FDA's Real Risk Communication Challenge

FDA is the first to admit that it hasn’t quite figured out the best way to communicate drug risks to patients—especially how to convey emerging risk information without scaring patients away from a helpful or life-saving treatment.

But it is also clear that FDA hasn’t quite figured out how to communicate within the agency on communicating risk to patients, either.

On Friday, FDA announced a major new policy on risk communication under which it will begin alerting the public to potential safety problems with a drug or biologic at the very beginning of the post-marketing drug safety process. (Check here for our earlier take on that initiative.)

On Monday, FDA’s senior advisor on risk communication in the Office of the Commissioner, Nancy Ostrove, spoke at the Food & Drug Law Institute’s annual meeting on advertising and promotion.

Given that the title of Ostrove’s speech was “FDA’s Initiatives in Communicating Risk Information,” it appeared to be the perfect venue for discussing the new program—so much so that one might have wondered whether the agency timed the announcement to coincide with Ostrove’s FDLI presentation.

Apparently not.

After avoiding mention of the program in her opening remarks, Ostrove gave the following disclaimer before the question and answer session: “I can tell you one thing I am not going to talk about…the press release that went out on Friday concerning the FDAAA provisions on quarterly reports. I didn’t even get it until today. So I can’t talk about it.”

Given the pains that FDA took in announcing the decision—a rare embargoed media call ahead of the official announcement with Office of Drug Safety director Gerald Dal Pan and Safety Policy & Communication associate director Paul Seligman—it was surprising that Ostrove wasn’t on the call herself, or, at the very least, aware that it had taken place.

There may be good reasons for Ostrove not to have been in on that decision. But given FDA’s recent focus on risk communication (check out our coverage in The RPM Report here and here), we can’t help but wonder whether the real communication on risk needs to first take place at FDA.

image from flickr user rubatacchini used under a creative commons license

Celgene and FDA’s New Drug Safety List

It’s over for Celgene. That’s it. Revlimid’s done. Investors should evacuate the premises immediately.

After all, a vital cog in Celgene’s cancer portfolio is on FDA’s first quarterly drug safety posting.

Sound too alarmist? Maybe a little extreme? Of course it is. But that’s how a good number of investors reacted to the posting.

Celgene lost about 3% of its value in the two days following the announcement. Not terrible. But if you look at trading the day of the announcement, volume more than tripled and the stock dropped 6% of its value in midday trading with a low of $63.00 per share before edging back up.

We’ve seen that investors and drug companies are finding it challenging to communicate and interpret risk, respectively. To read our take, click here.

FDA threw a new twist into the risk communication equation last week. In response to a specific provision in the FDA Amendments Act, the agency will be posting a list of drugs every three months that officials deem worthy of further risk evaluation following voluntary adverse event reports from patients and health providers. So for all of the FDA critics out there, this is something the agency had to do.

In a September 5 press release announcing the initiative, FDA tried to be as unalarmist as possible. “My message to patients is this: Don’t stop taking your medicine. If your doctor has prescribed a drug that appears on this list, you should continue taking it unless your doctor advises you differently,” said Janet Woodcock, M.D., director of FDA’s Center for Drug Evaluation and Research.

The agency was very explicit about what a drug showing up on the list actually means for that drug:

“The appearance of a drug on this list does not mean that FDA has concluded that the drug has the listed risk, or that FDA has identified a causal relationship between the drug and the listed risk. It is on the list only because FDA has identified a potential safety issue.”

In a media briefing prior to the official announcement, Office of Surveillance and Epidemiology director Gerald Dal Pan explained that a listing on quarterly report means FDA has begun an analysis of whether the drug needs further evaluation such as further information, clinical trials, epidemiologic study, need to conduct an epidemiologic study, and possibly the need to conduct a clinical study.

CDER associate director for Safety Policy and Communication Paul Seligman said two things have to happen to get on the quarterly list: first, a provider submits an AER report to FDA’s voluntary AERS reporting system. Second, our FDA staff have judged that further follow up or review is warranted.

Seligman highlighted that the work FDA is doing to support the quarterly list isn’t anything new. “This is work we’ve been doing for decades.” What’s new is, he says, FDA is telling the public what it’s working on in postmarket surveillance at the “earliest stage.”

