He's gunning for harmonization of both sides' requirements, with the goal of an integrated drug development process that meets the needs of both regulators and payors.

This isn't pie-in-the-sky, at least according to EMEA. "We could possibly get consensus on the assessment of relative efficacy [of a drug] in the scientific and clinical setting," argues Hans-Georg Eichler, EMEA's senior medical officer. His point is that the cost element can be added later onto an agreed assessment of a drug's medical value, which may include impact on quality of life, for instance. (No one, Eichler included, sees standardization of HTA methodologies across Europe as likely to happen soon, though the hurdles are more political than scientific, according to EMEA execs.)

Some kind of harmonization between EMEA and HTA agencies' clinical guideline standards seems logical, though, given that HTA bodies are already banging on EMEA's door for more detailed information about its decision-making processes as a result of converging timelines. "They [the HTAs] need information [sooner], and they get that from our decision. But they're saying they need more insights [into our processes] in order to make their judgments about value," says Lonngren.

The HTA agencies (or at least some of them; they're not a coherent unit across Europe, although they have created an informal network) want more color on the various steps in EMEA's decision-making process, such as the first list of questions sent by the CHMP (the actual EMEA committee which assess drug applications) to the sponsor, the sponsor's reply, the assessment of those replies, and the weighting/significance attributed by the regulators to the various elements of a product's benefit/risk profile.

Fortunately, those demands tie in with EMEA's own drive to increase transparency--something that others including the media could benefit from too. And the work's on track, according to Patrick Le Courtois, EMEA's head of pre-authorization evaluations for human medicines. "We'll be liaising with various HTA agencies," he says, and are working to improve our EPAR (the European Public Assessment Report published for every drug that's approved, which sets out the scientific grounds for the approval, plus an SPC and labeling and packaging requirements for the product).

Whether HTA agencies will play ball remains to be seen (we'll be asking NICE's Andrew Dillon at our forthcoming Pharmaceutical Strategic Alliances conference--to which you may register here). Without their cooperation, Lonngren's concern over duplicate or conflicting advice increasing the cost and time for drug development will remain. But where EMEA is a politically neutral, executive beast, HTA agencies are, whether they admit it or not, steeped in national politics. That always puts a break on consensus-reaching.

image by flickrer athousandwordsormore used under a creative commons license

Almirall Jumpstarts COPD Hopeful Aclidinium

In a bid to resurrect investors'--and perhaps potential European partners'--interest in its beleaguered COPD drug aclidinium (branded as Eklira), Almirall announced this week that it plans to file in Europe early in 2010, almost two years earlier than expected after disappointing Phase III data last year forced a re-think.

When Spain's largest pharmaceutical firm listed 30% of its share capital back in 2007, mouths were watering at the growth story it represented: here was a mid-sized group (2008 sales: €900 million) with a potential €2 billion drug in its pipeline that could double or treble the company's size overnight.

The drug was aclidinium, a long-acting muscarinic agonist in the same class as Pfizer/Boehringer Ingelheim's Spiriva. And it had a super-duper, easy-to-use device to go with it--better than Spiriva's. Unfortunately, Phase III results showed far lower efficacy than expected and fell short on two critical secondary end-points (quality of life, time to exacerbation).

The stock fell 40%, and continued downwards to a low of about €5 in October that year. Having ridden the 'exciting newcomer' wave in the public markets for a while, Almirall came splashing down. Phase III would have to be re-done, the company said, setting aclidinium back two years in a competitive, Big Pharma-dominated marketplace.

So why the change of heart, in Europe, anyway? Apparently because of two small but significant trials, one looking at onset-of-action (vs Spiriva), and the other at exercise endurance (vs placebo). The studies involved only 115 and 181 patients respectively--small fry compared to the 1600 or more patients treated in the Phase III studies.

But Almirall reckons these trials might just be enough to build a satisfactory submission to the authorities for once-daily use. "The exercise limitation study is a big deal," asserted Prof. Paul Jones from London's St. George's Hospital in the UK on a conference call to discuss the new plans, "because tiotropium [Spiriva] didn't show a clinically worthwhile response from day one, but only a slow improvement over the six-weeks of its study," he said. (Almirall's exercise study didn't compare aclidinium and Spiriva head-to-head.)

Now granted, secondary end-points such as these are important in Europe, perhaps more so than in the US. But an approval--certainly in one cycle--is still probably a long-shot. Sure, Almirall's original Phase III trials met their primary end-points (improvement in lung function vs placebo), but they met them with far-from-flying colors. For FDA, this was a non-approvable package, full stop (and Almirall and US partner Forest Labs haven't altered their expected US filing date of late 2011/early 2012).

