“The Issue is Credibility. . . in the Eyes of the Doctors” — Analyst

I think this reaction, earlier today — from a smallish-bank’s analyst — largely misses the mark as to whether there is a real problem with Vytorin, but he certainly gets it right about the crux of Schering’s most-vexing problem:

Credibility. Or the lack thereof.

. . . .The inconclusive finding Tuesday, based on further data analysis, leaves uncertainty about the safety of the drug, the New England Journal editors wrote, and many other doctors interviewed by journalists agreed.

Analyst Steve Brozak of WBB Securities said he’s never seen the medical community focus so heavily on the results of a study.

“The scrutiny isn’t because of the results,” Brozak said. “I think the issue is credibility” of the pharmaceutical industry in the eyes of doctors.

He said doctors feel so badly burnt by safety problems emerging after drugs become blockbusters that they have become hypercritical.

Both the new findings and a long-delayed study released in March indicate that Vytorin isn’t better than one of its components, now-generic Zocor, at preventing damage to the heart’s aortic valve from worsening or at limiting plaque buildup in arteries. . . .

That analyst got it at least half-right.

"The Issue is Credibility. . . in the Eyes of the Doctors" — Analyst

I think this reaction, earlier today — from a smallish-bank’s analyst — largely misses the mark as to whether there is a real problem with Vytorin, but he certainly gets it right about the crux of Schering’s most-vexing problem:

Credibility. Or the lack thereof.

. . . .The inconclusive finding Tuesday, based on further data analysis, leaves uncertainty about the safety of the drug, the New England Journal editors wrote, and many other doctors interviewed by journalists agreed.

Analyst Steve Brozak of WBB Securities said he’s never seen the medical community focus so heavily on the results of a study.

“The scrutiny isn’t because of the results,” Brozak said. “I think the issue is credibility” of the pharmaceutical industry in the eyes of doctors.

He said doctors feel so badly burnt by safety problems emerging after drugs become blockbusters that they have become hypercritical.

Both the new findings and a long-delayed study released in March indicate that Vytorin isn’t better than one of its components, now-generic Zocor, at preventing damage to the heart’s aortic valve from worsening or at limiting plaque buildup in arteries. . . .

That analyst got it at least half-right.

Ed Silverman, on a “Secret” SEAS Report to FDA — per Congressional Committees’ Letters, Today

I cannot do it justice — just go read it — and comment there.

H/T Salmon (in the comments, below)!

In any event, here’s the latest letter — in full text:

September 2, 2008

Mr. Fred Hassan
Chairman and CEO
Schering-Plough Corporation
2000 Galloping Hill Road
Kenilworth, NJ 07033

Mr. Richard T. Clark
Chairman, President, and CEO
Merck & Co., Inc.
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889

Dear Mr. Hassan and Mr. Clark:

Under Rules X and XI of the Rules of the U.S. House of Representatives, the Committee on Energy and Commerce and its Subcommittee on Oversight and Investigations are continuing to investigate the safety and effectiveness of Vytorin, a prescription drug manufactured by Merck and Schering-Plough.

We have received a copy of Sir Richard Peto’s consultant report on the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study, which was submitted to the U.S. Food and Drug Administration (FDA). At our July 22, 2008, meeting with your counsel, we were advised that Dr. Peto’s report would provide a complete assessment of Vytorin’s association with cancer in the SEAS study and provide a full review of available data. After reviewing the five-page report, however, we were somewhat surprised to discover that the report contains little more than the information that was presented at the July 21, 2008, press conference announcing the SEAS results. We are also at a loss to understand why this report was kept by you from our Committee and the public.

We are concerned that an esteemed scientific consultant to Merck and Schering-Plough may have generated a secret report to FDA—a report whose contents may have been misrepresented to our staff as the report itself appears to contain information which is publicly available. Therefore, we ask that you provide answers to the following questions in writing:

1. Is the attached report the totality of Dr. Peto’s submission to FDA?

2. Why was Dr. Peto’s consultant study not made publicly available?

3. When did Merck, Schering-Plough, the Merck/Schering-Plough joint venture, or any of their agents, attorneys, or lobbyists first contact Dr. Peto about his consultant report?

