Next Steps For Prasugrel: The Anatomy of an Advisory Committee

Eli Lilly and Daiichi Sankyo used the morning of New Years Eve (‘tis the season for hiding news) to announce that the delayed anti-clotting drug prasugrel will be considered by the Cardiovascular-Renal Advisory Committee February 3. (Shameless self-promotion alert: We predicted that February meeting in October.)

Now that a date has been offically set, let the next round of speculation begin.

That news can be viewed in two ways: optimists (like Lilly and Daiichi investors) will argue that the meeting is a signal that the review is wrapping up and a decision is close at hand. Pessimists will argue that the meeting is an indication of the internal strife at FDA over prasugrel’s benefit-risk profile—and that products that go before an advisory committee are less likely to be approved on the first cycle.

Here's our take. First, we should note that the confirmation of the advisory committee meeting is a milestone in prasugrel’s development. It’s the first word to come out of FDA on the drug since June, when the agency extended the review by three months. FDA then let the revised September 26 review deadline pass without an approvability decision.

Another positive indicator for Lilly and Daiichi is that FDA is only convening the Cardio-Renal committee—and is not asking for a joint review with the Drug Safety & Risk Management Advisory Committee. A joint meeting would indicate significant concerns at FDA regarding prasugrel’s safety profile, which we have delved into in this earlier post.

Of course, that certainly doesn’t preclude FDA from drawing from members of the Drug Safety & Risk Management Advisory Committee as needed—including its newest member, Public Citizen’s Sidney Wolfe, who is unlikely to look kindly upon the prasugrel NDA.

Wolfe is just one extra member that could be asked to show up on February 3, given the current vacancies on the Cardio-Renal advisory committee. There are just eight permanent Cardio-Renal members, including a consumer rep (Consumers Union’s Stephen Findlay) and a non-voting industry rep (AstraZeneca’s Jonathan Fox).

That can make for a lot of last-minute additions. At the committee’s last meeting, FDA added 13 temporary members, including two regulars: University of Washington statistician Thomas Fleming and Duke University human cognition expert Ruth Day.

So who might be asked to serve? With a product like prasugrel, one obvious choice for a temporary member is Steven Nissen, the head of cardiology at the Cleveland Clinic—an expert on cardiovascular drug safety and a former chair of the Cardio-Renal advisory committee.

Nissen’s participation on the committee would be a positive development for Lilly and Daiichi, given that he has come out in favor of prasugrel—first giving the drug a thumbs up for approval and then criticizing FDA for not delivering an on-time approvability decision. Nissen isn’t exactly a shrinking violet, so if he still favors a prasugrel approval, he stands a good chance of getting the committee to see things his way.

But those statements may prevent Nissen from serving—especially given FDA’s tougher line on conflicts of interest. Indeed, Nissen himself has questioned whether he is qualified to serve on an advisory committee under the new CoI guidelines. The meeting roster will be out in the next month. Lilly and Daiichi should hope Nissen's name is on it.

Human brain image courtsey of flickr user hduhadaway.

The Lesser Of Two Evils?

When Steve Nissen is not qualified to serve on an FDA advisory committee under the agency’s new conflict of interest guidelines, you know things are bad. Really bad.

According to Nissen, and as reported in "The Pink Sheet" DAILY, his position as chair of the cardiology department at the Cleveland Clinic likely bars him from serving another term on an FDA expert panel.

Nissen may not be exactly beloved by the pharmaceutical industry, but no one can argue that the man knows drug development, and is a global expert on cardiovascular drug safety. And when it comes to conflicts, Nissen prides himself in not only disclosing all the companies he has worked for, but also donating all his fees directly to charities so that he can't claim the tax benefit.

Plus, he has served as an advisory committee member before: Nissen was a permanent member of the Cardiovascular & Renal Advisory Committee from 2001 to 2005, that last year as chairman. Since then, he has served as a temporary member as duty calls, like the July meeting on type 2 diabetes clinical trial endpoints. So if he can't serve, then who can?

“The current rules are pretty bizarre,” Nissen told attendees at the recent FDC-Windhover FDA/CMS Summit. “The imputation of conflict of interest guidelines based on institutional contracts eliminates a lot of desirable people.”

In Nissen’s case, the trouble is with a section of the new CoI guidelines that bars the “head of a department” that is conducting or will conduct studies on a product (or its competitors) “that is the focus of a meeting and receives personnel or salary support, designs or advises on any aspect of clinical trials, or reviews data or reports from the trials.”

