(II)

(III)

EXECUTIVE SUMMARY

This staff report was developed over the last 2 years by U.S. Senate Committee on Finance investigators who reviewed over 250,000 pages of documents provided by GlaxoSmithKline (GSK/the Company), the Food and Drug Administration (FDA), the University of North Carolina, and others. Committee investigators also conducted numerous interviews and phone calls with GSK, the FDA, and anonymous whistleblowers.

Committee staff began this investigation in May 2007 after a study was published in the New England Journal of Medicine, showing a link between the diabetes drug Avandia (rosiglitazone) and heart attacks. However, the reviewed evidence suggests that GSK knew for several years prior to this study that there were possible cardiac risks associated with Avandia. As a result, it can be argued that GSK had a duty to warn patients and the FDA of the Company's concerns. Instead, GSK executives attempted to intimidate independent physicians, focused on strategies to minimize or misrepresent findings that Avandia may increase cardiovascular risk, and sought ways to downplay findings that a competing drug might reduce cardiovascular risk.

When an independent scientist sought to publish a study in 2007 pointing out the cardiovascular risk of Avandia, GSK acquired a leaked copy of that study from one of its consultants prior to the study being published. The company's own experts analyzed the study, found it to be statistically reliable, and then attacked the soundness of that study in press releases and public comments. GSK also sought to counter the study's findings by quickly releasing preliminary results from its own study on Avandia, even though the company's internal communications established that its study was not primarily designed to answer questions about cardiovascular risk.

INTRODUCTION

For the past 4 years, the staff of the Senate Committee on Finance (Committee) has been examining allegations that pharmaceutical companies attempt to manipulate science to improve the marketability of drugs, potentially at the expense of public safety. These allegations include intimidating scientists, ghostwriting studies for academic researchers, suppressing studies that may show that a drug could be dangerous, and selecting data to publish results that favor one product over another.

In November 2007, the Committee reported on the intimidation of Dr. John Buse, a professor of medicine at the University of

(1)

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North Carolina (UNC) who specializes in diabetes.¹ Based partly on internal documents from GSK, the Committee reported on what appeared to be an orchestrated plan by GSK to stifle the opinion of Dr. Buse in 1999. At that time, Dr. Buse argued at several medical conferences and in letters to the FDA that GSK's diabetes drug

Avandia may cause cardiovascular problems.²

According to GSK emails made available to the Committee, GSK executives labeled Dr. Buse a ''renegade'' and silenced his concerns about Avandia by complaining to his superiors at UNC and threatening a lawsuit. The call to Dr. Buse's superiors was made by Dr. Tachi Yamada, then GSK's head of research. In discussions with Committee investigators, Dr. Yamada denied that his call was meant to intimidate Dr. Buse. Instead, Dr. Yamada argued that he had made the call to determine if Dr. Buse was making legitimate statements or if he was possibly on the payroll of a GSK rival.

Dr. Yamada also made a call to the University of Pennsylvania (Penn) regarding two physicians who were about to publish a case study that Avandia may have caused liver problems in one of their patients.³ Committee investigators contacted the two Penn physicians. Both physicians chose to remain anonymous because of concerns about possible retaliation by pharmaceutical companies.⁴

In hindsight, both physicians agree that Avandia probably does not cause liver problems. However, in 1999 Avandia was a new drug and the two physicians wanted to publish a report on their patient who had liver failure while on Avandia. Both physicians also said that the calls placed by GSK officials, including Dr. Yamada, were highly unprofessional and had a chilling effect on their professional activity.⁵

Commenting on the calls by GSK, one of the two physicians told Committee investigators, ''It was really ridiculous. It was a case report and I had no intention of bringing down GSK. I just wanted people to know.'' The physician added, ''It left a really bad taste in my mouth. After that happened, I said that I would never work for

a drug company.'' ⁶

Also commenting on the calls from GSK, the other physician told Committee investigators, ''I have never encountered anything like this in my career. I don't even know how [GSK] knew that we were publishing. It's the kind of thing you imagine happening on TV.'' ⁷

¹ Committee Staff Report to the Chairman and Ranking Member, Committee on Finance, United States Senate, November 2007, ''The Intimidation of Dr. John Buse and the Diabetes

Drug Avandia.''

² Id.

³ According to GSK internal emails, Dr. Yamada placed a call to senior officials at the University of Pennsylvania Medical School after receiving the following email on August 4, 1999, from

a GSK executive:

Tachi, I need you to place another call to your contacts at U Penn. The situation is that

Dr. NAME REDACTED is apparently on the Takeda speaker's circuit. He is reported to be speaking about the case and implicating Avandia. Obviously, this is not in anyone's best interest.

The following day, Dr. Yamada responded:

What exactly do you want me [sic] ask for? Obviously, we are not going to be able to pre-

vent Dr. NAME REDACTED from speaking on behalf of Takeda. I would be happy to speak with either NAME REDACTED (Dept. Chair) or NAME REDACTED (Hepatology Chief) but we need to be clear on the message we want to send.

⁴ Staff interviews, December 2007. ⁵ Id. ⁶ Id. ⁷ Id.

