These Drugs Generated Most Adverse Event Reports

Ed, It is being reported that GSK has put out a 30 page rebuttal letter, is this true, and have you seen it?

Wow! This databasing is VERY impressive. KUDOS to ISMP. This is a VERY positive step! There will be many positive spin-offs. The potential to use this data to design new and SAFER drugs has arrived.

What is ISMP's relationship to FDA? to pharma? How is it funded? Is access to the complete database open to the public? Is the database secure? These are spontaneous reports, yes?

Survival and treatment outcomes would also be VERY useful info. Selection bias, underreporting of ADEs, and concomitant medications, are confounding variables. I assume that this data is from spontaneous reports. Its primarily the serious ADEs, drug-drug interactions, survival, and outcomes data, that interest me the most.

Patrons99, You should be able to access the information from the FDA website, be forwarned, the FDA data base is quite the challenge.

A similar database for all-cause mortality and survival benefit (if any) for biologicals, e.g. TNF inhibitors and vaccines, comparing treated versus untreated, would be useful, too. That is, if we can handle the truth.

Although a small amount of people use Gleevec, it ranked 15.

GSK has published a 30 page white paper responding to the story in the New York Times and the report of the Senate Finance Committee. http://www.gsk.com/media/GSK-White-Paper-Avandia-23-Feb-2010.pdf

Oh this rich. Avantia is #1 and Seroquel is #2.

So how about this?: An unknowing patient is drugged up with Seroquel, contracts diabetes from that medication. Which is then treated with Avantia.

He dies from a thousand side effect cuts of both drugs. The perfect circle!

Lisa - here's a link to GSK's white paper in response to the Senate committee report.

and, if you're interested, here's Cardiobrief's summation

Good notice smart patient. Although a small amount of people use Gleevec, it ranked 15th. And of those, most are given it for several months near the end of their life (because of its promise of being a miracle drug for treating GIST), and forced to stop taking it due to liver toxicity or heart failure. The dosage necessary to keep cancer in check is higher than a liver can tolerate. Gleevec will kill virtually anything if used at a sufficiently high concentration, but at what cost, killing the patient?

I agree with smart patient, to truly assess the level of "riskiness", you should look at the rate of AEs and not total AEs. The # of patients taking these products is known within estimation and will change these rankings. Many more patients have taken Avandia than Gleevec.

Thanks Harpy, GSK is better off just offering apologies to the American Public, their snickering doesnt do them any justice.

Keep in mind that these case reports. They need to be considered inm the totality of patient drug exposure. For example, in the VADT and ACCORD trials there were over 20,000 patient years of experience just in these two studies alone. You can't just go by raw numbers.

Pharmavet,.. I, personally, prefer to see raw data.

Steve: BINGO!

Nice work!

~ MB

Oooh, now this is juicy.

Thanks!

Hmmmm. An 8% increase per annum in reported serious, disabling and fatal adverse drug events reported to the FDA. This is the kind of information that needs to be presented to Congress the next time the PDUFA is up for renewal. There is a drug safety crisis in this country. It's not imaginary. It's not just my "passion for this stuff". Hard clinical endpoints: e.g. hospitalizations and deaths need to be independently and meticulously databased. All-cause mortality and survival benefit (if any) should be analyzed. The public deserves relatively safe drugs and biologicals in the marketplace.

I would certainly welcome the legal eagles amongst us to critique this statement:

The seriously disabled and dead victims of adverse drug events were deprived of their right to 5th Amendment Due Process and Equal Protection and their right to 9th Amendment Equal Treatment before Law under the U.S. Constitution. By reason of federal action under color of the PDUFA and each subsequent reenactment of the PDUFA, new drug, device, and biological approvals are “expedited”. Pharma’s payment of “user fees” to FDA are bribes. These expedited new drug approvals have resulted in waves of dangerous drugs in the marketplace and the endangerment, serious disablement, and death of millions of our citizens. Because these waves of dangerous drugs are rarely, if ever, removed from the marketplace, the incidence of reported serious, disabling and fatal adverse drug events will continue to increase. Ever since the initial enactment of the PDUFA in 1992, each seriously disabled and dead victim of adverse drug events has standing in federal court to move the court to declare the PDUFA unconstitutional under the Federal Declaratory Judgment Act.

