The Real Story Behind FDA’s Delayed Approval Of Eliquis

With what seemed to be stellar results from the ARISTOTLE trial, showing the first superiority over warfarin on bleeding and mortality for a novel oral anticoagulant, Bristol-Myers Squibb/Pfizer’s Eliquis (apixaban) was expected to have a clean trip through FDA.

So why was agency approval of the third novel oral anticoagulant to come down the regulatory pathway in recent years delayed by nine months?

The answer, which was largely hidden from investors and competitors, boils down to study conduct and oversight – things that should have been a piece of cake for experienced sponsors.

It turns out that the much-ballyhooed, 18,000-patient ARISTOTLE trial had a few problems, according to FDA review documents that are dissected in the June issue of Elsevier Business Intelligence’s Pharmaceutical Approvals Monthly, part of a regular series of drug review profiles (see the lead story, free for the next 30 days, here).

What were the problems? Well, for one thing there was documented evidence of fraud by employees of BMS and its contract research organization, PPD, at a Chinese study site. It seems these individuals altered source records ahead of an FDA inspection to cover up good clinical practice violations.

FDA’s need to further investigate this issue, as well as the data integrity for other Chinese sites and the impact on the overall ARISTOTLE results, led to a three-month extension in the original PDUFA date.

Publicly, BMS/Pfizer said only that the review extension resulted from its submission of a “major amendment to the application.” An accurate statement? Absolutely. But the fact that this “major amendment” comprised a more detailed accounting of the fraud was a juicy, and likely market-moving, tidbit not shared with the public at-large.

To its credit, BMS discovered the fraud and reported it to the FDA, and the alleged perpetrators were terminated. In contrast, the agency had to root out on its own answers to the second major problem that delayed apixaban’s approval – dispensing errors in ARISTOTLE.

Buried on page 88 of the clinical study report was a statement that 7.3% of subjects in the apixaban group and 1.2% of subjects in the warfarin arm received “a container of the wrong type” of medicine at some point during the double-blind, double-dummy study. This overall high rate of dispensing errors, and the disparity between treatment arms, troubled FDA, in part because these figures were based only on the sponsor’s analysis of one incomplete source of data.

FDA believed further investigation into the true rate of dispensing errors was warranted. Furthermore, agency reviewers seemed incredulous that the unusual number of medication errors failed to prompt a “serious inquiry” by the sponsor prior to NDA submission and that such errors occurred throughout the course of the trial without meaningful corrective measures, suggesting shortfalls in trial oversight.

So annoyed were agency reviewers by the whole situation, including BMS/Pfizer’s partial and evolving responses to FDA’s questions, that the team leader on the application said the NDA would have received a “refuse-to-file” letter had agency staff known about the dispensing errors issue at the time of submission.

Ultimately, FDA issued a “complete response” letter specifically directing the sponsor to get to the bottom of the problem – not that you would have known this from the sponsor’s public statements.

In a press release, BMS/Pfizer said only that the letter requested “additional information on data management and verification from the ARISTOTLE trial.” Again, not a falsehood, but also not exactly the type of information that would have been helpful to assessing what was really going on with apixaban’s prospects for a near-term approval.

Ultimately, the companies submitted data that convinced FDA reviewers that even under a worst-case scenario, the dispensing errors would not have disturbed the key efficacy and safety findings in ARISTOTLE.

So, all's well that ends well for BMS and Pfizer, right?

Well, not exactly. Eliquis failed to gain a coveted mortality benefit claim in the Indications statement, which would have set it apart from its two competitors who beat it to market, Boehringer Ingelheim GMBH’s Pradaxa (dabigatran) and Bayer AG/Johnson & Johnson’s Xarelto (rivaroxaban) (see PAM's analysis of how FDA reviewers picked apart the statistical significance here [$]).

Eliquis generated just $22 mil. in its first full quarter on the market, according to Bristol's first-quarter earnings report.

-- Sue Sutter (s.sutter@elsevier.com)

The Avastin Decision: Bad For Genentech, But Good For Industry?

On its face, FDA Commissioner Margaret Hamburg’s decision to rescind Avastin’s breast cancer claim is a clear (though likely not unexpected) blow for Genentech, which waged an aggressive, creative and undoubtedly expensive battle to maintain its blockbuster VEGF-F inhibitor’s accelerated approval for first-line metastatic disease.

But, look a little deeper and you’ll understand why the decision should be (and perhaps already is) being cheered by the larger biopharmaceutical industry.

Hamburg’s 69-page opinion is confirmation that the accelerated approval mechanism is alive and well, and this is because the regulatory pathway’s accelerated withdrawal mechanism has now been validated.

“The Pink Sheet” touched on this briefly in our initial coverage following the two-day Avastin hearing in June (“Avastin’s Breast Cancer Claim: Will FDA’s Hamburg Take A Middle Road?” “The Pink Sheet,” July 4, 2011). However, now that Hamburg’s verdict is in, we think the issue warrants further exploration.

Think of the chaos that would have been created for FDA and industry if Hamburg agreed with Genentech’s view that accelerated approval can and should be maintained until there is practically no hope of confirming clinical benefit?

How many CDER review division directors do you think would be willing to approve a novel therapy on the basis of an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint other than survival or irreversible morbidity, knowing that it would take an act of God to get a drug off the market when the sponsor ultimately either can’t (or won’t) confirm the benefit in post-marketing studies?

How many review division directors would want to go through the scrutiny, and at times embarrassment, that the oncology review division faced during the course of Genentech’s 11-month long battle?

Hamburg lays it all on the line on page 55 of her opinion:

“Withdrawal here is the essential counterpart to accelerated approval. When the accelerated approval pathway was established, it was done with full recognition of the risk that drugs might be approved and later found not to confer clinical benefit to patients. FDA deemed this risk worth taking for life-threatening illnesses in need of additional therapies, but also found it essential to mitigate that risk by providing for follow-up studies and withdrawal when benefit is not confirmed. The program has, on the whole, worked very well, making many new drugs available, particularly to cancer patients and AIDS patients, years before they would otherwise have been on the market. But when follow-up studies fail to confirm benefit, it is essential that approval be withdrawn in order to protect patients.”

If the accelerated withdrawal hammer had been rendered meaningless, we predict you would have seen a lot fewer accelerated approval announcements coming out of CDER in the years ahead. Better to wait three, four, five years for survival data, or confirmatory evidence on some other “hard” endpoint, before making an approval decision than having to face both the embarrassment and time-consuming work of defending your revocation decision at a public hearing, all the while wondering if your own commissioner was going to back you up.