4. When was Dr. Peto’s report submitted to FDA?

5. Was Dr. Peto’s report reviewed or edited prior to its submission to FDA by anyone from Merck, Schering-Plough, the Merck/Schering-Plough joint venture, or any of their agents, attorneys, or lobbyists? Please supply any drafts and all other documents that describe the review or editing of the report.

6. Has Dr. Peto prepared any other analysis of the association (or lack thereof) between Vytorin and cancer for any other regulatory agency or peer-review journal?

7. What role, if any, did Merck, Schering-Plough, the Merck/Schering-Plough joint venture, or any of their agents, attorneys, or lobbyists have in the preparation of the attached Peto report and decision to submit it to FDA?

Finally, we ask that you make Dr. Peto available for a staff interview as soon as possible.

Please deliver copies of your responses to the Subcommittee on Oversight and Investigations of the Committee on Energy and Commerce, Room 316, Ford House Office Building, no later than two weeks from the date of this letter. After review of your response, we may require additional records and/or staff interviews with company officials.

Thank you for your prompt attention to this matter.

Sincerely,

Perhaps the most-ominous development in this letter is the escalating sense that Chairmen Dingell and Stupak now believe Schering (and/or its counsel) has been less than candid in responding to the Congressional Committees’ processes. This is the sort of stuff that leads to Congressional subpoenas — and ultimately — indictments, if the subpoenas are unavailing.

[Here's the August 21, 2008 letter -- in full text.]

Ed Silverman, on a "Secret" SEAS Report to FDA — per Congressional Committees’ Letters, Today

I cannot do it justice — just go read it — and comment there.

H/T Salmon (in the comments, below)!

In any event, here’s the latest letter — in full text:

September 2, 2008

Mr. Fred Hassan
Chairman and CEO
Schering-Plough Corporation
2000 Galloping Hill Road
Kenilworth, NJ 07033

Mr. Richard T. Clark
Chairman, President, and CEO
Merck & Co., Inc.
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889

Dear Mr. Hassan and Mr. Clark:

Under Rules X and XI of the Rules of the U.S. House of Representatives, the Committee on Energy and Commerce and its Subcommittee on Oversight and Investigations are continuing to investigate the safety and effectiveness of Vytorin, a prescription drug manufactured by Merck and Schering-Plough.

We have received a copy of Sir Richard Peto’s consultant report on the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study, which was submitted to the U.S. Food and Drug Administration (FDA). At our July 22, 2008, meeting with your counsel, we were advised that Dr. Peto’s report would provide a complete assessment of Vytorin’s association with cancer in the SEAS study and provide a full review of available data. After reviewing the five-page report, however, we were somewhat surprised to discover that the report contains little more than the information that was presented at the July 21, 2008, press conference announcing the SEAS results. We are also at a loss to understand why this report was kept by you from our Committee and the public.

We are concerned that an esteemed scientific consultant to Merck and Schering-Plough may have generated a secret report to FDA—a report whose contents may have been misrepresented to our staff as the report itself appears to contain information which is publicly available. Therefore, we ask that you provide answers to the following questions in writing:

1. Is the attached report the totality of Dr. Peto’s submission to FDA?

2. Why was Dr. Peto’s consultant study not made publicly available?

3. When did Merck, Schering-Plough, the Merck/Schering-Plough joint venture, or any of their agents, attorneys, or lobbyists first contact Dr. Peto about his consultant report?

4. When was Dr. Peto’s report submitted to FDA?

5. Was Dr. Peto’s report reviewed or edited prior to its submission to FDA by anyone from Merck, Schering-Plough, the Merck/Schering-Plough joint venture, or any of their agents, attorneys, or lobbyists? Please supply any drafts and all other documents that describe the review or editing of the report.

6. Has Dr. Peto prepared any other analysis of the association (or lack thereof) between Vytorin and cancer for any other regulatory agency or peer-review journal?

7. What role, if any, did Merck, Schering-Plough, the Merck/Schering-Plough joint venture, or any of their agents, attorneys, or lobbyists have in the preparation of the attached Peto report and decision to submit it to FDA?

Finally, we ask that you make Dr. Peto available for a staff interview as soon as possible.

