Monday, November 30, 2009

Justice Breyer Did Ask "Something Like" The Question I Posited

Well, the questioning doesn't exactly tie Merck's position in settling the products liability claims for $4.85 billion, to the notion that Merck expects more of securities plaintiffs (as to "storm warnings") than it does of itself, as to safety -- but the embers of my earlier post do appear in the Justices' flames, as reported by The Wall Street Journal tonight:

. . . ."Companies can't have it both ways," Justice Anthony Kennedy told a lawyer for Merck. . . .

Justice Stephen Breyer said Merck's position, in effect, would require plaintiffs to file lawsuits before they had enough evidence to back them up. "That doesn't make sense to me," he said. . . .

This may well make for tougher sledding in Ex-CEO Hassan's (and Ex-EVP Cox's) defense of the Pharmacia/Celebrex launch-era securities fraud claims.

A Question Justice Breyer (Or Someone) Might Have Asked

I haven't seen the transcript yet -- or listened to the webcast stream of today's Supreme Court oral arguments related to Merck's certorari appeal, but it is being reported that the Justice asked what would "a reasonable person" have done, in connection with pursuing a securities fraud claim against Merck -- related to its disclosures about Vioxx's elevated heart attack risks.

If that is accurate, and we take as accurate that Merck's position is that it believes there was enough information in the public domain by November 2001 for the plaintiffs to have been "on inquiry notice" about its Vioxx (alleged non-)disclosures, such that they should have filed a securities suit by two years from that date. . . What are we to make of this, from last Monday? I think the Supremes should find this troubling:

. . . ."We fundamentally disagree with their conclusions that there was an actionable signal before September 2004," Doug Watson, PhD, senior director of medical science for Merck Research Laboratories, tells WebMD. . . .

The above is Merck's supposed-refutation of the notion that Merck itself should have known that Vioxx was associated with cardiovascular problems much earlier -- perhaps as early as January 2001.

Were I a Supreme, I might have asked, today, how it can be Merck's public position that the securities plaintiffs should have had enough information/certainty that Merck's overly-rosy view of Vioxx's risks was actionable as securities fraud as early as November 2001 -- when in the products liability cases, Merck itself (again!) claims that it was not in possession of enough information to necessitate acting on the Vioxx product until September 2004?

I wonder -- is it Merck's view that small stockholders should act with more vigilance, as to their investments -- than Merck is (in its view) required to exercise, in protecting the public from elevated heart-attack risks, associated with Vioxx's side-effects?

That seems an entirely untenable position. And that should be a question that the Supremes ask Merck's lawyers, or themselves, as they instruct their clerks to prepare the opinions in this case.

Putting Merck's Latest "Favorable" Fosamax® Ruling In Perspective

While I was off the grid (in the mountains), the very-able Judge Keenan, sitting in Manhattan's federal District courthouse, decided that Merck need not put on a defense in the second of five bell-weather Fosamax® cases -- individual test cases, if you will.

Before anyone begins to believe that this is the way all -- or even most -- of these cases might turn out, let's take a look at the actual facts in the now-dismissed case. The plaintiff was beset my a wide assortment of smoking-related ills -- and while I do not mean to pass judgment upon her for her personal health choices -- she did make personal choices that would make it a near impossibility that a jury could find Fosamax was the primary cause of her ills.

As such, this was one that almost everyone expected Merck to win -- if it had been tried to a verdict. Again, this one case (probably the one "ringer" -- of the first five -- for Merck) tells us very little about the overall strentgh of the federal Fosamax putative class action claims. It is also proof that "hard facts make bad law". Ms. Flemings is very ill, no doubt -- but it probably is not primarily the fault of Fosamax. Take a look, from Judge Keenan's order (a 22-page PDF file) allowing a dismissal against Merck:

. . . .Plaintiff Bessie Flemings is a 74-year old Mississippi resident who alleges that she developed ONJ in 2006 as a result of taking Fosamax. . . .

Flemings has a history of serious medical problems. Flemings has been smoking cigarettes since she was eight years old. She has long suffered from severe chronic obstructive pulmonary disease (“COPD”) and continues to smoke cigarettes even though she is now dependent on an oxygen tank. Among other health problems, she has congestive heart failure, peripheral vascular disease, and she developed skin cancer on the outside of her mouth.

Flemings was diagnosed with severe osteoporosis in December 1997. That month, her family physician, Dr. Walter Rose (“Dr. Rose”), prescribed Fosamax to treat her osteoporosis. Flemings has fallen several times since she was diagnosed with osteoporosis, fracturing her knee and injuring her back on two such occasions. . . .

As a scientist, I would call these confusing variables. As a lawyer, I would simply say that whatever small additional part Fosamax may have had in aggravating Ms. Flemings' various maladies, it would be fundamentally unfair to give the jury a pen, and a blank sheet of paper, and ask for a finding of damages against Merck, on these facts.