FDA’s new initiative is not without some irony. The first quarterly report, which is supposed to represent FDA’s work at the “earliest stage” is for January 2008-March 2008, not the just passed April 2008-June 2008 quarter. That is understandable since FDA has a seemingly limitless number of FDAAA provisions to implement and a very limited number of resources to get it done. We’re just pointing it out. There were similar issues with FDA’s “early communication” initiative, which appeared to be anything but early. To read more, click here (also one of our favorite blogs and blog pictures.)

Here’s the first list of 20 drugs on the quarterly post:

Potential Signals of Serious Risks/New Safety Information Identified by the Adverse Event Reporting System (AERS) January - March 2008

Product Name: Active Ingredient (Trade) or Product Class	Potential Signal of Serious Risk/New Safety Information
Arginine Hydrochloride Injection (R-Gene 10)	Pediatric overdose due to labeling / packaging confusion
Desflurane (Suprane)	Cardiac arrest
Duloxetine (Cymbalta)	Urinary retention
Etravirine (Intelence)	Hemarthrosis
Fluorouracil Cream (Carac) and Ketoconazole Cream (Kuric)	Adverse events due to name confusion
Heparin	Anaphylactic-type reactions
Icodextrin (Extraneal)	Hypoglycemia
Insulin U-500 (Humulin R)	Dosing confusion
Ivermectin (Stromectol) and Warfarin	Drug interaction
Lapatinib (Tykerb)	Hepatotoxicity
Lenalidomide (Revlimid)	Stevens Johnson Syndrome
Natalizumab (Tysabri)	Skin melanomas
Nitroglycerin (Nitrostat)	Overdose due to labeling confusion
Octreotide Acetate Depot (Sandostatin LAR)	Ileus
Oxycodone Hydrochloride Controlled-Release (Oxycontin)	Drug misuse, abuse and overdose
Perflutren Lipid Microsphere (Definity)	Cardiopulmonary reactions
Phenytoin Injection (Dilantin)	Purple Glove Syndrome
Quetiapine (Seroquel)	Overdose due to sample pack labeling confusion
Telbivudine (Tyzeka)	Peripheral neuropathy
Tumor Necrosis Factor (TNF) Blockers	Cancers in children and young adults

That’s it. That’s all you get. No numbers of reports and no nature of the seriousness of the adverse events reported.

So back to Revlimid. The drug was associated with reports of the serious skin rash Stevens Johnson Syndrome. As you may recall, SJS was the reason the COX-2 inhibitor Bextra was taken off the market.

We’re not doctors (we don't even play them on TV), but two observations which should quell any investor jitters based on the very little we know so far.

First, if you’re taking Revlimid, a drug used for MDS and multiple myeloma, the potential for SJS is likely the least of your concerns. Second, Revlimid carries one of the most comprehensive, thorough risk management plans (RevAssist) of any drug on the market managed by a company that revolutionized the efficacy of risk management plans for thalidomide, arguably the most dangerous drug ever marketed. If there are more cases, FDA can rest assured RevAssist will catch them.

So what do you think? Is this quarterly list a good idea or a bad one? Are we getting in too deep and too early when it comes to FDA’s postmarket responsibilities? Per usual, we’d love to hear your take.

Miscommunicating Risk (Part 2): The Byetta Disconnect Continues...

Byetta's back in the news, and once again not in a good way. "Amylin Reports Four Additional Deaths With Byetta" is how Reuters has it.

As we wrote last week, the Byetta experience underscores some fundamental challenges facing the industry (and investors) in the new era of drug safety. This is a case where there seems to be a big disconnect between the seriousness of a safety issue from the regulatory perspective (where a safety "update" by FDA treated two deaths from pancreatitis as important information for prescribers, but not a call to action) compared to the reaction of investors ("The sky is falling!").

But, whether or not FDA intended to sound the alarm about Byetta, the stock market reaction made pancreatitis a big story. Or, put another way, the sky may not be falling but Amylin's stock price certainly did.

Now, a week after the news broke, Amylin tried its hand at communicating safety information, hosting a teleconference to offer "context" for the FDA safety update.

That included the news of four additional case reports of Byetta patients who experienced pancreatitis and died. For analysts on the call, though, that "news "sounded like a non-event. Amylin carefully explained that those four deaths, though all associated with pancreatitis, were already reported to FDA, before the agency issued its recent safety "update" on the GLP-1 anti-diabetic. In other words, the agency agreed with the sponsor that they weren't worth talking about publicly. In three of the four cases, Amylin says, it has obtained case reports that support the view that the cause of death was unrelated to pancreatitis or Byetta. In the fourth case, Amylin says it has been unable to obtain any additional information.