Please deliver copies of your responses to the Subcommittee on Oversight and Investigations of the Committee on Energy and Commerce, Room 316, Ford House Office Building, no later than two weeks from the date of this letter. After review of your response, we may require additional records and/or staff interviews with company officials.

Thank you for your prompt attention to this matter.

Sincerely,

Perhaps the most-ominous development in this letter is the escalating sense that Chairmen Dingell and Stupak now believe Schering (and/or its counsel) has been less than candid in responding to the Congressional Committees’ processes. This is the sort of stuff that leads to Congressional subpoenas — and ultimately — indictments, if the subpoenas are unavailing.

[Here's the August 21, 2008 letter -- in full text.]

Latest Reuters Story — Filed From the 2008 ESC — in Munich

On the SEAS-Vytorin-cancer debate — do read the full article — some of the latest pull-quotes, from experts attending the debate:

. . . .an editorial in the influential New England Medical Journal, which published the full data from the Vytorin study online, said the safety of the drug was now in doubt, and several leading doctors also expressed concerns.

The full report on the trial, involving 1,873 patients, showed a total of 105 cancer cases among Vytorin patients compared with 70 taking a placebo. That was an upward revision from the totals of 93 and 65 reported in July.

Lead investigator Terje Pedersen of Ulleval University Hospital in Oslo, however, said cross-checks with cancer rates in two much larger, ongoing trials simply did not support the idea that Vytorin was linked to cancer.

Other leading cardiologists were not so sure.

“I think the jury is still out as to whether there’s a cancer signal,” said Dr. Gordon Tomaselli, chief of cardiology at Johns Hopkins Hospital, and spokesman for the American Heart Association. Tomaselli was not connected to the research. . . .

“I am quite concerned,” Heinz Drexel, professor of medicine at the University of Innsbruck in Austria told Reuters. “At the moment, I would not take ezetimibe myself,” Drexel said, although he urged patients not to stop treatment without consulting their doctor. . . .

This isn’t going to play very well. . . . for Schering-Plough. I cannot explain why this ESC debate isn’t the updated lede to the New York Times “Evidence Gap” series, this morning. . . .

Latest Reuters Story — Filed From the 2008 ESC — in Munich

On the SEAS-Vytorin-cancer debate — do read the full article — some of the latest pull-quotes, from experts attending the debate:

. . . .an editorial in the influential New England Medical Journal, which published the full data from the Vytorin study online, said the safety of the drug was now in doubt, and several leading doctors also expressed concerns.

The full report on the trial, involving 1,873 patients, showed a total of 105 cancer cases among Vytorin patients compared with 70 taking a placebo. That was an upward revision from the totals of 93 and 65 reported in July.

Lead investigator Terje Pedersen of Ulleval University Hospital in Oslo, however, said cross-checks with cancer rates in two much larger, ongoing trials simply did not support the idea that Vytorin was linked to cancer.

Other leading cardiologists were not so sure.

“I think the jury is still out as to whether there’s a cancer signal,” said Dr. Gordon Tomaselli, chief of cardiology at Johns Hopkins Hospital, and spokesman for the American Heart Association. Tomaselli was not connected to the research. . . .

“I am quite concerned,” Heinz Drexel, professor of medicine at the University of Innsbruck in Austria told Reuters. “At the moment, I would not take ezetimibe myself,” Drexel said, although he urged patients not to stop treatment without consulting their doctor. . . .

This isn’t going to play very well. . . . for Schering-Plough. I cannot explain why this ESC debate isn’t the updated lede to the New York Times “Evidence Gap” series, this morning. . . .

New England Journal of Medicine Editorial — On SEAS, and Cancers. . . .

Right here. Let’s listen in — on “efficacy” first, then cancer — shall we? Yes, let’s:

. . . .There was little uncertainty, however, that the primary end point was null, since the hazard ratio for treatment relative to placebo was 0.96, with a 95% confidence interval (CI) of 0.83 to 1.12.

There was, however, an unexpected finding in the trial. An excess of incident cancers was observed in the simvastatin–ezetimibe group, with 105 in that group as compared with 70 in the placebo group (P=0.01). There was an increase in the incidence of a variety of cancers, including prostate, gastrointestinal, and skin cancers. Also, deaths from cancer were more frequent in the active-treatment group (39 deaths, vs. 23 in the placebo group), although the difference achieved only borderline statistical significance (P=0.05).

