Blog Forecast — Decidedly Arid; Rainless, In Fact.

Off the grid, in the high mountains.

“. . . .Be excellent — to one another. . . .”

Back on Monday.

Arbiter 6 — Early Returns From The US Prescription Data Aggregators

Courtesy Marilyn Mann, from a CNN article, of yesterday afternoon:

. . . .Niaspan prescriptions among new patients who hadn’t taken any cholesterol drug in the previous 12 months rose 33.8% from the previous week, while prescriptions on that basis for Zetia dropped 24% and were down 16.8% for Vytorin. New Niaspan prescriptions among people who had taken a different cholesterol drug in the previous 12 months rose 45.6% from the week before, while Zetia declined 27.4% and Vytorin dropped 23.7% on similar bases.

Merck spokesman Ron Rogers said the company isn’t familiar with the SDI data, and that it would be “premature” to gauge the impact of the Arbiter 6 study on market trends. . . .

Vioxx: What Did FDA’s Post-Market Surveillance Reporting Rules Require of Merck, From 2000 — 2004?

Dr. Krumholz’s fine post hoc Vioxx study data analysis, published in an Archives of Internal Medicine article this afternoon, put me in mind of this highly-impertinent question:

What did the FDA rules, as the same were in effect in 2000 through 2004, require Merck to track, tabulate and report, in the way of post-market approval adverse event data?

This question is interesting to me — in view of Dr. Krumholz’s work — primarily because I am rather concerned that (1) either Merck did not collect and forward to FDA all the FDA-required adverse event data, or (2) it did collect it, but did not model it appropriately, to sniff-out emerging adverse event trends — trends like those that the article points out were in “hiding, in plain sight.”

So — from the then-applicable, relevant FDA rules:

. . . .Serious, unexpected ADEs must be submitted to the agency within 15 working days. [This requirement becomes 15 calendar days as of April 6, 1998.]

The 15-working day time frame begins on the date the manufacturer or any of its affiliates (including foreign) received the information. Sometimes an ADE report initially not classified as a 15-day report is reclassified as “serious and unexpected” after the firm’s follow-up investigation. In this case the 15-day time frame begins on the date the firm received the information that caused the report to be reclassified. If the applicant receives new follow-up information on a 15-day report, then the G4 date is the date of this new information. A follow-up 15-day report has to be submitted within 15 working days after receipt of the information. This requirement becomes 15 calendar days as of April 6, 1998.

An establishment’s report may include a causality assessment of whether the ADE was related to the drug. The regulations do not permit submission delays for 15-day reports pending completion of a causality assessment.

Periodic Reports

Spontaneous (not derived from a study nor literature), domestic ADEs that do not meet the criteria of a 15-day report are required to be submitted to the agency in periodic reports under 21 CFR 314.80 only. Periodic reports must be submitted quarterly for the first three years after application approval and annually thereafter. The periodic report submission date is usually based on the date the NDA/ANDA was approved. If a date other than the approval date is used to calculate the due date, determine if the firm received the required written FDA approval. . . .

So all of this should have been collected every 15 calendar days, and aggregated, and forwarded, along with statistical analysis, every calendar quarter, from 2000 thorugh late 2003. Did that happen? What sorts of statistical analysis packages were run on the quarterly, and cumulative data aggregations? Who at Whitehouse Station reviewed them, before forwarding the same to FDA (if they were in fact prepared, and forwarded, at all)?

Recognize here, that as Dr. Krumholz points out, FDA’s entire budget, for all human drugs, is smaller than what Merck spent promoting Vioxx in 2003, alone: $500 million.

Of the two, who should we most expect had the resources to ferret-out the emerging cardiovascular event pattern¹? Based on Dr. Krumholz’s analysis — even though hindsight is 20-20 — by 2002, a tripling of cardiac events was appearing, with a “p value” below 0.05, or less than a 5 in 100 chance that the events could be assigned to random chance.

Certainly, as to all plaintiffs who’ve opted out of the global Vioxx settlement (and are still pursuing individual claims), this will be available as evidence.

Most impertinently though, I wonder tonight — from the snowy mountain-tops of Colorado — whether a showing might now be made that some of the basic assumptions upon which the $4.5 billion settlement itself rests — were in error. Will it reopen the settlement? That would seem rather unlikely — but as ever, we will need to wait and see — when the other shoe falls.