Hamburg’s comments highlight the strengths and weaknesses of progression-free survival as a surrogate endpoint. Though the agency is still reticent of giving hard targets, as sponsors would prefer, it lays out that in many first-line settings, it is the only practical option and one the agency is happy to review. The level of benefit that counts as “clinically meaningful” may be a matter of debate, but even Genentech acknowledged during the hearing that FDA’s granting the MBC approval was “progressive thinking” on the part of the agency. For other sponsors, the Avastin process has added some clarity on FDA’s expectations surrounding PFS – in particular, that quality of life benefits could serve as evidence that the benefit is clinically meaningful. So the Avastin withdrawal shouldn’t just dissuade sponsors from using PFS, it should encourage them to design trials with supportive measures that can themselves turn into additional claims. (Indeed, Incyte’s Jakafi (ruxolitinib) just cleared FDA with a patient-reported outcome based symptom claim.)

By withdrawing Avastin’s MBC indication, Hamburg has introduced some predictability into the accelerated approval regulatory pathway, both for agency staff and drug developers. We’d be surprised if industry, and its investors, didn’t see that as a good result. -- Sue Sutter 

Deals of the Week's Stamp Of Approval

FDA made a pre-emptive strike this week – perhaps a move to forestall an Occupy FDA protest?

Making the most of the (political) capital it has, the agency put out a glossy report on its FY 2011 approval performance, noting that between Oct. 1, 2010 and Sept. 30, 2011, the agency cleared 35 innovative drugs. IN VIVO Blog can’t help but point out that when the numbers haven’t been as good, the fanfare has been, um, lacking.

It’s been clear for some time that 2011 was stacking up to be a stellar year for positive nods from the agency: as of October, FDA had already tied the 27 novel drugs and biologics cleared for marketing in all of calendar year 2010. Though the second-half has fewer review deadlines than the first, 2011 still stands to be a record year, helping defray criticism about an overly safety conscious regulatory body.

You can’t fault FDA’s timing. In what’s surely a happy accident, the news coincides with ongoing negotiations over the reauthorization of the Prescription Drug User Fee Act. Certainly the official report and positive press could deter Congress from tinkering with the legislation, something that might have been easier given the negative coverage bandied about.

But the presser wasn’t only about placating Congressional types. An underlying message also seemed to be that industry should stop its incessant FDA bashing. And just to show that it’s above holding a petty grudge, FDA even went so far as to share a little credit for its success with biopharma companies.

“None of FDA’s accomplishments would be possible without the innovation and hard work of large and small biopharmaceutical companies alike. Not only did the drug applications that the industry submitted to FDA represent important medical advances, but their generally high quality permitted FDA to reach an approval decision, in many cases, after a single cycle of review.”

Well, isn’t that special?

No doubt, biopharmas will find other reasons to point fingers – and this won’t stop the hand-wringing of the med-tech crew. Launching in Europe first via a CE mark is now a preferred strategy for many device companies as they juggle how to satisfy safety measures mandated by FDA.

Maybe the PR was designed to curry favor, or remind folks that FDA is the government’s Rodney Dangerfield. Still there’s no denying the agency is under continued budgetary pressure. And really, does anyone in the industry want to see PDUFA held hostage to partisan politics?

In the interim as you muse over the specifics of FDA’s approval memo, we hope Deals Of the Week garners a stamp of approval. It’s that time again.

Bristol-Myers Squibb/Aslan: Out-licensing alert! Bristol-Myers Squibb has formed a partnership with Singapore-based Aslan Pharmaceuticals to hasten the development of an early-stage compound, BMS-777607, an oral MET receptor tyrosine kinase inhibitor that it considers promising, but not core to the big pharma’s focus on more advanced oncology compounds. The Bristol compound is the second acquired by privately held Aslan, established last year by former AstraZeneca executive Carl Firth to in-license and develop early-stage compounds in oncology, respiratory and inflammatory indications and to take advantage of efficiencies in conducting trials in Asia. The companies didn’t release financial terms for the Nov. 3 deal, but Bristol said Aslan will run and fund development of ‘607 in gastric and lung cancer. Aslan obtains exclusive rights to develop and commercialize the compound in China, Australia, Korea and Taiwan, while Bristol retains Japanese rights to the drug. As opposed to its “String of Pearls” acquisition strategy, Bristol referred to the Aslan arrangement as part of its “Oyster” strategy. (Nope, we ain't gonna go there.) The goal of "OS"is to seek partners to run and fund early development of assets BMS presumably does not want to take forward itself. This is Aslan’s second acquisition – in July, it in-licensed HER2/EFGR inhibitor ARRY543 from Array BioPharma Inc.—Joseph Haas

AgonOx/MedImmune: Tiny Portland, Ore.-based startup AgonOx has been studying the OX40 receptor, a tumor necrosis factor superfamily member whose activation appears to trigger immune responses useful in fighting cancer. The company’s work has caught the attention of MedImmune, which will pay an undisclosed amount to develop oncology drugs using AgonOx’s platform. Although the companies aren’t releasing many details, MedImmune will apparently lead continuing preclinical and clinical studies on one OX40 agonist program, while supporting ongoing research on OX40 at Portland’s Providence Cancer Center. AgonOx has also studied one drug, an anti-OX40 monoclonal antibody, in 30 human patients over the past year, and further trials are in progress. In September, AgonOx said it received a patent covering OX40-related ligand fusion proteins for use in cancer. The company is seeking partners for combination therapies, potentially involving cytotoxic compounds, tumor ablation methods, and other immunologic therapies. Privately-held AgonOx hasn’t named any outside investors, but has acknowledged support from the Prostate Cancer Foundation. – Paul Bonanos

GlaxoSmithKline/DOJ: GSK's toughest negotiations this year have been with the federal government. On Nov. 3, the drug maker announced it had reached an agreement worth $3 billion (in principle) to resolve three separate government investigations tied to the following: its development and marketing of Avandia; sales and promotional practices relating to Wellbutrin SR, Advair and 7 other top selling products from January 1997 to 2004; and its nominal price exception to the best price reporting requirements of the Medicaid drug rebate program. Just to put the dollar amount in perspective, that $3 billion is more than a quarter of GSK’s Q3 2011 revenue of £7.1 billion, and in terms of potential deal value is the pharma's biggest transaction of the year thus far. Moreover, the sum is on top of the $750 million settlement GSK and DOJ reached last year tied to good manufacturing praction violations at a Puerto Rico facility. In case you are wondering, the new agreement breaks Pfizer’s 2009 record $2.3 billion settlement, which resolved allegations of off-label marketing of four drugs and kickbacks to health care providers involving nine other drugs. Still to be determined: whether any of GSK's officers will face criminal charges. The government has said for the past two years that it intends to hold individual executives responsible for health care fraud. Pfizer escaped such a fate even though the government slammed it for repeatedly violating the law. GSK attorney Lauren Stevens had previously been indicted for obstructing an FDA investigation of off-label marketing of Wellbutrin SR and making false statements. A judge acquitted her in May.--Brenda Sandburg

