Financings of the Fortnight Ponders Neurodegenerative Death And Taxes

The big funding news this fortnight doesn’t come from public or private investors, it comes from taxpayers. As "The Pink Sheet" DAILY reported May 15, the Obama administration formally rolled out its national Alzheimer’s plan, which has been in the works for more than a year.

Alzheimer’s and other dementia-related diseases were already slated to get $450 million in National Institutes of Health funding in 2012, with the same amount proposed by the White House for 2013, but the new plan adds extra money: $50 million right away this year and $80 million proposed for next year, with another $20 million for caregiver support, education, data collection and other services.

Intriguing, then, that in a field where clinical trial costs are often cited as a major barrier to an already-skittish industry getting more deeply involved, nearly half of the extra $50 million for 2012 is earmarked for clinical trials. It won't help struggling biotechs push promising treatments, mind you; $16 million is going toward a prevention trial using the Roche/Genentech-sponsored antibody crenezumab to test still-healthy members of extended families in and around Medellin, Colombia, who share a rare genetic mutation that almost assures them of early-onset Alzheimer’s. The study, which the sponsors consider to be a Phase II adaptive trial, will cost an estimated $100 million. A private research group, the Banner Alzheimer’s Institute of Phoenix, is in charge, and chose crenezumab as the agent last December because it has demonstrated a better safety profile so far in early Alzheimer’s trials conducted by Genentech.

In addition to the NIH’s $16 million, Banner is putting up $15 million. Genentech will pay the remaining costs, but it’s unclear who will pay if the cost runs beyond $100 million. (Genentech spokeswoman Robin Snyder declined to speculate on additional costs but said the company doesn’t expect funding to be an issue.)

However it plays out, the fact of mighty Roche getting subsidies for as much as one-third of a major trial is, at the least, a sign of the importance of making progress – any progress at all – in Alzheimer’s R&D. We’re not complaining; if $16 million of our national treasure brings about an Alzheimer’s breakthrough, or simply speeds the progress toward one, it’s money well spent and a pittance compared to the costly burden of the disease now and a generation from now.

But to be clear: Neither Banner nor NIH accrue any rights to crenezumab, which Genentech licensed from Swiss biotech AC Immune in 2006, so if the trial points toward crenezumab as a viable treatment, Genentech/Roche could be sitting on a gold mine. The trial is expected to run five years, with an interim analysis after two. At that point the investigators would evaluate continuation of the trial to support an application for approval, said Snyder. “We are hopeful that the trial will support an indication, the specifics of which are yet to be discussed with regulatory authorities,” she wrote in an email. “If it works we would like crenezumab to be as broadly available to patients who may be eligible.”

The Banner Institute plans at some point to test the same antibody in people at higher risk for the more common form of Alzheimer’s.

A side note: Steering millions of federal dollars toward potentially groundbreaking Alzheimer’s trials hasn’t yet provoked the same skepticism as the millions being steered toward other drug discovery and development efforts under the new translational center known as NCATS.

Funding crucial Alzheimer’s trials is of course a different proposition than, say, repurposing drugs that have sat on industry shelves or fallen out of use, one of the mandates of NCATS, which had a $575 million budget this year. But both efforts are dollars spent that, in a parallel universe, perhaps, might have gone toward basic biomedical research, a common refrain from critics. (Our START-UP colleagues, who profile a different source of funding for biotech innovation every month in the “Capital Matters” column, wrote about one of the NCATS programs, the Therapeutics for Rare and Neglected Diseases, or TRND, a few months ago. You can read it here.)

Our friends at Pink Sheet are all over the NCATS story, and we suggest you follow along. It will require a subscription, but to paraphrase the late Donna Summer, they work hard for the money. So hard for it, honey. Rest in peace, disco queen, and same to you, go-go king. No one loves to love you, baby, more than…

Arena Pharmaceuticals: Wasting little time, Arena announced May 16 it priced a secondary stock offering and grossed $60.5 million just six days after an FDA advisory committee voted 18-4 in favor of Arena’s weight-loss drug lorcaserin. Arena sold 11 million shares at $5.50 per share, although shares reached as high as $7.02 on May 11, the day of the committee vote. Shares closed May 16 at $5.67. The vote doesn’t guarantee approval of lorcaserin, but it’s a notable reversal. The panel voted down the drug in September 2010, largely due to data that showed an increase in tumors in rat studies. A reassessment of that data, plus new information on the tumors’ causes, reassured the panel this time around that the cancer risk is negligible. Obesity drugs need to meet only one of two criteria set out in FDA’s draft guidance on weight management products: they either must provide a 5% weight loss in 35% of patients on-treatment and twice as many patients on-treatment as on-placebo; or there must be at least a 5% difference between weight loss in the active-product and placebo groups. Lorcaserin met the former standard, but not the latter. (More details about the panel’s decision is here, courtesy of our Pink Sheet colleagues.) Lorcaserin’s PDUFA date is June 27, so Arena’s new cash reserves give it a boost for commercialization, although in a deal expanded just before the committee vote, Eisai owns commercial rights to the drug in the US, Mexico, Canada and Brazil. Underwriters Jeffries & Co. and Piper Jaffray & Co., with help from BMO Capital Markets, have the option to sell up to 1.65 million additional shares. Two other sponsors of obesity are vying for FDA approval. Qnexa from Vivus has a PDUFA date of July 17, and Orexigen Therapeutics, which agreed to conduct a cardiovascular outcomes trial, hopes to re-file Contrave for approval in 2014. -- Cathy Dombrowski and Alex Lash

OncoMed Pharmceuticals: One of the first cancer stem cell companies, OncoMed is now hoping to cash in on the cancer stem cell hype (which just happens to be the subject of a forthcoming feature in Start-Up magazine). After all, OncoMed, founded in 2004, is a relative graybeard of the field, with a couple of alliances under its belt and three programs in the clinic. Tiny Verastem notched a $63 million IPO in late January without anything yet in the clinic, and another company, Stemline Therapeutics, filed its IPO papers in April. OncoMed hasn’t set terms yet, but it won’t be a surprise if it aims sky-high. Venture backers have put at least $170 million into the company since its founding, most of it coming in a massive Series B in 2008. There are seven venture funds and one strategic investor with stakes of 5% or more in OncoMed, led by U.S. Venture Partners (17%), Latterell Venture Partners (12%), and GlaxoSmithKline (12%), which also owns options for worldwide rights to two OncoMed antibodies. GSK can exercise the options at either the end of Phase I or Phase II proof of concept trials. OncoMed owns exclusive rights to its lead compound, the antibody demcizumab, and is currently testing it in two Phase Ib trials, both in combination with chemotherapy agents.  -- A.L.

Egalet: In its second incarnation, Danish pain management firm Egalet Ltd. has raised $14.3 million in Series B financing. The firm restructured and recapitalized in 2010, shedding its cardiovascular program to focus on its abuse-resistant Egalet technology for the development of opioid and non-opioid pain medications.  The company is preparing to advance lead candidate EGP066, an extended-release form of morphine, into Phase III studies. The Egalet platform creates tablets that erode at a controlled rate to produce prolonged- or delayed-release delivery. It also prevents the drug ingredient from being easily extracted, which deters drug abusers from chewing, snorting, or injecting it. First-time investor CLS Capital joined returning shareholders Atlas Venture, Omega Funds, Sunstone Capital, and Index Ventures, which committed to a two-tranched €2 million ($2.6 million) Series A round in August 2010.  Prior to the recap, Egalet A/S had raised at least $60mm in venture financing. In December 2009, it out-licensed its CV compound, the beta blocker EGP042, to RedHill Biopharma. The firm has a second formulation technology, Parvulet, that creates a soft pudding-like substance that can be eaten with a spoon. Farther down its pipeline are extended-release versions of oxycodone, hydrocodone, and hydromorphone. -- Amanda Micklus

Dynavax Technologies: Like Arena, Dynavax is a veteran biotech hoping to soon celebrate its first product launch, with the hepatitis B vaccine Heplisav now before the FDA for review. Dynavax tapped the public markets, raising $74.4 million on May 9 before deductions and expenses. It sold 17.5 million shares at $4.25 apiece, adding more than 10% of its share count to the outstanding base. If that’s not enough dilution, underwriters have the option to sell another 2.6 million shares. What’s more, Dynavax also announced just before the share sale that longtime CEO Dino Dina will step aside for a more commercially experienced successor. He’ll remain CEO until the search is complete, and he’ll also keep his board seat, Dynavax said. Investors didn’t take kindly to the CEO news or the offering, which was priced 17% below the previous day’s close of $5.09. Shares have continued to decline, closing May 17 at $3.76. But Dynavax needs the cash, as it owns full rights to Heplisav, for now at least, and says it intends to launch it independently in the US. Historically, biotechs that keep worldwide or at least US rights to their first commercial products fare better in the long term, but a successful launch is no guarantee. Dendreon’s prostate cancer treatment Provenge (sipuleucel-T) and Human Genome Sciences’ breakthrough lupus drug Benlysta (belimumab), both hailed as welcome additions in under-served indications, have faltered badly out of the gate. That's led to new management for Dendreon and, for HGS, a hostile takeover bid from marketing partner GSK. -- A.L.

