Saturday, August 15, 2009

On Avoiding the Next "Iceberg": The SEAS "Press Event", Revisited . . .

One thing that struck me, earlier this week, in Dr. Califf's New England Journal of Medicine special report, was the role he had assigned to "SEC rules" -- in forcing his hand (here are some subsequent perspectives). He said that Schering-Plough (and Merck) lawyers essentially told him that SEC rules required the disclosure of the SEAS data, and that in turn, required him to provide the IMPROVE-IT data to Schering-Plough/Merck -- under the guise of preserving "patient safety". Safety is a weighty matter, no doubt -- but it certainly seems that safety's name was mis-used, to acheive a corporate investor/press relations goal, last July.

I will leave to another day, the explanation of all the reasons Schering-Plough felt pressure to quickly disclose SEAS top-line results (given its more than 18 month delay in disclosing ENHANCE top-line results), though that occurence plainly fed the frenzy, in the SEAS press event.

Today, I'll focus on what intrigued me, about SEAS. What intrigued me, was the way these corporate lawyers apparently lept from "we must disclose SEAS top-line results", to "we must have access to, and possibly disclose, portions of IMPROVE-IT and SHARPS". The SEAS disclosure was at least arguably required, to the investing public. I am very comfortable that the second part of that "leap" was. not. required. [I may line out the weedy SEC rules-analysis, on this, in the comment-box, below. We'll see.]

Dr. Califf conducts the IMPROVE-IT study under the Clinical Trials Progam at Duke -- so let's take a look at the Duke policies on when -- and how -- events like those seen in SEAS are to be communicated to the sponsor (in this case, the Merck/Schering-Plough joint venture for cholesterol management). Here is what the Duke materials (PDF file, at page 5, of 18) have to say:

. . . .Investigator Reports. 21 CFR 312.64, 21 CFR 54, ICH 4.10,4.11, 4.13

Submit reports to sponsor at times required by regulations and the sponsor:
• Progress reports

• Safety reports: adverse events (AE) and serious adverse events (SAE)

• Final Report at study end

• Financial Disclosure

Adverse Experiences. 21 CFR 312.64(b), ICH 4.11

Report adverse events (AEs) to the sponsor in accordance with 21 CFR Part 312.64: "the investigator shall promptly report to the sponsor any adverse effect that may reasonably be regarded as caused by the drug. If the adverse effect is alarming, the investigator shall report the adverse effect immediately." In that case, immediate reporting by telephone followed by a detailed written report (within one week) to both the sponsor, and the IRB is necessary. . . .

Follow sponsor requirements for expedited reporting of serious AEs (SAE). Sponsor will define SAE criteria and timeframes for reporting in protocol. . . .

Protocol Compliance. 21 CFR 312.66, ICH 4.5

Changes to the protocol to be made only after receiving sponsor and IRB approval except to eliminate hazard to human subjects. . . .

Note that the "adverse event" did not appear in Dr. Califf's IMPROVE-IT study -- it appeared in the entirely unrelated SEAS study (except that SEAS involved some of the same study meds). So, we may safely infer that even Dr. Califf's clinical trial agreement would not have required the data turnover, on these facts.

No, the IMPROVE-IT disclosure "mandate" was -- very likely -- manufactured (by someone in Kenilworth, or Whitehouse Station), to blunt the impact of the SEAS cancer-signal disclosure. To the extent Dr. Califf was told that SEC rules required him to share his IMPROVE-IT data, with Schering-Plough, mid-study -- I believe he was misled.

That is, it is certainly true that Dr. Califf could have been (and probably was already) monitoring longitudinal variables inside his patient data-sets (per Duke's IRB protocols), in IMPROVE-IT. If he had seen a spike in cancer deaths (as was seen in SEAS), he would have reported that -- separately -- to Schering-Plough (see the Duke PI/investigational policies, below). In short, he was under no obligation, as a matter of law to unblind the data (to Merck or Schering-Plough), just because SEAS had shown a cancer signal. All Dr. Califf was required to do, was to ascertain whether he was seeing a similar spike. He has repeatedly said that he saw no such spike.

Now, it may well be that Dr. Califf's clinical trial agreement (with Merck/Schering-Plough) doesn't afford him enough independence -- that is, he may be operating under an older, more pro-sponsor form of PI agreement -- one that grants corporate sponsors wide latittude in stepping into the PI's study -- and sequestering, disclosing or burying his or her data. I'll address that thought, tomorrow -- or on Monday.

Finally, the PIs on all of the studies could have convened, and shared data, and kept Schering-Plough and Merck entirely blinded to that data. They could have done so promptly, but not in a frenzy. Then, the ad hoc PI group could have authored a paper, indicating that the SEAS cancer signal data likely looked to be the result of a fluke -- a false signal.

Instead, Schering-Plough and Merck orchestrated a press event, delayed earnings releases, and announced very-confusing top-line data (on all of the studies, combined) in the middle of an NYSE-trading session. Nothing in SEC or NYSE rules requires (or even favors) that approach.

In fact (as I wrote a year ago), at a minimum, an NYSE trading halt would have been a better approach -- until the issues could be sorted out, and communicated more carefully, and thoughtfully.

Note how investors (all trades below the dotted line), above, were damaged -- by the SEAS premature/orchestrated disclosure press event. For a hilarious, and illuminating exchange, on SEAS -- consider this, from last summer.

More, tomorrow, on reformed corporate clinical trial agreements -- and helping to ensure protection of true PI independence -- in pharmaceutical company-funded trials.

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