Celgene/Quanticel: Forget the most interesting man in the world, methinks Celgene is gunning for most interesting deal maker of 2011 award. This week comes news that Celgene is teaming up with privately-held Quanticel Pharmaceuticals in a deal that is part option-to-acquire, part financing, and all around interesting. Versant Ventures has launched Quanticel, a start-up with genomic analysis technology aimed at discovering and developing cancer drugs that target the unique genetic makeup of patients' tumor cells, after incubating the idea for more than a year. The tie up with Celgene is unusual, underscoring how VCs are desperately seeking new biotech investment models that tie early stage companies closer to potential pharma acquirers. Although details regarding the deal were light, what's know is that Celgene is committing $45 million to Quanticel in return for an undisclosed equity stake in the biotech as well as an exclusive three-and-a-half-year technology license. Celgene has sway over Quanticel in another way: more than one exclusive time-based option to buy Quanticel outright. "We hope it ends in an acquisition by Celgene," said Quanticel CEO Stephen Kaldor. "That's the design." All parties involved declined to discuss the size of Celgene's ownership stake or the details of its acquisition options. But the arrangement effectively limits Quanticel's potential buyers to one and thus caps the potential return for Versant. "This is a different risk-reward ratio than traditional venture," says Versant managing director Brad Bolzon. The trade-off, he says, is a higher ownership stake for Versant than it would have in a syndicated deal. (The amount of Versant's investment was also left undisclosed.) For more see coverage in Elsevier's Pink Sheet Daily and November's START-UP. --Alex Lash

Pfizer/Ablynx: Ablynx said today that Pfizer had returned all rights to the companies’ anti-TNF-alpha nanobodies program, which emerged over the last five years from a 2006 deal between Ablynx and Wyeth; that deal was extended in 2010 and has thus far generated two clinical candidates. Ablynx recovers full rights to ATN-103 (aka ozoralizumab), which this past May achieved positive Phase II proof-of-concept data, and PF-05230905, a pegylated backup compound in Phase I, along with clinical supplies of ‘103, IP and knowhow around the programs and manufacturing. In return Ablynx will owe Pfizer a share of milestones received from a future partnership around these assets, capped at $50 million, plus royalties. The ‘103 program was among Ablynx’s furthest along nanobodies (the camelidae-inspired, single-domain, antibody-derived proteins are so named because of their small size, and, presumably, because “Camelbodies” just didn’t sound right), and possibly its biggest commercial prospect. As such the market reacted poorly to the news today, sending Ablynx shares down 18% on the day to levels not seen since the company began public trading in 2007. During a call with analysts today CEO Edwin Moses said the assets were still “very valuable” before quoting a “former Pfizer SVP”’s morning email to the company that suggested the development would be positive for Ablynx. In fact, he suggested, were Ablynx still working with an un-Pfizerized Wyeth, the asset might "be in Phase III by now," and that plenty of companies will show interest in the newly-partnerable program. Pfizer, he noted, has other options, including its late-stage JAK3 inhibitor, and a different senior commercial team committed to that program. That may be true, but unless the company opts to find a partner straight away, it could also be expensive transition for Ablynx and have an impact on the progress of the company’s existing pipeline. Moses noted that the company would almost certainly conduct a strategic review “in the coming weeks” to reprioritize, but would probably not cut its Eur60-70 million R&D budget.--Chris Morrison

Image by flickrer Avius Quovis, courtesy of creative commons. FDA commentary written by Mary Jo Laffler and Derrick Gingery. Editing this week by Ellen Licking. 

We Bet No Champagne Corks Popped at AZ

Brilinta's long-delayed FDA approval yesterday should have meant party-time at AstraZeneca. After all, this blood-thinner showed itself, in head-to-head trials, to be better at preventing heart-attacks than the $8.8 billion Plavix, the number-two drug in the world. And unlike in the case of beleaguered dapagliflozin, AZ doesn't have to share Brilinta profits with anyone.


We suspect there weren't many champagne corks popping, though. FDA's nod was reluctant, to say the least, and came with a sting in the form of a boxed warning about bleeding risk and the aspirin-problem: if patients are on too much aspirin (more than 100mg per day), Brilinta ain't so brilliant. Most if not all heart patients take aspirin. And most also take host of other pills, too -- meaning that Brilinta's twice-daily dosing could be a significant turn-off.


No wonder that, despite a small share rise for AZ yesterday, the analyst reaction was muted. Jefferies' Jeffrey Holford halved his peak sales estimates for the drug to $1 billion, calling the FDA victory 'pyrrhic' and advising investors to sell. Indeed, even the $1 billion, if it's reached, won't come fast: AZ is talking about a 12-month roll-out period, given reimbursement hurdles (raised, probably, by today's planned merger of Express Scripts and Medco, giving buyers even more clout to squeeze prices) and a REMS that calls for the company to educate physicians as to the aspirin problem.


By then, generic Plavix will have flooded the U.S. market (multisource generics are expected in May 2012), providing yet more compelling reason -- cost -- for payers to dismiss, or at least disadvantage, Brilinta.


They certainly aren't embracing Effient, Lilly's blood-thinning offering, launched in 2009. Granted, that drug came with a narrower label than Plavix, and additional bleeding risk (and not only among high-dose aspirin patients). Despite some advantages over Plavix -- it doesn't share the blockbuster's efficacy problems among slow metabolizers, and can be used in conjuction with PPI drug omeprazole -- Jefferies expect Effient sales to reach only $244 million this year.


The bottom line is that Brilinta won't do much to plug the gaping, multi-billion dollar revenue hole left at AZ after the likes of Seroquel, Nexium, Symbicort, Atacand and Zomig (worth about $14 billion in 2010) lose exclusivity in 2014 or sooner. Not to mention the $5.7 billion Crestor, which goes off in 2016 but whose growth is already slowing ahead of generic competition to class-competitor Lipitor this year.


So AZ's in the same boat as Lilly: sitting there (albeit while re-organizing its R&D), faced with the harsh reality of today's pharma scene: if there's a big drug out there that works good enough, and is about to become a lot cheaper, don't bother trying to better it. Better has to be so much better these days; and safer has to be safer in all patients, not just those going easy on the aspirin.