Amylin also discussed the deaths in the broader context of outlining the overall risk of pancreatitis seen with Byetta (about 1 in 3,000) and the more severe hemmorhagic/necrotizing pancreatitis that triggered the latest alert (less than 1 in 10,000). And, the company says, there is no indication whatsoever that the rate of pancreatitis associated with Byetta is any higher than the expected rate in the overall patient population.

Well, Amylin shares are down again today (as are marketing partner Lilly's).

This raises two more questions in our minds for others in industry to ponder as the new drug safety era takes shape.

(1) FDA recognizes that it needs to do better when it comes to risk communication. But do sponsors?
(2) In a world where the line between partner and prey (cf. Roche/Genentech, Bristol/ImClone) is always fuzzy at best, how does "Safety First" volatility affect the stability of partnerships?

Amylin's investors haven't been shy about voicing their feelings that FDA is being unduly alarmist about the pancreatitis issue. (And, privately, we've heard the same thing from executives who work for the sponsors.) But this is a case where FDA issued safety information in about the least alarmist way it could have--short of keeping its mouth shut.

And if you think keeping its mouth shut is an option for FDA right now, you haven't been paying attention.

But what about the sponsors? The question that begs to be asked is why Lilly and Amylin waited a week to hold a conference call. Analysts who put that question to Amylin say the answer was that the company didn't want to upset FDA by appearing to challenge or contradict its safety communication. (And in holding the call at last Amylin carefully avoid doing so.)

Our response to that objection is: what would an angry FDA do that is worse than what is already happening to Amylin? The stock was down 20% and investors are starting to write off hopes for Byetta LAR.

Still, if Amylin and Lilly were afraid of annoying FDA, then why hold a call at all? The delay made the issue seem ominous. Just the scheduling of the call caused Amylin shares to fall. Then the company said very little that isn't already in the public domain about the context of pancreatitis--and apparently by failing to offer anything new its reward is to see another stock price decline.

We don't claim to know the right way to manage investor communications about these kind of emerging safety issues, but we're pretty sure this isn't it.

What we do know is that sponsors have to prepare now for how they are going to handle a circumstance like this. Amylin and Lilly may have been caught flat-footed by the reaction to the FDA safety notice, but that is no excuse. In today's world, the news could just as easily have been sparked by an international regulator, or by a prominent academic (say, Steve Nissen has been quiet lately hasn't he?), or in the favorite phrase of former FDA deputy commissioner Scott Gottlieb, by any 18 year old with a computer and access to Wellpoint's database.

Our modest proposal for a better way: why not hold this conference call before FDA issues a safety update? It would take a brave sponsor to do that -- in effect announce to investors that it has submitted six fatality reports to FDA. Still, in hindsight, we bet Lilly and Amylin would be better off right now if that was the approach they took.

Which leads into the second issue, since an effective communication strategy presumes that the two sponsors have the same objectives in mind.

Viewed from the standpoint of the Byetta brand team, there is no doubt that the partners' interests are aligned and this safety scare is a huge problem.

But what about from a strategic perspective? The Roche/Genentech deal has already triggered speculation about other biotech buyouts to come, and Lilly/Amylin is on everyone's list of possibilities. Lilly, remember, already showed its willingness to go down this path when it bought its Cialis partner Icos.

If the market is overreacting to the pancreatitis issue, Lilly can do more than just assert its confidence. It can put its money where its mouth is and buy Amylin out. It wouldn't be cheap: Amylin is valued at just under $3 billion. But that is less than half its value a year ago before the pancreatitis issue first emerged.

Then there is this: a new posting on ClinicalTrials.gov showing that Lilly is moving its own GLP-1 agent into Phase III. That certainly got investors' attention. Does Lilly think it has a better product than Byetta?

(Lilly may even have an extra incentive to buy Amylin: according to our Strategic Transactions database, the Byetta contract includes "option compounds" in both Lilly's and Amylin's pipelines to which the partners have reciprocal rights. While the names of the compounds and the option periods have been redacted out, our bet is that the "option compounds" represent possible competitors to Byetta. So if Amylin has got any claims to Lilly drugs -- maybe indeed this Lilly-discovered GLP-1 -- then Lilly would have some extra incentive to buy out Amylin now).