3

In an interview with Committee investigators, Dr. Yamada stated that he had no intention of intimidating the two physicians at Penn, and that he had merely placed the call because he was concerned that Avandia may cause liver problems.

In a December 2007 floor speech, Senator Grassley revealed that Dr. Steve Haffner, a professor of medicine at the University of Texas Health Sciences Center, San Antonio, and a consultant for GSK, leaked to GSK the draft of a study critical of Avandia that was to appear in the New England Journal of Medicine (NEJM).⁸ Dr. Haffner was entrusted with a confidential copy of the manuscript draft because he was peer-reviewing the study for the NEJM. The study's lead author, Dr. Steven Nissen, professor of cardiology at the Cleveland Clinic, found that Avandia was associated with a 43-percent increased risk of heart attacks, one of the main health outcomes physicians hoped to avoid by treating diabetic patients with medication.⁹

According to documents produced by GSK, the leaked manuscript was widely disseminated within the Company, and allowed GSK to launch a public relations plan to protect Avandia, a multi-billion dollar product.¹⁰ The Committee staff reviewed documents showing that over 40 executives at GSK received and/or learned of the results in the leaked study, including then CEO Dr. Jean-Pierre Garnier; head of research, Dr. Moncef Slaoui; Vice President of Corporate Media Relations, Nancy Pekarek; and GSK Senior Advisor, Sir Colin Dollery.¹¹

Before Dr. Nissen's study on Avandia was published, GSK's statistical experts were examining the study for potential flaws. In addition, GSK officials were drafting ''key messages'' to undermine the main conclusion of the Nissen study. GSK had already published several large trials on Avandia (rosiglitazone) including studies named ADOPT and DREAM. After Nissen's study was published, GSK began publicly referencing those trials, as well as another trial called RECORD, in what appeared to be an effort to further repudiate any link between Avandia and heart attacks. RECORD is a study GSK had been conducting for several years. GSK later published the interim results of the RECORD trial in what appeared to be an attempt to cast doubt on Nissen's results.

However, internal GSK emails indicate that GSK executives, not the study's independent steering committee, made the final decision to publish the RECORD trial results. Further, based on a review of emails, it can be argued that the authors of the RECORD trial appeared more concerned about countering claims that Avandia may be associated with heart attacks, than in trying to understand the underlying science. While circulating a draft of a manuscript on the RECORD trial, one of the authors wrote to his

⁸ Stephanie Saul, ''Doctor accused of leak to drug maker,'' The New York Times, January 30, 2008.

⁹ Steven E. Nissen et. al. ''Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes'' the New England Journal of Medicine, May 21, 2007.

¹⁰In 2006, global sales of Avandia reached nearly $3.4 billion. Citation: Gardiner Harris, ''Report Backs Up Warnings About Drug Avandia,'' The New York Times, July 27, 2007.

¹¹ Letter from Daniel F. Donovan III, counsel to GSK, to Senator Grassley, dated May 23, 2008.

4

colleagues, ''[W]hat's to stop [Nissen] adding the events from

RECORD to his meta-analysis and re-enforcing his view?'' ¹²

Further, after the authors of the RECORD study submitted their paper to the NEJM, one of the peer reviewers and several of the NEJM editors replied, ''an explanation for the continued use of

[Avandia] is needed in this manuscript.'' ¹³

Committee investigators also learned that GSK was aware since at least 2004 that the RECORD trial was statistically inadequate, or ''underpowered'' ¹⁴ to answer questions regarding cardiovascular safety. Such ''inconclusive'' results could be favorable to GSK and the marketing strategy for Avandia. Further, experts were advising GSK since 2004 about the possible biological mechanisms related to why Avandia may cause an increased risk for heart attacks. However, GSK appeared eager to design studies to prove that Avandia was safer than its competitor ACTOS (pioglitazone), which is manufactured by Takeda.

At a July 30, 2007, safety panel on Avandia, Food and Drug Ad- ministration (FDA) scientists presented an analysis estimating that Avandia use was associated with approximately 83,000 excess heart attacks since the drug came on the market.¹⁵ Had GSK considered Avandia's potential increased cardiovascular risk more seriously when the issue was first raised in 1999 by Dr. Buse, as well as by some of their own consultants in later years, some of these heart attacks may have been avoided.

RESPONSE TO THE NISSEN STUDY

In March 2007, GSK held a meeting with company officials and

academic advisors to discuss several studies on Avandia and its cardiac risks and benefits.¹⁶ Several presentations were made about studies on Avandia's possible cardiac risk. During the discussion of a GSK meta-analysis (integrated study) and a study GSK commissioned by Ingenix, GSK noted that the academic advisors

stated the following:

Dr. NAME REDACTED commented that the [cardiovascular] effect seen in the Integrated Clinical Trials Analyses with rosiglitazone was small but real, and that it is counter to the proposed [cardiovascular] benefits associated with Avandia. Dr. NAME REDACTED agreed, noted that all data point to rosiglitazone having a hazard ratio greater than unity. . . . Dr. NAME REDACTED summarized the discussion on the Integrated Clinical Trials data by stating that rosiglitazone causes weight gain and

edema, leading to a greater number of events.¹⁷

¹² Email ¹³ Letter

1, 2007.

from John McMurray to Nigel Jones et al., dated May 29, 2007.

from the New England Journal of Medicine to Philip H. Home, M.D., dated June

¹⁴ A study is underpowered if it does not meet the statistical requirements to adequately measure a medical outcome or study endpoint.

