Provenge Activists Lose Court Appeal

This tangentially relates to the preemption discussion in the other thread. As I indicated, the FDA's decision is viewed as final and authoritative when it comes to drug approval. For whatever the reason, the FDA decided that the evidence does not support approval of this drug. The verdict is final and authoritative. From what I understand, this is the second or third time that a court has ruled the FDA's decision cannot be challenged. The drug company (and hence patients) are stuck with the decision of the FDA.

Yet, when it comes to marketed drugs, the FDA's decisions are NOT viewed as authoritative. Consumers regularly challenge the FDA's decisions via a lawsuit against pharma all edging inadequate warnings, etc. Yet, the FDA deemed that the warnings WERE adequate.

Does it strike anyone else as being inconsistent enforcement? Either the FDA has complete authority for drug approval or they don't. The courts seem to want it both ways: They completely trust the FDA's decisions in the pre-launch period, but they second guess the FDA's decisions in post-launch periods. It needs to be one way or the other. As I said before, when a drug is rejected by the FDA, the pharma company has NO rights for an appeal. Our only hope is to resubmit the data package with new clinical information or new analysis -- which can take years and tens of millions of $$.

Yikes. No need to repeat same discussion as elsewhere. I would recomment other thread - all these question are explored pretty thoroughly.

Nathan's comment that

"when a drug is rejected by the FDA, the pharma company has NO rights for an appeal."

is simply false.

Drug companies have very clear rights for appeal that are spelled out very clearly in the Food Drug and Cosmetics Act and federal regulations. However it first requires a final decision to be made by the FDA. So far the FDA has not made a final decision but has instead asked for more information. Once a final decision has been made then the company can appeal above Dr. Pazdur and if they still don't like it they can then go to court for judicial review.

The fact is they've jumped the gun and haven't gone through the normal appeals process. This appears to be why the linked judgement indicates the case is "unripe".

As for safety issues even then citizen's petitions have to wait until after an unsafe drug has been approved, safety issues have been ignored and people have died.

The company and patients may not like it and they may even be right in their complaint and in what they're asking for, but like it or not the process still needs to be gone through. More righteous causes have been derailed by 'the process' being too long and onerous. Unfortunately that's the way the game is played and unless they can get Congress to rewrite the laws for appeals then the court is right.

Nathan's complaint that a pre-approval appeal process doesn't give them the same rights as a post-approval appeal process is simply barking up the wrong tree.

This case is another reason why I believe that the laws regarding the content and format of complete response letters along with the letters themselves and the safety and efficacy data and complete reviews need to be made publicly available.

Salmon although you are correct that companies do have some rights/appeal recourse there is a practical matter of how far do you think a company is going to get in future any applications, especially if they succeed in getting FDA over ruled?

The present laws do not restrict companies who get CRLs from publishing the full contents of FDA communications (only FDA can not make public) but again there are practical/business reasons to withhold all the details that typically come into play.

I actually think that companies will get quite far in the future, however it depends on the company and how much political clout they have as well as their connections inside FDA.

It certainly doesn't seem to have hurt Wyeth or Merck that they worked hand in hand with FDA management to attack and retaliate against reviewers. Plus the ex-CEO of Wyeth just a few months ago suggested suing over the nonapproval of bifeprunox, so he certainly thinks it's worth it.

On the other hand although smaller companies may not get a fair shake I know a number of cases where smaller companies have blown their size out of proportion in order to simply get their products on the market when they don't deserve to be. For example Cephalon claimed in the NYTimes in Sept 2006 that FDA prevented approval over a simple rash, then low and behold 11 months later FDA places a bold warning in the labeling that it shouldn't be given to children as it causes Stevens Johnson's Syndrome. In fact if you watch the publically available video of the advisory committee meeting you can see the company changing what they were saying every few minutes depending upon what evidence FDA presented. This is clearly in my opinion a case of a company trying to manipulate public opinion.