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_{1. On that score, at page 25 of this March 2006 GAO report — on ways to improve timely FDA recognition of adverse event trends in previously approved drugs — we run across this startling observation:}

. . . .In addition, it can be difficult to attribute adverse events to particular drugs when there is a relatively high incidence rate in the population for the medical condition. For example, ODS staff analyzed adverse event reports of serious cardiovascular events among users of the anti-inflammatory drug Vioxx in a 2001 consult. However, because Vioxx was used to treat arthritis, which occurs more frequently among older adults, and because of the relatively high rate of cardiovascular events among the elderly, ODS staff concluded that the postmarket data available at that time were not sufficient to establish that Vioxx was causally related to serious cardiovascular adverse events. With AERS data it is also difficult to attribute adverse events to the use of particular drugs because the AERS reports may be confounded by other factors, such as other drug exposures. . . .

Could Merck Have Known About Vioxx’s Elevated Cardiovascular Event Risks As Early as Late 2001?

This post hoc analysis of aggregated trials data from multiple sources, published just now, suggests so.

. . . .The association between Vioxx (rofecoxib) and risk of CVT adverse event or death strengthened with the additional of subsequently collected data. As of January 2002, 14,406 subjects had been observed for 7,806 patient-years and Vioxx (rofecoxib) was associated with a 39% increased risk of a CVT adverse event or death (RR 1.39; 95% Cl 1.07-1.80)(P=.02). . . .

So, by January 2002, there would have only been two chances in 100 that the 39% higher risk of cardiovascular events or death being seen in connection with Vioxx were the result of random chance.

That is fully two and a half years earlier than when Merck “folded the tent“, on this largely ineffectual, and more than occasionally-lethal drug. And to be clear, yes — it is true that several of the authors of the above-study served, at one time or another, as experts of various sorts for the plaintiffs’ consolidated federal court cases alleging injuries from Vioxx. Significantly, however, these findings have been independently peer-reviewed, and now represent rather stark evidence that the one entity with access to essentially all of this information — and likely in the best position to have “caught it” — would have been Merck, itself.

More in a moment, on the relatively low likelihood that all the FDA rules were being meticulously followed, in the reporting of Vioxx-related adverse events, by Merck.

Look above in a few moments.

What Did Merck Know — And When Did It Know It?

First things, first: under applicable United States law, the party primarily responsible for the safety of any FDA-regulated pharmaceutical product is manufacturer. Note that FDA’s role, post market-approval is to monitor; the manufacturer is supposed to do that, and more. Now, with those general rules in mind, take a look at this — it is simply a jaw-slacking visual indictment of the manufacturer of Vioxx, offered in the form of post hoc analysis — and brilliantly executed, as well (click to enlarge):

. . . .This safety record is at Merck’s feet. More, in a few moments. . . .

Merck Wins Texas Gov’t Vioxx Dismissal — At Least 11 Other States To Go

Merck has won a trial level dismissal of claims brought by the State of Texas, alleging that its Vioxx promotional and sales efforts amounted to a fraud on the state pharmaceutical purchasing authorities. From the Yahoo! News version:

. . . .In its motion for summary judgment, Merck maintained, among other things, that the evidence showed that the company acted responsibly and truthfully in its communications about VIOXX with the State of Texas, doctors in the state and the U.S. Food and Drug Administration. . . .

Marginally-related aside, from the blog-author: Mr. Michael Specter, please see me after-school, this afternoon, for a tutorial — and some Socratic Q & A.

Will Michael Specter Be The One In “Denialism” — By Tomorrow Afternoon?

As no less a science authority than The New York Times recently breathlessly relayed (on November 4, 2009), Mr. Specter has written a book about “Firing Bullets of Data at Cozy Anti-Science“. Uh-huh. Catchy.