Said another way, there will likely never be any way to discern the extent to which (or whether), Ms. Flemings' jaw difficulties are a by-product of the spread of her cancers, and continued smoking -- or the result of Fosamax-induced bone death.

So -- my object lesson: beware early signals on these bellweathers -- the first, Boles, was a "runaway jury" mistrial; the second was a non-starter. Let's see what the third, fourth and fifth bring.

Merck's Securities Fraud "Inquiry Notice" Case To Be Argued In Highest Court Today

As word, web-wide, leaks out -- from the live-blawgers -- of the "Kentucky windage", via the questions asked by various Supreme Court Justices at oral argument this morning at 11 am EST, I will add word of the same, with analysis, here.

Per's fine United States Supreme Court web-collection:

. . . .Investors brought a securities fraud class action suit against Merck & Co. in a New Jersey federal district court. They alleged the company had misled investors about the drug Vioxx's safety and commercial viability. Merck moved to dismiss the claim arguing that the investors had been put on "inquiry notice" more than two years before they filed suit, and thus the statute of limitations had run. The federal district court agreed and dismissed the suit.

On appeal, the U.S. Court of Appeals for the Third Circuit reversed. It recognized that under the "inquiry notice" standard, plaintiffs are put on notice for the purpose of the statute of limitations in federal securities fraud litigation at the "possibility" of wrongdoing. Moreover, the court held that the investors had not been put on "inquiry notice" more than two years before they filed suit, and thus the statute of limitation had not run.


Did the U.S. Court of Appeals for the Third Circuit err in its application of the "inquiry notice" standard?. . . .

The answer to this inquiry will likely also impact the statute of limitations defenses being raised in the Hassan-Cox securities fraud class action (while leading Pharmacia -- an early 2000s-era case background, here, and earlier background may be found, by clicking the Celebrex image, at right), called Alaska Electrical Pension Fund, et al. v. Hassan, Cox, Pharmacia, et al. (3d Circ. Appeal No. 07-4500). Additional action on that matter has been stayed, pending the outcome of this Merck appeal, filed as a writ of certorari, back in January 2009.

Wednesday, November 25, 2009

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. . . .

Tuesday, November 24, 2009

We Veer Off-Topic -- But Only Slightly -- For A Thanksgiving Blog Rally. . . .

Last Thanksgiving weekend, many of us bloggers participated in the first documented “blog rally” to promote Engage With Grace – a movement aimed at having all of us understand and communicate our end-of-life wishes.

It was a great success, with over 100 bloggers in the healthcare space and beyond participating and spreading the word. Plus, it was timed to coincide with a weekend when most of us are with the very people with whom we should be having these tough conversations – our closest friends and family.

Our original mission – to get more and more people talking about their end of life wishes – hasn’t changed. But it’s been quite a year – so we thought this holiday, we’d try something different.

A bit of levity.

At the heart of Engage With Grace are five questions designed to get the conversation started. We’ve included them at the end of this post. They’re not easy questions, but they are important.

To help ease us into these tough questions, and in the spirit of the season, we thought we’d start with five parallel questions that ARE pretty easy to answer:

Silly? Maybe. But it underscores how having a template like this – just five questions in plain, simple language – can deflate some of the complexity, formality and even misnomers that have sometimes surrounded the end-of-life discussion.

So with that, we’ve included the five questions from Engage With Grace below. Think about them, document them, share them.

Over the past year there’s been a lot of discussion around end of life. And we’ve been fortunate to hear a lot of the more uplifting stories, as folks have used these five questions to initiate the conversation.

One man shared how surprised he was to learn that his wife’s preferences were not what he expected. Befitting this holiday, The One Slide now stands sentry on their fridge.

Wishing you and yours a holiday that’s fulfilling in all the right ways.

To learn more please go to This post was written by Alexandra Drane and the Engage With Grace team. If you want to reproduce this post on your blog (or anywhere) you can download a ready-made html version here.

Monday, November 23, 2009

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 Achives 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.


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 by the Achives of Internal Medicine, suggests so. [Previous version contained an inaccurate journal reference.]

. . . .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.

Sunday, November 22, 2009

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.

Saturday, November 21, 2009

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.


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.

Friday, November 20, 2009

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.

Is The Old Schering-Plough Consumer Health Biz On P and G's "Shoppin' List"?

At a Morgan Stanley presentation this morning, per the online WSJ Deals page, P&G looks to be putting together a "Chopin Liszt" (figure it out!):

. . . . Procter & Gamble Co. said it is open to deal making, but the consumer giant emphasized that acquisitions aren't a core part of its strategy to grow and that it doesn't pursue hostile acquisitions. . . .

P&G Chief Financial Officer Jon Moeller said at a Morgan Stanley conference Friday that the company would be most interested in making acquisitions to bolster its household, beauty and consumer health-care portfolios. . . .

Stay-tuned. CEO Clark did repeatedly say it was clear the Consumer Health businesses, pre-merger, would "need a partner".