I also believe that if an individual reviewer were to hold it against a company that the reviewer would probably be forced to leave FDA. Look at what happened to the medical reviewer John Guergian (sp?) simply because he got a little hot under the collar at a meeting with Glaxo over troglitazone and he was eventually vindicated.

You are of course correct about it being up to the company to make public the CRL and whether it's in their best interest or not. That's why I think that making not only the CRL but all safety and efficacy information public will help level the playing field for everyone, and if the company truly has a valid case then there's no reason they shouldn't make the information available in this case. However, regardless of what happened with the AC meeting due to the scheduling of these meetings safety or efficacy issues could have surfaced afterwards that we're unaware of.

I don't know whether Provenge has a valid claim or not. I've seen numerous cases where companies simply see patient advocacy groups as suckers and use them to help the company make a buck. On the other hand, as I alluded to in my previous post I don't trust FDA either in this case.

I believe that others also lack trust in both FDA and companies. FDA needs to be considered trustworthy and this and other cases should illustrate the need for a complete house cleaning at FDA and also holding some company executives criminally liable.

Unfortunatley the way the system is designed it can be abused, and right or wrong it's possible that this may be what happened to Provenge in spite of the judge doing the right thing.

Personally I feel for the patients. They're the ones who are paying the price. If they trusted FDA then perhaps they wouldn't feel the need to try to force some sunlight on what is truly going on with this drug.

I believe only time will tell the truth.

Salmon

Just re: the either/or on FDA's authority, it is perhaps relevant to note that, even when there is a version of preemption as in mandated vaccines, it is partial and conditional. That is, it only applies to a dozen or or vaccines _and_ patients retain the right to go to court if they choose to, even over issues with these vaccines.

In general, I think the "either FDA has the power or doensn't" argument is almost always misleading. There are few institutions or agencies that aren't "second-guessed" in one way or other - even the Constitution needs to be interpreted by courts.

Up until the Troy era, the great majority of courts viewed FDA approval/compliance as _minimal_ requirements - a floor, but not a ceiling. The preemption folks have done everything they can to reframe that, and decleare that FDA always knows what is "optimal," makes all the relevant investigations, and has all the relevant data.

A company's liability enters in when that is not true as a result of that company's demonstrable delinquence. This challenges FDA authority not a whit.

As unfortunate as it may seem, the court's decision seems entirely the right one under the law. The agency had not issued it's final ruling on Provenge. Hence, the lack of subject matter jurisdiction. Typically, it's seen as a failure to exhaust administrative remedies before seeking relief in the courts.

That's not to say that the FDA's actions were entirely proper. I don't doubt there was probably some hanky panky.

What's the remedy? Congress can always require more accountability. Or, the agency itself can revise its rules through the normal process of revising the regulations via notice and comment.

Let's hope the ongoing trials are successful and that Provenge is approved.

JIM writes: "Up until the Troy era, the great majority of courts viewed FDA approval/compliance as _minimal_ requirements - a floor, but not a ceiling."

I'll remind you that in some circumstances, there is not "minimal" - it's either "yes, you complied" or "no, you didn't comply". Needlessly adding extra warnings can carry unintended risks. As I've said before, I think that warnings need to be carefully worded in order to adequate warn the affected population while not "scaring away" the unaffected population from the benefits of a life-saving or life-enhancing drug.

So here's a question relating to this: Are you aware of any situations in which the FDA ruled that a pharma company OVERWARNED about the risks of a medication? Or deliberately listed warnings in order to protect against lawsuits? In other words, has the FDA rejected any warnings that pharma WANTED to include on labeling? If I recall, that *seems* to be Wyeth's argument in the Levine case.

Nathan - Your precise question is addressed in the NEJM brief in Levine. You may want to read the section in which they take up the "over-warning" issue directly.

But the short answer is that the brief argues (and I agree) that the over-warning argument is bogus. The few cases that preemptors have repeatedly tried to use to support it (the same three appear in every pro-preemption brief) all had _nothing_ to do with lawsuits. And, even then, they are all questionable about making any point whatsoever re: "over-warning."