Where am I wrong?

Disclaimer: I am not an attorney and the viewpoint expressed in this comment is solely opinion and is not in any way intended to represent either legal or medical advise.

HealthQuest radio (WIND Chicago) reported today that Avandia may have caused 80,000 heart attacks! As I recall, Della Reese of 'Touched by an Angel' used to promote the drug on TV ads. For once there was "truth in advertising" -- if you did take the drug, most likely you would soon be touched by an angel! Why are these drugs even on the market -- like the incessantly-advertised Chantix suicide pills? I think we need a TV D-chip to blank out all the ads!

Patrons, before the introduction of user fees, the average approval time for NCE'S was 42 months and there was no effective fast-track mechanism in place for life-saving drugs. We had to run large compassionate use programs for critical drugs due to the long approval waiting periods, and it still didn't get the drugs to everyone who needed it. I remember CHF patients who died because of FDA dalliance, and the fact that FDA limited the compassionate use drug supply. I don't think that a return to the old ways of doing things pre-user fees would be terribly useful to all parties concerned.

I agree that there were good consequences of supplementing CDER's budget in order to expedite reviews. I disagree that PDUFA was the way to do it. By federal agency standards, the 250-300 M that PDUFA contributes is pocket change. The "PDUFA clock," as it was institutionalized, created a "sweat shot environment" as even Janet Woodcock put it. And scientific disagreement was squashed even more than it was, as a number of FDA's own surveys have shown.

In retrospect, PDUFA was a mistake, as even its then supporters (e.g., David Kessler) agree. By whatever standard--16 hours in Iraq; a few hours at AIG; insurange pay-outs for Dick Cheney's heart--we can publicly cover the cost.

(Dan Carpenter of Harvard has shown the the "drug lag" was mythologoical during the years immeediately before 1992 because of the addition of publically-funded reviewers.)

I don't blame the industry, of course. Congress (and I include Sen. Grassley even though Lisa and others will carpet bomb me) has, as always, refused to take responsibility for the agency it loves to criticize.

Pharmavet - I do not dispute the need for compassionate use drug supply, especially in the area of terminal pain and cancer. What I strongly dispute, however, is the need to apply fast track mechanisms to the approval of ALL drugs, biologicals, and devices. This is what has taken place under the PDUFA. It basically comes down to an Equal Protection argument. Not all citizens want or need expedited new drug approvals. For most of us, knowing that marketed drugs bear some reasonable assurance of relative safety, would suffice.

Directly relevant to this discussion is a nuanced study in NEJM that is available to all:

http://content.nejm.org/cgi/reprint/358/13/1354.pdf

Carpenter, et. al. suggest that is specifically drugs approved just before PDUFA deadline where there is a correlation with increased safety issues later--not drugs approved earlier (which happens often enough) or later.

So the issue may not time, per se, but time in the form of deadline. The authors suggest that increased stuffing could solve that issue. Whether that increase should come from PDUFA, or elsewhere, is left open

The pharma lobby has persuaded our lawmakers using bogus economic arguments that expediting new drug approvals under the PDUFA is a societal good for ALL citizens. This is a seriously-flawed assumption. Dangerous drugs in the marketplace have resulted in an increasing incidence of serious disability and death.

Even so few as one seriously disabled or dead victim may have standing to sue in federal court under the “selective enforcement” and “class of one” doctrines. See Village of Willowbrook v. Olech, 528 U.S. 562, 564 (2000). While the principal target of the equal protection clause is discrimination against members of vulnerable groups, the clause protects class-of-one plaintiffs victimized by “the wholly arbitrary act”.

In some instances, even invidiously discriminatory animus can be inferred, e.g. where fraudulent clinical research was involved and/or where a whistle-blower was involved.

Time in the marketplace is driving the entire issue as to serial reenactments of the PDUFA. It is quite literally worth billions to pharma. Illegal off-label marketing begins almost immediately, upon market approval.

