This is what he has to says about preemption:

“And when the attorneys generals of all 50 states sought to investigate subprime lending, believing that some lending practices might be toxic, we were blocked by a coalition of the major banks and the Bush adminisitration, which invoked a rarely used statute to preempt states’ ability to probe. The administration claimed that they had the situation under control and that our inquiry was unnecessary.”

Salmon

According to what has come out, it appears to be a classic case of “camoflage” compliance. A special way of counting was devised apparently to minimize the signficance of these events in the data submitted to FDA. The way of counting is indirectly referred to in one obscure bit of a 400 page document.

You be the judge.

Must have spaced out. I was looking at the last table. I have to agree with your statement that the numbers may reflect a couple of major drugs. It could also be a true trend due to increased awareness. We don’t know without a lot more details.

I can’t remember how many drugs (different chemicals) there are on the market however it’s well over 1000. However there are only about 200 or 300 widely prescribed drugs.

Considering that there were 17,000 in 2005 right after Vioxx became public and about 50 K for the remaining years from 2000 - 2006 and also a big hump from Zyprexa we might ordinarily be talking about 5 - 7 K lawsuits filed per year. Of course it can’t be distributed evenly across drugs. From what I’ve read the ones with massive numbers of suits are largely ones where the toxicities were especially egregious and companies and even FDA hid them.

When you consider drugs like Seroquel having a fes hundred lawsuits and similar drugs like risperidone having resulted in the reported deaths of well over 1000 people (likely 10x more in actuality), the number of lawsuits is likely an underreflection of the true harm being done.

I personally wouldn’t be surprised if there has been a true increase. My impression is that Pharma is putting out more and more dangerous drugs simply because they need to in order to maintain sales figures. Plus FDA has been talking the past several years about making people aware that drugs are dangerous and they should get used to it.”We can’t call a drug that kills 1 in 10,000 people toxic” Even though that might mean that 1 in 1000 are seriously maimed and 1 in 100 are have a related injury. It is also my impression talking to lawyers that they are more aware of bringing lawsuits against pharma.

I’m not one to bring lawsuits. I’ve been seriously injured myself through the negligence of others and even though I could have brought a nonfrivolous lawsuit I didn’t. I still have problems with preemption. If you read a previous post of mine you’ll see I believe the evidence suggests that Lilly marketed Zyprexa intentionally to the elderly off-label even when they knew the FDA turned it down for this indication because FDA felt it was too dangerous. Plus they also hid the diabetes. Now it looks to me like they’re going after off-label sales to kids when it may kill and maim in this group also and they likely know it. We need some way to reign repetitive behavior like this. Unfortunately lawsuits may be the only way. Show me that the FDA can really do what the people who want preemption says it does, and show me a way that you can reign in actions like I describe.

I’m not so sure that Health Courts are the way to go. Professionals are more likely to dismiss injuries as they become immune to them, you can see this by simply showing specialists AEs in their own field and in other fields. Plus the experts under the Daubert rules are typically made experts by manipulations by the pharmaceutical companies. Believe me I’ve seen it.

There is no perfect system, but I think that preemption will only make the current system worse.

It would be a very interesting graph and one that I would think should be known, published and examined often.

It is also inexcusable in this day and age that one would have go hunting for such information.

When people’s life, health and wellbeing are at issue we shouldn’t be debating which numbers are correct or even where and how to find them.

Happy hunting, if I find any data that I think might be valid, I’ll let you know.

That’s not the case at all. Read it carefully and here’s the numbers I gleaned:
-There were 17,027 lawsuits filed against pharma in 2005. (more than 5x the number for any other industry)
-There were 6000 lawsuits filed against Wyeth for Premarin “in recent years” (not 2005)
-Between 2000-2006 there were ~65,000 lawsuits filed against pharma
-There are still 14,000 outstanding lawsuits for Vioxx alone. (as of when this article was written)

I’ve been looking for more recent numbers, but haven’t been able to find them. In all fairness, I agree that these numbers may reflect a couple of major drugs (Vioxx, Premarin among them) rather than a true trend. Also, it would be interesting to plot # of lawsuits alongside the total drug usage. As drug usage skyrockets (as it has), it would make some sense that lawsuits would also skyrocket. Unfortunately, these numbers seem very hard to come by. (probably because they are handled state-by-state rather than nationally)

The vast vast majority of these cases are against premarin, prempro. This drug has been on the market since the 1940’s and breast cancer is extremely common (1 in 7 women) no wonder there is a lot of potential cases here.

As for the other drugs actually I’m amazed at how few there are.

I’m not sure that a single drug that’s an exception proves a rule.