So the "scared away" business appears to be entirely mythological.

Re: Wyeth/phenergan specifically, I need to do a 'refresher' myself. From what I recall, there is also mythology that has developed about the company _wanting_ a warning that FDA rejected. Rather, the question had come up _between_ FDA and company a few times (need to reconfirm who initiated those discussions) and was still somewhere "under review" at FDA at the time of Diana Levine's push IV.

As noted, I do think there are more ambiguities in this case than, say, Paxil, fen-phen, Trasylol, et. al., which is why, in my view, preemptors worked toward it being the one the Supreme Court would use to decide wider question.

Nathan appears to be setting up a straw man argument. Look closely at what he asks:

"So here’s a question relating to this: Are you aware of any situations in which the FDA ruled that a pharma company OVERWARNED about the risks of a medication? Or deliberately listed warnings in order to protect against lawsuits? In other words, has the FDA rejected any warnings that pharma WANTED to include on labeling? If I recall, that *seems* to be Wyeth’s argument in the Levine case."

For other than apparently the Phenergan case for anyone the to answer this in the affirmative they would have to be an FDA insider and know of specific cases. Even if the FDA itself wanted to answer this query in the affirmative they would have to hide the drug and the specifics in such a way so as to prevent identification. Otherwise it would be a violation of trade secret laws and the Food Drug and Cosmetics Act.

Salmon

John said, "As unfortunate as it may seem, the court’s decision seems entirely the right one under the law. The agency had not issued it’s final ruling on Provenge. Hence, the lack of subject matter jurisdiction."

My opinion is the lower court and the court of appeals were not looking at this case properly.

1) There are Federal Regulations for processing a BLA and they were ignored in this case. That should overrule the ripeness argument. For if the regulations were adhered to, men would be taking Provenge today. At the very least, Provenge should have received Conditional Approval.

2) If survival is the gold standard and Provenge showed that, FDA is blatantly denying a man a right to live, a constitutional right. There is very strong evidence of survival despite what a few conflicted doctors say. And note, these same doctors have no experience with immunotherapy.

Then we get to how the FDA explains it today. They can't comment on it right now because it is an unapproved treatment. See point #1. If the BLA process was followed according to Federal Regulations and Congressional mandates, the treatment is approved. It passed the Congressional guidelines.

So why doesn't the FDA want to talk about it? The FDA knows exactly what it did here. It used a small group of conflicted doctors to stop a treatment they did not want on the market. Scher made it be known at the Provenge Advisory Committee hearing he was worried about other drugs under development. What? We can't have more than one on the market? For erectile dysfunction men can choose from Viagra, Cialis, or Levitra. Why weren't they permitted to choose from Provenge, Asentar, and GVAX? That is a very huge tell.

After Scher explained why he could not vote for Provenge, because he was worried about other treatments under development, he followed up with that same idea in a leaked letter he signed. Of course we now know he had NCI folks help him write that letter but he mentioned in the Cancer Letter that he was leading a trial for a competitor of Dendreon, namely Novacea. Here's a guy admitting to the world he is passing judgment on a treatment as a member of the Provenge Advisory Committee while he's working for another company developing their treatment. That is another giant tell in this story.

Next, Thomas Fleming wrote a letter and reiterated the same thing. He said Scher couldn't sleep. How did he know? Fleming said he, too, couldn't sleep because he, too, was worried about other treatments under development.

Then Fleming did something very peculiar. He attacked the Spokesperson for the Provenge Advisory Committee, Dr. Celia Witten, and then he attacked immunotherapist, Dr. Franco Marincola, and then he attacked patient advocate, Robert Samuels who is a prostate cancer survivor. And Fleming only used part of Samuels' testimony and not the complete statement Robert made that the patients were aware of the risk and were willing to take it. A third big tell.