¹⁵ FDA, ''Assessment of the cardiovascular risks and health benefits of rosiglitazone,'' presented July 30, 2007. Estimate presented publicly at FDA advisory committee meeting.

¹⁶ Internal GSK report, ''GSK Diabetes Franchise Cardiology Advisory Board,'' meeting held March 1-2, 2007, report dated March 16, 2007.

¹⁷ Id.

5

Moreover, during the discussion of the DREAM ¹⁸ trial, a cardiologist from Stanford stated:

[T]he diabetes prevention afforded by rosiglitazone was

very impressive, but there was no cardioprotective benefit. He then asked what the point of diabetes prevention is if there is no cardiovascular benefit.¹⁹ [Emphasis

added]

When discussing ADOPT,²⁰ the academic advisors concluded

that, ''The data in ADOPT and DREAM as well as in the CV Clinical Trials are consistent in indicating a signal for heart failure and ischemic events.'' According to GSK interal documents, GSK's experts were discussing problems with DREAM as early as 2006.²¹

Around this same time, Dr. Steven Nissen began studying the potential cardiac risks of Avandia, by reviewing data found in previously published studies. He placed several requests to GSK asking for patient level data on several studies published about Avandia. However, GSK would provide the requested data only if Dr. Nissen agreed to use a GSK statistician for the analysis.²² Dr. Nissen refused to use the Company's statistician, citing a need to

maintain independence.²³

On May 2, 2007, Dr. Nissen submitted an analysis of 42 published and unpublished clinical trials on Avandia to the NEJM for peer review and publication. NEJM then sent confidential copies of the study to several independent experts, including Dr. Steve Haffner, to peer review the Nissen study. According to NEJM, peer reviewers must acknowledge in writing that the material they are reviewing is confidential, not to be shared with others, and is to be destroyed or returned to the medical journal after a review is com-

pleted.²⁴

However, the very next day, May 3, 2007, Dr. Haffner faxed Dr. Nissen's unpublished study to a GSK executive. Dr. Haffner wrote ''confidential'' on the fax cover sheet and checked a box marked ''urgent.'' ²⁵

LEAKED MANUSCRIPT AND A SCRAMBLED DEFENSE

One day after receiving the unpublished study from Dr. Haffner,

GSK produced a detailed, 8-page analysis of Dr. Nissen's paper,

¹⁸ DREAM is an acronym for ''The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication.'' DREAM is an international, multi-center, randomized, double-blind diabetes trial involving 5,269 patients from 21 countries. The DREAM study was conducted by the Population Health Research Institute and published in the middle of 2006.

¹⁹ Internal GSK report, ''GSK Diabetes Franchise Cardiology Advisory Board,'' meeting held March 1-2, 2007, report dated March 16, 2007.

²⁰ ADOPT is an acronym for ''A Diabetes Outcome Progression Trial.'' ADOPT is a randomized, double-blind, parallel-group study conducted on ∼3,600 drug-naive patients designed to

measure the efficacy of rosiglitazone in controlling the glycemic levels of Type 2 diabetes patients.

²¹ Internal GSK slide show, ''DREAM: Results of the Rampiril Arm,'' undated but several slides state ''updated Sept 6/06.'' One particular slide titled, ''DREAM vs. Previous Trials,'' notes that DREAM ''was low power to detect differences in CVD events (short duration, low risk participants).'' The summary and conclusions slide on DREAM finds that the study had ''too few

events to draw any conclusion re the effect on other CV events or death.''

²² Internal GSK emails, dated May 3, 2007. ''I have made oit [sic] clear in my letter of Feb 26 [to Dr. Nissen] that analyses should be conducted by GSK personnel pursuant to prospectively agreed analyses plan.''

²³ Multiple staff discussions with Dr. Steven Nissen, from June 2007 to the present. ²⁴ Email from NEJM editor to Committee staff, dated December 18, 2007. ²⁵ Steven Haffner, fax to Alex Cobitz, dated May 3, 2007.

6

weeks before the paper's public release.²⁶ The GSK statistician attempted to find deficiencies in Nissen's meta-analysis but noted, ''The selection of trials therefore appears to be thorough, though others more familiar with the trials can comment more knowledgeably.'' ²⁷

The GSK statistician also performed a regression analysis ²⁸ on each study that Dr. Nissen used in his meta-analysis to see if the effects of myocardial infarction and/or cardiovascular death would still appear. The statistician stated, ''These results are very similar to the conclusion from the [Nissen] paper using the Peto method.²⁹ As such there is no statistical reason for disregarding the findings

as presented.'' ³⁰

The GSK statistical analysis was circulated to senior executives within GSK. These executives then discussed several large trials, such as RECORD, DREAM and ADOPT that GSK could use to combat Dr. Nissen's analysis. RECORD was an ongoing trial that had not been published. On the other hand, DREAM and ADOPT were published and were included in Dr. Nissen's analysis. GSK, as well as the FDA, had also performed their own meta-analyses.