Salmon

I may not have been clear, but you made my point for me. A single hydroxy group can totally change the effect of a drug. For those of you who don’t know sufentenil is Viagra. It was originally developed to treat pulmonary arterial hypertension (I don’t know the proposed mechanism offhand) however it was found to induce erections as a side effect. The PAH indication was put on the back burner until recently (Good move if you think this orphan indication may soon explode as a generic would not be able to be reimbursed for this indication under Medicaid if there’s another version of the drug from Pfizer approved for it with exclusivity.) However since PAH can be caused by stimulation of 5HT2B (the mechanism of Phen-Fen’s toxicity) it’s possible that viagra actually downregulates this while the hydroxy might actually stimulate it. Thus ‘herbal viagra’ might be exceptionally dangerous. This is speculation on my part but my point as CRH also points out is that a minor change in a molecule can have huge consequences.

Now I want to discuss something that I’ve been alluding to but I am not going to talk about my concerns explicitly and how I came to them.

About a year ago for my own sake I decided that I needed to get up to date on the new antipsychotic medications. I used to know antipsychotics in depth nearly 25 years ago so I started to build all sort of comparison tables, indications, receptor binding, study designs, toxicities, kinetics, etc.. Then last April I was talking to a colleague from one of the big Pharma companies about the atypical antipsychotics and how I needed to bone up on all the different serotinin receptors. He encouraged me and I said maybe some day I’ll get around to it. Well instead that night at home I did take a look at them and what the different receptors did and it refreshed me on 5HT2B Phen-Fen aortic valve stenosis, PAH and all the symptoms and complications. As well as all the effects for the other serotonin receptors. A few days later I decided to start working again on my knowledge of the different atypical antipsychotics and since I had gotten as much as I could from the labeling. I decided to look at the summary basis of approvals and decided to start with olanzapine (Zyprexa) (you can look it up yourself on http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/). As I was going through it I noticed the warning letter on PAH and then as I tried to make sense of the SBA. I found a number of things.

Paul Leber who was the Director of the Division of Neuropharmacologic drug products at the time wrote a very strange memo to the file talking about how toxicities in the 3 different cohorts may be different and that this might become apparent post marketing. I then tried to figure out what these different cohorts (groups) were but they were often redacted. Also there was an indication that was not approved but was also redacted. From the list of phase III studies it became apparent that the 3 cohorts were adults, children, and the elderly with psychosis related to dementia and this last cohort was probably the indication that was not approved. There were also an exceptional number of cardiovasculat deaths and toxicities in this group, but it was explained away as being simply that they were old. (However I was looking at this after the off-label push of this indication by Lilly and the black-box warning not to give it due to the risk of CV death and stroke (stroke with antipsychotics is thought to be related to serotonergic effects on platelets among other mechanisms.)

As I went through the SBA I found a number of symptoms that could potentially due to 5HT2B stimulation including a neonatal death, (just like the warning letter.)

Then if you look at the metabolism of Zyprexa 80% of the circulating radioactivity from a mass balance study isn’t identified. Which leads to the question of what other metabolites are there that Lilly doesn’t want anyone to know about. Then there’s a figure of the metabolic scheme, but it doesn’t include a 7-OH metabolite that’s mentioned in the text that’s formed by CYP3A4. Yet hydroxylaton at this position would be expected to be the most facile metabolic route and it and secondary metabolites such as sulfate, glucoronide, or even methylated metabolites via COMT would be expected. Then Lilly clearly used the lowest possible dose of carbamazepine and incredibly potent inducer of CYP3A and claimed that the entire decrease in olanzapine was due to effects on CYP1A. Then in clinical studies for adjunctive treatment of bipolar disorder they studied other drugs in combination but not carbamazepine but still got an indication for combination with all other drugs used for bipolar. (this is a way to avoid finding side effects due to a drug interaction if you really expect one.)

If you look at the receptor binding they talk about inhibition or binding of various 5HT2 receptors that are very close to 5HT2B but don’t mention 5HT2B or whether agonism was looked at yet the experiments will always tell you if there is upregulation or down regulation, but they don’t mention it, and they don’t mention many different 5HT receptors. Plus they clearly don’t mention effects of various metabolites. (If you look at other atypicals it’s the same with varying reporting).

There’s simply too much information missing and according to the FD&CA it’s clear that Zyprexa should have been turned down for lack of information. Companies are supposed to provide all safety information to FDA, however in a case like this it they suspected something what they could have done is examined other backup compounds in development or clozapine itself and looked at activity of metabolites on 5HT2B, yet they would never have to report any of this to the FDA.

For many similar drugs from the past there’s a history of severe reactions when given with a MAOI, which would result in a buildup of a 7-OH metabolite

According to the SBA Safra Ibrahim was the reviewer of this metabolism data. I know Safra and she wouldn’t have the right experience to have picked up a problem but even she was concerned about the lack of information on the metabolism.

Also Lilly only studied Symbyax (Prozac and Zyprexa) for bipolar depression for only 8 weeks whereas standard study periods for depression are always 12 weeks. However with phen-fen 30% of people had symptoms on 2D echo after 3 months (and symptoms began to become apparent). I also knew that Indocin is used to treate Patent Ductus Arteriosus and they Vioxx tends to cause the symptoms with the opposite effect and they become apparent largely after a year.