The FDA and NCI made sure they hit every angle when they sabotaged Provenge. They disregarded and disrespected prominent immunotherapists on its way to stop Provenge from getting to the men who severely need it and want it. They sided with four people who voted no and who are in with the chemotherapy groups. Three of them refused to answer the regulatory question. Chemotherapy zaps cancer, immunotherapy needs time to ramp up. These chemo doctors were evaluating Provenge like a chemotherapy. It is an immunotherapy! Then they went out of their way to leak deceptive information. This is what the courts should have looked at. Everything else is a smokescreen.

At its basic root, while preliminary studies failed to demonstrate that the drug could slow progression of the cancer, patients receiving Provenge lived an average of 4.5 months longer than patients taking a placebo. Survival is the gold standard!

Now take note of the Federal Regulations Scher and Pazdur, and those who colluded with them, violated to get what they wanted and not what was best for American men:

- They disrespected US Code 18 Section 208 by not checking COIs and by granting waivers and SGE forms without making sure they match up with the applicant's employers, their portfolio and their family's portfolio.

- They disrespected the regulatory question for efficacy as set by Congress.

- They disrespected the 180 day regulation to respond to Citizens Petitions.

- They disrespected FOIA laws by redacting things and not responding in a timely manner as stated by the FOIA. We are still waiting for the documents of Richard Pazdur. What is he hiding?

- They disrespected Advisory Committee laws that say the Chairman of the AC, in this case James Mule, should be at every hearing. We don't see his name in the NCI FOIA documents and e-mails. We don't think he presided over those meetings.

- They worked with the Goldbergs of the infamous Cancer Letter to talk when they are prohibited by law from talking.

The Goldbergs also act like they respect Federal Laws. In their "Distribution Policy for The Cancer Letter" they write, "If you are sending the newsletter to an unauthorized list, please stop; your actions are against Federal law." And on August 5, 2002, look at what the Washington Post said about Paul:

"Goldberg smelled a rat. He knew the FDA was prohibited by law from talking, which left the company free to say what it wanted. He used his long-standing contacts in the cancer research world to get his hands on a letter from the FDA to the company."

So if Paul knew the FDA was prohibited from talking how did he think it was ok for him to speak for them? He gave them a way around the Federal law.

And if Paul knew the FDA was prohibited by law from talking, does Paul agree that that means releasing letters Scher, Hussain, and Fleming wrote to the FDA? And did he use his long-standing contacts in the cancer research world (that wouldn't be NCI would it?) to get his hands on letters the doctors sent to the FDA? Of course, we all now know that included NCI doctors.

Yeah, regulations are nice to stand behind, especially when you are trying to defend the times you ignored them.

The issue being raised by the suit, and by other patients and patient advocates who watch the FDA's cancer division closely, is that the regulatory, scientific, medical and ethical integrity of the agency's approval process for cancer drugs is systemically compromised. Provenge is just a recent and public example of the problem.

The federal courts, unfortunately, have always ruled that FDA cannot be successfully sued by anyone if the subject at issue is how it does its job. This precedent precludes discovery and preserves the black box nature of the FDA. No one outside the agency has a clear view of what is going on inside the FDA.

There considerable evidence supporting suspicions that the approval process was corrupted in the case of Provenge; enough to merit a court review, but the FDA is very practiced at manipulating the courts, and the decision issued in this case is not that FDA acted appropriately, but rather that FDA has not acted at all. Close observers of the FDA recognize this tactic as one of FDA's favorites, used routinely by the agency to avoid review of its actions.

How many people know, for example, that FDA's administrative procedures mechanism that allows a member of the public to seek redress is the Citizen's Petition. FDA avoids review by simply never responding to Citizen's Petitions it doesn't like, without consequence. One can sue the FDA if the agency fails to respond to a petition, but the federal courts have consistently decided that the FDA is subject only to rational basis review, which means they don't have to be doing their job properly or in the best interests of the public, only doing it in a way that bears some identifiable relationship to what they are supposed to be doing.

Of course, terminal patients trying to get a look beneath the FDA's cloak of secrecy usually die before a case even makes it to the first rote dismissal by a federal judge. If the plaintiff somehow gets past that first judge, the FDA's strategy is always one of delay and obstruction, thus running out the clock if the plaintiff is a terminally ill patient.