Both meta-analyses were consistent with Dr. Nissen's results.³¹

On May 8, 2007, Dr. Moncef Slaoui, head of research at GSK, wrote an email to several company executives.³² Commenting on the meta-analyses, he wrote:

—FDA, Nissen and GSK all come to comparable conclusions regarding increased risk for ischemic events, ranging

from 30 percent to 43 percent!

—FDA and Nissen (but no final data from GSK [to] date)

reach the conclusion of an [hazard ratio] for death (CHF

+ IHD) of 1.72 or 1.75! ³³

Dr. Slaoui also noted in this email that a GSK commissioned

study by Ingenix did not find any significant problems with rosiglitazone. Ingenix had performed an epidemiological study of Avandia. While medical experts place greater importance on a clinical trial over an epidemiological study, Dr. Slaoui sought to highlight the Ingenix results. He also expressed concern that a beneficial effect was observed (6 to 16 percent) in the PROactive ³⁴

study of ACTOS in high-risk cardiovascular disease patients.³⁵

²⁶ Internal GSK document, ''Report on the article by SE Nissen & K Wolski 'Effect of rosiglitazone on the risk of myocardial infarction and cardiovascular death.' '' Research Statistic Unit, GSK, DRAFT May 4, 2007.

²⁷ Id.

²⁸ A statistical method that allows data to be simultaneously adjusted for differences in the

distribution of a wide variety of measured risk factors that may exist between patients in a study treated with one therapy compared to those treated with another or with placebo.

²⁹ Peto Method is a widely used way of combining odds ratios in meta-analysis.

³⁰ Internal GSK document, ''Report on the article by SE Nissen & K Wolski 'Effect of rosiglitazone on the risk of myocardial infarction and cardiovascular death.' '' Research Statistic Unit, GSK, DRAFT May 4, 2007.

³¹ Internal GSK email from Moncef Slaoui to multiple GSK executives, dated May 8, 2007. ³² Id. ³³ Id.

³⁴ PROactive—''PROspective PioglitAzone Clinical Trial In MacroVascular Events Study.'' The

PROactive Study was initiated as a randomized, double-blind, placebo-controlled cardiovascular outcome study to determine the effects of pioglitazone on reducing the risk of a wide variety of cardiovascular events as well as to determine its ability to control blood glucose levels of patients with Type 2 Diabetes. The study was commissioned by Takeda pharmaceuticals, a company that competes directly with GSK and produces a similar diabetes medication called ACTOS.

³⁵ Internal GSK email from Moncef Slaoui to multiple GSK executives, dated May 8, 2007.

7

Dr. Slaoui asked, ''How can we reinforce the value of the

[Ingenix] study? The FDA criticizes the fact that we excluded cases of sudden cardiac death.'' ³⁶ He then asked his team to strategize

further on the issue:

[W]hat studies could we offer the FDA to further assess

the contradictory data between the integrated study and the two others? can we expand Record? Propose something else (very high risk patients? ok? ethical?), compare to

Actos for superiority on some end points? ³⁷

By May 9, 2007, GSK began drafting ''key messages'' to counteract the findings of the Nissen study.³⁸ In an email, GSK's Vice President for Corporate Media Relations noted, ''The Nissen analysis is one way of looking at the data, but it doesn't reflect all we know about the safety of this medicine. . . . [W]e are not seeing a proven link between Avandia and increased cardiovascular

deaths. . . .'' ³⁹

On May 9, 2007, Sir Colin Dollery, a senior consultant to GSK, laid out many of the problems with Avandia in an email to Dr.

Slaoui and others. He wrote:

To a great extent, the numbers are the numbers, the [Nissen] analysis is very similar to our own. . . . We cannot undermine the numbers but I think they can be explained so

we must concentrate on effective risk management.⁴⁰

Later in the email, Sir Dollery noted that the PROactive study

on ACTOS (pioglitazone) is undermining Avandia (rosiglitazone).

He wrote:

The main argument here lies in that pioglitazone [ACTOS]

causes a small reduction of LDL [Low-Density Lipoprotein] and rosiglitazone causes a small elevation. . . . [W]e should search for evidence that the use of statins in diabetics generally and with rosiglitazone in particular has risen steeply over the time the thiazolidenediones have been on the market. We can then argue that any problem that existed with LDL is now controlled or controllable. It would also be worth obtaining the evidence that the use of antihypertensives in diabetics has also been increasing rap-

idly.⁴¹

On fluid retention and links with cardiovascular disease, Sir

Dollery mentioned a possible mechanism to explain how Avandia

may cause heart attacks. He wrote:

If [fluid retention is] substantial in patients with an impaired myocardium it can lead to [cardiac heart failure] and to cardiac ischemia by decreasing myocardial efficiency in the face of existing coronary disease. . . . If there is criticism of GSK it might be that we were a bit slow off

³⁶ Id. ³⁷ Id.

³⁸ Internal GSK email from VP Corporate Media Relations, US GlaxoSmithKline, dated May

9, 2007.

³⁹ Id.

⁴⁰ Internal GSK email from Colin Dollery to Moncef Slaoui and other GSK officials, dated May

9, 2007.

⁴¹ Id.