Image courtesy of flickr user brain_blogger. How appropriate.

Financings of the Fortnight Puts On The Weight

Was FOTF the only one to notice that anti-obesity drug maker Vivus aced its FDA advisory committee review on Feb. 22, one day after Mardi Gras?

It didn't take long for the company to digest the impact: one week later, it went to the public markets for a stock sale, which we describe below. And Vivus' two main competitors, both of whom have had the FDA send their dishes back to the kitchen at one time or another, saw action as well. Arena Therapeutics spiked briefly to $2.11 a share on Feb. 23 with about 8 times its typical trading volume, only to drop back down under $2. The firm also triggered a sale of 14.4 million shares to Azimuth Opportunity that netted nearly $25 million; not exactly selling high. It's part of a $50 million line of credit opened last November that lets Arena put a sale of stock to Azimuth at a pre-arranged discount.

Arena is next up at FDA, with an advisory committee hearing scheduled in the second quarter, but by then Vivus could know its fate, with a PDUFA date of April 17. Orexigen Therapeutics' shares have traded as high as $4.37 a piece since the good Vivus news, their highest in about a year. So far Orexigen hasn't made any related financing moves, but it did announce Thursday that it would slim down at its San Diego-area headquarters.

Meanwhile, the prospect of a new fat-fighting drug finally reaching the market has generated takeover talk as breathless as Dom DeLuise trying to run up a flight of stairs. Potential buyers might want to wait to see if FDA requires a pre-marketing cardiovascular outcome study. Our Pink Sheet colleagues noted recently that the advisory committee seemed satisfied with the prospect of a post-marketing study, but as we all know, it's not unusual to see a gap between the ad-com opinions and final FDA rulings. An overview of cardiovascular assessments by the Endocrinologic and Metabolics Drugs Advisory Committee in late March could shine more light on what extra clinical hoops the three drugs -- Vivus' Qnexa, Arena's Lorquess and Orexigen's Contrave -- will have to pass through.

If any of those drugs actually work, perhaps we'll pay more attention to what Shakespeare called the food of love than the love of food. Which brings us to our off-topic financing of the fortnight: our favorite pending IPO is Fender Musical Instruments Corp., which wants to go public after 65 years of shredding, twanging, picking and reverberating. We wouldn't care if those shares were a good investment as long as owning them made us sound, at least in our mind, just a little bit like this guy. Or perhaps more appropriately, The Ventures. This is, after all...

Vivus: Following the old adage to strike while the FDA is hot, Vivus parlayed the green light an FDA advisory committee gave its Qnexa (topiramate/phentermine) weight-loss drug into a $202 million public offering on Feb. 29. The San Francisco Bay Area company sold 9 million shares at $22.50 a piece, and underwriters led by J.P. Morgan could sell up to 1.35 million more. The funds will go in part to build a sales force for Qnexa, which has navigated a tortured path to date. It received strong backing last month from the FDA's Endocrinologic and Metabolic Drugs Advisory Committee, a 20-2 vote, in part because panelists were assured that Vivus would be held accountable if it didn't conduct a post-marketing cardiovascular outcomes study. The near-unanimous vote more than doubled the price of Vivus shares, from $10.55 on Feb. 22 to a high of $25.14 on Feb. 27. It closed March 6 at $21.52. Rejected by the FDA in 2010, Vivus resubmitted its marketing application last October with a curtailed patient population, excluding women under 55 to eliminate the chance of the topiramate component of the drug causing birth defects. If approved, Qnexa  initially will be indicated for obese patients with a body mass index (BMI) over 30 or overweight patients with a BMI over 27 who do not have child-bearing potential, and who have at least one comorbidity such as high blood pressure, type 2 diabetes, or abdominal obesity. Qnexa's PDUFA date is April 17. -- Staff reports

Aragon Pharmaceuticals: After mulling an IPO and a partnership, cancer drug maker Aragon Pharmaceuticals opted for door number three: a $42 million Series C round that CEO Richard Heyman said strengthens the company if it eventually chooses to pursue either of the first two. The Topspin Fund, the personal investment vehicle of a small group of high-net-worth individuals including billionaire hedge fund manager Jim Simons, led the round, investing alongside existing backers Aisling Capital, OrbiMed Advisors and The Column Group. Along with former Honeywell executives Leo Guthart and Steve Winick, Simons also manages $213 million fund Topspin Partners, but the three chose to invest in their sidecar fund instead; Guthart said the primary fund is “fully invested.” There are personal connections behind the scenes: Simons also is an investor in OrbiMed's funds and Guthart is treasurer of Cold Spring Harbor Laboratory, where Aragon co-founder Charles Sawyers is on the board of trustees. Aragon intends to complete Phase II work on ARN-509, a candidate for castration-resistant prostate cancer that eventually could compete with Johnson & Johnson’s Zytiga (abiraterone) for the sub-market of men in whom prior treatments have failed. It also intends to bring a selective estrogen receptor degrader into Phase I for breast cancer. If Aragon aims for an IPO, it hopes Topspin's experience investing in public companies could lead the firm to cross over and take a piece. Having insiders take part in an IPO has practically become a prerequisite for going public these days. -- Paul Bonanos

4s3 Bioscience: An investment firm connected to one of the world’s wealthiest families has supplied a $20 million Series A round to 4s3 Bioscience, a start-up investigating new treatments for rare muscular disorders. KLP Enterprises, a trust managed by the family office of Karen Pritzker and Michael Vlock, made the investment. The Pritzker family’s legacy includes ownership of the Hyatt hotel chain, electric and industrial equipment holding company Marmon Group, and credit bureau TransUnion. KLP’s investment builds on a seed round from Genzyme Ventures in 2008, as well as grant funding from Massachusetts Life Science Center, the Muscular Dystrophy Association, National Institute of Health and the HHS Therapeutic Discovery Project. 4s3 is developing drugs that use an antibody technology to deliver muscle-building proteins and enzymes into cells, which could yield treatments for muscular dystrophy and other disorders affecting skeletal muscle. The start-up is housed at the University of Massachusetts-Boston’s Venture Development Center, and its founders are working closely with KLP drug development subsidiary Alopexx Enterprises as they build the company. -- P.B.

Amicus Therapeutics: The developer of treatments for lysosomal storage disorders and other rare diseases topped off its public stock offering March 7 with underwriters taking their full over-allotment, making a total of 11.5 million shares sold at $5.70 a share for net proceeds of $62 million. The firm, whose tale was told in the film Extraordinary Measures (with Brendan Fraser playing CEO John Crowley), last raised cash when it sold worldwide rights to its lead drug Amigal (migalastat HCI), for Fabry disease, to GlaxoSmithKline for $60 million upfront in October 2010. Part of that payment bought GSK a 19.9% equity stake in Amicus at $4.56 a share, at the time a 15% premium. Announcing the GSK deal, Crowley said it would sustain Amicus at least until U.S. approval of Amigal, which has not proved out. The drug is currently in Phase III in a monotherapy trial co-sponsored by Amicus and GSK and in a separate combination therapy trial that is still recruiting patients. -- A.L.