And it works for them - every time.

Why is the FDA such a confusing, failing ineffective mess? Because it is utterly opaque and unchallengeable. It's course is never corrected because the public doesn't know what it's course is.

So where does that leave us? Congress can investigate the FDA, can issue subpeonas, and can take testimony under oath. In other words, Congress can and should pierce the veil of secrecy. Most of us think that our elected representatives are supposed to know what is going in places like the FDA, and also are supposed to let us in on it.

Given that patients have virtually no court-mediated rights to challenge anything the FDA does, or even to find out what the FDA is or has done in making or not making a decision - shouldn't Congress be all over this?

The FDA is not a branch of government expressly created in the Constitution, it is a regulatory agency created out of thin air by Congress, then progressively strengthened in its reach and power. It is an agency that operates almost entirely out of public view and wields, in the case of the seriously and terminally ill, near absolute power over whether we live or die.

The devil is always in the details, and the details of what we know about the Provenge fiasco are highly indicative of corruption and incompetence.

So in the absence of any oversight by the courts, and any effective or properly targeted oversight by Congress, patients (and not just CTL) are trying to find out what is going on, because the FDA is quite literally, killing us.

Congress was asked once before by patients and several of its own members to investigate the Provenge fiasco and declined - a tragic mistake. They should do so now. At the very least, the drug approval process for cancer treatments lacks integrity and competence, and at worst laws were broken.

So what now? Is the FDA, an immensely powerful bureaucracy, to be immune from review of its actions by the public, the courts and Congress, even when those actions could well be causing the premature deaths of tens of thousands of Americans?

If so, then who are the courts and Congress serving?

Steven Walker Abigail Alliance

Justice -- read Steven's last sentence: "Is the FDA...to be immune from review of its actions by the public, the courts and Congress, even when those actions could well be causing the premature deaths of tens of thousands of Americans?"

That's exactly what my concern is with the current preemption dialog. We don't hear from those people. We only hear from all the people that were hurt by a drug. We don't hear from the people hurt by delays in approval and hurt by inappropriate/excessive warnings. Yet those people surely exist. Do they not? You may not be able to hunt them down and get a signature from them -- but they DO exist. If you believe that drugs help people, then you must surely believe that at some point delays and excessive warnings on drugs can HURT people. It goes hand-in-hand.

Lawsuits represent those that are hurt by drugs. Sometimes they win, sometimes they lose. I have yet to hear of a successful lawsuit from the people (or families) hurt by delays, inaction, or overwarnings by the FDA. There is no compensation for this group of people. They receive no representation at trials and have no legal recourse to the FDA. Essentially, preemption already exists for this group of people. Would you disagree?

Once again, I just think that both groups of victims should be treated equally. They aren't under current law. Under preemption, at least both groups would be treated equally. You could argue (maybe rightly so) that two wrongs don’t make a right. If that’s the case, then we should also be pushing to get rid of the current preemption for this group of people.

Nathan - Can you give me just one example of "inappropriate/excessive" warnings? (And just because people decide that taking a given drug is not worth the risk (whatever it is) does not mean that the warnings were inappropriate or excessive.)

Nathan,

I was not making an argument for or against pre-emption, and the issues here are quite different. I am talking about transparency, not case-specific FDA's in the form of lawsuits filed against drug companies in each state. Those suits would be governed by variable laws and precedents, and mediated by juries and judges that would more often than not lack the requisite knowledge to make good judgments. The obvious solution is to fix the FDA.

My point was that the FDA needs a lot more transparency and a means by which to force that transparency upon it. Why shouldn't the public be able to find out what the FDA is doing and how it is doing it? Lawsuits filed in state courts against drug companies regarding specific drugs would not do that because they would impact law only in the state where the suit was filed, and for the very narrow subject matter of the suit. They would not impact the FDA at all. A state court cannot order the FDA to change.