Looking at a similar compound clozapine I found lots of black box warnings on the same side effects as Zyprexa including heart attacks and RBBB which all can be secondary symptoms of PAH and 5HT2B stimulations.

I then did a search on PAH and found the symptoms of carbegoline and pergolide associated with 5HT2B stimulation was the same as the constellation of symptoms with clozapine and olanzapine.

I now strongly suspected that Zyprexa is another Phen-Fen and it was being intentionally promoted off-label for children, but that the phen-fen like toxicities may take a long time to show up.

It’s recently been reported by Pharmalot that Sen Grassley’s office released info that 1% of all children on Medicaid are on antipsychotics.
Even if this was only children from 6 - 18 yo this would be 1% of ~60,000,000 (5,000,000/yr). Yet since mania and schizophrenia are each 1% of the adult population and don’t tend to be diagnosed until 18, 19, or more so the early 20’s and the younger you go the more rare the diagnosis is (it’s even rare at 16 yo) to have 1% of all kids on these drugs points to incredible amounts of misuse even if you believe that it’s appropriate and can diagnose these disorders in children as the usage is likely concentrated in the older kids and so over time may easilgy grow into several % of the pop. These drugs are also now being prescribed off label for bipolar II (hypomania and even being promoted by NIMH for kids with ADHD who have temper tantrums (it might eventually be bipolar and maybe we can prevent it) What if it’s like antidepressants where it only works in the more severe cases) then you could get an indication in mania but including a lot of hypermanics in the study even if it doesn’t work in mania. Plus they’re being studied for bipolar depression (2.5% of the pop) quicker onset of antidepressant activity (5%) of the pop, and even GAD another 3 -4% of the pop. For adults the median duration on an antipsychotic is 3.7 months but a child has forced compliance. So several years down the line from now we might be looking at several % of the pediatric population being treating with drugs that if given long enough might cause permanent cardiac problems in nearly everyone who takes them. It this is the case then if I was Lilly’s CEO I would be concerned about lawsuits just like he said he was back in 2004.

When you look there’s also evidence that cardiac toxicity with Zyprexa may be a class effect, with different degrees of severity for different drugs. Right now this is a hypothesis but it can be easily examined. However how are we going to get the information?

There’s other things also. We know that Lilly hid the diabetes yet when you look at the PDR for the very first year they put advertisements for diabetes education of their drugs right after Zyprexa. (Believe me the placements are carefully thought out). Plus there was a lot of hepatotoxicity especially if people also had a history of viral hepatitis, which is now a standard exclusion criteria in studies. Then after approval Lilly published and article about an N-formyl metabolite that they don’t mention in the SBA. They would not have gone back and done another mass balance radiolabeled drug study to do this so they had to have had this information prior to submission of the NDA and didn’t report it. (A friend told me that Pfizer did the same thing with ziprasidone and there’s some very interesting side effects and possible structure activity relationships regarding toxicities with ziprasidone and some other drugs. Getting back to this N-formyl metabolite it reminds me very much of both Vertex’s and Schering’s drugs for treating viral hepatitis.

To all the preemption folks when drug companies don’t look into things there’s usually a reason. It looks to me like Lilly was definitely trying to hide something. Plus you have to realize that maybe 5 people at FDA are reviewing a drug and each person has to cover a half dozen specialized fields and it’s likely that they may not know very much about a couple of them. So it’s relatively easy to pull a fast one past the reviewers, even without all the tricks that have been described. It’s only the super-overeducated and experienced reviewers who even have a chance to pick up on things.

As an example look at troglitazone (Rezulin) it was pulled from the market for being hepatotoxic but only after 3 different medical reviewers were harassed and 2 of them lost their jobs and went public. Yet if you look at the original labeling it says right in there that it’s metabolized to a quinone, and quinones are incredibly reactive. In fact the hepatotoxicity of tylenol is due to a semi-quinone. So it’s very likely that Warner Lambert knew that this drug was very likely hepatotoxic even before they saw their first case. Yet no one at FDA picked up on this due to a lack of expertise of the pharmacologist and pharmacokineticist who worked on the drug and they even put the mechanism right in the labeling without even knowing it. Yet to the company with multiple experts looking at it for years and having the clinical data they probably knew but just kept their mouths shut and hoped FDA would overlook it like they did (except for the medical reviewers who were then forced out.)

Interesting also to hear from Lars Noah, who is a committed critic of the tort system. His comment that pharma is “in tobacco-land in terms of how much people hate it” should certainly give pause, as well as his view that none of this impacts development of new drugs (which the Chamber of Commerce person contests).

Read this article from USA Today, then we’ll talk. There *IS* an explosion of lawsuits. We can debate the reasons — but there is no denying an increase in numbers.

http://www.usatoday.com/money/industries/health/drugs/2006-08-23-drug-lawsuits-usat_x.htm