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Professional Egos, Cultural Norms Clash At Xarelto AdComm

Let’s be honest – we look forward to some FDA advisory committee meetings more than others. Some meetings, such as those convened only because a product is a new molecular entity but with no controversial safety or efficacy issues attached, can be a bit of a yawn from a newsgathering perspective.

Give us a drug that has hit some regulatory bumps in a hot and highly lucrative therapeutic area, and it raises our journalistic antenna.

So, when we saw the FDA staff’s strongly negative review of the atrial fibrillation claim for Bayer/J&J’s Xarelto (rivaroxaban) – a review that went so far as to recommend a “complete response” action – we knew we were in for an interesting meeting of the agency’s cardio-renal committee on Sept. 8.

Couple that with the revelation that there were going to be some big names participating in the proceedings (Rob Califf! Steve Nissen! Sanjay Kaul! Tom Fleming! – none of whom could be accused of being afraid to share their views on a subject), we were practically salivating.

Our giddiness was further heightened when we saw FDA’s draft questions, which spanned six pages. FDA wanted to know whether rivaroxaban’s efficacy was appropriately studied against warfarin in the ROCKET AF trial, or whether the drug’s efficacy is best viewed against that of Pradaxa (dabigatran), Boehringer Ingelheim’s oral direct thrombin inhibitor that was approved last October.

Most of the committee members – and FDA’s cardiology guru himself, ODE I Director Bob Temple – were pretty clear in their views that the Xarelto sponsors shouldn’t be required to show rivaroxaban’s efficacy against that of another drug on the market for less than a year. (This week’s issue of “The Pink Sheet” offers in-depth analysis of how FDA might continue to use its “as effective” standard.)

Thanks to these views, drug developers appear to have escaped the potential calamity of having to go back to the drawing board to compare their late-stage compounds to the newest kid on the block for FDA approval. (Reimbursement is another story, but we digress.)

Nonetheless, the discussion over the appropriate comparator for rivaroxaban raised the lingering problem of how well clinical trials mimic real world use when it comes to establishing efficacy against another drug, and whether it’s wise to attempt to mimic actual medical practice when that offers a comparison that is far from ideal.

While warfarin may be the appropriate comparator in the eyes of most committee members and top FDA brass, a debate over how well warfarin is used in clinical practice and in the ROCKET AF trial led to a clash of egos and a lesson in cultural norms at the meeting.

One key issue before the committee was how well anticoagulation control with warfarin was managed in ROCKET AF, as gauged by International Normalized Ratio time in therapeutic range (TTR).

In their briefing documents, FDA reviewers took the ROCKET AF investigators to task for what they considered to be the less than “skillful” use of warfarin when compared to other anticoagulant studies.

The mean time in TTR was 55% across the ROCKET AF program, compared with 64% for dabigatran’s pivotal RE-LY trial. The lower TTR in ROCKET so distressed the agency reviewers that they used the word “skillfully” 16 times in their briefing document as they sought to drive home the point that it is difficult to ascertain rivaroxaban’s true efficacy when compared against warfarin that is well managed.

But some in the meeting room didn’t take too kindly to FDA’s characterization of unskillful use of a drug that has been a standard of care for stroke prevention in atrial fibrillation patients for years.

Duke University Vice Chancellor of Clinical Research Robert Califf, appearing on behalf of the sponsors and the study’s executive committee, maintained that the average TTR of 64% for North America was better than U.S. practice in general and comparable to the North American results in other anticoagulant studies.

“This is hardly a result that should be attributed to unskillful clinicians,” Califf said. “I have to say on behalf of the executive committee and over 1,000 investigators, we don’t think we’re unskilled. We think we’re pretty good.”

Califf maintained that the lower overall mean TTR in ROCKET AF was due in large part to the geographical diversity of the study population and the inclusion of patients at higher risk of stroke than in other anticoagulant trials. More than 38% of the patients were enrolled in Eastern Europe, where TTR was 49.7%. Another 15% came from the Asia-Pacific region, where TTR was only slightly better, 52.4%, according to FDA’s calculations.

Regional variations in how quickly patients were brought back for INR assessment resulted in an “artificial” lowering of TTRs in areas where there was a longer delay, such as in Asia-Pacific and Eastern Europe, Califf said.

Warfarin dosing was managed at each site according to local standards, and there was no centralized protocol for managing patients who fell outside of therapeutic range. Site investigators were educated on the importance of keeping INR within the 2.0-3.0 target range.

The geographical distribution of patients, coupled with the absence of a single warfarin dosing protocol, touched off one of the more interesting debates of the day between Califf and Cleveland Clinic’s Steven Nissen, a temporary voting member on the panel.

“Given the fact that I think you guys knew that the TTR was going to be a critical factor in the approvability of the drug, I’m just puzzled why you didn’t make an effort to give sites, particularly Third World sites, some guidance about what to do,” Nissen said to the sponsors. “Basically, you sort of left them on their own, and my concern is that’s why you got such a low TTR” across the ROCKET AF study.

At this point, Califf embarked on a lesson in global diplomacy.

“Dr. Nissen I’m sure you didn’t mean to use the term Third World, because I don’t think that’s an appropriate term anymore, and in fact if you look at the news today you would find what you’re calling Third World actually owns most of our national debt,” said Califf, whose remarks were met with laughter in the room.

“I think the investigators around the world will be highly offended by the sort of American exceptional tone of some of the discussion, not you personally, but – ”

At this point, Michael Lincoff, Nissen’s colleague at Cleveland Clinic and acting chairman of the committee, attempted to redirect the discussion away from geopolitical issues and back to anticoagulants.

“Let’s focus on the subject,” Lincoff said, before he was cut off by Nissen.

“Rob, you showed us that those sites in those countries didn’t do a very good job of managing warfarin. That’s where all this comes from,” Nissen said to Califf.

“But these two concepts are related,” Califf responded. “It’s not that doctors do a lousy job. This is a really hard drug to use and it’s especially really hard to use in various social, economic personality characteristic circumstances. You know that as well as I do.”

“What we felt obligated to do was to do better than standard of practice given the heterogeneity of the practices in those centers,” Califf said. “We spent a lot of time at every site saying how do you do it? Let’s make sure what you’re doing is OK, but let’s not force you to use one specified algorithm. Let’s make sure you make the appropriate dosing changes. I showed you that it wasn’t that they weren’t making the appropriate dosing changes. They just brought the patients back when it was feasible to do it.”

With the sparring over lesser developed countries behind them, the committee continued with its questions and discussion, though later in the meeting other panel members felt the need to weigh in on the skillfulness issue.

TTR is “certainly a marker of skillful care” but is not an effect modifier, Cedars-Sinai cardiologist Sanjay Kaul maintained.

Yet, fellow panel member and cardiologist Darren McGuire, University of Texas Southwestern Medical Center, was quick to take offense. McGuire conceded the TTR rate at his institution is only about 54%, but he noted that numerous patient level characteristics, and not the treatment provided by a given physician, play a role in how well TTR is maintained.

“I will agree with Dr. Califf’s comment earlier. I take some offense at the term unskillful use, because it’s a little bit accusatory and it’s a complicated therapeutic strategy.”

Some committee members said they appreciated the lack of a standardized dosing protocol in ROCKET AF because it more closely mirrored how warfarin is used in clinical practice, which is imperfectly.

The issue of how well INR was maintained came up in the advisory committee review of Pradaxa as well. Boehringer was lauded for the level of control achieved for warfarin in RE-LY, which had an open-label design for that reason (though the trial design also drew criticism). But the INR variability also kept FDA from granting an outright superiority claim; the agency included cautionary language in labeling noting that the benefit was driven by centers where INR control was poor.

The back and forth at Xarelto review begs the question of whether better data is gained by mimicking real world use, though it may mean imperfect use of a standard of care, or if tightly controlled trial practice is a better comparator for convincingly demonstrating efficacy in the minds of regulators and payers.