We emailed Nissen to clarify, and he pointed out that the cardiology department has more than 100 faculty members. So “for most advisory committees, it is highly likely that someone within our department is involved with the company in some fashion.” And given the size of the Cleveland Clinic, Nissen said, “the likelihood that someone...receives funding from the sponsor or its competitors is 100%.”

Of course, Nissen’s inability to serve on an advisory committee is most likely be welcome news for drug sponsors, who see him as, frankly, a pain in the derriere. Granted, this is the man who prevented Bristol/Merck’s Pargluva (muraglitazar) from ever seeing the light of day, and crippled the commercial future for GlaxoSmithKline’s Avandia. So you can understand that angst.

But industry should not be breaking out the champagne quite yet. If it is true that Nissen is no longer eligible to serve on an advisory committee, it underlines a disturbing trend at the agency: FDA’s continued inability to fully staff its expert panels with individuals that qualify under—and are willing to serve despite of—more stringent conflict of interest guidelines.

When we last looked at the staffing problems in the advisory committee system in The RPM Report, there were 83 vacant seats, and three-quarters of the panels did not have permanent chairs. That was despite a major recruitment effort at the agency. Things haven’t improved much since.

And when drug sponsors start to see who is qualified to serve as permanent advisory committee members under FDA’s conflict of interest rules, they may be wishing for Nissen. You tell us. As a sponsor, who would you rather have: Nissen, or Public Citizen’s Sidney Wolfe and Center for Science in the Public Interest’s Merrill Goozner?

FDA's Internal Advisory Committee Meetings

Avandia. Vioxx. Ketek. Elidel. Palladone.

What do those drugs have in common? The obvious answer is that they are all associated with a major safety problem that resulted in a significant FDA regulatory action—either a “black box” warning in product labeling, or, in the case of Palladone and Vioxx, outright removal from the market.

But they have something else in common as well. In the months preceding those major regulatory steps, each product was the subject of a relatively unknown internal meeting at the Food & Drug Administration: a regulatory briefing.

Regulatory briefings can be described as “internal advisory committees” at FDA—a chance for review divisions to ask others in CDER for advice on how to handle a tricky regulatory or scientific decision. (For more on regulatory briefings, check out our coverage in The RPM Report. If you’re not a subscriber, you can sign up for a free trial to view the article.)

If you’ve never heard of a regulatory briefing, you’re not alone. Regulatory briefings have been kicking around FDA’s Center for Drug Evaluation & Research for more than a decade, but because they are closed to industry—and review divisions don’t always inform sponsors when one is held—many companies are unaware that they exist. But now FDA is holding more of them, as many as one per week. And they are quite popular with reviewers.

The good news for drug sponsors is that regulatory briefings are not intended to be decisional meetings; the final approvability decision remains with the review division after the meeting is over. But given the typical attendance list—John Jenkins, Janet Woodcock, Bob Temple, Doug Throckmorton and 50-100 other drug reviewers—it would be hard to ignore any advice.

A drug does not have to rise to the level of an Avandia or a Vioxx to be discussed during a regulatory briefing—given the frequency of such meetings, that could not possibly be the case. But, as the list above indicates, they do tend to skew toward the more problematic end of the continuum. The need for a regulatory briefings should not spell doom and gloom for a sponsor, but it could be an indication that something is wrong. That alone makes them worth watching.

image via FDA

Nearing an End to the Longest Review?

Ovation reached a milestone this month in its quest to get its GABA-transaminase inhibitor vigabatrin (Sabril) on the market: It received confirmation from the Food & Drug Administration of a tentative date for an advisory committee meeting.

Given that FDA has held 30 advisory committee meetings so far this year, that doesn’t sound like groundbreaking news. But in the case of Sabril, it’s a major development given the difficulty FDA has had in finding enough qualified advisory committee members under the new conflict of interest guidelines.

We wrote about Sabril as a worst-case example of the approval delays in the new user fee era in last month's issue of The RPM Report. But is also a poster child for what can go wrong under FDA's new conflict of interest guidelines. (We'll have more on that on this blog and in the next issue of The RPM Report.)