New Merck's Elonva®: Next Step Toward EU Approval, For Fertility Stimulating Injection

From the PR Newswires/First Call version:

. . . .Merck today announced the Committee for Medicinal Products for Human Use of the European Medicines Agency has recommended approval of Elonva® (corifollitropin alfa injection) as a treatment in controlled ovarian stimulation in combination with a GnRH antagonist for the development of multiple follicles in women participating in an assisted reproductive technology program. . . .

To be fair, Merck has a dense forest of tremendously-thick-trunked trees , for its newly-combined science programs -- and these will continue to drop a significant bevy of acorns.

Thursday, November 19, 2009

Sanity Makes A Comeback: Gardasil Jab No Longer Required For Green Card

Ed Silverman's Pharmalot had essentially this story up a few days ago, and he was instumental in bringing to the world's attention the crashingly off-key note the original effort sounded. So -- I've been meaning to add a squib on it, since Monday. . . but here it is, Thursday night. Ah, well.

The below appears in the New York Times' version:

. . . .Immigrant girls and women will no longer have to be vaccinated against a sexually transmitted virus to get their green cards. Starting December 14, the human papillomavirus vaccine will no longer be on the list of immunizations female immigrants ages 11 to 26 must receive before becoming legal permanent residents. . . .

This finally begins to put to rest the undercurrent of an awfully stereotyped notion -- that (somehow) immigrants just-arriving in America are more likely to harbor, or contract, this viral disease (primarily transmitted via sexual activity) than native-born Americans are.

So slowly, ever so slowly, sanity is finally making a comeback. [Even if one is not inclined to buy into the previously-discriminatory whiff here, the now widely-available NNT figures, on Gardasil, may well make this one vaccine-too-far -- at least if we intend to use the full-force of law to mandate its injection -- into the bodies of young women.]

Google's SideWiki: Love the Immediacy, Ubiquity and Intimacy -- BUT. . .

Okay -- I also love the content (thanks, Anonymous!) -- but can I trust Google to remain true to the "Don't Be Evil" motto?

Do I really believe that Google's "comment on anything, anywhere" technology isn't also a data-mining/sales operation? Of course not. So -- while I love the content the SideWiki will show me (especially that depicted above -- click to enlarge!) -- I will probably pass on installing the toolbar, and SideWiki, for now.

What are your thoughts? Am I overly focused on data privacy (and safety of preserving anonymous identities)? Am I being silly? Is SideWiki effective, as a pharma-commentary tool? Let me know.


Merck's Massive "Head-to-Head" IMPROVE-IT Study May Never Reach A Meaningful Endpoint

Given the outstanding quality of my anonymous commenter audience of late, I probably ought to just let my commenters write this blog -- as they are far more adept at pointing these things out, and succinctly so, than I -- very nice work, "Anonymous" [BTW, the image at right is a letter, from the Congressional investigations begun last year into these matters -- click it to get all the background on other arguable cholesterol-study shenanigans, circa Summer of 2008]:

. . . .Mark these words: IMPROVE-IT will be at the very best a neutral study -- it will show no definitive difference at all between Vytorin and generic simvastatin. Given the number of events recorded to date (~2,300) in 15,000 patients enrolled and with enrollment having started in October of 2005, the PIs retained by Merck actually should have enough statistical power to detect a clinically meaningful difference in events. [Editor's Note: Remember here also that the PIs unblinded the IMPROVE-IT data, to an independent safety panel, immediately after the SEAS cancer signal -- and then the IMPROVE-IT study size was increased. Interesting, no? -- But back to the main story, now.]

The problem is, they haven't, and this is mainly due to two arguably errant assumptions by Merck's study designers:

(1) all LDL-C lowering is not equal in terms of its association with event reduction, and

(2) Merck's assumed relationship between LDL-C reduction and cardiovascular event risk is not linear.

On the latter point, Merck believes that for every 1.6 mg/dL decrease in LDL-C, cardiovascular event risk is reduced by a relative 1%. What Whitehouse Station is too blind to see is that this relationship does not hold true at the LDL-C values expected in this study (baseline ~100 mg/dL, and on-Rx values in the 50-65 range. In fact, this relationship is actually curvilinear, and the cardiovascular event reduction gets progressively smaller and smaller as LDL-C declines below 100. The "joke" will be on New Merck. It would be funny if it weren't for the tens of millions of patients that will get Zetia/Vytorin instead of a more beneficial therapy (niacin, anyone?) at an aggregated spend of $4 billion/year until we find that out.

-- Anonymous, November 18, 2009 10:15 PM. . . .

I think that has it just about perfectly right. For its part, New Merck is supposed to release a newly revised/projected end-date for IMPROVE-IT in the coming weeks, according to on-the-record remarks made by the study PIs, at AHA in Orlando, this week. Will the new date be in 2013? 2014? Or later? We'll see -- but my money's on the above analysis, regardless of what Merck "forecasts" (or guess-timates, more pointedly) here, as 2009 draws to a close.