Safety and tolerability might have been great, but efficacy was missing, at least with a once-daily dose--which is why the partners are now running a study using twice-daily dosing vs placebo in the US. What's more, European regulators like head-to-head studies, which Almirall doesn't have (apart from the small secondary ones).

Still, "they've got nothing to lose," comments one analyst. "I suspect they may have to top-up the submission with additional data," the analyst continues--probably from the US study--"but this way at least they get the process going." Not a bad idea, given that Novartis' once-daily LABA indacaterol has shown promising Phase III data this year.

And perhaps Almirall's bullish news will trigger some interest among potential European partners for the drug, for which the hunt's still on. (With a smaller drug, Almirall might be stepping up its own commercial participation, however; even before the disappointing Phase III data, the company told IN VIVO it would like to at least participate in the key five markets.)

Indeed, this surprise move hasn't changed analysts' sales forecasts for the drug--most still sit at about $200 million in Europe, a fraction of the multi-billion dollar figures of yesteryear. Nor will it alter the fact that aclidinium isn't going to push Spiriva off its post. Far from it; with lesser efficacy "it will be the second choice to Spiriva, there's no way round that," says the analyst.

But Almirall's not Pfizer, so a $200 million 'niche' drug would still be very useful--if far from transforming.

image from flickr user .:sandman used under a creative commons license

"Lagging Indicators:" Does Europe Approve Drugs Faster Than The US?

We heard a phrase we haven't heard in a long time this week: "Drug Lag."

Merck EVP Worldwide Regulatory Affairs & Product Safety Peter Honig used the phrase during his introductory remarks to an Institute of Medicine workshop on drug safety, intended as part of a series of updates on IoM's past review of the US Food & Drug Administration's safety regulation.

Drug lag is a term straight out of the 1980s, when the pharmaceutical industry argued that excessive conservatism by FDA meant plenty of lifesaving drugs came to market first in Europe, while US patients suffered or died waiting for the agency to act. We've since seen analyses claiming the whole notion of a "drug lag" was hooey, but that didn't matter: the perception, as Honig noted, was a key motivating factor in helping push through the Prescription Drug User Fee Act, which undeniably led to a rapid increase in the number of new drugs first marketed in the US.

Indeed, a generation of pharmaceutical industry managers grew up in a world where the industry's largest market (the US) was also its fastest growing market, and the one most likely to grant market entry first. Quite a trifecta.

Well, the US is still the largest pharmaceutical market in the world, but it sure isn't the fastest growing. And Honig, at least, thinks it is also showing signs of lagging behind Europe in market entry. The Merck exec didn't press his case hard, but he did prompt a response from FDA's top new drug review manager, John Jenkins (pictured above).

There are really "two issues people are raising" about new drug reviews, Jenkins noted. One is the undeniable fact that there are some delays associated with new processes and procedures, like the Risk Evaluation & Mitigation Strategies or "safety first" initiative. Jenkins acknowledges that FDA has "taken on a huge process burden" and "the money has not followed at the same pace as the new responsibilities." So some "lag" may be inevitable, at least until resources and habits catch up with the new workflow.

But, Jenkins continued, that isn't really what people worry about. They worry about whether "FDA is becoming more conservative."

And that, Jenkins said, is very hard to quantify, because "we have lagging indicators." Economists, he noted, prefer to focus on leading indicators, but the only was to tell what is happening with approvals is to look at statistics for various application cohorts, and the data inevitably trail months or even years behind the calendar.

So "the most recent data we have is from fiscal 2008, and you really can't see any kind of fall-off or change that is dramatic for first cycle approvals of new molecular entities."

But, to Jenkins' credit, he doesn't just drop the issue there. "It is hard to quantify if my division directors or my office directors are affected by the drug safety debate that has been raging in this country for the last five or six years." The issue "has calmed down a bit recently," Jenkins said, but "have they been impacted?" Are "they less likely to approve a drug today with the same data package that they might have been five years ago?"

"It is impossible to make that assessment because you just can't answer those questions," Jenkins says. "What you have to look at is the data over time to see if you see any trends."