This is about fundamentally changing the FDA, and the FDA is a federal, executive branch agency. Consequently, the change has to come at the federal level.

Congress has spent a lot of time over the last several years investigating drug safety issues, and the FDA has scrambled under that pressure to make changes. In typical FDA fashion, the changes have been inadequate and crafted to make sure that the change they cause is as minimal as possible (the FDA deplores real change), but scramble they did. After all, Congress holds their purse strings and actually can (but rarely does) impose real change on the agency.

But Congress has done virtually nothing in more than 10 years to assess and correct the much more devastating errors you correctly note FDA has made in denying and delaying the delivery of new safe and effective medicines for serious and terminal diseases. The FDA has become little more than an immensely powerful barrier to progress against disease, a point that most of the media, and most of FDA's higher-profile critics, have ignored.

It is clear at this point that the courts are not going to allow patients to succeed in lawsuits that question the FDA on its aggressive failures to make progress available in a timely and medically correct manner; consequently, Congress must do so because no other entity can.

The post leading to this string was about Provenge, a safe and effective therapy that was improperly handled by the FDA (and certain of its special employees) to the lethal detriment of tens of thousands of cancer sufferers, many of whom have since died, waiting. There is no drug company to sue here in any court, which is what the pre-emption debate is about. Dendreon has acted responsibly, tried to make the drug available by conducting well-run clinical trials, proven to the experts (but apparently not to a couple of bureaucrats at FDA) that the treatment is safe and effective, applied for approval, and is still trying to get the FDA to approve it - at considerable expense and effort.

The problem is the incompetence, unresponsiveness and lack of integrity of the FDA, especially its cancer drug division.

No lawsuit brought in a state court is going to fix the FDA. This is a federal governance issue that falls squarely into the jurisdiction of the federal courts and Congress. The courts have repeatedly declined to allow a review of the FDA's incompetence, lack of professional integrity, and the resulting lethal abuse of power. So we are left with Congress, whose job it is to oversee executive branch agencies like the FDA.

Nothing at all to do with the pre-emption debate. It's about good governance, and while the FDA's problems have become more visible under the Bush Administration, the agency has been spirlaing downward and fostering scientific stagnation and unresponsiveness as its core cultural values, for decades.

At this point only Congress can fix the mess. They have already been presented with multiple opportunities to engage through introduction (twice) of the Access Act in both houses of Congress, and through the call for hearings on the Provenge fiasco. So we need to apply our efforts at reforming FDA and getting to the bottom of FDA shenanigans like the Provenge fiasco, to Congress. Only Congress has the broad authority needed to look into matters like FDA's handling of Provenge, and to dig deeper to find the root causes, then fix them. They have subpeona power, they can obtain documents, and they can take testimony under oath from anyone they wish. In fact, Congress' investigative authorities are less limited than those of courts.

It's time they got started, and finding out what happened with Provenge would be very, very good place to start.

Steven Walker Abigail Alliance

Steven - I understand completely that you weren't making a point about preemption. My only point is that the FDA can hurt people in two ways: 1) By approving unsafe drugs or unsafe labeling 2) By NOT approving lifesaving drugs or by approving excessive and unneeded warnings

We spend a lot of time and energy talking about #1 -- yet very little talking about #2. Both situations cause harm to patients. In my mind, the provenge situations clearly illustrates #2.

Chris, I respectly ask you to thouroughly read the adverse effects reported for Naproxen at the FDA website. (link below) Remember that this is an OTC drug. Then we'll discuss your question.

http://www.fda.gov/cder/drug/InfoSheets/HCP/Naproxen-hcp.pdf

Are you referring to this actual link? If so this is an alert of potential findings, and does not list adverse effects.