Meanwhile in Europe (where, in those patients included in the 18,000-strong Phase III PLATO trial, the aspirin problem didn't show up), Brilique (as it's known there) is already reimbursed in seven countries (including Iceland) and the company expects decisions this year in France (following an earlier withdrawal), Germany (where it's the first to test a new reimbursement system) and the U.K, where the drug received a preliminary approval in June.

image by flickrer creative tools used under creative commons

New Year’s Resolution for Biopharma: Submit Better NDAs

It’s official. The year 2009 was better than 2008 for innovative drug developers in the US, at least by the most common measure: the number of new molecules approved by the Food & Drug Administration.

The Center for Drug Evaluation & Research approved 25 new therapies during the year—one more than 2008. That’s not a big increase, but it is the second year in a row of higher approval totals. That is just one of many reasons for innovator companies to feel good about the improving new drug review process heading into 2010. (You can read the first of several installments about the state of the new drug review process in the US in The RPM Report, here.)

Drug development companies should feel good about the increasing approval tally—especially since it comes at a time when FDA’s reviewers were missing deadlines set by the user fee program.

But they should also take to heart the advice of Office of New Drugs Director John Jenkins during The RPM Report’s FDA/CMS Summit for Biopharma Executives last month. Jenkins, to put it bluntly, thinks industry should submit better applications. In his view, too many new drug applications are filed prematurely to meet a sponsor’s internal goals, all but guaranteeing that a review will end with a complete response letter rather than an approval.

In Jenkins’ view, if sponsors put together a more thorough, complete application—dotting all the “I”s and crossing all the “T”s—a first-cycle approval would be more likely. So, Jenkins says, taking a few extra months preparing to file would pay off with an earlier launch.

Now, it is safe to say not everyone in industry agrees that sloppy applications are a reason why many applications go through more than one review cycle. But a lot of folks in regulatory affairs know it does happen, and we know for certain of at least a few cases that look black-and-white.
You can read more about Jenkins’ views in “The Pink Sheet” here, and we'll take a deeper dive in the January issue of The RPM Report.

But for now, we’d encourage innovator companies to take advantage of the New Year to make a new resolution: make sure your internal filing deadlines encourage earlier launches—not earlier submissions.

Stealth Comparative Effectiveness in U.S.

Are you sitting down?

The FDA is practicing stealth comparative effectiveness.

Or at least that's one of the claims to come out of a lively panel discussion that attempted to grade the regulatory agenda of the new leadership at FDA during the first day of The Pink Sheet's annual FDA/CMS Summit.

The discussion was sparked some provocative data released by the Director of the Office of New Drugs, John Jenkins, during his status report on new drug approvals. (You think he only took industry to task for submitting incomplete applications? Guess again.)

In an effort to silence critics who charge the FDA is becoming more conservative, approving fewer drugs because of its safety first initiatives, Jenkins and his team parsed applications data for the past 17 years, looking at the percentage of new molecular entities approved on first action during five-year increments. Here's what they found: NMEs with priority review did pretty well; in the most recent period, 68% of the compounds won approval, up from 58% in the previous time period. But for standard NME applications, the story was far different: 70% of the medicines were not approved on first action.

Calling this failure rate "a huge burden on the system," Jenkins challenged the drug industry to do some more navel gazing. "The industry needs to ask itself why the failure rate [for standard NMEs] is so high," he says.

It's not like execs haven't been asking that question. Perhaps the only issue causing more hand-wringing than comparative effectiveness is the lack of R&D productivity in the industry. That's why folks at Lilly, for instance, are aiming to expand their highly publicized Chorus experiment, which aims to identify earlier--and more cheaply--whether new compounds even have a shot at becoming viable medicines.

Mary Pendergast, the former deputy FDA commisioner and now President of Pendergast Consulting looked at Jenkins' data and came up with one possible answer that takes some heat off the industry. Maybe one reason it's so much harder to get the second, third, fourth, and fifth drugs in a class approved these days stems from FDA's desire to see superiority data. "What we are seeing--and should be paying attention to--is [the emergence of] stealth comparative effectiveness," she claims.

Note that current laws stipulate explicitly that FDA does not have a mandate to practice comparative effectiveness. But in Pendergast's view, the emphasis on superiority data "is a tiny loophole that the FDA is driving a truck through."

Better that than a camel through the eye of a needle, eh?

Image courtesy of flickrer (cup)cake_eater used with permision through a creative commons license.

Never Mind The Delay, Amgen Puts D'mab on its Website

The Amgen team must have felt rather bullish that the FDA would approve denosumab today, since it is the PDUFA date. So they loaded this link on the biotech’s web site for anyone seeking information on reimbursement issues. [UPDATE: Amgen has removed the page and we didn't take a screengrab, but we have the new logo, below. UPDATE 2: Here's the page, rescued by commenter rob using Google cache.]

Never mind that it was still possible the agency would issue a complete response letter, which would cause a delay. And sure enough, that’s just what happened. The agency is requesting several items, including more detail about a post-marketing surveillance program (see the statement).

Reimbursement info is rather important to place on web sites, of course, given that more and more people are having difficulty affording their meds, especially during the recession. So this is a good public relations move, not just a genuinely helpful gesture. Pricing for denosumab, which Amgen has dubbed Prolia, is expected to cost about $1,000 a month, according to earlier reports, although that may change.

In any event, this isn’t the first time that Amgen has somehow gotten ahead of the FDA over a drug approval. In July 2008, BusinessWire issued a press release saying the agency had approved the Nplate blood clotting drug, albeit with certain risk management requirements. But the premature release embarrassed Amgen, which forced the news service to issue a retraction.

'false start' image via nfl.com

Is There a Drug Lag? We Still Don't Know

Is there a difference in the pace of approvals between the US and Europe? We asked, and you answered, with a clear, unambiguous "maybe."

The results of our poll are below, and glance at the responses makes it clear: about half of you think that yes, FDA has become too conservative and therefore drugs are more likely to make it to market first in Europe. And about half of you think there is really no difference.

There isn't much support for the idea that maybe the problem is that Europe hasn't learned to be appropriately cautious. We, however, feel compelled to point out that many in FDA might feel that way, raising the distinct possibility that if there is a drug lag, it will only close if Europe starts to slow down.

Thanks to all who commented, including a few who proposed "other" responses. Our favorite: "Both yeses are correct."

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

Is There a Drug Lag? Polls NOW Open

Apologies to all who tried to vote in our poll on the so-called "drug lag" between the US and FDA. The link in our email yesterday was incorrect. Fraud? Ballot box stuffing? No. Typo? Yes.