8

the [mark] in making firm recommendations about the use

of diurectics . . .⁴² and recognizing that the sodium retention is mediated via distal renal tubular ENaC.⁴³

On May 21, 2007, NEJM published online Dr. Nissen's metaanalysis that found a link between Avandia and heart attacks. That same day, GSK responded, ''GSK strongly disagrees with the conclusions reached in the NEJM article, which are based on incomplete evidence and a methodology that the author admits has significant limitations.'' ⁴⁴ Instead, GSK highlighted the results of company sponsored trials like RECORD as ''the most scientifically rigorous way to examine the safety and benefits of a medicine.'' ⁴⁵

In a subsequent letter to The Lancet, GSK maintained that the RECORD trial is ''compelling evidence'' for the safety of Avandia.⁴⁶

On May 23, 2007, a GSK official emailed members of the RECORD steering committee, the group of independent academics overseeing the study, to alert them of a teleconference to be held the following day.⁴⁷ GSK officials also emailed internal talking points to help guide their discussion with the steering committee. However, it appears that prior to receiving input from the steering committee, GSK had already decided to publish the RECORD results. Later that same day, a GSK official wrote, ''. . . we've decided

to disclose the results. . . .'' ⁴⁸

The following day, GSK officials discussed potential problems if the academics on the RECORD steering committee raised concerns about publishing the interim results of the RECORD trial.⁴⁹ In an

email, one GSK official wrote:

[I]f the Steering Committee [SC] are reluctant to publish—

Frank and I will argue the case that there is a balance to be drawn between very negative press coverage and specific reassurance for the patients in the study. However if the SC believe that publishing interim data will fatally damage their ability to bring the study to a completion— Frank and I will bring that opinion with reasons back to GSK, before pursuing the line—that a decision has been

made—live with it.⁵⁰

⁴² Diuretics are blood pressure medications that cause the body to excrete water and sodium (salt).

⁴³ Internal GSK email from Colin Dollery to Moncef Slaoui and other GSK officials, dated May 9, 2007.

⁴⁴ GlaxoSmithKline press release, ''GlaxoSmithKline responds to NEJM article on Avandia,'' published online May 21, 2007.

⁴⁵ Id.

⁴⁶ Ronald Krall M.D., Chief Medical Officer, GlaxoSmithKline, ''Cardiovascular Safety of

Rosiglitazone,'' The Lancet, letter published online May 30, 2007. ''The most compelling evidence comes from RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes), an open-label, 6-year, cardiovascular outcomes trial (with prospectively defined cardiovascular endpoints) in 4458 patients that started in 2000.''

⁴⁷ Email to GSK officials and RECORD steering committee, dated May 23, 2007. ⁴⁸ Internal GSK email, dated May 23, 2007. ⁴⁹ Internal GSK email, dated May 24, 2007. ⁵⁰ Id.

9

A few hours after this email, the acting chair of the RECORD

steering committee, contacted the NEJM to inquire about publishing the interim results.⁵¹ The editor of the NEJM responded

that the journal would be interested in publishing the study.⁵²

By May 29, 2007, several authors of the RECORD study began passing around a manuscript, discussing the results, and offering suggestions for improvement. The third author on the RECORD study wrote, ''We do not find more myocardial infarctions with rosiglitazone treatment, but again there is a tendency supporting the Nissen argument. It is important to stress that it does not affect cardiovascular death.'' ⁵³

That same day, a senior author of the RECORD study, wrote:

There are several striking issues:

(1) The HR ratio (and 95 percent CI) for MI in RECORD

is not inconsistent with Nissen's—and he had more events; what's to stop him adding the events from RECORD to his meta-analysis and re-enforcing his view? . . .

(2) Same is for CV death, although the number of events

in RECORD and in the meta-analysis are similar and at

least in RECORD the HR is in the other direction!

(3) Manuscript looks to downplay the 239 percent INCREASE in HF. I have taken the liberty of doing some rewording.⁵⁴

Once a study is submitted to a journal, the journal editors then

send the article to several experts for peer-review. After the review, the editors send the peer-review comments back to the author. On June 1, 2007, the RECORD authors received a reply from NEJM regarding their earlier submitted manuscript. The NEJM editors summarized the issues presented by all 8 peer reviewers, many of

whom were highly critical of the study in their reply.⁵⁵

Reviewer A, along with other reviewers, asked that the authors ''modify the language in multiple locations in the manuscript to tone down your conclusions.'' ⁵⁶ The editor also noted, ''[I]n the opinion of all the readers, the data that you present are completely compatible with the results of the meta-analysis by Nissen and the meta-analysis for myocardial ischemic events posted on the GSK

Web site.'' ⁵⁷

Regarding the comments of Reviewer B, the editors wrote that for myocardial infarction the ''estimates in the RECORD trial and the Nissen meta-analysis'' overlap in their confidence intervals, meaning that they found a similar trend for heart attacks.⁵⁸ They continued, ''The editors feel strongly that your data do not support

⁵¹ Email from Acting Chair of the RECORD trial to Editor at NEJM, dated May 24, 2007. The Acting Chair wrote, ''We the Steering Committee of the RECORD Study would like to submit a brief report of the current interim findings of this ongoing trial concerning the key cardiovascular outcomes.''