The SEAS investigators suggested that the difference in incident cancers could have occurred by chance but acknowledged that the unanticipated findings should be pursued through additional studies. Using existing data, the Clinical Trial Service Unit and Epidemiological Studies Unit at Oxford University were able to undertake such a study. The researchers had access to interim cancer data in two large ongoing clinical trials, the Study of Heart and Renal Protection (SHARP) (NCT00125593 [ClinicalTrials.gov] ) and the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) (NCT00202878 [ClinicalTrials.gov] ), which were unblinded only for cancer outcomes but provided relatively short follow-up (a mean of 2.7 years and 1.0 year, respectively, as compared with 4.1 years in the SEAS trial). Because of the large size of these trials, however, they provided more cancer data than the SEAS trial, even in patients with 3 or more years of follow-up. The Oxford researchers examined the data to determine whether the imbalance in incident cancers and cancer deaths observed in the SEAS trial was replicated in the ongoing trials. They asked whether the increased risk of cancer in the SEAS trial reflected a previously unobserved true signal or was simply the play of chance. It should be noted that the Oxford group is also conducting the SHARP trial and received research funding from Merck and Schering-Plough for the work. The authors note, however, that their analyses were performed independently of the companies.

The analysis by the Oxford group, reported in this issue of the Journal failed to confirm the increase in cancer incidence noted in the SEAS trial (P=0.61 for the incidence of all cancers in the combined IMPROVE-IT and SHARP active-treatment groups as compared with the placebo groups). However, as in the SEAS trial, a nonsignificant increase in cancer mortality was observed (P=0.07). It is important to note that none of the three trials were designed primarily to address cancer risk. However, cancer mortality is an end point that would be expected to be reliable.

. . . .Although the Oxford group may ultimately prove to be correct, it is appropriate to raise a note of caution. Whether the increased mortality risk is due solely to the play of chance is uncertain. Ezetimibe interferes with the gastrointestinal absorption not only of cholesterol, but also of other molecular entities that could conceivably affect the growth of cancer cells. The fact that the combined data from all three trials showed an increase in cancer mortality with ezetimibe should not be assumed to be a chance finding until further data are in. It is appropriate that SHARP and IMPROVE-IT continue. Careful follow-up of the patients in these trials will be essential, and other existing data sets on ezetimibe-treated patients should be analyzed for cancer end points. The Food and Drug Administration has already announced that during the next few months it will conduct its own analysis of the potential cancer hazard of ezetimibe. . . .

[Emphasis supplied.]

I think it is high-time to listen to these independent experts’ voices — voices that stand to make no money from the companies involved. Voices that want science, not just commerce, to be advanced.

New England Journal of Medicine Editorial — On SEAS, and Cancers. . . .

Right here. Let’s listen in — on “efficacy” first, then cancer — shall we? Yes, let’s:

. . . .There was little uncertainty, however, that the primary end point was null, since the hazard ratio for treatment relative to placebo was 0.96, with a 95% confidence interval (CI) of 0.83 to 1.12.

There was, however, an unexpected finding in the trial. An excess of incident cancers was observed in the simvastatin–ezetimibe group, with 105 in that group as compared with 70 in the placebo group (P=0.01). There was an increase in the incidence of a variety of cancers, including prostate, gastrointestinal, and skin cancers. Also, deaths from cancer were more frequent in the active-treatment group (39 deaths, vs. 23 in the placebo group), although the difference achieved only borderline statistical significance (P=0.05).