Wednesday, November 18, 2009

Latest Hit From Harry Reid and the Blenders -- "Pharma's IMAB Blues"

Latest word from "Harry Reid and the Blenders" -- we'll see if this Senate version will hold (Reuters reporting):

. . . .However, the bill allows an Independent Medicare Advisory Board to make recommendations to lower Medicare payments for private drug insurance plans, which could in turn reduce prescription drug usage. . . .

Stay tuned.

UnitedHealth Post Hoc Analysis: Treat 1,250 People With Vytorin To Prevent One CV Event, When Compared To Atorvastatin?

Here's a great comment, just now posted -- about today's UnitedHealth study presentation at AHA, in Orlando; it deserves "front-page" exposure:

. . . .Let's do a little "Number-Needed-to-Treat" (NNT) and economic analysis, shall we?

From the Stockl presentation of these data at AHA, today:

Vytorin (simvastatin/ezetimibe) 96 events/9983 patients over 1.06 years of follow-up = 0.91%/year event rate

Atorvastatin 115 events/9983 patients over 1.16 years of follow-up = 0.99%/year event rate

Simva 124 events/9983 patients over 1.08 years of follow-up = 1.15%/year event rate

NNT = 1/absolute risk difference

Vytorin (simvastatin/ezetimibe) vs atorvastatin NNT = 1,250. This means you'd have to treat 1250 patients to prevent one event with Vytorin compared to atorvastatin.

Vytorin vs. simvastatin NNT =417

Assuming simvastatin costs 84 cents/day, atorvastatin $3.91/day, and Vytorin $3.74/day:

You'd have to spend $1.7 million to treat 1,250 patients for one year with Vytorin vs. atorvastatin to prevent one event, or spend $570 million for Vytorin vs. simvastatin, for one to prevent one event.

Since your average stroke/MI hospitalization costs about $30,000, we would have to spend way too much money to use Vytorin vs. either atorvastatin or dirt-cheap generic simvastatin. I'm no Peter Orszag, but I'm pretty sure there's no way that will ever be viewed as cost-effective.

Don't think we'll be seeing any such analysis out of the Merck health outcomes shop any time soon.