While answers may not be quickly or easily forthcoming, it’s an issue that other anticoagulant sponsors should be prepared to address.

– Sue Sutter

Photo, "Triplets of Cap Hill," by Flikr user daniel spils, reproduced under Creative Commons license

Navigating The FDA Advisory Committee Road To Success … Or Not

On the eve of FDA’s Antiviral Drugs Advisory Committee reviews of the first protease inhibitors for hepatitis C, the drugs’ sponsors – Merck (boceprevir) and Vertex Pharmaceuticals (telaprevir) – are no doubt scrambling to make sure everything is in order.

Presumably, the companies have already locked down their slide decks, put the finishing touches on their presentations, researched the backgrounds of the committee’s standing members and shipped their AdComm teams off to hotels near FDA’s White Oak headquarters, where the meetings will take place.

Boceprevir and telaprevir are viewed as therapeutic breakthroughs in the treatment of HCV, both having shown improved cure rates when added to the current standard of care. However, the drugs have complicated and differing dosing regimens, which are likely to be an area of AdComm discussion.

Merck, which will present its case on April 27, is an old hand at the AdComm process, having most recently gone before a panel in December when it unsuccessfully sought to add prostate cancer risk reduction language to the label of its BPH drug Proscar. Vertex, on the other hand, is making its maiden voyage on the USS AdComm. The company will present its case on April 28 and should benefit from hearing panelists’ questions and concerns in their review of boceprevir the day before.

No matter how well prepared the sponsors think they might be, the AdComm road is littered with landmines. That, in a nutshell, was the message conveyed by AdComm meeting veterans at the Center for Business Intelligence’s Second Annual Forum on Effective Preparation for FDA Advisory Committees in Washington, D.C. last month.

At the two-day conference, battle-hardened veterans of the AdComm process – including pharma employees and consultants who make their living preparing drug companies for meetings – shared experiences from the trenches and offered some best practices to consider when tackling what has become a significant hurdle in drug development.

Some suggestions fall in the common sense category. It's imperative not only to have good communications with FDA leading up to an AdComm, but also to begin the meeting planning process early. Practicing presentations and Q&A is not surprisingly also considered good AdComm hygiene. But the CBI speakers voiced some additional pearls of wisdom that sponsors appearing before FDA committees might want to keep in mind, starting with…

Know Your AdComm
Pete Taft, founder and CEO of PharmApprove, a company that provides AdComm meeting preparation services, said sponsors should be ready to deal with four general types of personalities on FDA panels:

the expert – someone who knows a lot about your field and possibly your product, and is going to be well prepared for the meeting;

the judge – an individual who is swift to make judgments about your product or argument;

the thoughtful one – a quiet panel member; and,

the naysayer – the “Simon Cowell of AdComs” who you can either fight or forget about securing their vote.

PharmApprove has interviewed former AdComm members to find out how they prepare and what they expect from sponsors. At the top of their list is this nugget of wisdom...

Keep It Simple, And Don’t Be Irritating
The importance of clarity and simplicity in a sponsor’s presentation was echoed by FDA Director of Advisory Committee Oversight Michael Ortwerth, the lone agency presenter at the CBI conference. “That’s a really important thing, that the message is clear … and slides are very well put together,” Ortwerth said. “When you have slides that are so busy and so ladened and heavy, then you can’t focus on what the actual issue is.”

If AdComm members don’t like busy slides, they’re also not thrilled with sponsors or presenters who come off as cocky or overconfident. “I’ve always had this intuitive sense that if we press the committee or cause them to feel irritated, that some of that emotion will be transferred to their rational thinking,” said Taft, whose suspicion has now been confirmed. He noted the comments of a former AdComm chairman, who said: “You don’t want to make me angry about you, because then I transfer that from you onto the data and onto the drug.”

AdComm prep needs to be heavy on practice, planning and contingency planning, the speakers said. In the course of advance planning, it’s important that sponsors …

Don’t Let Belly Dancers Get In The Way
Don Cilla, vice president and product development team lead at AstraZeneca’s MedImmune division, led the company’s AdComm team for the June 2010 review of motavizumab for prophylaxis of respiratory syncytial virus. He recommends conducting AdComm team practice sessions and holding pre-meeting preparations in the same hotel ballroom that FDA will use for the meeting (when they’re not being held at White Oak). At the time of the motavizumab meeting “there was a convention of belly dancers that had that room booked for the three days leading up to it, so we couldn’t get in there to practice.”

If the company's AdComm team is all staying, and eating, together as a group for two or three days before a meeting, they should …

Avoid Eating The Mayonnaise
One of the speakers at the CBI conference recounted how a consultant, upon seeing open mayonnaise sitting at a buffet, banned all condiments at future meals so as to avoid the risk that team members would come down with a debilitating case of food poisoning on the day of the big meeting. “We had backups for everybody,” Cilla said of his team for the motavizumab meeting. “We didn’t know if they were going to get the bad mayonnaise or the Mexican food the night before or if they just couldn’t get there.”

While sponsors should plan for anything and everything to go wrong logistically, there are some factors they may have no control over. This includes the possibility that committee members will be suffering from …

An Avandia Hangover
Back-to-back scrutiny of different drugs on consecutive days can have a detrimental effect on those coming at the end of a multi-day meeting, suggested Alexander Fleming, president and CEO of the consulting firm Kinexum.

Case in point is Vivus’ obesity drug Qnexa. At a July 15 meeting, FDA's Endocrinologic and Metabolic Drugs Advisory Committee voted 10-6 against approval due to safety concerns. The negative vote took some FDA officials by surprise, but Fleming believes timing was a crucial factor. The Qnexa review marked the third consecutive day of work for the committee, its two previous days having been spent on an extensive and intensive review of the cardiovascular safety of GlaxoSmithKline’s diabetes drug Avandia.

“If nothing else, the advisors had to be exhausted” by the time they got to Qnexa, Fleming said. Calling the AdComm timing “pure bad luck” for Vivus, Fleming said the company knew “this was going to be a real disadvantage to them ... and only in retrospect do you see how it really had a major effect.”

Sponsors also may have no control over an AdComm’s walk down the path of …

Comparative Effectiveness And Cost
Disease background presentations by the sponsor are a hallmark of any product-specific AdComm. A good presentation will include a comparison of products that are on the market, including mechanism of action and limitations, said Mary Rofael, COO of scientific and regulatory communications at ProEd Communications, a firm that provides AdCom prep services.

“Many of you will say we’re here at an advisory committee, the committee should focus on evaluating the benefit/risk of a particular product,” Rofael said. “In this day and age you can’t stop people from thinking about comparing it to what they’re using currently or what’s on the market. It’s just a discussion that’s going to take place. Whether or not you engage in it, that’s a different story, but it’s important to anticipate it because these kinds of questions are being asked more and more today.

“It’s almost like the question of cost,” Rofael continued, venturing down a road that almost no sponsor wants to travel during an AdComm. “The advisory committee room is the only room where cost is not discussed … but eventually I think it’s going to make its way in. People are starting to ask about the cost of products and what the burden of cost is on the health care system.”

Aside from the detour down the cost path, what’s a sponsor to do when an AdComm’s discussion of the data starts …

Spiraling Out Of Control?
If the panel’s conversation has gone awry at some point after the sponsor’s presentation, the best a company can hope for is that the meeting agenda includes an upcoming break, said PharmApprove principal Martha Arnold. “If there’s a situation where things just are spiraling out of control, and … you think perhaps the committee is dealing with information that is just plain wrong, that there’s been a misinterpretation either of your data or FDA’s data, if there’s a break you have an opportunity to at least approach the chair” and express concern, she said.