We don't pretend to know Lilly's plans for its Amylin partnership, but we do know that the challenges of mastering risk communication aren't any easier when there are two sponsors involved.

Miscommunicating Risk: The Byetta Disconnect

First things first: we have no idea how serious the risk of pancreatitis with Amylin’s type 2 diabetes agent exenatide (Byetta) really is. Nor do we pretend to be able to guess how the brand will be affected commercially in the hypercompetitive diabetes market by the report of two deaths associated with the drug.

But this we do know: there seems to be a disconnect between the level of warning that FDA chose to issue for Byetta and the size of the financial market’s reaction. And that disconnect underscores an ongoing, critical issue facing the entire pharmaceutical industry in the world of “Safety First” regulation: how to communicate a risk associated with a product without scaring patients that could benefit.

You have to give the Food & Drug Administration credit for diagnosing the problem. The agency is the first to admit that it simply doesn’t know the best way to meet the public demand for transparency in regulatory actions—especially anything involving safety—without needlessly scaring patients, confusing providers, and sacrificing its ability to speak authoritatively on behalf of the public.

That, in a nutshell, is why the agency formed a new advisory committee on Risk Communication in the hopes of bringing a little science to the question of how best to warn consumers about emerging and inherently uncertain safety issues.

Based on what happened to Amylin yesterday, it’s safe to say there is still a lot of work to do.

In case you missed it, FDA issued an update for health care professionals on August 18 about the risk of pancreatitis associated with Byetta. FDA and the sponsors (Amylin and its partner Lilly) first alerted prescribers to the risk back in October, citing 30 reports of acute pancreatitis associated with the brand.

The update cites six new, more serious cases reported since then, involving what the agency describes as “hemorrhagic or necrotizing pancreatitis.” All six cases led to hospitalization, and two patients died. In light of the apparently more serious reports, FDA says it is working with Amylin and Lilly on stronger warnings and advises discontinuation of Byetta when there are any signs of pancreatitis in the meantime.

Amylin’s investors certainly think that’s a big deal: the company’s shares dropped 15% almost instantly on the news, stayed down to the close, and opened even lower today. You can't blame investors for being skittish. Byetta is a huge product for the biotech and has already been struggling a bit commercially. In this climate, the impact of even uncertain safety risks can be dramatic. (Remember Vytorin?)

Last but not least, the issue certainly raises more questions about the regulatory prospects for Amylin's long-acting version of Byetta. (We have written previously about why we think Byetta LAR could benefit from the focus on cardiovascular outcomes for type 2 diabetes products--but if there is some reason to suspect the long-acting version is worse for the pancreas, all bets are off.)

But here’s the thing: FDA chose to disclose the new information about Byetta without much fanfare, simply posting the update on its “MedWatch” drug safety page, with a prominent link on the “What’s New” column of the Center for Drug Evaluation & Research’s home page. The agency did not issue a press release, a formal public health advisory, or host a media conference call, the way it does in other cases where it wants to amplify its warning.

In fact, we first heard about it from the ever vigilant David Kliff, whose Diabetic Investor issued a note at 1:45 pm—by which time the sell off was well underway. (For the record, our copy of the alert via FDA's email list serve arrived at 2:52 pm.)

In other words, Wall Street’s reaction is driving coverage of this particular drug safety issue—not the public health judgment of the regulatory agency. Think about it: if Byetta happened to be sold by a privately held company, or exclusively by a global Big Pharma where it was not the exclusive focus of investor attention, the media coverage would certainly be much reduced.

Again, we don’t claim to know the right outcome here. Maybe it’s best if everyone stops using Byetta altogether. Maybe it’s best that no one stop. But it seems safe to bet that more people will be aware of this risk than would have been without the Wall Street reaction—and that means the impact of the FDA warning will be larger than the agency might otherwise have anticipated.

You don’t have to be an Amylin investor to think that may not be the best way for risk communication to work.

FDA’s Risk Communication Advisory Committee: An Ineffective Beginning

If you’re an executive for a company with an FDA-regulated product, the agency’s inaugural Risk Communication Advisory Committee meeting had to make you a little nervous.