-- Anonymous, November 18, 2009 10:00 PM. . . .

~~~~~ Later ~~~~~

Now let's get really re-dick-ulous! How about a pairing? . . .The UHC report with the known curvilinear relationship between LDL and events at the far low end of the LDL curve (think, IMPROVE-IT). Yes folks, the answer is the same. An LDL from 65 to 55 with a predicted 0.1% absolute risk difference in meaningful events (heart disease death, heart attack). That's a NNT of. . . . 1000. Hmmm. . . there's some symmetry there with the UHC findings. So, just go ahead boys and girls, keep those prescriptions coming. . . or, maybe with those odds, patients should save the money and play some powerball. There's a better chance of meaningful return on investment, and it goes to a better cause. . . .

November 18, 2009 11:25 PM

"Make-Whole Call" Rights Expire Tomorrow, November 19th, 5 p.m., E.S.T.

Yesterday, I answered some questions on another chat-board about the Old Schering-Plough, now "New" Merck 6% Convertible Preferred issue, and how it is affected by the reverse merger. Given that tomorrow is the last day to make this election, I though I'd re-print some of those observations, slightly massaged, here.

[Editor's aside: Almost by dint of capital markets dark-magic, tonight, the Preferred closed at $250.90. Astute readers will recall that the preferred was originally-issued in connection with the financing of the acquisition of Organon by Schering-Plough, in August of 2008, at. . . Yep! $250 per preferred unit (imagine that!), and bearing a 6% annual coupon, or $15 per year, paid in quarterly chunks.]

Okay -- putting aside my mutterings about the uncanny symmetry of tonight's closing price -- and tomorrow's expected "Make Whole conversion" events -- here are some more-general caveats.

First, and most importantly, these observations were made for an investor who is decidedly-bullish on New Merck's prospects, in the near and mid-term. Second, this particular investor is not sitting on an (unrealized) capital loss in the Preferred 6% issue. Next, he asked me to ignore taxes. Finally, he had no near-term liquidity event that he needed to fund (however, in this regard, the running 6% dividend pay-out on the preferred is rather tempting -- but one can only collect that higher dividend if one doesn't choose the "Make-Whole Call"). On the other hand, choosing the Make Whole call puts $86.12 of cash into one's account, for every Preferred 6% Unit turned in -- so, cash available in either scenario.

So now, if you, too, are bullish on New Merck (even with it sitting at a new 52 week high), and want to get more common shares of the company in your hands as soon as you can, here is the conversion math, for tomorrow:

. . . .From the completion of the merger [on Nov. 3, 2009] through 5:00 p.m. ET on November 19, 2009, the 6.00% Mandatory Convertible Preferred Stock of Schering-Plough will be convertible at a make-whole conversion rate of 8.2021. For each share of preferred stock converted during this period, the holder will receive $86.12 in cash ($10.50 x 8.2021) and 4.7302 “MRK” common shares (0.5767x 8.2021). Holders will also receive, for each share converted, a dividend make-whole payment of between $10.79 and $10.82, depending on the date of conversion. . . .

Again, I am ignoring taxes, as I suggested at the outset -- though it seems a shame to pay taxes on April 15, 2010, on all that cash (albeit at capital gains rates).

If you wait beyond the 19th, your conversion ratio will yield a smaller number of Merck common shares, unless New Merck common stock prices on the NYSE dip significantly from here. Under the post-November 19, 2009 conversion mechanics, a persistent decrease in the NYSE price of New Meck common will cause an upward adjustment in the conversion ratio. But if the NYSE prices are stable or rising, between November 20, 2009 and August 13, 2010, here is what happens:
. . . .Conversion After the Make-Whole Acquisition Conversion Period

If a holder does not elect to convert shares of Preferred Stock during the Make-Whole Acquisition Conversion Period, the holder’s shares will remain outstanding and subject to automatic conversion into Cash Consideration and Share Consideration on the mandatory conversion date of August 13, 2010 (the “Mandatory Conversion Date”), or may be converted into Cash Consideration and Share Consideration, in whole or in part, at the option of the holder at any time prior to the Mandatory Conversion Date.

Each share of Preferred Stock that is converted into Cash Consideration and Share Consideration at the option of the holder at any time after the Make-Whole Acquisition Conversion Period and prior to the Mandatory Conversion Date will be converted into Cash Consideration, based on a fixed “Minimum Cash Conversion Rate” of 7.4206 that will not be subject to “anti-dilution adjustments,” and Share Consideration, based on a “Minimum Share Conversion Rate” that will initially be 7.4206, but will be subject to “anti-dilution adjustments” as described below.

Accordingly, for each share of Preferred Stock so converted, the holder will receive:
Δ $77.9163 in cash ($10.50 multiplied by the Minimum Cash Conversion Rate of 7.4206); and

Δ a number of shares of New Merck Common Stock equal to 0.5767 multiplied by the Minimum Share Conversion Rate then in effect. . . .

As you can readily see, the conversion ratios are lower (again, assuming that New Merck common holds most of its value, through August 2010).

If New Merck common stock dips significantly before the August 2010 forced convert date, the conversion ratio will rise modestly -- but given a bullish view of Merck, it would seem imprudent, from that perspective, to pass-up tomorrow's Make Whole Call, and sit idly by (but collecting the 6% dividend, paid in quarterly installments), waiting for a big Merck downturn, all in the hopes of getting more shares -- especially when you can have the certainty of "more shares" now, simply by exercising your "Make-Whole Call" rights, before tomorrow evening, at 5 PM EST.

The mundane mechanical steps for doing that, tomorrow may be found in the middle of the third page of this New Merck PDF file.