If there are no further scheduled breaks, the sponsor could pass a note to the panel’s industry representative “or tap them on the shoulder and say, ‘Hey, can you help us out here,’” said Bruce Burlington of DB Burlington Consulting, who often serves as the industry rep on AdComms. “Alternatively, if it’s really outrageous, just stand up and say, ‘Mr. Chairman, I request your permission to insert a correction in the discussion at this point.’”
It may be more problematic, however, for sponsors to insert themselves into the process of …

Question-Morphing
Anyone who has sat through at least a handful of AdComms can confirm that panelist confusion over the wording of FDA’s questions is a fact of life, often leading to discussions as to whether and how the questions should be re-written on the fly. While these question-writing “audibles” can be disconcerting for sponsors, so can the initial questions themselves.

CBI conference attendees cited tremendous variability among review divisions in the types of questions posed at AdComs, ranging from straightforward questions on risk/benefit to queries that run multiple pages and “in essence make the FDA case in the form of a question,” one conference attendee said.

FDA’s Ortwerth acknowledged room for improvement in how review divisions ask questions. “It is important that there be consistency in the way we try to communicate. … There needs to be the right way to communicate something and a clear way to communicate something and not to drive the direction of the answer.”

Even if sponsors are able to navigate all the trouble spots outlined above, they need to keep in mind that they can …

Spend Big Money, But Still Lose Big
Preparing for an AdComm involves shelling out big bucks, all of which can be for naught if a drug is decimated when it comes to the panel’s vote. MedImmune’s Cilla said his company spent approximately $900,000 on AdCom preparations for motavazimub, which included the cost of consultants, meeting space and four mock panel meetings at approximately $60,000 each. The investment resulted in a 14-3 AdComm vote against approval, which was followed by an FDA “complete response” letter and the company’s decision to withdraw the BLA.

Sanofi-Aventis Associate Vice President of Global Regulatory Affairs Kevin Malobisky said his company spent about $1.3 million preparing for one meeting that resulted in a 14-0 vote against approval – an apparent reference to the unsuccessful June 2007 AdComm for the obesity drug Zimulti (rimonabant).

Were IN VIVO Blog writing an AdComms for Dummies manual, we might put it this way: it's expensive and a lot of work to prep for an AdComm, but you have to do it. Even so, there's no money-back guarantee.

Maybe we should start consulting--at least we've got a sense of humor.

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

Today’s FDA Advisory Committee Meeting, Brought To You By …

… FedFinancial Federal Credit Union, serving federal employees and their families in the Washington and Baltimore areas since 1935.

OK, so maybe the credit union was not the “sponsor” of Arcapta Neohaler, the chronic obstructive pulmonary drug reviewed by FDA’s Pulmonary-Allergy Drugs Advisory Committee on March 8 (the NDA sponsor is Novartis).

Nevertheless, the bottled water provided to committee members and FDA staff was courtesy of FedFinancial. The bottle’s label bore the credit union’s name and the slogan “Member Benefits Set Us Apart.” Also, included were the credit union’s toll-free phone number, website and the location of a branch office at FDA’s White Oak headquarters (Building 2, Room 1041).

As jaded attendees of FDA advisory committee meetings, the seemingly innocuous, though incongruous, presence of a promotional item struck us as odd, so we investigated further with the assistance of fellow colleagues from “The Pink Sheet."

(Full Disclosure: This reporter took a warm, unopened bottle of FedFinancial water following the Arcapta meeting because agency staff removed her personal bottle of water during their aggressive clean-up efforts of the White Oak Conference Center.)

Similarly labeled FedFinancial water was provided to the head table two days later at the Anesthetic and Life Support Drugs Advisory Committee’s March 10 meeting on pediatric use of sedative/anesthetic agents. Both the Pulmonary-Allergy and Anesthetic-Life Support committee meetings were held at FDA’s White Oak campus.

In contrast, the Peripheral and Central Nervous System Drugs Advisory Committee convened at the Hilton in Silver Spring, Md., on March 10 to discuss a monotherapy indication for GlaxoSmithKline’s anti-seizure drug Lamictal XR. No FedFinancial water for that meeting, however, as committee members and FDA staff had to make do with pitchers of water provided by the hotel.

So, what gives? In these desperate fiscal times, is FDA so tight on funding that it has turned to financial institutions to help defray costs of holding advisory committee meetings?

Not so, the agency says. In response to a question from “The Pink Sheet,” the CDER trade press office had this explanation:

“The water bottles just happened to be left over from a function within CDER in which the credit union, which has a branch on campus for employees, supplied water. The credit union did not (at least not intentionally) provide water to staff and panel members for last week’s meetings.”

So, that’s that. And yet, we can’t seem to let this go, because seeing high-level staff in FDA’s Office of Drug Evaluation II and the Division of Pulmonary, Allergy and Rheumatology Products swilling FedFinancial water gave us an idea.

What if FDA were to offer promotional opportunities during the course of its advisory committee meetings? Oh, we’re not talking about allowing Boehringer Ingelheim and Pfizer to advertise their COPD drug Spiriva during the committee’s review of Arcapta, as that would be an obvious conflict.

Instead, why not offer non-pharma companies, such as vendors or service providers, an opportunity to sponsor ads or “commercial breaks” in the meetings? We can see it now:

A full-page ad, attached to the meeting agenda, highlighting the Silver Spring Hilton’s banquet facilities as the perfect place for that Fall 2011 wedding reception.

The panel chairman’s announcement of the mid-morning meeting break: “The morning break is sponsored by Roto Rooter Plumbing and Drain Service, where their motto is ‘And away go troubles down the drain.’”

Or, “The voting results on Arcapta’s efficacy and safety are brought to you by the international accounting firm Ernst & Young. Ernst & Young – Quality in Everything We Do.”

Then again, the text of voting questions and the electronic voting process itself tend to cause so much confusion among advisory committee members that no reputable accounting firm might want its name attached to the process.

We’ll keep working on this one while we sip our FedFinancial water.

– Sue Sutter (s.sutter@elsevier.com)

Wolfe vs. Rappaport (Part 2): Embeda Warning Letter Raised During Abuse-Resistant Opioids Ad Comm

Advisory committees are always interesting, but you really have to expect the unexpected when Public Citizen Health Research Group Director Sid Wolfe is on the panel.

The last time the FDA Drug Safety & Risk Management Advisory Committee member participated in a panel discussion, he wanted to discuss a past off-label promotion settlement during a review of a pending application from Jazz Pharmaceuticals seeking an expanded label for sodium oxybate to treat fibromyalgia.

As we reported at the time, Wolfe was cut off by the committee chair and then chastised by Division of Anesthesia & Analgesia Products Bob Rappaport for bringing up a topic that was not relevant to the discussion—and for not at least bringing it to the agency’s attention in advance as something he wanted discussed. As we first reported, Rappaport then read into the record a statement essentially telling the committee to disregard the issue.

To us, it seemed like Wolfe had a point, that a discussion focused entirely on the appropriate method for marketing a drug like sodium oxybate should at least consider the question of whether the sponsor would or would not actually follow the pathway set down by the agency. Whether or not the committee agreed with Wolfe on that point, they agreed almost unanimously that Jazz needed to rethink its approach to managing this product in the post marketing setting, and voted overwhelmingly against approval. (The agency formally rejected the application this month.)

Wolfe is back on a panel today, part of a meeting to review post-marketing study requirements for opioids that are designed to be abuse resistant. The purpose of the meeting is to determine what standards FDA should set for demonstrating abuse resistance in the real world. (Read the preview in "The Pink Sheet" DAILY, here.)

That is a fascinating topic in itself; probably a glimpse of the future (or a potential future) for essentially all big drug classes.

But the meeting began with Rappaport pointing out an unusual late addition to the committee’s briefing materials: a copy of the warning letter FDA sent to King Pharmaceuticals in 2009, shortly after it launched the abuse-resistant product Embeda. The letter, Rappaport noted, is not the type of thing FDA typically gives to committees, but Wolfe emailed the agency yesterday to ask for it to be distributed. And so it was handed out at the meeting (even though, Rappaport stressed, it is a marketing issue and so not really relevant to a scientific discussion about post-marketing study designs).

The letter hasn't been mentioned since--but King doesn't present until tomorrow morning.