Here is the correct link to the poll: http://answers.polldaddy.com/poll/1955904/

And here is the original post (with the poll embedded).

"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.)

FDA Gives Cimzia the Thumbs Up in RA—At Last

UCB’s Cimzia deserved a break. After a troubled developmental and regulatory history (read about it here and here) the drug finally received FDA approval for RA today, earlier than most expected, and with a label that analysts describe as “the best possible.”

Brussels-based UCB received a complete response letter for the pegylated anti-TNF antibody in January, requesting a new safety update. That led most analysts to predict approval towards the end of this year at best—even though UCB had submitted its safety update at the end of April. Nor had anyone held much hope of approval with a pre-filled syringe and the option of dosing both fortnightly or once-monthly, since neither were tested in all Phase III trials. The approval grants both.

That’s lucky, since UCB will need all the tail-wind it can find to gain market share in a highly competitive market. Already on the market since last May for Crohn’s disease, Cimzia will be the fifth anti-TNF in RA, joining well-established incumbents including Abbott Laboratories’ twice-monthly Humira, which sold over $1 billion in the first quarter of this year, and Johnson & Johnson’s recently-approved once-monthly golimumab (Simponi). Humira’s pre-filled syringe formulation has already given it a huge lead over J&J/Schering-Plough’s Remicade, which is given by infusion. As such, “we have cautious expectations for Cimzia,” writes Piper Jaffray’s Richard Parkes, adding that the drug might eventually garner a 5% share of the RA biologics market, or about €593 million in peak sales.

But UCB is doing its damnedest to trump even Humira’s pre-filled syringe with a device, developed in conjunction with consumer products company OXO, that it describes as state-of-the-art. According to the press release, it’s ‘easy-to’ everything: open, grip, plunge, read….in sum, it’s a device designed to make self-injection as simple as pie for RA patients.

UCB isn’t solely banking on super-duper finger grips and easy-to-push syringe plungers to provide sufficient differentiation versus Simponi, and on a once-monthly dosing option to help it steal share from Humira, though. “We’ll sell it on efficacy,” a company spokesperson told The IN VIVO Blog, pointing to the drug’s fast-onset and long-lasting effects that result from its being the only pegylated anti-TNF. “I think it will go beyond $1 billion,” the spokesperson continues.

That would certainly be nice, since UCB faces a tough 2010, with its biggest-selling epilepsy drug levetiracetam (Keppra) facing generics in Europe (it’s already generic in the US), allergy drug levocetirizine (Xyzal) losing exclusivity in the US (and in the EU in 2011), and a loss of royalty income inherited from its 2004 acquisition of Celltech.

“You don’t have to be first to be best,” points out UCB, and that’s true. It’s also true that docs are calling for more choice in a market that’s growing, and where many patients don’t respond to existing drugs. But it will be an uphill battle for UCB even with a favorable label and a snazzy device—particularly now, when even Humira is suffering a growth slowdown as patients back away from pricey biologics.

UCB is desperate to prove the skeptics wrong. “I don’t blame them [the analysts] for their caution,” says the spokesperson, given Cimzia’s dodgy track record with FDA. But now that it’s through, UCB’s 150-strong US RA sales force is in place and the drug will go to its first patient within 24 hours, the company says. “We’ll prove we can get more than 5% market share,” the spokesperson says. “We’ll walk the talk.”

image of delirium tremens (belgian ale) by flickr user Nic Launceford used under a creative commons license

Vanda's Iloperidone: Not Something You See Every Day

The recently and some-say miraculously approved iloperidone (Fanapt) from Vanda Pharmaceuticals is certainly a rare bird. (Full coverage of the approval in today's Pink Sheet ($), here.)

Rare in that, in just nine months, it went from not-approvable to FDA-approved.

But also rare because it is one of only a handful of unapproved assets out-licensed to a small biotech by a Big Pharma and which eventually found its way to the market. (This phenomenon was pointed out to us by eagle-eyed IVB reader and COO of Versant's EuroVentures incubator Tom Woiwode. In fact, iloperidone was out-licensed by TWO pharmas, but we'll get to that in a minute.)

In any case, we agree: despite the interest among VCs in backing ex-Big Pharma assets and spin-outs, and Big Pharma's seemingly increased willingness to part with shelved assets, few have so far meandered their way to market a la iloperidone.

Of the ones that have there have been some doozies, though.

Cubist has built its anti-infectives business on the back of the success of Eli Lilly's unwanted antibiotic daptomycin (now sold as Cubicin), for example. Actelion's bosentan (Tracleer)--a blockbuster on the market to treat pulmonary arterial hypertension--began life at Roche. And Novartis' first-in-class renin inhibitor aliskiren (Tekturna) was championed by Speedel Group founder Alice Huxley. The drug's clinical successes led Novartis to pick up its option to market the drug and eventually to buy Speedel in July 2008 in a deal valued at nearly $900 million.

Surely we're missing some, so please let us know in the comments. But we think the point remains: few drug candidates, once abandoned by their original Big Pharma developers, go on to reach the market. At least so far.

There have however been other pharma-to-biotech success stories (or qualified successes, like Adolor/GSK's alvimopan (Entereg) which was originally developed by Lilly). Some deals involved geographically restrained smaller pharmas without the urge or wherewithal to compete in every market. For example Cephalon licensed modafinil in 1993 from French pharma Groupe Lafon and wound up acquiring the pharma in 2001 on the back of Provigil's success. And after all, a drug doesn't need to be approved to spark a solid return for a biotech in-licensor.

Just ask Vicuron's investors. That company's pipeline included the antibiotic dalbavancin and the anti-fungal anidulafungin, the delayed promise of which helped spur Pfizer to buy the biotech in 2005 for a whopping $1.9 billion. Anidulafungin had been licensed by Lilly (Lilly again!) to Versicor, one of Vicuron's predecessor companies, in 1999. Pfizer eventually launched anidulafungin in 2006 under the Eraxis brand -- but the acquisition was a bust for the Big Pharma. Eraxis sales in 2008 were microscopic. Dalbavancin, which originated in a unit of Hoechst Marion Roussel and was spun off into Vicuron's other predecessor company, Biosearch Italia, remains disappointingly unapproved.

Domain Associates has made a business out of in-licensing development assets from pharma (usually Japanese companies), creating companies around them, developing the assets further -- and then selling them to Big or Mid-Sized Pharma pre-approval (as it did, for example, with Peninsula, Cabrellis and NovaCardia).