⁵² Email from Editor at NEJM to the acting chair of RECORD trial, dated May 24, 2007. ⁵³ Email between members of the RECORD trial, dated May 29, 2007. ⁵⁴ Email between members of the RECORD trial, dated May 29, 2007.

⁵⁵ Letter from the New England Journal of Medicine to Philip H. Home, M.D. dated June 1,

2007.

⁵⁶ Id. ⁵⁷ Id. ⁵⁸ Id.

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the statement that the RECORD results for MI contradict the Nissen meta-analysis; this statement must be removed or modified.''⁵⁹

Reviewer C noted that the RECORD trial is not blinded,⁶⁰ and pointed out ''the serious problem of the low event rate, especially for MI events, in this study.'' ⁶¹ He continued to ask, ''Do you have an explanation for the very low event rate?'' This reviewer also noted the ''need to greatly tone down your language to reflect the

substantial level of uncertainty in the data.'' ⁶²

Reviewer D questioned the need for keeping rosiglitazone on the market. ''The editors also agree that an explanation for the continued use of rosiglitazone is needed in this manuscript.'' ⁶³

The NEJM published the interim analysis of the RECORD study on July 5, 2007. The GSK study authors concluded that the data was ''insufficient'' to find a link between Avandia and heart attacks.⁶⁴

However, an editorial by the NEJM questioned the RECORD study, as well as several of GSK's studies of Avandia such as DREAM and ADOPT. The authors of the editorial wrote, ''The DREAM trial and ADOPT focused largely on marketing questions and failed to address questions of myocardial infarction-related risk or benefit directly.'' In addition, the editorial noted that the RECORD trial had ''several weaknesses in design and conduct'' including a lack of blinding when treatment was assigned. The authors also pointed out that events of myocardial infarction would have been a preferred clinical endpoint for the study. Studies are normally designed to evaluate certain clinical endpoints or disease symptoms such as heart attack, tumor size, or depression. The authors also added that the RECORD study was not powered (or designed) to detect a myocardial infarction as an endpoint.⁶⁵

On June 6, 2007, the House of Representatives Committee on Oversight and Government Reform held a hearing on Avandia. Despite mounting criticism of the RECORD trial, Dr. Slaoui again highlighted the study in his sworn testimony. ''I will say that we found the RECORD data which we published yesterday in the New England Journal of Medicine very reassuring, recognizing that it

is interim and therefore not fully conclusive.'' ⁶⁶

That same day, GSK dismissed the idea that Dr. Nissen's study spurred the publication of the RECORD interim results. Instead, the Company placed blame on the media. In talking points created for its sales force, GSK stated, ''Because of the widespread media

⁵⁹ Id.

⁶⁰ A blinded study is a study done in such a way that the patients or subjects do not know

what treatment they are receiving to ensure that the results are not affected by a bias on the part of patients, doctors, or the sponsors who are paying for the study.

⁶¹ Letter from the New England Journal of Medicine to Philip H. Home, M.D. dated June 1, 2007.

⁶² Id. ⁶³ Id.

⁶⁴ Philip D. Home et al., ''Rosiglitazone Evaluated for Cardivascular Outcomes—An Interim

Analysis,'' the New England Journal of Medicine, July 5, 2007. The study authors concluded, ''Rosiglitazone was associated with an increased risk of heart failure. The data were insufficient to determine whether the drug was associated with an increase in the risk of myocardial infarction.''

⁶⁵Bruce M Psaty, et al. ''The Record on Rosiglitazone and the Risk of Myocardial Infarction,'' the New England Journal of Medicine, July 5, 2007.

⁶⁶ House of Representatives, Committee on Oversight and Government Reform, ''Hearing on FDA's Role on the Evaluation of Avandia's Safety,'' June 6, 2007, preliminary transcript, page 168 (see also http://oversight.house.gov/documents/20071114160344.pdf ).

11

coverage of the NEJM [Nissen] meta-analysis and the confusion it

has created, the RECORD Steering Committee decided it was important to publish the interim analysis in the interests of patient

safety.'' ⁶⁷

Regarding its competitor Takeda, which sells ACTOS, GSK advised its sales force if asked questions about the PROactive study:

Please do not discuss Actos or the Proactive study with

your physicians. For questions regarding Actos or the Proactive study, healthcare providers should contact Takeda. GSK's focus is on Avandia. Communicate the key points from the interim analysis of RECORD to your physicians.⁶⁸

THE RECORD TRIAL AS A MARKETING

TOOL FOR COMPETITION

Despite attempts to highlight the RECORD study, it appears

that GSK knew for years that the study was ''underpowered,'' i.e., the study did not provide sufficient data to test for cardiovascular safety. And executives appeared more concerned about designing a study to limit competition from ACTOS. Such evidence can be found in a GSK slide presentation, emails, and other documents created in 2004 to 2006.