Granted this was the first time the group was brought together so you’d expect some wandering by the committee. Still, there was a lot of wandering. And the last thing the industry or the agency needs is more unknown variables thrown into the risk communication equation. From the hour-long introductions on the first day to the back-and-forth open public hearing portion of the meeting, the committee was like a Super Bowl half-time show gone bad. There appeared to be little focus on any particular area of discussion and much of the conversations between panelists lacked meaningful direction—a telltale sign of a bad committee.

Here’s the issue for biopharma companies: FDA typically follows advisory committee recommendations, although they certainly aren’t required to. With a committee this inexperienced and seemingly unfamiliar with FDA regulations, procedures and protocols, how will their opinions be interpreted into final risk communication decisions? How will the media report recommendations from a newborn committee that may be clearly out of whack with FDA standard procedures?

The Institute of Medicine’s report on drug safety called for the creation of a risk communication advisory panel similar to FDA’s other scientific drug review committees except focused on how FDA should best communicate safety and risk-related issues to the public.

In other words, how to alert the public without alarming them. To read our initial story on the new committee, click here.

What FDA, and the drug industry for that matter, really requires from this committee is a strong group of advisors to provide practical guidance to FDA on how to address risk concerns quickly, proportionally to the risk presented with new information emerging continuously. If the inaugural meeting serves as any guidepost, FDA won’t be getting that guidance.

The agency has had a mixed record recently dealing with these types of situations. In May, FDA was criticized heavily for reacting too slowly to the publication of meta-analysis data on GlaxoSmithKline’s diabetes drug Avandia showing more than a 40% increased risk of heart attack associated with patients using the drug. In fact, the House Committee for Oversight and Government Reform was able to announce a hearing before FDA could even respond to the analysis with a press release or conference call. We all know how that turned out.

Then there was a rather awkward “early communication” call in August with the media over potential cardiovascular risks linked to AstraZeneca’s blockbuster proton pump inhibitor Nexium found in two small studies. But after discussing the possible risks uncovered by the trials, the agency said on the same call there were no risks related to Nexium. “FDA has concluded preliminarily that these data do not suggest an increased risk of heart problems for patients treated with either of these products,” Center for Drug Evaluation and Research associate director for safety policy and communication Paul Seligman said.

The Nexium communication was followed by a January “early communication” briefing by FDA on Merck/Schering-Plough’s ENHANCE study of the cholesterol combo drug Vytorin almost two weeks after data from the study were made public by the companies and commented on at length by cardiologist Steve Nissen in the mainstream media.

On the call, FDA officials summarized the results already made public by Schering-Plough, and said it would review the data fully once it is submitted by the sponsor. To read a recap, click here.

The risk communication committee is supposed to help FDA avoid situations like that. What the agency appears to have on its hands, though, is a motley crew of experts with very different fields of expertise who don’t necessarily fit together or fit the purpose they were meant to serve—at least based on the initial two-day meeting.

The purpose of this first meeting was not to make specific recommendations on a specific product or issue but rather a more general discussion of risk communication. So there will be wandering. What should be alarming to drug companies, however, is how pronounced the absence of direction was during question and answer sessions and the level of inexperience displayed by individual panelists.

FDA senior risk communication advisor Nancy Ostrove explained in her overview presentation to the panel that this particular committee is supposed to be different. But in this case, different does not necessarily mean better.

The open public hearing encapsulated how the two-day meeting went. A free-lance reporter spoke endlessly (public speakers are generally given five minutes to make a statement during advisory committee meetings, this went way over) about how reporters used to be able to interact directly with FDA officials but now must go through the press office to seek permission to speak with an official and often aren’t granted access. Committee chairman Baruch Fischhoff, Carnegie Mellon, and other panelists engaged in a prolonged Q&A session with the speaker. It was painful.

Not everything was bad. FDA assistant commissioner for accountability and integrity William McConagha delivered a clear and important presentation on legal authorities and protections related to the First Amendment and communicating risk. One interesting suggestion to come out of the meeting from consultant Steve Gorelick, Hunter College, was that FDA hold a daily media briefing similar to the Pentagon.

All in all, though, the first risk communication panel meeting was a dud. Although it takes time for FDA advisory committees to develop personality and voice, this is one committee that won’t be afforded the time to do that. With arguably unprecedented public scrutiny of FDA and the next drug safety event around the corner, the agency will need to mine the expertise of the panel—sooner rather than later.