The SEAS investigators suggested that the difference in incident cancers could have occurred by chance but acknowledged that the unanticipated findings should be pursued through additional studies. Using existing data, the Clinical Trial Service Unit and Epidemiological Studies Unit at Oxford University were able to undertake such a study. The researchers had access to interim cancer data in two large ongoing clinical trials, the Study of Heart and Renal Protection (SHARP) (NCT00125593 [ClinicalTrials.gov] ) and the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) (NCT00202878 [ClinicalTrials.gov] ), which were unblinded only for cancer outcomes but provided relatively short follow-up (a mean of 2.7 years and 1.0 year, respectively, as compared with 4.1 years in the SEAS trial). Because of the large size of these trials, however, they provided more cancer data than the SEAS trial, even in patients with 3 or more years of follow-up. The Oxford researchers examined the data to determine whether the imbalance in incident cancers and cancer deaths observed in the SEAS trial was replicated in the ongoing trials. They asked whether the increased risk of cancer in the SEAS trial reflected a previously unobserved true signal or was simply the play of chance. It should be noted that the Oxford group is also conducting the SHARP trial and received research funding from Merck and Schering-Plough for the work. The authors note, however, that their analyses were performed independently of the companies.

The analysis by the Oxford group, reported in this issue of the Journal failed to confirm the increase in cancer incidence noted in the SEAS trial (P=0.61 for the incidence of all cancers in the combined IMPROVE-IT and SHARP active-treatment groups as compared with the placebo groups). However, as in the SEAS trial, a nonsignificant increase in cancer mortality was observed (P=0.07). It is important to note that none of the three trials were designed primarily to address cancer risk. However, cancer mortality is an end point that would be expected to be reliable.

. . . .Although the Oxford group may ultimately prove to be correct, it is appropriate to raise a note of caution. Whether the increased mortality risk is due solely to the play of chance is uncertain. Ezetimibe interferes with the gastrointestinal absorption not only of cholesterol, but also of other molecular entities that could conceivably affect the growth of cancer cells. The fact that the combined data from all three trials showed an increase in cancer mortality with ezetimibe should not be assumed to be a chance finding until further data are in. It is appropriate that SHARP and IMPROVE-IT continue. Careful follow-up of the patients in these trials will be essential, and other existing data sets on ezetimibe-treated patients should be analyzed for cancer end points. The Food and Drug Administration has already announced that during the next few months it will conduct its own analysis of the potential cancer hazard of ezetimibe. . . .

[Emphasis supplied.]

I think it is high-time to listen to these independent experts’ voices — voices that stand to make no money from the companies involved. Voices that want science, not just commerce, to be advanced.

What Will ESC Bring to Vytorin’s SEAS, in Munich, Germany, on Tuseday Morning?

The full results of the Vytorin SEAS trial will be vetted and analyzed — and not just by individuals paid by the companies involved.

What will the ESC Meeting in Munich, Germany bring? [Here's Matt Herper's most-recent piece on it, FYI.] Will it all be as dramatic — and disastrous — as the ACC was — at the end of March 2008? We’ll soon know. I’ll have it all — right here — essentially live. Or, live-blogged, at least.

Do tune in.

~~~~~~~~~~~~~
UPDATED — 09.02.08 @7 AM EDT
~~~~~~~~~~~~

The results are in — and two slides tell the story — a link to the full PDF of slide deck here — but pictures are worth thousands of words, no? [As ever, click to enlarge.]

And, for what it is worth — Dr. Peto’s defense of his SEAS conclusions (cancer incidence likely due to “chance“) may be found in the NEJM.

Matt Herper, of Forbes, has an updated, and rather comprehensive piece out this morning (Tuesday, September 2, 2008), too.

What Will ESC Bring to Vytorin’s SEAS, in Munich, Germany, on Tuseday Morning?

The full results of the Vytorin SEAS trial will be vetted and analyzed — and not just by individuals paid by the companies involved.

What will the ESC Meeting in Munich, Germany bring? [Here's Matt Herper's most-recent piece on it, FYI.] Will it all be as dramatic — and disastrous — as the ACC was — at the end of March 2008? We’ll soon know. I’ll have it all — right here — essentially live. Or, live-blogged, at least.

Do tune in.

~~~~~~~~~~~~~~
UPDATED — 09.02.08 @7 AM EDT
~~~~~~~~~~~~~

The results are in — and two slides tell the story — a link to the full PDF of slide deck here — but pictures are worth thousands of words, no? [As ever, click to enlarge.]

And, for what it is worth — Dr. Peto’s defense of his SEAS conclusions (cancer incidence likely due to “chance“) may be found in the NEJM.

Matt Herper, of Forbes, has an updated, and rather comprehensive piece out this morning (Tuesday September 2, 2008), too.