For instance, in an undated slide show, apparently created in 2004, GSK noted that RECORD does not have sufficient ''power.'' ⁶⁹ The slide presentation also noted that GSK was trying to create studies to counter the PROactive study on ACTOS that Takeda

planned to release.⁷⁰

Slide number 6 titled, ''PROactive: Potential Impact,'' noted that GSK's challenge was to ''maintain share in growing market over

next 2-3 years.'' ⁷¹

Slide number 8 reads:

Situation Summary:

• We have a gap

—In 2005 Actos will have some [cardiovascular] outcome data

• To keep our share of the growing class

—Additive benefit to RECORD of non-inferiority result

• However this gap may be permanent

—RECORD has a lower event rate than expected

PROPOSAL

Fill this gap with an outcome study reporting in 2007

Slide number 10 compared the potential impact of a new GSK

study to counter the marketing danger of PROactive and the potential impact on sales in UK pounds in 2010. The slide reads: ''Timely CV Outcomes data would more than fill the RECORD 'potential gap' and would have twice the impact on our sales than PRO-

⁶⁷ GSK's RECORD Study Questions, dated June 6, 2007, for GSK Internal Use Only. ⁶⁸ Id.

⁶⁹ GSK Internal Slide Show, ''European Commercial Need for a Post-ACS Study Proposal,'' undated.

⁷⁰ Id. ⁷¹ Id.

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active.'' ⁷² The final slide pointed out that GSK should do a ''kick off study only after review of results from Proactive in Sept 2005

and assessing benefits/risks.'' ⁷³

A second instance is found in a June 2005 email where GSK executives discussed the need for a study to counter PROactive. In the email, a GSK official wrote, ''Clearly no patients will be re- cruited until [we] have made a decision based on the go-no go cri- teria from the PROactive data. However, there is a great deal of

EU commercial push to initiate this study in 2005.'' ⁷⁴

A third case is found in an internal GSK document outlining an upcoming meeting for December 2004. Several points were discussed about RECORD and PROactive. Regarding RECORD, the document noted that RECORD has ''low events rates.'' This means that the study did not have the statistical ''power'' to give sufficient cardiovascular event data. The document also stated, ''PROactive results to be coming soon—need to be able to respond to a variety of different outcomes. Communications plan in place for various

possible outcomes of PROactive.'' ⁷⁵

A fourth instance is found in a briefing document for a June 2005 meeting on Avandia's cardiovascular plan. The document

notes several ''important limitations of RECORD.'' ⁷⁶

—the study will not be available until 2009

—the current observed rate for the primary endpoint is very

much lower (approximately 3.5 percent per annum) than that anticipated in the original protocol (11 percent per annum).⁷⁷

A fifth case is found in another GSK email. On July 26, 2005,

GSK officials began emailing each other about potential problems with RECORD and how the PROactive study by Takeda on ACTOS

will create problems for Avandia. One official wrote:

Ron Krall [then GSK Chief Medical Officer] has asked

Lawson [unknown GSK executive] to provide an urgent update to David Stout [then GSK President of Global Pharmaceutical Operations] regarding RECORD. In particular he has asked for our ''intent to manage information flow in Europe to manage the competitive situation.'' Clearly we can provide a summary of the communications around PROactive but I wonder if you could put a few sentences together regarding the communications piece

around RECORD.⁷⁸

A sixth incident is documented in July 2005, when GSK officials

continued expressing concerns about cardiovascular problems with Avandia and potential problems arising from the PROactive study which focused on positive findings with ACTOS. GSK held a meeting on July 18, 2005 to discuss the need for a study to compete

⁷² Id. ⁷³ Id.

⁷⁴ Internal ⁷⁵ Internal ⁷⁶ Internal

GSK email, dated June 16, 2005.

GSK document, untitled, unknown date.

GSK document, ''Briefing Document for 27 June 2005 PMB Avandia Cardiovascular Modeling Plan.''

⁷⁷ Id.

⁷⁸ Internal GSK email, dated July 26, 2005.

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with PROactive.⁷⁹ The briefing document from this meeting discussed the ''European Commercial Need'' for a study:

A recently completed evidence gap analysis completed by

the Metabolic Centre of Excellence has identified the need for the rapid generation of clinical endpoint data to support the superiority of rosiglitazone [Avandia] for the prevention of future cardiovascular clinical events in patients with [type 2 diabetes mellitus]. Publication of the PROactive data may result in important commercial disadvantage in Europe. We therefore have the opportunity to start a CV outcomes study with the aim of getting superiority

data in 2007.⁸⁰

The document also noted that GSK's studies provided insufficient

data on cardiovascular outcomes:

The primary endpoint in RECORD is powered for noninferiority and taking into account the low observed event rate, it is unlikely that this study will demonstrate any potential for [Avandia] combination to be superior in terms of the primary endpoint compared to SU+MET combination therapy. DREAM and ADOPT are collecting CV safety data, but these are low risk populations and it is unlikely that [Avandia] will be superior to controls for the prevention of CV events.⁸¹

CONCERNS ABOUT AVANDIA RAISED PRIOR TO 2007

In June 2004, GSK's leader for a cardiac safety study called the

''Avandia 211 Cardiac Heart Failure Study'' ⁸² reported on a meeting with a consulting academic. The academic was the chairman of the independent clinical endpoint committee for the Avandia 211 study.⁸³ The study leader's report of the academic consultant's

feedback on Avandia 211 follows:

With regard to CV mortality and morbidity data, [the academic consultant] said that the results were 'almost identical' to the results he had seen from a previous glitazone study as a member of the DSMB with increased CV events, hospitalizations, and ischaemic events. [The academic consultant] said that he felt this was a class effect as a result of reduced oxygen carrying capacity as a result

of haemodilution to fluid-retention.⁸⁴

The report of the Avandia 211 meeting noted that the academic

consultant said he would not stop prescribing Avandia, as the study was too small, and that he ''would continue to use [Avandia]

⁷⁹ Internal GSK document, ''MDC Briefing Document: Ad-hoc meeting 18th July 2005.