In sum, then -- assuming that New Merck common stock doesn't dip significantly, between now and August 2010, you'll get more cash, and more New Merck common shares, if you convert by tomorrow night (you cannot hold the preferred forever, it is a forced convert in August of 2010), thus:

4.28 shares (after Nov. 19, 2009) v. 4.73 (before Nov. 19, 2009) shares.

Of course, you'll forego the $15 annual (6% nominal) dividend -- as you'll be holding New Merck common shares, not the higher-yielding preferred.

David Rind, M.D., Internist -- Beth Israel Deaconess Medical Center (Boston) -- Launches A Very-Promising Blog

[Earlier today, I ran some content derived from his nascent blog -- and it looks to be a good one. Do go take a look at all he's offering, but this is a reprint, as it kinda' got buried in a flurry of rather-silly posts I tossed up, this afternoon. . . .]

On the "Fragility" of the Arbiter 6 - HALTS Cardiovascular Events-Data

Thanks to reader Marilyn Mann -- for this link to an article in Evidence in Medicine:

. . . .Now, soon after that study, we have ARBITER 6, showing that niacin plus a statin seemingly reduced cardiovascular events compared with ezetimibe plus a statin. There were 2 events in the niacin arm (1%) and 9 in the ezetimibe arm (5%) and this was statistically significant. So, what can we conclude from this?

One possibility is that niacin actually does add some clinical benefit to a statin in secondary prevention, while ezetimibe does not.

Another possibility is that ezetimibe is actively harmful, while niacin is neutral. There were slightly more events in ENHANCE in the ezetimibe arm, but the numbers were tiny.

A third possibility is that this was due to chance. The actual results are quite "fragile" in the sense that only a few events moving from one arm to the other would make the difference disappear. While, in theory, a statistical test captures this, there's been a sense in the EBM world that very small event numbers create a fragility of results not adequately captured by a p value. It seems extremely unlikely that niacin really reduces events by 80%, since this should have been obvious in prior trials of niacin. As such, either niacin combined with a statin is much superior to niacin alone, or these results are in part due to the play of chance. (It's not likely that ezetimibe raises events by this degree when used with a statin, since we would likely have noticed this in other trials.). . . .

Interesting. Do go read it all. Back later with more, but here is Marilyn's take:
. . . .A fourth possibility is that niacin adds a small cardiovascular benefit and ezetimibe adds a small cardiovascular harm.

Question: you seem to be saying that ARBITER was a secondary prevention trial. Yet some of the patients did not have known vascular disease. The trial included patients with a calcium score over 200 for women or 400 for men or Framingham risk scores over 20%. (There were also patients with diabetes who did not have known vascular disease, although diabetes is usually classified as a coronary risk equivalent.) Admittedly the primary prevention patients were *very* high risk. Still, if someone is totally asymptomatic but either has multiple risk factors giving them a high FRS or known extensive atherosclerosis as indicated by a high calcium score, isn't that still primary prevention?

In my view, the issue of whether ezetimibe promotes cancer and/or cancer death is still unresolved, although I know you are a skeptic on that issue. This trial does not tell us anything about that.

Posted by: Marilyn Mann | Nov 18, 2009 at 09:37 AM

Arguably Onion-Worthy, I Think (For Insiders)


Warburg Pincus Opens Satellite Office

Dateline: Newark, NJ
November 18, 2009

In a bold and innovative move, the venerable New York private equity firm of Warburg Pincus LLC has leased just 45 square feet of office space in the federal district courthouse — in Newark, NJ.

The refurbished janitors’ closet sits seven steps from the walnut-paneled door to Judge Cavanaugh’s trial courtroom.

The sign outside the closet-cum-office reads:

Fred Hassan — Senior Adviser,
Warburg Pincus — NJ Branch Office

Asked to comment, a senior Warburg human resources executive said that this takes the idea of "hotelling" one’s office space — in a logical and convenient place — one step beyond "tele-commuting":

. . . .It just makes sense — Mr. Hassan will spend endless weeks on trial here, in the coming year, so why not leverage this, and reduce his commute time?

Yeh — the Choo-Choo to arrive ultimately at 450 Lex, in Manhattan (or a stretch Bentley-limo and driver, more likely) — are both so passe, right?

Merck Director Late In Filing Her "Insider Trading" Report With SEC?

On Monday, at about 11:04 AM EST, New Merck board of directors member Rochelle B. Lazarus filed a SEC Form 4 that -- apparently -- disclosed the conversion of her previous Schering-Plough stockholdings, into "New Merck" holdings -- along with those of her spouse.

The problem is that the filing was arguably at least 12 days late. The rules in this area are very-strict, when it comes to alerting the investing public promptly, to insiders' sales or purchases of the securities of a given public company. Per the SEC rules:

. . . .Changes in ownership are reported on Form 4 and must be reported to the SEC within two business days. . . .

Note that the form lists the date of the event requiring disclosure as November 3, 2009. That's the reverse merger date. Note also that the form, on its face, was not filed until November 16, 2009. Finally, Ms. Lazarus filed two other change of ownership reports (here and here), in a timely fashion, as a result of the reverse merger. It is particularly puzzling, then, that she would have missed filing this one in a timely fashion.

I wouldn't have bothered to mention it, at all -- but it turns out there were several (arguably material) events underway, on that very same Monday morning, with Merck executives, many of EVP stature, or above -- in Orlando, Florida and New York City, darting about and making sweeping-statements -- with respect to one of the company's key franchises.

Insurer-Sponsored Post Hoc 30,000 Patient Study: "Merck's Vytorin Of No Incremental Benefit"

