Comments on: These Drugs Generated Most Adverse Event Reports

By: patrons99

patrons99 — Tue, 02 Mar 2010 01:41:15 +0000

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.

By: pharmavet

pharmavet — Mon, 01 Mar 2010 17:19:05 +0000

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.

By: patrons99

patrons99 — Mon, 01 Mar 2010 13:24:39 +0000

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.

By: Justice in MI

Justice in MI — Mon, 01 Mar 2010 00:10:11 +0000

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.

By: JaT

JaT — Sun, 28 Feb 2010 23:01:17 +0000

There it is- patrons99

By: patrons99

patrons99 — Sun, 28 Feb 2010 20:07:18 +0000

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.

By: patrons99

patrons99 — Sun, 28 Feb 2010 19:31:27 +0000

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.

By: Justice in MI

Justice in MI — Sun, 28 Feb 2010 18:41:41 +0000

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

By: patrons99

patrons99 — Sun, 28 Feb 2010 17:54:10 +0000

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.

By: Justice in MI

Justice in MI — Sun, 28 Feb 2010 17:52:08 +0000

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.