But for now, here's the short story: An advisory committee meeting for Sabril was originally scheduled for August, but there was one (tiny) hiccup. It turns out that the only pediatric neurologist on the committee, Dartmouth Medical Centers Greg Holmes, did work on the original NDA when it was owned by Sanofi-Aventis predecessor company Marion Merrell Dow.

That’s a definite no-no under FDA’s new guidelines. Holmes was recused, and it has taken until now for the agency to reschedule the meeting for January 7-8, as reported in this week's issue of "The Pink Sheet." Of course, that’s assuming FDA can find a qualified pediatric neurologist who hasn’t run a clinical trial for vigabatrin (or a competitor), or invested more than $50,000 in Ovation (or a competitor), or is conflicted in some other way.

But perhaps the Greg Holmes snafu is only fitting for a drug like vigabatrin, which has already had an excruciatingly long pathway toward approval.

Vigabatrin was developed in the 1980s by Merrell Dow as an anticonvulsant. Three advisory committee were convened (in 1984, 1985 and 1989) in light of toxicity signals seen in animal models. An NDA finally was submitted in 1994 by Marion Merrell Dow; FDA turned it down twice before it was outlicensed to Ovation in 2004 by Aventis (now Sanofi-Aventis).

Ovation has had much more success with vigabatrin, having moved from the licensing deal to a priority review for a more targeted indication of infantile seizures in three years. (Ovation also is pursuing the original indication for use in complex partial seizures; the company submitted a response to FDA's questions about that application late last year.)

FDA's deadline for a decision on both indications was June 27--more than three months ago. Between the missed user fee deadline and the immense difficulty in finding enough experts to staff an advisory committee, Sabril is the worst-case example of drug regulation today.

Will there be more? Probably. Will it be yours? Stay tuned.

GSK’s Promacta at ASCO: Advisory Committee “Show and Tell”

When it comes to finding ways to recruit new members for its advisory committees, the Food & Drug Administration is getting pretty creative.

Having already undertaken various activities to fill vacancies among its expert panels, FDA embarked on the Ultimate Roadshow at the American Society of Clinical Oncology’s annual meeting last week in Chicago: a committee review of GlaxoSmithKline’s eltrombopag (Promacta), a non-peptide oral platelet growth factor for the treatment of idiopathic thrombocytopenic purpura.

As the saying goes, if you can’t bring the candidates to the advisory committee, bring the advisory committee to the candidates. And we’ve got to hand it to FDA: what better opportunity to attract new members then to hold a meeting smack dab in the middle of one of the biggest medical conferences of the year?

FDA has been working to fill advisory committee vacancies for some time—by creating a central database for committee openings and asking medical associations to nominate potential candidates. But there are still more than 100 openings between the drugs and biologics review centers alone. (For a breakdown by advisory committee, check out this chart in the latest issue of “The Pink Sheet.”)

The committee that reviewed Promacta at ASCO, the Oncology Drugs Advisory Committee, or ODAC, currently has four vacancies. Compared to other advisory committees, oncology isn’t doing too badly: the Dermatologic and Ophthalmic Drugs Advisory Committee, for example, has 12 vacancies, and the Anesthetic and Life Support Drugs Advisory Committee has nine.

But the decision to hold Promacta’s review at ASCO is based less on ODAC’s relative need for additional committee members, and more on the vision of the lead oncology reviewer at FDA, Richard Pazdur. (For more on Dr. Pazdur, check out our earlier story in the The RPM Report; those who don’t subscribe can sign up for a free trial.)

Pazdur is quite dedicated to an open, transparent review process. Summaries of ODAC’s meetings, for example, are published in peer-review journals. By scheduling the Promacta meeting during ASCO, oncologists have a “convenient opportunity to observe first-hand the processes and issues that are considered during an ODAC meeting,” FDA says.

With any luck, the agency says, some of those oncology experts in the audience might become interested enough to serve on the committee. Hence, “it can also serve as a recruitment tool.”

Pazdur has done this sort of thing before: Promacta is actually the second committee meeting to be held off-site at a medical conference. At Pazdur’s suggestion, Bristol-Myers Squibb’s dasatinib (Sprycel) for chronic-phase chronic myeloid leukemia was the lucky subject of a committee review during the ASCO conference in June 2006.

We say “lucky” because Sprycel was unanimously recommended for approval, and was quickly cleared for marketing later that month. Likewise, Promacta was recommended for approval by a 16-0 vote, despite concerns that eltrombopag’s marketing plan includes, according to FDA, a risk management program that encourages off-label use.