Expedited market approvals qualify as “wholly arbitrary acts”, motivated solely for financial reasons. It’s a rigged contest between a tortoise and a hare. Under the PDUFA timelines, the hare (pharma) quite often makes it to the finish line (expedited market approval) long before any regulatory sanctions or formal legal proceedings as to research fraud. Again, it’s all about time in the marketplace. U.S. citizens are being endangered, seriously disabled, and killed by reason of “wholly arbitrary acts” by FDA.

JiM - Thank you for the NEJM citation. I agree with their conclusion. Their methods, however, leave a bit to be desired.

"The indicators of safety problems that we used included new black-box warnings, withdrawals because of safety problems, and dosage-form discontinuations."

They used surrogate endpoints as measures of drug safety, instead of hard clinical endpoints, e.g. hospitalizations and deaths. "Withdrawals because of safety problems" should not be used as a surrogate endpoint because many, if not most, dangerous drugs are not withdrawn. They are left in the marketplace. There are many examples.

There it is- patrons99

99--I follow you, but Ithink deaths and hospitalizations would, inevitably, be a much fuzzier number. I suppose one could use the same fuzzy number to compare drugs approved close to PDUFA deadline and otherwise. If one did so, it would be surprising if the results were different. Perhaps interesting to see.

I know you know this, but black box warnings also mean, by definition, the drug has not been withdrawn. Since 20% of drugs eventually get either black boxed or withdrawn (about 3%), I would be more confident that this is a good way to count.

JiM - a potential downside to the continued use of drug withdrawals (and Black Box warnings) as proxies for drug safety is that Congress will continue to be presented with studies such as that by economists like the University of Chicago's Tomas Philipson at the Milken Institute, and MIT's Ernst Berndt at the Sloan School of Management, the next time that the PDUFA is up for renewal. See Tomas J. Philipson et al., Nat'l Bureau of Econ. Research, Working Paper No. 11724, Assessing the Safety and Efficacy of the FDA: The Case of the Prescription Drug User Fee Acts (Oct. 2005), available at http://www.nber.org/papers/w11724 (Finding user fee regime saves 180,000 to 310,000 life-years at a cost 56,000 life-years).

http://www.opednews.com/populum/print_friendly.php?p=Are-Big-Pharma-and-the-PDU-by-Robert-Davidson-091126-534.html

The really striking number from Ed’s post, is the ca. 8% per annum increase in serious, disabling, and fatal adverse drug events reported to FDA. The relationship of this number to drug safety is direct, not “fuzzy”. On the other hand, drug withdrawals and Black Boxed Warnings are “fuzzy”, not as closely-related to drug safety. Quite often, Black Warnings completely skate around the most relevant statistics, all-cause mortality and survival. For example, if a respiratory drug is really causing primarily cardiac-related, and the ony statistic that is captured is asthma-related deaths, the net effect on drug safety may be completely missed.

I would be interested to know what the effect of the increased number of black box warnings has on drug promotion and advertising. Even before the new PHRMA code, BB warnings had a chilling effect on the number of "leave behinds" a rep would give to a doctor's office. The reason was that these are considered as "reminder ads", and any drug that has a BB warning has to have that warning attached to the ad. Marketeers don't like to have docs being "reminded" of the BB warnings, so they discontinue the leave behinds.

I would also suggest that BB warnings be periodically reviewed for certain drugs in light of updated safety information or medical practice. For example, I ran the levothyroxine clinical research program for a pharma company for a number of years. LT4 products have had a BB warning since such warnings came into existence. The reason was sound many years ago when many doctors were prescribing LT4 for obesity, depression and a variety of other disorders, sometimes with dangerous consequences. With education and newer drug alternatives, virtually nobody prescribes LT4 for these disorders anymore; hence, do we still need a BB warning for LT4 products? I"m sure that the same pertains to other older drugs with BB warnings.

There's much more wrong with the PDUFA than just providing pharma with a platform for influence-peddling directly to FDA. I can tell you, from first hand experience, that the PDUFA timelines for market approvals take precedence over both pro forma and "for cause" FDA regulatory inspections of clinical research establishments, the so-called EIR (establishment inspection report). This is by design. The market approvals under the PDUFA are jet-propelled. Under the PDUFA, whistle-blowers are simply road kill, allegations of research fraud notwithstanding.