Apparently, one of Mr. Specter’s chapters is devoted to exposing poor pharma science (as a killer of what Specter tells us are “these good things“). That essay includes lamenting the “black eye” given to that noblest of compounds, rofecoxib, also known as. . . Vioxx — its Merck-branded name:

. . . .”Denialism” makes good use of drugs. An opening chapter about the anti-inflammatory drug Vioxx describes the mess that resulted from efforts by Merck, the manufacturer of Vioxx, to obscure the fact that the medicine posed cardiovascular risk to some patients. This action led to Vioxx’s being removed from the market, even though many of its users, including a cardiologist who wound up being a whistleblower against Merck’s tactics, personally found Vioxx very helpful for treating his own arthritic knee. But the drug went out of circulation. Big Pharma ended up with a black eye. And “Denialism” got a case in point to illustrate why scientific advances made by drug companies can’t be trusted. . . .

Uh-huh. See ya’ tomorrow evening, Mr. Specter.

Sanofi CEO: No Decision on Intervet Call Option Until Q1 2010

Quoth The Financial Times, in an extraordinarily-candid, wide-ranging interview — with the CEO of Sanofi-Aventis — thus:

. . . .He said a decision would be made during the first quarter of next year on whether to make fresh investments to combine Meriel – the animal health joint venture it runs with Merck of the US – with the extra products Merck has acquired in its recent take-over of Schering-Plough. . . .

So by then, it will have been going on for three solid years [since early 2007, when rumors first surfaced of an Intervet sell-off to old (legacy) Schering-Plough], that the legacy Organon-Intervet workforce will have been “living in limbo” — not knowing who will own it, who they’ll work for, or whether they will have ongoing, long-term work prospects, at all.

Evidence In Medicine — Stellar New Post — Great Weekend Background Reading

UPDATED: 11.22.09 @ 9:30 am EST – With an uncanny sense of prescience, this morning, a commenter at David’s site wrote — in part — thus:

. . . .I think the most critical issue in the evaluation of new drugs is post-market monitoring, which inexplicably has only been recognized as an important FDA empowerment recently. Obviously new things show up when the patients number in the millions rather than hundreds. . . .

Indeed. The commenter bevMD is clearlly correct. And in that regard, watch this space, tomorrow afternoon.

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This carefully-written new blog is going to become a “must read” for all of us who are serious about trying to constructively address what we see as pharma’s current shortcomings. [It will also serve as a great backdrop for a pair of (in my opinion) rather shocking commentaries, to come out on this coming Monday afternoon, regarding Merck's marketing of a certain drug.] Do go read it all, but here is a snippet:

. . . .I’ll write about other ways of manipulating results in future posts, but for today I want to comment on one pernicious effect of this behavior — I have come to distrust and then dislike the companies that provide the (often useful) drugs I must use on patients. When the new HDL-raising drug torcetrapib went down in flames a few years ago, I was actually pleased: I was furious with Pfizer for having tried to get torcetrapib approved in a way that would have only marketed it in a combo pill with atorvastatin. Objectively, it makes no sense that I should be happy at the failure of a drug that would have helped my patients had it worked.

Pharma not only tries to manipulate the interpretation of results of trials, in the design, analysis, and publication phases, they apparently also try to sow doubt about existing competitors. Adriane Fugh-Berman wrote in 2005 about how she was recruited to be the author on a ghost-written manuscript intended to highlight the importance of herbal interactions in patients on warfarin (interactions that Dr. Fugh-Berman felt were overstated). The company recruiting her was presumably working for AstraZeneca, the manufacturer of ximelgatran. Ximelgatran, a direct thrombin inhibitor that aimed to replace warfarin, was eventually withdrawn from the market in Europe (never approved in the US) because of hepatotoxicity. . . .

Do go read David’s — his conclusions may surprise you. They did, me — pleasantly.

A Legacy Schering-Plough Consumer Health Care to Reckitt Deal, Debunked?

Hat-tip to an anonymous commenter, below — but the UK-based Reckitt doesn’t seem to be a likely deal candidate, if FT’s sources are to be believed. Here’s the snippet from the online London version of Financial Times, which would suggest that Reckitt is not seriously interested in these legacy-Schering’s Consumer Health Care assets:

. . . .However, there was some skepticism around Reckitt acquiring Schering Plough’s OTC, two of the industry bankers said. The third banker said he personally did not believe Schering’s OTC unit was the greatest asset, due to products such as OTC allergy medication Claritin, which has reported declining sales. He did, however, mention that Dr. Scholl’s foot care products was one of the few strong businesses in the portfolio. . . .

Thus my recurring graphic, at right. We shall see.