With a sample size of two—and FDA's final say on Promacta's approvability still outstanding—we suppose it is premature to assume that a cancer treatment would have an easier time getting past an FDA advisory committee held in the midst of the greatest oncology R&D love fest in the world. But it is something to think about.

So far, none of the other FDA review divisions have followed Pazdur’s lead. But it may make good sense. Consider this: the Dermatologic and Ophthalmic Drugs Advisory Committee May 29 review of Sirion Therapeutics’ difluprednate (Durezol) convened with just four voting members. That's a lot of power in the hands of just a few people.

Cephalon's Fentora Rejection: The Challenging Environment

Cephalon CEO Frank Baldino’s characterization of the May 6 FDA advisory committee review of Fentora (fentanyl buccal tablets) as “challenging” is a masterpiece of understatement.

Here is the crux of Baldino’s post-mortem on the failed attempt to get a major label expansion for the pain control product from the current limitation for breakthrough cancer patients to more generalized breakthrough pain patients: Cephalon was not surprised by the 17-3 vote against an expanded indication in the current cautious approval environment at FDA, according to Baldino.

Although we're disappointed,” the CEO declared, “we're not surprised in the results.” Cephalon recognize[s] that it faced a panel “at this challenging time with the FDA” with an application for a “challenging subject.”

How “challenging?"Well, the fundamental dichotomy between the company’s interpretation of current use patterns for the drug and FDA’s is about as far apart as any sponsor can expect to face.

Cephalon felt that extensive off-label use of the product in the marketplace (up to 80% of the drug use going beyond approved patient populations) would convince FDA of the real-world demand for different labeling. Cephalon’s application embodied the logic of those advocates who believe that the medical community and a lightly controlled medical market will get the best medicines to the appropriate patients.

Showing how far the regulatory system is moving away from those arguments, FDA said that the existing prescription patterns for Fentora do not indicate demand; instead they demonstrate that the company cannot control appropriate use of the product—a drug which relies on an active ingredient with a very tricky, narrow therapeutic range.

The agency’s internal reviewers had harsh words for the company about its existing attempts to control use of the product. A new risk management system based on spoken acknowledgments of risks and appropriate use to permit prescribing (by physicians) and receiving prescriptions (by patients) was submitted too close to the date of the advisory committee for FDA or its advisors to give it full consideration.

How’s this for FDA’s introduction to a request for expanded use? The agency told its advisory committees (two were combined for the Fentora review) that fentanyl can quickly be lethal in kids and the elderly, so it will demand an effective risk mitigation program.

And, the agency is changing the environment in some other important ways. Its advisory committees are getting tougher.

To judge the Cephalon request for an expanded indication, the agency assembled a group of advisers who were anything but sympathetic to the drug sponsor and wider use of the product.

When the Cephalon team got up to support the expanded indications, they faced a committee that included Public Citizen’s Sidney Wolfe, MD (right), as a “temporary voting member” of the Drug Safety & Risk Management Committee, which met with the Anesthetic & Life Support Drugs Advisory Committee on Fentora on May 6.

For Cephalon and the rest of the industry, the recruitment of Wolfe creates, as Baldino so gently puts it, a “challenging” time.

Wolfe is legendary in the drug industry and has embodied persistent and effective attacks on the industry for over 30 years in Washington as the indefatigable voice of the Nader movement in health care from the 1970’s. Now the agency has brought him into the fold to act as an official advisor. Wolfe was a “temporary” member at the May 5-6 meetings.

The word among FDA observers is that industry will be seeing Wolfe more frequently on the agency side of the table at advisory committees.

Wolfe has been a frequent public speaker at advisory committees as an outside commenter over the years. Politically, he would be an astute selection as a permanent member. He would bring immediate credence and credibility to the first wave of the agency’s risk management decisions following the new FDA Amendments Act. As part of FDA’s advisory committee team, Wolfe can push the agency to use its new tools aggressively. If his opinions are built into the standard risk management reviews, then his concurrence should shield the agency (and drug sponsors) from further criticism.

And Wolfe performed right to form at the Fentora meeting. He engaged a top FDA official in an unofficial colloquy at the advisory committee meeting on how the agency can and should use its new post-marketing powers to correct prescribing practices: for current drugs and future uses. (For further coverage see "The Pink Sheet").