Jenkins noted that he presented an analysis of recent drug approvals last year (at, we might add, our very own FDA/CMS Summit for Biopharma Executives in Washington DC). That data showed seven drugs approved in Europe at that time, but not in the US, and only two in the US but not Europe. (Read our coverage here.) But that data is "now close to a year old. We've been looking at it again, but we haven't reported any more recent analyses." (We hope that will change this Dec. 3, when Jenkins opens the fifth annual FDA/CMS Summit.)

But even a clear indication that there are more drugs approved in Europe first may not be persuasive. "There are a handful of drugs approved in Europe that we haven't approved," Jenkins said. "We'd be happy to argue in public why we didn't approve them, but we can't always do that."

One of those drugs, Sanofi Aventis' weight loss agent Accomplia, was ultimately withdrawn in Europe for safety reasons. So, Jenkins said, "Only time will tell: are we being too conservative and depriving patients of needed drugs, or are they being too aggressive and going to run into the same safey buzz saw that we blew through in the 2000 decade."

Time will tell indeed, but we are impatient here, so why don't you all tell us instead: respond to our poll and let us know what you think. Is there a drug lag? And if there is, is it because FDA is too conservative or EMEA is too reckless? Look for the results next week. (If you are reading via email, click here to take the poll.)

Novo Hopes Victoza’s EU Clearance Bodes Well for US

As the European Commission today gave its final green light to Novo’s much-anticipated GLP-1 inhibitor liraglutide (Victoza) (no surprise, given the CHMP’s positive recommendation back in April), the company’s still bullish on the drug’s prospects in the US—anticipating not only approval but a none-too-severe risk-management plan as well.

“Our expectation is that the whole post-marketing system that we’ll agree and adhere to in the US will not be of a severity that will be commercially destructive to the product, not prohibitive for easy daily use in the doctor’s surgery,” Novo’s CMO Mads Thomsen told us (but enough, one assumes, to give practitioners comfort and get a leg in versus Byetta…).

Thomsen’s taking heart, perhaps, from the squeaky clean EU approval, which came with no usage restrictions and no contra-indications—despite an earlier split vote from an FDA advisory committee in April over whether Victoza should be approved in the US at all, due to increased cases of thyroid tumors seen among rodents.

The European authorities apparently liked the sound of Novo’s commitment to undertake a global, 9000-patient, five-year post-approval cardiovascular outcomes trial, including not just the classical MACE analyses of CV risk, but also various thyroid-related parameters, according to Thomsen. “The plan is to have the study protocol negotiated with the FDA as well [as the Europeans] by year-end,” he told The IN VIVO Blog—and to start recruiting a couple of months later.

So does that mean US approval’s likely before year-end? Not all analysts are that bullish, given the challenges of monitoring any potential thyroid risk in humans (though the worst-case scenario for some, a black-box warning, doesn't necessarily kill sales--just look at Actos). But as far as Thomsen’s concerned, yes, “we’re assuming that either we have US approval by then, or that we’re so far down the regulatory process that the CV study design will be part of the discussions,” he continues.

Novo’s in a hurry because liraglutide is already late (speed-to-market hasn’t always been Novo’s strength, as we reported in more detail here, although product quality has more often than not made up for this). Lilly/Amylin’s long-acting Byetta (taken once-weekly vs once-daily for liraglutide) is close on Novo’s heels, and these companies, unlike Novo, have an existing GLP-1 platform to build on.

Still, Novo’s going to do its damnedest to leverage its own insulin sales force to get liraglutide out as quickly as possible to a broad prescriber base, says Thomson. Not unusually, the UK and Germany, two of Europe’s largest markets where up-front pricing is free, will be the starting points. “We’ll make some minor adjustments to sales force size in Europe,” he says, “but we’re only talking an additional 100 or so.” Thomson says that a “sizable” part of the insulin sales force will be re-allocated to liraglutide, at least during the launch phase, as the company tries to capture what it hopes will be “positive perception of innovation” at Novo among diabetes drug prescribers.

It won’t just be the specialists, though: since liraglutide is easier to use than insulin (it doesn’t require blood sugar monitoring or dose titration), “we anticipate a broader prescription base [than insulin] and moving into the GP market within several months,” says Thomsen.

Liraglutide will be positioned as “the natural second-line therapy after metformin failure,” explains Thomsen, given its “superior clinical profile, effect on body weight and lack of hypoglycemia.” In this regard, Novo’s racing not just against Byetta and family, but against the (oral, and thus highly convenient, and cheaper) DPP-IV inhibitors, too—like Merck’s Januvia and, shortly, AstraZeneca’s saxagliptin (Onglyza), which last week received a positive EU opinion. Indeed, “the question is whether second-line therapy is liraglutide, or another oral therapy,” summarizes Thomson.