Yes, the sponsor of the study has a financial incentive to see patients take less pricey medicines (especially if the results don't really differ, between outcomes from the pricey and the cheap drugs), and yes it was not peer-reviewed, or vetted, as a NEJM article would be, but it did examine 30,000 patients' histories. That makes it twice the size of the much debated IMPROVE-IT trial, still stuck at 15,000 patients.

Peter Loftus, for the Wall Street Journal, reporting from the AHA, in Orlando:

. . . .A new study by health insurer UnitedHealth Group Inc. concludes Merck & Co.'s cholesterol drug Vytorin didn't significantly reduce the risk of heart attacks or strokes compared with a generic alternative or Pfizer Inc.'s Lipitor. . . .

"Treatment with the combination Vytorin drug really showed no significant difference in those clinical results when compared with what we tried to match up as equipotent doses of simvastatin and [Lipitor] alone," said Brian Solow, senior medical director at Prescription Solutions. . . .

* * * *


* * * *

. . . .The analysis suggests that heart patients may fare just as well by taking the least-expensive cholesterol-lowering pill. Simvastatin costs 84 cents for a 40 milligram dose, compared with $3.91 for the same dosage of Lipitor and $3.74 for Vytorin. A study last year showed that Vytorin worked no better than simvastatin at reopening arteries and a separate study reported this week found that Abbott Laboratories’ Niaspan may be superior to Vytorin in certain patients. . . .

"This looks at a real world context of 30,000 total lives and we are looking at the lives they would normally lead while on these medications," said Brad Curtis, a vice president and medical director for Prescription Solutions. "We are showing how it looks out there in the real world. . . ."

The evidence continues to pile up, here.

Courtesy Marilyn Mann -- On The "Fragility" of Arbiter 6 Cardiovascular Event Data

Thanks to reader Marilyn Mann -- for this link to an article in Evidence in Medicine:

. . . .Now, soon after that study, we have ARBITER 6, showing that niacin plus a statin seemingly reduced cardiovascular events compared with ezetimibe plus a statin. There were 2 events in the niacin arm (1%) and 9 in the ezetimibe arm (5%) and this was statistically significant. So, what can we conclude from this?

One possibility is that niacin actually does add some clinical benefit to a statin in secondary prevention, while ezetimibe does not.

Another possibility is that ezetimibe is actively harmful, while niacin is neutral. There were slightly more events in ENHANCE in the ezetimibe arm, but the numbers were tiny.

A third possibility is that this was due to chance. The actual results are quite "fragile" in the sense that only a few events moving from one arm to the other would make the difference disappear. While, in theory, a statistical test captures this, there's been a sense in the EBM world that very small event numbers create a fragility of results not adequately captured by a p value. It seems extremely unlikely that niacin really reduces events by 80%, since this should have been obvious in prior trials of niacin. As such, either niacin combined with a statin is much superior to niacin alone, or these results are in part due to the play of chance. (It's not likely that ezetimibe raises events by this degree when used with a statin, since we would likely have noticed this in other trials.). . . .

Interesting. Do go read it all. Back later with more, but here is Marilyn's take:
. . . .A fourth possibility is that niacin adds a small cardiovascular benefit and ezetimibe adds a small cardiovascular harm.

Question: you seem to be saying that ARBITER was a secondary prevention trial. Yet some of the patients did not have known vascular disease. The trial included patients with a calcium score over 200 for women or 400 for men or Framingham risk scores over 20%. (There were also patients with diabetes who did not have known vascular disease, although diabetes is usually classified as a coronary risk equivalent.) Admittedly the primary prevention patients were *very* high risk. Still, if someone is totally asymptomatic but either has multiple risk factors giving them a high FRS or known extensive atherosclerosis as indicated by a high calcium score, isn't that still primary prevention?

In my view, the issue of whether ezetimibe promotes cancer and/or cancer death is still unresolved, although I know you are a skeptic on that issue. This trial does not tell us anything about that.

Posted by: Marilyn Mann | Nov 18, 2009 at 09:37 AM

Matt Herper -- Of Forbes -- Picks Up Our Meme of Sunday Night

In fairness, Larry Husten of CardioBrief flagged it, as part of a much longer article of his -- but I amplified it -- and ran it as my Arbiter 6 story lede, on Sunday night.

Now Forbes is fully on to it, thus:

. . . .Many researchers worry the study [IMPROVE-IT] could take years longer than this. In an editorial published in the New England Journal of Medicine Monday, John Kastelein of Utrecht Medical Center in the Netherlands wrote that it was "uncertain whether the trial will ever reach completion". . . .

Some say even 18,000 patients may not be enough to settle the question. Rory Collins, an Oxford University researcher who believes Zetia does prevent heart attacks, says there is a chance the study will give a false answer that there is not a difference. Heart attack rates in the study may be so low that it will be difficult to prove any difference between drug regimens. . . .


Senator Grassley's Letter On Arbiter 6, And Medicare Part D -- Merck's Zetia/Vytorin

Last week, we learned from Natasha Singer of the New York Times, that Sen. Grassley had written to seek a review of the level of reimbursement that federal programs might, in the future accord Vytorin/Zetia, in view of what would likely be a third unfavorable study -- a study called Arbiter 6 -HALTS. Arbiter 6 was in fact unfavorable to Zetia. Below is that letter, in full-text.[H/T to Ed Silverman at Pharmalot, for the Pdf-file linked-letter.]