King’s management team told us in an interview earlier this year that the video news releases that prompted the warning were a mistake that it would not repeat. But—as we discussed here—it certainly sets a standard for getting off on the wrong foot with an important new product.

And Wolfe, at least, sees it as evidence that FDA cannot rely on sponsors to do things the right way when it comes to making sure new drugs are used appropriately. So far (the meeting is two days and things are just getting going), Wolfe is pushing for more of the research in the pre-market setting. That doesn't seem to be getting any traction with FDA.

Interestingly, Wolfe doesn’t seem to have asked for any materials to be shared on the other product directly affected by the ongoing meeting: Purdue’s Oxycontin. That company, of course, was prosecuted for misbranding, with the government claiming Purdue’s marketing helped contribute to the widespread abuse of the drug.

Since the entire FDA effort on abuse resistance essentially flows from the Oxycontin controversy, Wolfe apparently doesn't feel like he needs to do anything to draw that connection for the committee.

Should Have Stayed at a Holiday Inn: Orexigen's "Tremendous" Advantage Going Third

The three obesity drugs—Vivus’ Qnexa, Arena’s Lorqess, and Orexigen’s Contrave—pending at FDA haven’t suffered from a lack of buzz in the investment community.

The trio of therapeutic candidates have the high-risk/high-reward profile that Wall Street typically flocks to.

In fact, the drugs are being so closely monitored by investors that two peripheral y relevant events—one that has happened and one that will happen—are garnering almost equal attention because of their impact on the three obesity drugs: the FDA advisory committee safety reviews of GlaxoSmithKline’s diabetes drug Avandia and Abbott Laboratories’ diet pill Meridia.

Qnexa was recently voted down by FDA’s Endocrinologic & Metabolic Drugs Advisory Committee due to concerns over the drug being used by large populations and a lack of long-term cardiovascular safety data (See “Weighing the Regulatory Climate,” The RPM Report, September 2010). In that instance, there was clearly an echo-effect from the prior two days of deliberations over the cardiovascular risks associated with Avandia.

Now investors are wondering if the case will be the same for Arena: Lorqess will be vetted by the Endocrinologic & Metabolic Drugs panel on September 16, the day after a joint committee review with the drug safety panel of Meridia to determine whether that drug should be taken off the market due to an increased risk of nonfatal myocardial infarction and stroke.

Orexigen’s Contrave is tentatively scheduled to go before an FDA panel on December 7.

Orexigen CEO Michael Narachi believes going third is an advantage, he explained during an interview with “The Pink Sheet” after announcing a partnership deal with Takeda.

“Being last up for review will provide tremendous learnings for our own regulatory review process. This will enable us to better understand the FDA's approach to evaluating the risk/benefit of obesity therapies, their perspective on potential post-marketing requirements and which of those may be broadly applicable versus drug specific.” (read coverage of Orexigen’s partnership deal with Takeda in “The Pink Sheet” by clicking here).

In other words, Orexigen is sitting back and watching—up close.

One detail that demonstrates just how important the regulatory lessons from Avandia, Qnexa et al. are to Orexigen was the company’s physical presence for the three-day advisory committee reviews of Avandia and Qnexa in July.

The July advisory committee meetings were held at the Hilton Hotel in Gaithersburg, Maryland, where FDA hosts more high-profile panel meetings due to more space.

We’re not sure Orexigen officials were there in person at the Hilton but the company showed up in force at the Holiday Inn just down the street.

We doubt Orexigen got lost. The firm had a pseudo-command center set up apparently to monitor the developments of the Avandia and Qnexa reviews as preparation for what may lie ahead in December.

That’s a smart strategy considering many of the themes from prior reviews, such as the need for long-term cardiovascular outcomes data beyond one year and an appropriate risk evaluation and mitigation strategies (REMS) program, will repeat themselves at the Contrave meeting.

Maybe Vivus should have stayed at a Holiday Inn too.

Wolfe vs. Rappaport: A Standoff Between FDA and One of Its Advisory Committee Members

There was some disharmony at Jazz Pharmaceuticals’ FDA panel review of its drug Rekinla for fibromyalgia.

FDA’s Arthritis Drugs Advisory Committee and Drug Safety & Risk Management Advisory Committee voted 20-2 against recommending Rekinla (sodium oxybate) for a supplemental indication for treatment of fibromyalgia on August 20; sodium oxybate is currently approved for the reduction of daytime sleepiness and cataplexy in patients with narcolepsy under the trade name Xyrem. (See our coverage in "The Pink Sheet" DAILY, here.)

Anyone that has been to an FDA panel meeting knows there are ebbs and flows that contribute to the final outcome.

One of those critical points came in the late morning during the FDA question and answer session, following the agency’s formal presentations.

Enter Drugs Safety & Risk Management committee member and outspoken drug industry critic Sidney Wolfe (director of Public Citizen’s Health Research Group). Wolfe explained that he had obtained publicly available documents that cast negative light on the trustworthiness of the sponsor to responsibly market Rekinla if the panel delivered a positive recommendation and FDA approved the drug.

To resolve parallel criminal and civil allegations of off-label marketing for Xyrem by their Orphan Medical division, Jazz entered a guilty plea and paid $20 million in monetary penalties as part of a settlement with the US Attorney’s Office for the Eastern District of New York. (To view the press release, click here).

Committee Chair Kathleen O’Neill (University of Oklahoma College of Medicine) tried to cut Wolfe off, saying the session was only for questions to FDA and could only address the material in front of the panel on that day.

Wolfe continued to read a summary of the off-label marketing settlement and said he eventually would have a question.

With Wolfe unwilling to stop reading, FDA took the seemingly unprecedented action of cutting off Wolfe’s microphone. That step has become routine during the open public hearing where there is a time limit but this was one of their own advisory committee members.

Wolfe turned the microphone back on and finally got to his question: Why, he asked, did FDA not mention the Xyrem off-label settlement in its presentations to the committee? After all, he argued, it was relevant to the decision at hand: could the sponsor be trusted to market Xyrem—also known as gamma-hydroxybutyrate (GHB)—to a much broader indication than it was already approved for?

FDA Division of Anesthesia & Analgesia Products Bob Rappaport stepped in and first instructed Wolfe to stop talking when the panel chair requests that he stop talking, explaining that it was her prerogative.

Rappaport continued that Wolfe’s reading of the documents were the first time he had ever heard of the off-label case and that it was not relevant to the Rekinla review despite the fact that both Xyrem and Rekinla are the same drug (sodium oxybate). Rappaport then admonished Wolfe for not providing the documents to FDA earlier, noting that he had called FDA's advisory committee management staff earlier in the week to raise an issue, but not provided the information he was reading at the meeting.

[UPDATE: Wolfe tells us "I had never previously told FDA officials that I had obtained these documents since I assumed, as it turned out incorrectly, that they were aware of them because FDA's Office of Criminal Investigation had been involved in the criminal prosecution. Why they were unaware, as Rappaport said, is another issue."]

The drama appeared to have come to a close with Rappaport’s comments; however, the FDA official returned after the lunch break and the open public hearing with a prepared statement:

“The issue that Dr. Wolfe raised this morning is a matter related to compliance and is not related to the topic under discussion today, unless there has been an accusation of data integrity problems with this application – and I’m not aware of any data integrity concerns. The only other way that the case referred to by Dr. Wolfe could be pertinent to this application would be if it was brought up to impugn the sponsor in the hopes that the committee would be punitive towards them in your deliberations and recommendations regarding this application. However it is important for you to recognize that that would not really be punitive to the sponsor but would really be punitive to the patients.”

At that point, Jazz Pharmaceuticals' Chief Compliance Officer Janne Wissel added a few remarks.

"We do have a corporate integrity agreement because we assumed responsibility for the acts of Orphan Medical at the time we purchased the company. The Department of Justice, as well as the OIG concluded at the end of their investigation that the behaviors of Jazz Pharmaceutical were not the same as those of Orphan Medical. However, we assumed responsibility for those actions.