Novo’s leading position in the insulin market means it isn’t about to admit that liraglutide’s success will eat into its core franchise. But even if it does delay progression to insulin somewhat, Novo’s hoping the drug allows to it capture patients earlier on in the course of their disease. The idea is that pre-insulin diabetics become loyal Novo followers, “using our services and devices, and…that later on, when they go onto insulin, they’ll add [Novo’s basal insulin] Levemir”—and not Sanofi-Aventis’ competing Lantus—on top of liraglutide, explains Thomsen.

That argument might well be boosted by recent data—albeit still controversial—linking Lantus to an increased cancer risk, a link Novo is trying hard to ring-fence as a Lantus-specific problem, not one that affects all basal insulins.

For the next chapter in Victoza’s US story, we’ll have to wait until August 6th and Novo’s half-year results. The company in early June met FDA to talk risk-management and to discuss Victoza’s victorious performance in a gutsy two-year head-to-head trial versus Byetta. FDA "didn’t have access to this material prior to the [April] advisory committee meeting,” clarifies Thomsen.

In this trial, liraglutide also showed itself as “drug squeaky clean with regard to calcitonin levels compared to comparator drugs…” hence “the [US] regulators will also believe, like us, that the benefit-risk profile of performing invasive procedures to monitor patients’ calcitonin levels is negative,” asserts Thomsen.

Are you listening, FDA?

FDA and EMEA: Minding the Gap

“EMEA is not the FDA of Europe, and the FDA is not the EMEA of the United States.”

That’s how Richard Pazdur – the head of FDA’s Office of Oncology Drug Products – started off a panel on oncology regulatory initiatives at ASCO on May 30. “We recognize that there are different laws, different interpretations of existing laws and different cultural issues that can be brought into play in making regulatory decisions,” he added.

But with consistency, and transparency, in mind, the two regulatory bodies do practice openness. FDA’s entire oncology review team has monthly teleconferences with key EMEA officials. They go over pending regulatory actions, recent meetings with sponsors, proposed regulatory initiatives and even occasional staff exchanges (a regulate-abroad program?).

There is also a free exchange of documents – minutes from end of Phase II meetings, important regulatory letters. “Really the oncology program with this interchange has been one of the models that the FDA and the EMEA want to emulate in other therapeutic areas,” Pazdur said.

Still, Pazdur, who received a personal plaudit for his stewardship of cancer drug approval process with a career recognition award, kept honing in on the differences between the European regulatory system and the FDA process. The way Pazdur referenced some of those differences could constitute a wish list for additional authorities the FDAer would like to have.

One key difference is in the enforcement mechanisms for early approval of innovative therapies – accelerated approval in the US, and conditional approval in Europe. Pazdur deems these functionally equivalent: “it’s a matter of terminologies.”

“But there are differences here. Both of the programs have options to take the drug off the market if clinical benefit or subsequent trials are not done,” Pazdur pointed out. With its longer experience with accelerated approval (EMEA only adopted conditional approvals last year), there have been more tests in the US. And even when a drug has failed in its mandatory trial to confirm the benefit that was the basis of the accelerated approval (AstraZeneca’s lung cancer therapy Iressa), FDA opted not to outright rescind the marketing authorization, instead laying on marketing restrictions and limiting distribution. Still, “most of our drugs have not faced that issue of coming off the market,” Pazdur admitted.

The US legislation on accelerated approval stipulates that sponsors should approach confirmatory trials with “due diligence” – which, Pazdur added, “really is in the eyes of the beholder. Let’s face it, it does not have a legal definition. Whereas I noticed the Europeans were a bit more clever and probably learned from our experience. They put a one-year review, and we don’t have that.”

The EMEA’s Francesco Pignatti made clear that they don’t really have the explicit authority to rescind the approval for compliance reasons, though the one-year re-review remains untested. “It’s only in the case of adverse new information that one could see this change,” he predicted. But the opportunity to reconsider the emerging knowledge of a drug’s risk-benefit was clearly an aspect Pazdur admires.

The FDA official expressed some frustration with the way sponsors handle confirmatory trials for accelerated approval. “Several ODAC meetings have discussed the sometimes lack of due diligence on the part of sponsors in fulfilling these commitments,” Pazdur pointed out. “They are mandatory commitments and should be taken quite seriously by the sponsor.”