The agency clearly intends to take the development of more effective post-market control programs more seriously. They are not going to be shy about demanding tighter control of products in the post-market. And they are going to get advisory committee members who agree with them on that authority.

Baldino calls the situation “challenging.” It may be more accurate to call it a sobering look at the future for drug sponsors.

Amgen Braces for Another Review of EPO Safety: How Bad Will it Be?

Investors loved what they heard from Amgen CEO Kevin Sharer at the JP Morgan conference in San Francisco.

The stock price jumped nicely when he announced that the company’s cost-cutting plan is paying off already, with earnings per share for 2007 expected to come in well above Amgen’s revised guidance—and in fact almost in line with the low end of the company’s original forecast for the year before the EPO disaster unfolded.

Investors also responded to Sharer’s assurance that EPO sales have stabilized now that the market has had time to adjust to new restrictions on coverage imposed by the Centers for Medicare & Medicaid Services in the chemotherapy induced anemia market.

You have to feel good for people at Amgen to see a bit of positive news after a dreadful year. (How bad was 2007 for Amgen? The 5% jump after Sharer’s January 8 presentation brought the company back within range of $50 per share—which is where the stock was five years ago. Ouch.)

What we took away from the presentation, though, was not quite as rosy. The company is bracing for another potential hit to the EPO franchise when it goes back before the Oncologic Drugs Advisory Committee to review still more negative safety data about EPO. (Amgen markets epoetin as Epogen and darbepoetin as Aranesp; the company also manufactures Johnson & Johnson’s epoetin brand Procrit.)

It was ODAC that really started Amgen’s headaches in 2007 when it made unexpectedly harsh recommendations about restricting use of EPO, so there is obviously reason for Amgen to be nervous.

Sharer stressed that Amgen is prepared for ODAC and urged investors to focus on how the company fared during a Cardio-Renal Drugs Advisory Committee discussion of EPO safety in the kidney failure market, rather than the ugly discussion that took place during an ODAC meeting in May.

But he also kept mentioning the meeting.

When he said “the ESA revenue picture is stable,” he added, “but obviously the dialogue isn’t over.” Then he talked about the timing of Amgen’s annual business review, which was supposed to take place in February—but, Sharer said, will now be “in the June timeframe.”

Why? “We want to make sure our team is fully focused on giving the very best preparation for the March ODAC. If we have the business review as we originally thought in February, that would be a conflict for the same people. I think you as shareholders and I certainly as management want those people focused on ODAC. So we’ll pick another date for you.”

“It will be obviously after ODAC and we will have more to talk about then.”

Hmmmm.

Here’s what we had had heard about the ODAC meeting before Sharer spoke.

(1) It would take place in March;

(2) FDA would in essence be asking the committee to support another relabeling of the drugs to bring the FDA label more explicitly in line with CMS’ coverage policy; and

(3) There would be discussion of additional post-marketing requirements, and in particular a demand by FDA for a placebo arm in a study the sponsors are proposing that would compare the historical dosing paradigm for EPO head-to-head against the intermittent model covered by CMS.

We asked both Amgen and FDA to confirm those details, but both said that they were not in a position to discuss anything about the advisory committee review because the date is not yet set.

Well, it sounds like our sources were right about the March date, at least.

EPO’s Future Back in FDA’s Hands

FDA Commissioner von Eschenbach: Whose Side is He On?

That sigh of relief you heard on Tuesday came from Amgen and Johnson & Johnson, when an FDA advisory committee declined to recommend significant changes in the labeling for EPO products in renal failure patients. As a commenter put it in response to our preview of the meeting, “history didn’t repeat itself.”

Probably just as important for the companies was the tone of the meeting. It was a tough meeting—any advisory committee focusing on safety concerns with your biggest products is going to be tough—but in general FDA officials avoided making inflammatory comments or otherwise suggesting that they are going to somehow make life even tougher for the anemia therapy sponsors.

After the meeting, a bunch of Wall Street analysts did something they haven’t done in a long time: they raised their forecasts for 2008 revenues from Aranesp, Epogen and Procrit, and Amgen’s stock responded accordingly.

So is the worst over?

Well, that depends. After the meeting, FDA officials said they plan to finalize the new labeling for the EPO therapies in a matter of weeks. The new labeling will address use of the drugs both in the renal failure/dialysis setting and in oncology.