"We have completed three years under our corporate integrity agreement where we have reports that are based on information and an audit conducted by an independent review organization with respect to our compliance for promoting our product within our labeling. All of those reports have concluded that we are promoting our product within labeling and that we are compliant with respect to the aspects of our corporate integrity agreement."

Wolfe was not given an opportunity to respond at the meeting, so we asked him if he would care to after the fact. He emailed us the following statement:

The previous RiskMap program and the Xyrem Success Program, that were agreed upon in 2002 by Orphan as a condition of approval of Xyrem for narcolepsy, included extremely restricted distribution through one pharmacy, education of doctors and patients and a registry of patients getting the drug.

One of the questions our advisory committee was being asked to respond to was the adequacy of the new REMS program for the expanded use of oxybate for treating fibromyalgia .

Xyrem’s manufacturer, Orphan, violated the above mentioned restrictions on distribution by illegal, criminal off-label marketing and was successfully prosecuted for this. When I discovered this, a week before the hearing, I assumed that the reason why it was not included in the Advisory Committee’s briefing materials was that for some reason the FDA did not want us to know about it. This seemed peculiar, since the prosecution of the company seemed quite relevant to our evaluation of whether the new REMS program could be expected to be effective.

As I asked in my question to FDA, following the material I read from the US Attorney’s prosecution of Orphan, Why didn’t the agency provide the material to us?

Dr. Rappaport’s surprising answer was that they were not aware of the criminal prosecution. He later added that this was really a matter involving FDA compliance and that it was not “related” to the issues being discussed by the committee because it did not involve data integrity.

Although it is the compliance part of FDA that was involved in investigating this (the FDA Office of Criminal investigation was also involved), the idea that the details of this criminal prosecution involving violations of the agreed-upon restricted marketing of this dangerous drug were not relevant to our deliberations seems irrational.

Dr. Rappaport went on to say that since it was not relevant to our discussion, the only reason I brought it up was to “impugn the sponsor” and thereby turn the vote against them. This would, he said, “not really be punitive to the sponsor but would
really be punitive to the patients.”

Following Dr. Rappaport’s after-lunch statement, Jazz Pharmaceutical, the owner of Orphan since June, 2005—including, according to the US Attorney, for at least seven months while the illegal activities were occurring--stated to the Advisory committee that the company had been essentially exonerated by the US Attorney’s office and was under a corporate integrity agreement with the HHS Inspector General. This statement, like Dr. Rappaport’s, is also incorrect since, in its non-prosecution agreement with Jazz, the US attorney stated on July 13, 2007:

“Based on the evidence gathered during this investigation, the government maintains that it would be able to prove that JPI [Jazz Pharmaceutical Incorporated], as a consequence of the criminal conduct committed by its subsidiary Orphan ("the Unlawful Conduct"), is likewise guilty of introducing and causing the introduction of a misbranded drug into interstate commerce, in violation of 21 U.S.C. 331(a) and 333(a)(2).”

It’s unclear how much of an impact the Wolfe-Rappaport discussion had on the final 20-2 negative vote for Jazz. But it’s clear the public disagreement was a notable turning point in the panel deliberations.

The agency later said “the issue raised this morning by Dr. Sidney Wolfe related to Jazz Pharmaceuticals marketing practices and compliance activities for sodium oxybate is not related to the topic (that was) under discussion. The FDA weighs all of the comments made by committee members equally but will only be considering the safety and efficacy information discussed today as it evaluates sodium oxybate to treat patients with fibromyalgia.”

--Ramsey Baghdadi

Times Are A-Changing and Tough, Says Roche

Roche's CEO Severin Schwan isn't the only pharma CEO facing a highly unappealing economic reality (and not just talking of it) – executives of practically every pharma reporting for the second quarter to date has laid made this point. But Schwan's remarks to analysts on today's half-year earnings call were particularly harsh, especially coming from one of the industry's best long-term performers. "The financial crisis has arrived for the pharmaceutical industry," he stated.

Not only did Roche suffer two important clinical development setbacks in the past month, but it, like the rest of the industry, is facing accelerating pricing pressure—a point which he and his top lieutenants honed in on repeatedly. These hits will fall through to the bottom, he noted, adding, 'We won't suddenly have more products [to offset the shortfall] because prices are coming down."

To some extent, he was playing to analysts, who are wary of Roche's promises to cut cuts in the face of a slowing top line. After all, the company, which has demonstrated its scientific prowess by launching a series of unexpected blockbusters, isn't, as one analyst put it, known for being "mean and thin."

But on another level, the setbacks to Avastin and the experimental Type 2 diabetes drug taspoglutide, really hurt --especially if FDA ultimately decides to take up ODAC on its recommendation earlier this week against full approval of Avastin in first-line metastatic Her-2 negative breast cancer. In that case, Roche will have to stop promoting the drug and re-educate physicians about its use for first-line breast cancer (it now is available for that indication under the accelerated approval process) – which could cost the company hundreds of millions of dollars in sales.

And the hypersensitivity issues that arose during a Phase III trial of taspoglutide, Roche's first drug for Type 2 diabetes, mean a delay of 12 to 18 months in the regulatory filing, which Schwan called "a big disappointment." That is likely to translate into some restructuring in the U.S., including of the U.S. primary care sales force – a group of about 750 reps – executives said, although they weren't specific about details of what they would do.

Meanwhile, Stefan Frings, Avastin Franchise director, was less circumspect in his response to the ODAC committee vote. Accusing the agency of having "stacked the deck against Avastin by choosing voting members who were previously negative" on the drug, he also noted that the briefing booklet "honed in on median PFS [progression-free-survival], ignoring hazard ratios."

And Roche, he added, wasn't alone: immediately after the vote, he told analysts, thought leaders contacted the company to say they "were appalled" by the committee's decision. "This is not a Mylotarg situation," he went on, referring to Pfizer's recent decision to withdraw that acute myeloid leukemia drug from the U.S. market because of excessive mortality. "Avastin mortality isn't excessive and risk factors work in its favor," he insisted, adding "Avastin is a meaningful option for certain patients with breast cancer."

Pascal Soriot, chief operating officer of Roche Pharma, took a less acerbic, more diplomatique tone, stating that the company "needs to work with FDA" to understand the relationships of PFS and hazard ratios and to have clear "expectations for rules of the game for all projects going forward."

Whatever the outcome of the Avastin decision - due in mid-Sept - this is a year when Roche steps in line with its pharma counterparts and focuses on the new frontier of "operating excellence."

Avandia: It's All About Question 7

Today, FDA released an army of briefing documents ahead of the advisory committee re-review of GlaxoSmithKline's diabetes drug Avandia (rosiglitazone). To read all of the documents for yourself, click here.

While one could argue that any number of issues will be key in helping FDA determine what regulatory action to take on Avandia, we believe the key to the whole debate is quite simple, actually: question 7.

FDA asked the joint Endocrinologic & Metabolic and Drug Safety & Risk Management Advisory Committees a large number of questions--six of which are formal voting questions with multiple options.

Most of the headline attention will be focused on question 8: "What regulatory action does the panel recommend FDA take on Avandia? A) Allow continued marketing and revise the current label to remove the boxed warning and other warnings regarding risk of ischemic CV events, or B)Allow continued marketing and make no changes to the current label, or C) Allow continued marketing and revise the current label to add warnings, or D) Allow continued marketing, revise the current label and add additional restrictions on use, or E) Withdrawal from the US market."

But none of the questions may be more important to FDA decision makers than the preceding question, number 7:

"Rosiglitazone and other oral anti-diabetic therapies share the same indication of improving glycemic control in patients with Type-2 diabetes. Based on the available data, please discuss the benefit-to-risk profile of rosiglitazone in the context of other available anti-diabetic therapies."

In other words, does Avandia provide a unique benefit over existing therapies on the market? Our bet is that FDA decision makers will be paying particularly close attention to the answers provided by committee members to question 7.

FDA knows what its regulatory options are when it comes to Avandia. But the agency will be looking for arguments--even if they are in the minority--that make the case for a unique Avandia benefit over everything else.

It will be a difficult argument to make.