In truth, it is only a matter of time -- time for the gears of the machinery of the governmental reimbursement bureaucracy to fully-engage -- before Vytorin/Zetia is a Tier III drug, or dropped to the lowest tier of reimbursement, and thus assigned the highest level of out-of-pocket co-pay -- often over 70 percent for Tier III drugs. In other words, the consumer will pay over 70% of the cost for a drug that costs ten times what a generic statin, plus niacin, does.

Here is the letter from Senator Grassley:

Novemeber 14, 2009

Via Electronic Transmission

The Honorable Kathleen Sebelius
U.S. Department of Health and Human Services
200 Independence Avenue, SW
Washington, DC 20201

The Honorable Margaret A. Hamburg, MD
U.S. Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857

Dear Secretary Sebelius and Commissioner Hamburg:

The United States Senate Committee on Finance (Committee) has jurisdiction over, among other things, the Medicare and Medicaid programs. Accordingly, the Committee has a responsibility to the more than 100 million Americans who receive health care coverage under those programs. In this capacity, I have a duty under the Constitution to conduct oversight into the actions of executive branch agencies, including the activities of the Centers for Medicare and Medicaid (CMS) and the Food and Drug Administration (FDA). Specifically I am committed to overseeing the proper administration of these agencies to ensure that taxpayer dollars are appropriately spent on safe and effective drugs and devices.

Back in February 2008, I began an inquiry into Vytorin, a drug made by Schering-Plough and Merck. Vytorin is a pill that combines the statin, simvastatin, with a drug called ezetimibe [branded as Zetia] that decreases absorption of cholesterol by the digestive tract. I initially sent the companies a letter because of reports in the media that they were not releasing the results of a trial called ENHANCE. In response to my concerns, Schering-Plough and Merck explained to me that in 2006 and 2007 they made over $300 million in Medicare Part D sales for Vytorin. When the trial results for ENHANCE were released, the companies’ own press release stated that there is no apparent gain in health benefits from using Vytorin over the much cheaper generic statin, simvastatin.

Yesterday, I read reports that the latest trial of Vytorin again found that the drug provides no apparent health benefit over a much cheaper statin. Accordingly, I would like to understand what actions that the Department of Health and Human Services, CMS, and/or the FDA may be taking in light of this information I look forward to hearing from you by no later than December 4, 2009. All documents responsive to this request should be sent electronically in PDF format to B[XXXX]_D[XXXX] If you have any questions, please do not hesitate to contact Emilia DiSanto or Paul Thacker at (202) [XXX-XXXX].


United States Senator
Ranking Member,
Committee on Finance

[Emphasis supplied.]

I think it likely that, within a year from now, Vyotrin/Zetia will be Tier III.

Tuesday, November 17, 2009

Ex-CEO Hassan Joins Warburg Pincus -- So, No Pharma Seat/Non-Compete

Peter Loftus, for Dow/WSJ, reports that Fred Hassan will advise the private equity firm -- in what Hassan calls "generalist" matters -- on behalf of clients. Okay. Check that.

. . . .Hassan told Dow Jones Newswires he would advise the firm on deals in a variety of industries. "I'm seen as a generalist," he said. . . .

Why did he say that? Well, because -- as you can readily see, Warburg Pincus' single largest investing sector is health-care, nearly double its next largest sector (click to enlarge):

And, of course, although the announcement places him in Warburg's Healthcare Group, Fred cannot advise on any Merck-competitive situations involving more than $10 million in annual revenue -- for a year -- if he wants to keep his perhaps $178 million in 'chutes. And he does. I guarantee it.

A Good Start -- On Getting At Conflicted Research

That gentleman Ed Silverman, over at the shiny new Pharmalot, has a great piece up this morning -- on efforts to encourage NIH to fund research into the effects of conflicted drug and device clinical trials:

. . . .Dozens of researchers, clinicians, and ethicists sent a letter asking the NIH to fund research on medical ethics, conflicts of interest, and industry influence on prescribing behavior. Why? They note that stimulus funding has increased the NIH budget significantly, but the agency has "no mechanism for funding research on how commercial interests affect the choice of medical therapeutics. . . ."

[The letter-signing effort is being sponsored by] Do go read it all. This is an important moment -- a point of inflection -- where we may all change the [largely non-] system, for the betterment of patient outcomes. Here is a link to the full-text letter.

Monday, November 16, 2009

The Singular Form of "Data"? Anecdote. But A Good One, Nonetheless.

This is from a CafePharma board, for Old Schering-Plough -- in a thread on Arbiter 6 - HALTS learnings -- it clearly speaks for itself:

. . . .I work for Merck and I have been taking Zocor and Niaspan for the last two years because my HDL was low and my LDL was high. I have a family history of heart disease and my doctor was concerned about me developing CAD with my numbers. I did have some flushing early on with Niaspan but it went away withing a couple of months and I have only flushed 3-4 times in my entire two years taking Niaspan. It sucks for Merck that this ARBITER-6 trial looks bad for Zetia but as a patient I am happy to know what I am taking is a better option than Vytorin. No one here should be bashing Niaspan, this drug has raised my HDL from 33 to 48 and from what my doctor says, it helps take a away the plaque in my arteries. Maybe I should be more of a company guy, but I would rather live to see 80 than die early when I could prevent it by taking Niaspan. . . .

This Arbiter 6 - HALTS Finding Was Statistically-Significant

Sometimes, a picture is worth 1,000 words.
This is one of those times (click to enlarge):

. . . .Zetia: 5% major cardiovascular event risk v. Niaspan: 1% major cardiovascular event risk. . . .