But back to iloperidone, and what a long strange trip its been. In fact two separate pharmas have out-licensed the compound. In January 1997, Hoechst licensed the drug to now-tiny Titan Pharmaceuticals. (Titan, still kicking around and trading as a penny stock, was up an insane 1500% on the approval news.) Titan turned around later that year and licensed the drug to Novartis. Novartis and Titan ran into trouble in Phase III when the drug was shown to cause QT prolongation; Vanda took on development of the drug in 2004, and received the Not Approvable letter from FDA last July.

There are a few other ex-Pharma assets coming up to their days of regulatory reckoning before too long. Cadence's Acetavance (from BMS), Movetis's prucalopride (from J&J), and Basilea/J&J's (those lovebirds!) ceftobiprole (originally from Roche) are all before or about to be before FDA and/or EMEA. VCs remain eager to back in-licensing based companies--Versant, for example, is involved in Cadence, Flexion (a POC play modeled on Lilly's Chorus division), and Synosia (CNS assets from Roche and others).

The dearth of Big-Pharma-to-Biotech asset successes may be a reflection of smart moves by pharma pipeline pruners or just the difficulty of drug development no matter a drug's provenance. But with Big Pharmas like Pfizer making for the past couple years an ever-bigger deal about its spin-off and out-partnering activities, nine months on from the iloperidone Not-Approvable, perhaps we're on the brink of something different.

Fanapt may be an outlier, for several reasons. But it may also be a reason for biotechs to be hopeful.

Dodo image from flickr user kevinzim used under a creative commons license

WTF? Regulatory Victory for Vanda's Iloperidone after FDA U-Turn

Does the approval of Vanda's iloperidone (now given the 'just for you, crazy sportsfan!' name of Fanapt)--deemed Not Approvable by FDA only nine months ago--signal a shift at the agency around use of comparative effectiveness considerations in approval decisions?

The atypical antipsychotic was approved yesterday for acute treatment of adults with schizophrenia, and marks a significant turnaround from last July. As we wrote then:

The company and its rejected investigational atypical antipsychotic drug iloperidone appear to be a marker in the ongoing debate over whether FDA is increasingly using a comparative efficacy standard when considering new drug approvals.

There was plenty of reason to draw that conclusion. Though Vanda said FDA deemed the drug effective against placebo and having similar efficacy to Pfizer's Geodon, it was concerned about how the drug fared against other comparators, specifically Lilly's Zyprexa or J&J's Risperdal. It also wanted more safety data on the drug's higher, 24mg, dose. The agency was requiring further studies, Vanda said.

Remarks by FDA's 'dean of the drug approval process' Bob Temple at an Institute of Medicine meeting only days later seemed to support the notion that comparative effectiveness was becoming a standard hurdle in certain crowded drug classes. He clarified those remarks in an interview with RPM Report's Ramsey Baghdadi a few days later.

“At the IOM, I was explaining what I perceive drug companies to be perceiving and doing, not describing an FDA standard. That is what I was referring to when I said that ‘It’s getting harder to develop the third, fourth, fifth, and sixth member of a class of drugs because when there’s a generic available [within a class], people are inclined to use the cheap one. ...

"It seems apparent that in my statement I was referring to my impression of what companies are doing to have a commercially viable product when there is a generic available for the drug class, and was not referring to any FDA requirement. In most settings, especially for symptomatic treatments, we do not get or ask for comparative data and are perfectly willing to approve a drug that is shown effective."

And in the end, FDA didn't require the kind of large and expensive head-to-head trial that seemed on the cards for Vanda. In September 2008 Vanda reported it had met with FDA to make its case, and that it would file a complete response to FDA's letter. In November, the agency accepted the resubmitted NDA with a decision deadline of May 6, 2009.

It has been far from smooth sailing for Vanda in the meantime. The company did some December restructuring and earlier this year has spent time fending off activist shareholder and 15% Vanda owner Kevin Tang, who proposed back in February to install himself and a colleague at Tang Capital Management on Vanda's seven-member board, presumably to facilitate the liquidation of the company that he has been calling for. The situation escalated only a month ago (See The Pink Sheet Daily for details.).

And yesterday came the approval--hardly a nuisance for Tang, considering the biotech's shares were up more than 800% (yes, EIGHT HUNDRED, that's not a typo) in after-hours Nasdaq trading. Maybe he'll send flowers. (UPDATE: Vanda says Tang has formally withdrawn his proposal to replace the board and call for a shareholder vote on liquidation. Still no word on flowers.)

So what on earth has changed? Vanda's case to FDA must have been convincing. Today the company is trumpeting Fanapt's mild effects on weight in a space where weight gain is a significant issue, and the way patients often switch between antipsychotics--making any safe and effective option worth having.

Does that explain the U-turn? Given the stock's movement, clearly few investors were betting on a happy FDA outcome for Fanapt. Perhaps more complex, political forces are at work?

image from flickr user mag3737 used under a creative commons license.

Why Plan B Still Matters

Politics played a role in the review of Plan B? We’re shocked—shocked I say—to hear it.

That “gambling in Casablanca” moment is courtesy of New York federal court Judge Edward Korman who deemed FDA’s decision to set an age limit and behind-the-counter marketing conditions on Barr Labs (now Teva’s) emergency contraceptive to be “arbitrary and capricious” decision-making.

The March 23 ruling cites “repeated and unreasonable delays, pressure emanating from the White House, and the obvious connection between the confirmation process of two FDA Commissioners and the timing of the FDA’s decisions.” (You can read our coverage of the ruling here; the opinion itself is available here.)

Now, most biopharma companies may be tempted to dismiss the whole Plan B controversy as just a tempest in a teapot: further evidence that anything touching on abortion rights is political dynamite, perhaps, but not relevant to their day to day commercial lives.

We disagree.

In the second issue of The RPM Report, three-and-a-half years ago, we noted the irony of Plan B: despite the fact that Barr Labs’ application for an over-the-counter switch of the emergency contraceptive was making national headlines—and even played a role in the Presidential campaign in 2004—it was at best the third most important commercial issue for Barr at the time.

And even less important commercially for the rest of the biopharma industry.

But, we argued, biopharma companies could ill afford to ignore the controversy over Plan B. The political firestorm over Plan B would have long term consequences for the agency, we argued, as well as an immediate impact on the framework for over-the-counter switches across the board. (You can read that story, “Why Plan B Matters,” here.)

We feel the same way now—this is a case with limited commercial impact but big policy implications. Here are seven ways that the Plan B ruling could affect the entire biopharma sector:

(1) A Wild-Card for the Hamburg Confirmation

On paper, the ruling dovetails nicely with some themes of the incoming Obama Administration, offering another case study for the White House to use to argue that it is committed to science-based public health policy. (See, for example, stem cell research.)