And right now at least, the oncology setting is where the action is. Amgen, J&J and the oncology profession are waging an all fronts campaign to reverse the restrictive coverage policy put in place by the Centers for Medicare & Medicaid Services in that setting.

A key point of contention is whether CMS’ policy contradicts the FDA-approved labeling for the drugs. (The RPM Report has just published its latest coverage of that issue online. Not a subscriber? You can read the story for free by registering for a 10-day trial here.)

The argument that CMS is restricting access to FDA-approved uses of EPO clearly resonates politically. ASCO’s point about the conflict between CMS’ policy and the EPO label was cited in a “sense of the Senate” resolution urging reconsideration of the coverage decision.

So when FDA issues final labeling plenty of people will be paying close attention. The sponsors hope that FDA will reinforce their view that CMS’ treatment model is ridiculous—in particular, by repudiating the ceiling that CMS has set on hemoglobin levels for chemo patients. If that is how the final labeling reads, the pressure on CMS to reconsider its policy is sure to intensify.
Of course, there is another possibility: FDA could back up CMS instead.

FDA is not likely to insist on labeling that requires treatment exactly along the lines proposed by CMS, but FDA could try to tweak the labeling so that it more clearly states that treatment should maintain hemoglobin levels at the lowest level to prevent transfusions.

Or the agency could support CMS less formally, simply by stating publicly that the coverage policy is consistent with FDA approved labeling. FDA Commissioner Andrew von Eschenbach is an oncologist by training, the former head of the National Cancer Institute, and a prostate cancer survivor. With the political pressure on CMS ratcheting up, the Medicare agency is surely rooting for some show support from the commissioner of FDA.

But will they get it?

So far, there has been nothing. An FDA spokesperson says she is unaware of any plans for the agency or the commissioner to weigh in on the coverage policy, saying that falls outside the agency’s “central mandate to review drugs for safety and efficacy.”

The head of FDA’s Office of Oncology, Richard Pazdur, participated in the September 11 advisory committee review of EPO use in renal failure, but he did not use that forum to make any comments about the CMS coverage policy.

But stay tuned. The September 11 advisory committee review is definitely not the last word on EPO.

EPO Fatigue: Amgen Hopes History Doesn’t Repeat Itself

Did you ever have a recurring nightmare? That is what Amgen Inc. and Johnson & Johnson want to avoid next week when another panel of expert advisors to the Food & Drug Administration weighs in on the safety profile of EPO therapy to treat anemia in chronic renal failure patients.

The Cardiovascular & Renal Drugs Advisory Committee will discuss the safety profile of Amgen’s Epogen and Aranesp, as well as J&J’s Procrit, on September 11.

Amgen has been making the rounds on Wall Street, assuring investors that it is ready for anything at the Cardio-Renal Committee.

Why? Because the last time an FDA advisory committee met to discuss those same products—the Oncologic Drugs Advisory Committee in May—it did not go well. The committee recommended much stronger restrictions on use of the drugs than anyone anticipated. And things got even worse a few days later, when the Centers for Medicare & Medicaid Services issued a proposed coverage policy that sharply limited the drugs.

CMS compromised a bit when it issued a final coverage policy in July, but not enough to spare Amgen. The new payment rules prompted a major restructuring by the company in anticipation of a big drop in Aranesp revenues.

Now Wall Street is wondering what to expect from the nephrologists when it is their turn to review EPO.

In recent weeks, Amgen has been making the rounds to large investors and analysts with to assure them that it has a solid game plan in place for the meeting. The company says it has seen FDA’s briefing materials and they don’t look surprising or onerous. (The public will be able to see those materials on Friday or Monday, on FDA’s website.)

What will Amgen do? Here is how SVP-North American operations Jim Daly described the company’s approach back in June. Asked during a Goldman Sachs conference what the company would do differently to prepare for the Cardio-Renal Panel, Daly replied: “I think we’ve learned a lot from ODAC, which is go in prepared for a scientific discussion but also be prepared for wherever it goes.”

“I think that community also needs to play a more proactive role, and the good news here is that the nephrology community already has been very active with the FDA. Their primary concern is that they are taking an oncology dosing paradigm and imposing it on nephrology patients, and it’s a very different disease state.”