There too the EMEA built in a mechanism that FDA would find useful: the European regulators can impose financial penalties if the postmarketing studies are not delivered as agreed.

Consultation with external experts is one area where Pazdur seems to prefer the US system, though he handled the comparison with diplomacy. Unlike the FDA advisory committee system, the EMEA’s Scientific Advisory Group meetings are closed to the public. They’re even mostly closed to the companies involved (there are open portions of the meeting for the sponsor to make a presentation, but then the discussion is closed off again). Pazdur questioned whether the process would be improved or hindered by having public involvement.

Without any experience with that, Pignatti declined to speculate, although he did note the EMEA is “rather far” from having public access for those meetings. Pazdur, however, jumped in – having attended both SAG and CHMP meetings “and obviously the ODAC meetings.”

“To be honest there’s a remarkable similarity as far of the discussions,” he said. In fact, the consistency – reassuringly – holds up with the internal regulatory processes as well, he noted. “Although we’re independent agencies and usually have not discussed the applications prior to our teleconferences, many of the exact same issues come up. And although people love to point to the differences between decisions that the EMEA and the FDA make, by far there’s more similarities than any differences.”

Despite the “lack of transparency” Pazdur noted in the European system for external consultations, the FDAer openly admired the transparency that EMEA gives regarding negative regulatory decisions. The EMEA publishes its negative opinions and reviews on withdrawn applications as well as the positive opinions. “One of the issues that we have in the FDA, which is quite problematic for those of us that work in the FDA,” Pazdur noted, is that when the agency does not approve a drug, the review documents and even the complete response letter that lays out the deficiencies in that application are not released to the public. Companies could release that information (although trust us, they don’t), but FDA is tied from even commenting.

“So this I think is one of the main reasons that we have this apparent lack of transparency, because we cannot release negative information. When we approve a drug, all that information goes out on the web. But for non-approvals, it’s truly the black box warning, so to speak, in its ultimate form,” Pazdur said. --Mary Jo Laffler

At Least the Europeans Appreciate Novo's Victoza

It’s all smiles again at Novo Nordisk following yesterday’s news that EMEA has recommended approval of its GLP-1 agonist liraglutide (Victoza).

The positive opinion followed a decidedly lukewarm US advisory committee outcome earlier this month, where concerns were raised not over cardiovascular safety (a possibility, given FDA’s more stringent diabetes guidelines) but over a raised incidence of thyroid c-cell tumors in rodents during pre-clinical trials. (We cheekily suggested thereafter that Novo might not mind so much about GLP-1s anyway.)

The European regulators, however, appear to agree with Novo’s CSO Mads Thomsen that “the mechanism [behind the raised incidence of thyroid c-cell tumors] is one that mice and rats are sensitive to, but that monkeys and humans are not.”

The regulators haven’t even requested that the company take any additional measures—such as thyroid cancer screening—to rule out the potential risk. “There are no restrictions on usage” as a result of the pre-clinical thyroid cancer data, Thomsen told The IN VIVO Blog. “It was a clean approval.”

Well, a clean recommendation anyway; the European Commission must still issue the final marketing authorization, expected in about two months. With that in hand, Novo will begin to sell Victoza in various European markets over the summer.

This un-restricted European thumbs-up for Victoza matters not just for the drug’s EU commercial potential. China, for instance—a key emerging market for Novo--requires a sponsor to have home-market approval before it can even submit a new therapy. And there will be positive knock-on effects of a European approval in other markets, too, adds Thomsen, since "some countries simply base their approval decisions on the European outcome."

Unfortunately, the US is not one of them. FDA is due to decide late next month whether to approve Victoza, but based on the split advisory panel outcome and an almost entirely risk-focused (as opposed to benefit-focused) discussion, things don’t look good. Analysts including Matthew Osborne, SVP at Lazard Capital Markets, reckon that the best case would be that Victoza launches on time during the second half of the year but with a black box warning and/or monitoring for thyroid cancer. Other options: a 6-12 month-delay due to a request for additional data, or outright rejection. Not a great outlook for a drug predicted to become a blockbuster by 2012.

This isn't the first time European regulators have approved a drug that FDA has rejected or at least prevaricated over. Sanofi-Aventis' obesity candidate rimonabant (Acomplia; Zimulti in the US) was another. Given what happened to that (rejection in the US, withdrawal in Europe), it's interesting--comforting?--to see that FDA's ultra-risk-focused conservatism isn't rubbing off too hard on the Europeans just yet.

image by flikrer sean-b used under a creative commons licence