Indeed, it is perfectly possible that the new FDA team—led by Commissioner-designate Margaret Hamburg—would have reopened the Plan B decision of its own volition to make that very point.

But we are betting that the Obama Administration would rather not have this come up in the context of the confirmation process. And biopharma companies—who stressed the urgency of filling the FDA vacancy during the transition—should be wary of any wrinkle that could delay the confirmation.

Plan B was a rallying cry for Democrats nationwide in 2004, but was more specifically associated with the Hillary Clinton campaign in 2008. And if the Obama Administration wanted to make it a rallying point this year, it could have embraced calls to name Susan Wood—the former FDA official who resigned over the handling of the application—as commissioner of the agency.

Regardless of what the new FDA team actually would have done with Plan B, it now has no choice but to revisit the application—and Hamburg is certain to be asked about it in the confirmation process. As the ruling itself notes, Plan B already helped delay the confirmation of the last two commissioners (Lester Crawford and Andy von Eschenbach). It is not out of the question that Plan B will cause another delay this time around.

(2) Reopening Old Wounds Inside FDA

To critics of the agency’s handling of Plan B, Sue Wood is the hero of the story. Now on the faculty at George Washington University, Wood has been an outside advisor to the HHS transition team. So when she was quoted by the Washington Post pointing out that two of the key figures in the review—Steven Galson and Janet Woodcock—still have jobs, that sounded ominous to us.

Galson is now acting Surgeon General, and, as we have written previously, he is considering various options once a new Surgeon General is appointed. Woodcock, of course, is the head of FDA’s drug review center and one of the agency officials considered most vital to a functional review process by most folks in industry.

Woodcock is a career civil servant, and no one we’ve talked to thinks it is likely that she would be pushed out because of Plan B or for any other reason. Still, after a long career at FDA, no one would be surprised if Woodcock decided this was her last transition.

(3) Raising the Bar for Top-Side Involvement in Approval Decisions

Much of the ruling focuses on the degree of top-level involvement in the decision on Plan B, in effect defining a direct, hands-on role by the commissioner (actually, three commissioners: Mark McClellan, Lester Crawford and Andrew Von Eschenbach) as indicating some form of undue political interference in its own right.

That by itself is a potential concern for industry. In this case, the commissioner’s involvement appeared to delay an approval—but what of David Kessler’s hands-on role in shepherding some of the earliest HIV therapies through the agency, in effect inventing accelerated approval in the context of a specific application?

More importantly, the ruling also highlights the unusual level of involvement of the center director (Galson) in many aspects of the review. The ruling stops far short of saying the CDER director can’t weigh in on approval decisions—but it sure seems to suggest that FDA may want to better define when or how the director can get involved.

That could have big implications if it takes some discretion away from the center director. Sponsors upset by a decision rendered at the top (cf. Momenta and generic Lovenox) may applaud; others hoping for a chance to head off a negative outcome may find it harder to engage FDA’s top management without going through a formal appeals process.

(4) The End of “Behind the Counter”?

Plan B’s currently approved OTC application dictates availability solely “behind the counter,” a development that took FDA a big step closer to the long debated idea of a formal “third-class” of drugs, somewhere between prescription only and traditional over-the-counter.

Politically expedient or not, that made it a precedent setting approval.

That precedent, though, may be overturned. The court ruling specifically addresses a petition seeking to have Plan B made available over-the-counter without restriction. The ruling does not change Plan B’s behind the counter status, but directs FDA to re-review the question based on the science (with a strong indication that the judge views the science as supporting unrestricted access).

Coincidentally, the Government Accountability Office released a report on BTC status the same day as the ruling, and let’s just say that GAO is skeptical about the entire idea. (Read our coverage here.)

(5) Discouraging “Creative” Risk Management Ideas

While the court is leaving it to FDA’s discretion to reconsider the question of behind-the-counter status, the order does change one condition of the approval right away: Plan B is to be relabeled for use by those age 17 and up, rather than the current 18 and up restriction.

That overturns a last-minute change to the proposed label for the OTC version of the drug that the court attributes to former Commissioner von Eschenbach.

He “decided that 18, rather than age 17, is the ‘more appropriate cutoff point’ for OTC use of Plan B because of ‘well-established state and private-sector infrastructures [which] restrict certain products to consumers 18 and older,’” the judge wrote.

That, in the judge’s view, was entirely unsupported by FDA’s administrative record.

It does, however, seem logical: 18 is a well-defined milestone defining the boundary between teenager and adult. That rationale reminds us, at least, of some of the types of suppositions the agency is starting to make more routinely in negotiating risk management plans with sponsors. (Now formalized as Risk Evaluation & Mitigation Strategies authorized by statute.)

At its heart, the risk management process involves additional controls in the commercial setting intended to align better with real world practices. The logic of the Plan B ruling suggests that FDA may need more than common sense to justify a restriction on access that isn’t supported in the clinical database.

(6) Less Predictability in the Advisory Committee Process

We’ve written lots and lots about the ever evolving role of advisory committees in the review process—and the loss of any measure of predictability for sponsors facing a make-or-break event for their products. (Latest update: Sid Wolfe calling on FDA reviewers in the audience to offer an opinion.)

The Plan B ruling highlights the advisory committee process for two reasons. First, the court puts great weight on the fact that the advisory committee reviewing the switch voted overwhelmingly in favor of approval—but FDA ended up sending a “not approvable” letter. The court notes that FDA is not bound by advisory committee rulings, but cites a Government Accountability Office review of Plan B showing that the agency never previously overruled an OTC switch recommendation.

Any sponsor to get a positive committee review and then a rejection from FDA may think that’s good news, but we don’t see it that way. First, as we’ll argue below, no one we’ve talked to thinks a sponsor would win a case against FDA solely on those grounds. More importantly, if FDA is (or perceives itself to be) bound by advisory committee rulings, the agency will be much more conservative in its approach to those meetings, and is probably unlikely to even ask approvability questions if it is concerned about a “wrong” answer.

The ruling also touches on a more current issue about staffing committees, concluding that FDA’s leadership tried to stack the committee with people who would vote against the application. The court found that “the Office of the Commissioner appointed members to the advisory committee not for their expertise, but to achieve what the Office of the Commissioner called a ‘balance of opinion’ on the panel.” The ruling then notes that CDER officials say that is contrary to standard practice: “CDER is ‘not . . . looking for people who have an opinion coming in. That’s exactly what we don’t want. We want people who can look at what’s before them and render an assessment and recommendation on the basis of that.”