Still, Daly said, “we need to be prepared in case the agenda goes into other areas, whether it be the cost of ESAs, whether it be the utilization patterns as a result of reimbursement, I think we need to be prepared to address those.” Daly recalled a “pointed moment” in the ODAC review when “one of the physicians said does anybody here know what community oncologists do and why they do it? And the response was no, but I do know they make $1,200 a dose, therefore we can’t leave the prescribing decision in their hands.”

If the Cardio-Renal meeting “goes to that level I think that would be very disappointing, but I think we have to be prepared to deal with that. The best response will come from someone in the audience that says that is preposterous.”

In other words, expect plenty of patient and provider representation ready to speak up on Amgen’s behalf.

But will that be enough to ensure no unpleasant replay of the May ODAC meeting? Citigroup Yaron Werber doesn’t think so. The headline to Citigroup’s Aug. 30 note says it all: “Beware of CRDAC—the Bite May be Worse than Expected.”

Why is Werber concerned? Because “we have learned that Rich Pazdur, head of FDA’s oncology division, will be present in an oversight role. Given his aggressive stance, his presence in CRDAC is a clear concern.”

That seems like a lot to read into one FDA official’s participation in the meeting, but it does underscore a larger point about the regulatory response to the EPO safety issues. As Werber puts it, there is a “theme that FDA/CMS view EPO to have modest benefit w/growing evidence of harm. Thus, panel might be more contentious than expected even on dialysis.”

Werber isn’t alone in worrying. After all, several analysts note, Amgen assured them it was on top of the situation before the May ODAC meeting.

One other thing: Citigroup expects CMS to follow close on the heels of the advisory committee with a national coverage decision about use of EPO in nephrology. And, Werber warns, it is possible that the combined impact could be to make Citigroup’s forecast of a 10%-15% decline in the nephrology market in 2008 overly optimistic.

If Werber is right, Amgen investors have another tough three months to look forward to. Should make for an interesting week next week.

Provenge, the Pazdur effect, and looking for a silver lining

Dendreon’s "approvable" letter for its cutting-edge prostate cancer vaccine Provenge this week asks for—among other things like further manufacturing specs—more clinical data, a request that sliced over 60% from the biotech’s market cap. (For more on Provenge’s rollercoaster background, see here and here.)

But why were Dendreon shares priced so high to begin with? An FDA advisory committee shocker in March, where FDA’s advisors voted 13-4 in favor of approving the vaccine. Indeed Provenge’s prospects for a positive ruling from the FDA panel looked slim going into that meeting: two Phase III studies supporting the application missed the primary endpoint target of time to progression as well as failing to meet secondary endpoints of clinical and pain progression and treatment failure.

And that’s not a good thing when you’re trying to prove you’ve got an effective product.

What won over the committee? Two things: First, an analysis of data from a subset of patients in one of the Phase III trials demonstrated a statistically significant increase in time to progression. Second, and perhaps as importantly, the review of the therapeutic vaccine falls under the purview of the agency’s Center for Biologic Evaluation & Research—not the Center for Drug Evaluation & Research’s Office of Oncology.

Provenge therefore avoided CDER’s Oncology Drugs Advisory Committee, which is now considered to be a stricter committee to go through because of the tone set by oncology director Richard Pazdur, MD.

One scenario that did not bode well for Provenge is the involvement of Pazdur himself in the review. When cancer drug reviews were organized under a newly created Office of Oncology in 2004, biologics and chemo-preventative drugs fell under the CDER office, while vaccines remained under the CBER umbrella. But Pazdur still has a hand in cancer vaccine reviews; for example, he consulted on the approval of Merck’s human papillomavirus vaccine Gardasil and has helped evaluate GSK’s competing HPV vaccine Cervarix.

Whether Pazdur is personally involved or not, FDA officials often say that they pay just as much attention to minority opinions as those in the majority when it comes to advisory committees. And the minority "no" opinions for Provenge were particularly unwavering.

It’s tough to say where Dendreon goes from here. Recovery from an FDA rejection can be agonizingly slow (see, for example, Xoma). Dendreon can at the very least hang its hat on the positive panel review as evidence of advocacy by a key body in the regulatory process. And the market potential for cancer vaccines—analysts expect it could grow to $6 billon by 2010--could dull the market effect of a negative FDA decision as investors hold firm with an eye toward the long-term possibilities.

Sanofi-Aventis’ recent acquisition of OxfordBiomedica’s renal cancer vaccine Trovax for approximately $700 million is hard evidence of interest in the field. That sustained interest could be Dendreon’s saving grace.