Chris - my appologies. I sent the wrong link. Try this one. Remember your question from above: "Can you give me just one example of “inappropriate/excessive” warnings?"

http://www.fda.gov/cder/foi/label/2004/17581s99,100,18164s50,51,18965s9,10,20067s4,6lbl.pdf

I would suggest that this is certainly one of those cases. This is an OTC drug with the following adverse events listed. (long list below) Who in thier right mind would take this drug after reading this material? I suggest that warnings such as the one below have completely lost any relevance to the consumer. They serve only these purposes: 1) Cover the butt of the manufacturer in case of a lawsuit 2) Scare away patients that may actually benifit from treatment 3) "Desensitize" patients from hearing about real side effects.

Quote from the above link: -------------------------------- In patients taking naproxen in clinical trials, the most frequently reported adverse 585 experiences in approximately 1 to 10% of patients are: 586 Gastrointestinal (GI) Experiences, including: heartburn*, abdominal pain*, nausea*, 587 constipation*, diarrhea, dyspepsia, stomatitis 588 Central Nervous System: headache*, dizziness*, drowsiness*, lightheadedness, vertigo 589 Dermatologic: pruritus (itching) *, skin eruptions*, ecchymoses*, sweating, purpura 590 Special Senses: tinnitus*, visual disturbances, hearing disturbances 591 Cardiovascular: edema*, palpitations 592 General: dyspnea*, thirst 593 * Incidence of reported reaction between 3% and 9%. Those reactions occurring in less 594 than 3% of the patients are unmarked. 595 In patients taking NSAIDs, the following adverse experiences have also been reported in 596 approximately 1 to 10% of patients. 597 Gastrointestinal (GI) Experiences, including: flatulence, gross bleeding/perforation, GI 598 ulcers (gastric/duodenal), vomiting 599 General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding 600 time, rashes 601 The following are additional adverse experiences reported in <1% of patients taking 602 naproxen during clinical trials and through post-marketing reports. Those adverse 603 reactions observed through post-marketing reports are italicized. 604 Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual disorders, 605 pyrexia (chills and fever) 606 Cardiovascular: congestive heart failure, vasculitis 607 Gastrointestinal: gastrointestinal bleeding and/or perforation, hematemesis, jaundice, 608 pancreatitis, vomiting, colitis, abnormal liver function tests, nonpeptic gastrointestinal 609 ulceration, ulcerative stomatitis 610 Hemic and Lymphatic: eosinophilia, leucopenia, melena, thrombocytopenia, 611 agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia 612 Metabolic and Nutritional: hyperglycemia, hypoglycemia 613 Nervous System: inability to concentrate, depression, dream abnormalities, insomnia, 614 malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen suspension) 17 Respiratory: eosinophilic 615 nophilic pneumonitis 616 Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis, erythema 617 multiforme, Stevens-Johnson syndrome, photosensitive dermatitis, photosensitivity 618 reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria) 619 or epidermolysis bullosa. If skin fragility, blistering or other symptoms suggestive of 620 pseudoporphyria occur, treatment should be discontinued and the patient monitored. 621 Special Senses: hearing impairment 622 Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, 623 nephrotic syndrome, renal disease, renal failure, renal papillary necrosis 624 In patients taking NSAIDs, the following adverse experiences have also been reported in 625 <1% of patients. 626 Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death 627 Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, hypotension, 628 myocardial infarction 629 Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, glossitis, 630 hepatitis, eructation, liver failure 631 Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia 632 Metabolic and Nutritional: weight changes 633 Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, 634 tremors, convulsions, coma, hallucinations 635 Respiratory: asthma, respiratory depression, pneumonia 636 Dermatologic: exfoliative dermatitis 637 Special Senses: blurred vision, conjunctivitis 638 Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria

(I am probably more familiar with adverse event reports than most.) This is a laundry list of adverse events seen in clinical trials. In this setting, there is no requirement that they even been related to the drug, and thus do not constitute a warning IMO. (BTW - for those not bothering to look at the link, the numbers represent line numbers in the document, not events.) I would refer to the warnings section of the label, not this section.

As usual trial lawyers who have ruined our legal system are at the root of all the problems noted in this discussion. Until and unless our system changes to negate their power the irrational systems that are in place will continue to plague this country and sabotage our way of life and standard of living.