That sentiment now goes by the name “intellectual conflict of interest,” and if the recent advisory committee review of prasugrel is any indication, FDA still has some work to do on that policy. (Look for more coverage of that point soon in The RPM Report.)

(7) A Chilling Effect on Pre-NDA Commitments

Last but not least, the ruling could affect FDA’s communication about approvability issues in the pre-NDA setting.

The judge cites FDA’s pre-NDA discussions with Barr about its “actual use” study plans for Plan B as evidence that its subsequent concern about use in adolescent girls was a fig-leaf for political issues. As with the advisory committee vote, the ruling stops well short of declaring that the agency’s pre-NDA discussions should be treated as binding.

Still, some sponsors may read the case as a reason to rethink the conventional wisdom that suing FDA is a waste of time and money at best—and counterproductive at worst.

Food and drug lawyers we spoke with are unanimous in saying that there is no reason to change the conventional wisdom. In their view, Plan B is an outlier, a rare circumstance where suing the agency can (and did) work. And, they note, Barr didn’t file the suit—women’s health advocates did.

However, even if FDA doesn’t face a wave of lawsuits from sponsors asserting that, for example, the new diabetes endpoints are arbitrary and capricious, the ruling could cause the agency to consider new policies about pre-NDA communications.

That raises at least the potential that advice to sponsors may be less valuable because the agency will be more careful about avoiding any implication that any given data set will justify approval without further review.

For all those reasons, biopharma companies will need to keep their eye on the fallout of Plan B. The Obama Administration may be only too happy to play down the ruling and let the controversy over this application die.

But the Plan B controversy illustrates one other thing: you can’t keep politics out of the FDA. Even with a court order.

Surprise! Drug Approvals Increase In 2008

Missed user fee deadlines. Multiple cycle reviews. A regulatory posture defined by the phrase “Safety First.” Complex new legislation. Understaffed, overworked review divisions. A hostile Congress eager to second-guess any and every decision. Divergent viewpoints built into the review process. Demands for more advisory committees with fewer conflicts of interest.

No wonder it is harder than ever to get drugs through FDA.

Maybe not.

The approval of Eisai’s antiseizure medicine Banzel (rufinamide) on November 14 marked a quiet milestone for FDA’s Center for Drug Evaluation & Research, the group charged with reviewing all new drugs and most therapeutic biologics: it is the 18th new molecule approved by the agency this year.

That matches the full year tally for 2007, and there are still six weeks left in the year. [UPDATE: With two approvals in the 24 hours since this was first posted, FDA is now at 20 new molecules for the year.]

Don’t run out and buy all the champagne quite yet: remember, 2007 was the single worst year for new drug approvals in a quarter century. Matching that performance is hardly cause for a parade.

But it is good news nevertheless. As recently as July, it looked like FDA might be on track for yet another new low in output: with only six approvals in the first half of the year—one fewer than the first half of 2007.

Well, the pace has picked up (as we predicted it would). And with at least 10 more applications still pending with a shot at approvals this year, it may turn out that 2008 is the best single year for approvals since 2004. (CDER approved 36 novel products that year. Don't expect miracles: five or six more approvals maybe, but 18 more approvals in the next six weeks is out of the question.)

Even a really strong finish by FDA in 2008 wouldn’t mean that much in the grand scheme of things. After all, 2004 was just a one-year blip in what has been a prolonged drought in new product approvals—at least compared to the 1990s. What industry needs is not one big year, but a long term, sustained increase in the output of new products coming to market.

Still, the thought that FDA will end up approving more drugs this year than last offers a much needed sign of hope for the biopharma industry. Maybe—just maybe—the new era in drug regulation ushered in by the FDA Amendments Act of 2007 won’t be so bad after all.

Industry accepted FDAAA as a tough but necessary trade, hoping that the tighter safety regulation would give FDA more confidence to approve drugs that would otherwise languish at the agency. There’s no question about the tougher regulation: as “The Pink Sheet” reported, about one-third of new molecule approvals have a formal Risk Evaluation & Mitigation Strategy attached to them, and more than half have mandatory post-marketing study requirements.

Its impossible to say for sure whether the other half of the trade will come to pass, but at least the trend is in the right direction.

In fact, Banzel may be the perfect emblem for the year 2008. It was a multi-cycle review (the application was first submitted almost exactly three years ago); it slipped passed the final review deadline (Eisai’s resubmission was due for action on Aug. 29); and the approval carries with it a formal REMS requirement as well as some mandatory post-marketing trials.

But it is approved for marketing. And, despite everything, that is something that seems to be happening a bit more often this year than last....

FDA Advisory Committees: Who’s Running the Show?

You wouldn’t think of running your company without a CEO, right? Sure, from time to time, your company might find itself with an acting chief executive due to a merger or sudden departure. Maybe it’s a member of the board, or a former company official that comes out of retirement. But since that’s not a great situation for anyone, you try to quickly find a permanent replacement.

So it may make you a bit uncomfortable to know that at your next FDA advisory committee meeting, chances are that not only will the committee be lacking a permanent chair, it’s likely it won’t have had one for quite some time.

In fact, three quarters of advisory committees in the Center for Drug Evaluation & Research do not have a permanent chair. That’s 12 out of 16 committees. Only four—Anethestic & Life Support Drugs, Pharmaceutical Science, Psychopharmacologic Drugs and Reproductive Health Drugs—have permanent leadership.

(For an analysis of the advisory committee system—including a handy chart of vacancies in each committee—read this story in the October issue of The RPM Report.)

Chairs play a big role in the way advisory committee meeting is conducted. They can steer the discussion one way or another, tweak the questions from FDA, and be more or less forgiving in allowing the sponsor to clarify discussion points. Some chairs are better at managing meetings than others, and the absence of a clear leader can make the process less predictable for drug sponsors.

The absence of leadership at the top is really indicative of the systemic problems across FDA’s advisory committee system. Chairs are typically “promoted” from within, so when there aren’t enough committee members to go around, chairs—with the extra responsibilities that come with the job—are even harder to find.

And FDA is having a hard time finding committee members. Between the new conflict of interest rules and the existing downsides to serving on a committee, FDA has a major problem on its hands.

That might not be such a big deal, so long as FDA wasn't holding many advisory committee meetings. But that’s not the case. In fact, the agency will bring more new products before an advisory committee this year than it has since at least 2004. That’s a lot to juggle at a time when FDA is having a hard time filling those seats with permanent members.

Given the amount of time spent on preparing for an advisory committee review—including those mock panels—it would be nice to at least know who you’ll be facing across the conference table. And in case you’re still not convinced that FDA's problem with filling vacancies is also your problem, consider this: how would you like to have Sid Wolfe as a voting member at your next review?