InterMune’s Pirfenidone: No + No = No, After All

InterMune’s roller coaster ride with the idiopathic pulmonary fibrosis therapy pirfenidone took a steep dive back down when FDA issued a “complete response” letter asking for another clinical trial on May 4.

That decision, in one sense, is hardly surprising: FDA already made public the conclusion of its statistical reviewer that the NDA for pirfenidone didn’t meet the definition of “substantial evidence” for efficacy. Slam dunk non-approval.

Except that conclusion was presented to an FDA advisory committee in March for its consideration—with the remarkable outcome that many committee members seemed to agree that the data wasn’t sufficient to meet the “substantial evidence” standard, yet they voted for approval anyway.

It sure looked like a case where FDA was ready to be very flexible in the interest of making a potentially useful drug available for a horrific and untreated disease. One committee member actual voted “no” on the whether there was sufficient proof of efficacy, “no” on whether there was sufficient evidence of safety—and then “yes” on approvability. (Or, as we put it at the time, “No+No=Yes.”)

Apparently “substantial evidence” isn’t as flexible as all that. According to InterMune, FDA says it needs another trial to demonstrate sufficient evidence of efficacy. It may have to be a survival trial, or perhaps a trial with forced vital capacity as an endpoint.

InterMune says it won’t know for sure what will be required to support approval until after it meets with FDA to discuss the complete response letter. Still, the pivotal trial included in the NDA took three years from start to finish; replicating it means a prolonged delay.

So much for a “flexible” standard for substantial evidence, huh?

Maybe not. There is one wildcard in all this: pirfenidone is approved in Japan and marketed there by Shionogi. FDA wanted to review the Japanese trial data, but InterMune provided only summaries; the company didn’t think it would be worthwhile investing the time and resources to make individual case-level data available to the agency.

Our impression of the advisory committee was (and is) that the agency wanted the committee to, in effect, give them permission to approve pirfenidone based on something much less robust than you would expect for, say, a COPD therapy. FDA got that permission.

Still, it isn’t hard to understand why FDA would at least want that data before taking a chance on approving this application.

It may be that the “substantial evidence” standard still turns out to be more flexible than it appears to be—but with the caveat that, no matter how “substantial” it is, FDA expects to see all the data.

image from flickr user RubyJi used under a creative commons license

Yes+Yes=No? Forest's Daxas and the Pull of Comparative Studies

That wacky Pulmonary-Allergy Drugs Advisory Committee is at it again!

Last month, we noted the remarkable outcome of the review of Intermune’s pirfenidone, where the vote in favor of approval was stronger than the vote that the drug was effective enough to approve—in part because one committee member pulled the nifty trick of voting against efficacy and against safety, but in favor of approval.

The rationale: the drug may not meet the letter of FDA’s definition of substantial evidence, but in a condition as horrible as idiopathic pulmonary fibrosis, evidence of activity is enough to allow approval.

Now, Forest Labs brings it COPD drug Daxas to the same committee and wins a narrow vote that the drug is effective (9-6), a narrow vote that it is safe (9-6)—but a fairly firm vote against a favorable risk-benefit profile (10-5). As we put it in the headline of “The Pink Sheet” DAILY here, the committee said it is safe and effective but not both.

That sounds like a real head-scratcher, though the truth is that the vote is more rational than it looks. In fact, nine committee members voted “no” to either safety or efficacy or both, so it is not surprising that a majority voted against approval. (Trust us: the math works—if you would like a complimentary copy of our analysis of the votes, email us here.)

Of course, there is that one outlier: Richard Honsinger of Los Alamos Medical Center Clinic, who voted yes on safety, yes on efficacy, but no on approvability. His rationale? That while the drug may meet a minimal standard of safe and effective, it should only be approved if it is shown to be better (either more effective or more safe) than alternative therapies prior to approval.

That would obviously be tough for Forest if FDA agrees.

However, we suspect there will ultimately be a different outcome. As we noted in The RPM Report here, Forest made some important changes to the NDA after submission—and FDA basically said it was too late to talk about those before the committee. But we suspect the path forward for Daxas will involve putting brackets around the patient population and applying a robust post-marketing program—which may very well include comparative trials.

Still, let’s hear it for the Pulmonary-Allergy Drugs committee for once again tapping into the important themes of the regulatory process these days.

With pirfenidone, it was a perfect marker for one theme: the way the new regulatory process can make it easier for products to treat unmet medical needs (especially in relatively small patient populations) to reach the market.

With Daxas, the vote is a perfect marker for what happens to products where you cannot find such a population: there will be a strong desire for a de facto superiority standard for approval.

We look forward to the next meeting of this committee—no matter what is on the agenda.

image from flickr user RubyJi used under a creative commons license

No+No=Yes: Pirfenidone and the Power of Orphan Drugs

Two wrongs may not make a right, but when it came to Pulmonary-Allergy Drugs Advisory Committee member Les Hendeles' views on the approvability of InterMune's idiopathic pulmonary fibrosis therapy pirfenidone, two "no's" made a "yes."

Hendeles, whose day job is professor of pharmacy and pediatrics at the University of Florida Health Science Center, first voted "no" to the question of whether InterMune's pivotal trials showed "substantial evidence" of efficacy in IPF, as measured by changes in forced vital capacity.

Hendeles was one of five committee members to vote "no" on that question; there were seven "yes" votes. Hendeles noted FDA's definition of "substantial evidence" and his view that the dataset--one study showing improvement in FVC, one failing to show a change, and no unequivocal indication of an overall survival benefit--didn't make the cut.

Then he voted "no" on whether InterMune had provided sufficient evidence of safety; there he was one of three "no's," vs. seven "yes" votes. Hendeles described pirfenidone as a "theophylline-like drug" and explained his vote by asking, "have you ever heard of Vioxx?"

Then he voted "yes" on approvability. That made him one of two committee members who ended up taking the formal position that InterMune failed to demonstrate "substantial evidence" of efficacy but that the drug should be approved.

His explanation of the apparent contradiction (as we note in "The Pink Sheet DAILY") was simple. Based on the indication of a mortality benefit and the complete lack of effective alternatives, he "would be on the first Delta flight to Japan," where pirfenidone is approved already, if faced with a diagnosis of IPF.

That, in a nutshell, explains the committee vote (and what is likely to be FDA's final action on the appication) perfectly.

Bear in mind that Hendeles is not some naif from academia with no idea how the regulatory process works. He has been involved in FDA advisory committees for three decades and has weighed in on many different aspects of the regulation of pulmonary drugs in that time. He knows the regulatory process pretty well.

The fact is that InterMune's dataset doesn't meet the letter of FDA's definition of substantial evidence. That's not just our opinion: FDA's own statistician says just that in her written summary provided for the committee.

But FDA is prepared to approve this application anyway, because the concept of substantial evidence is and always has been more flexible than that.

Plenty of sponsors have learned that the bar is often higher than the definition makes it sound. But this is an important case of where and when it can be lower.

IPF is a disease that all parties agree is horrific, involving a steady decline in lung function towards a certain and unpleasant death, with absolutely no treatement options that seem to do anything to help. It also has a relatively small (approximately 100,000 patients in the US) and reasonably well-defined patient population.

And these days FDA has the tools to approve drugs like this with more confidence. InterMune is proposing a Risk Evaluation & Mitigation Strategy to highlight the need for liver monitoring and limit the risk of phototoxicity. The company also plans to sell the drug via a centralized distribution system, though it is not proposing that as part of the REMS per se. (That seems like an increasingly common strategy, by the way--read more here.)

Committee members urged a registry, as well as deeper dives into potential markers of response. All that seems very easy for InterMune to do--and for FDA to accept as a reassurance that it will ultimately gather sufficient data to prove (or disprove) a mortality benefit from therapy.

Hendeles put it perfectly: Who wouldn't take pirfenidone, given its success in improving lung function scores in one trial, and consistent albeit not statistical signficiant sign of an increase in survival?

That may not be "substantial evidence" by the letter of the definition. But these days and for this type of therapy, it is probably sufficient.

image from flickr user RubyJi used under a creative commons license