AVD104821: rosiglitazone in post-acs patients.''

⁸⁰ Id. ⁸¹ Id.

⁸² Internal GSK slide show titled ''Avandia 211 CHF study: Senior Review of Additional Analysis,'' undated.

⁸³ Internal GSK report, ''Avandia 211 CHF study—Review of Study Results, Feedback from Professor NAME REDACTED,'' dated June 3, 2004.

⁸⁴ Id.

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as a second or third line therapy whilst taking appropriate precautions.'' ⁸⁵

Later that month, several GSK representatives met with the advisory board for study protocol 211.⁸⁶ The meeting notes state:

There was disappointment verbalized about the morbidity

and mortality table that showed that there were ten ischemia-related adverse events in the rosiglitazone group versus five events in the placebo group. . . . Dr. NAME REDACTED found [it] unusual that there was an increase in edema and cardiac events despite the fact that there was significant improvement in glycemic control in the rosiglitazone arm of the trial. He thought the glycemic control and pleitrophic [sic] effects of rosiglitazone would have predicted a different outcome than what was observed.⁸⁷

In late 2005, GSK published a draft retrospective analysis of cardiovascular events in Avandia clinical trials discussing the underlying cause for the increase in ischemia.⁸⁸ In a section of the analysis that examined myocardial ischemia, the authors mention a ''hypothesis that small degrees of fluid retention may be an important contributor to the development of worsening myocardial ischemia in high risk patients.'' ⁸⁹

After GSK reviewed the evidence found in this analysis, it appears that the Company was aware of the potential cardiovascular risks associated with Avandia in late 2004 or early 2005. In 2005, GSK commissioned an ''observational'' trial study that was conducted in two parts: the first part in 2005 and the second in 2006. The results of these studies support the further investigation of the cardiovascular risks associated with Avandia.

The first study included 11,586 subjects randomly placed in clinical trials before September 20, 2004. The analysis of the trials was completed during the fall of 2005, giving a hazard ratio for myocar- dial ischemia of 1.29, meaning that rosiglitazone increased the risk of heart-related ischemia by 29 percent. This number was statistically significant.

GSK's second observational study involved analyzing 14,237 patients by the summer of 2006. The results found a hazard ratio of 1.31, meaning that Avandia increased the risk of myocardial ischemia by 31 percent.⁹⁰

CONCLUSION

In preparing this report, Committee investigators reviewed over

250,000 pages of documents provided by GSK, the FDA, the University of North Carolina, and others. Anonymous whistleblowers who contacted Senator Grassley's investigators provided hundreds of other pages. For well over a year, Committee investigators also

⁸⁵ Id.

⁸⁶ GSK Internal Meeting Minutes, ''Summary of the feedback from the Advisory Board Meeting held on June 23rd, 2004, the Philadelphia Airport Marriot to discuss Study Protocol 211.''

⁸⁷ Id.

⁸⁸ Internal GSK document titled, ''Rosiglitazone: Further Interim Results from Retrospective

Analysis of Cardiovascular Events in Clinical Trials DRAFT,'' undated.

⁸⁹ Id.

⁹⁰ GlaxoSmithKline, Studies ZM2005/00181/01 and HM2006/00497/00/WEUSRTP866; http://

ctr.gsk.co.uk/Summary/rosiglitazone/studylist.asp.

15

conducted numerous interviews and phone calls with GSK, the

FDA and anonymous whistleblowers.

The totality of evidence suggests that GSK was aware of the possible cardiac risks associated with Avandia years before such evidence became public. Several years prior to Nissen's study, it can be argued that GSK was on notice that Avandia may have problems. Based on this knowledge, GSK had a duty to sufficiently warn patients and the FDA of its concerns in a timely manner. Instead, GSK executives intimidated independent physicians, focused on strategies to minimize findings that Avandia may increase cardiovascular risk, and sought ways to downplay findings that the rival drug ACTOS (pioglitazone) might reduce cardiovascular risk.

In recent years, pharmaceutical companies have committed acts that forced them to pay the largest criminal fines in American history.⁹¹ In cases involving Pfizer, Eli Lilly, Bristol Myers Squibb and four other drug companies, these fines and penalties have totaled over $7 billion since May 2004.⁹² In particular, Pfizer has been fined multiple times in the past 6 years for illegal off-label promotion of their drugs. In its latest plea agreement, which took place last September, Pfizer paid $2.3 billion in fines and penalties for off-label promotion of Bextra. This settlement was the largest criminal fine in U.S. history.⁹³ Such an environment requires diligent oversight by the FDA to protect the citizens of this country and to ensure the safety of American medicine.

⁹¹ David Evans, ''Pfizer Broke the Law by Promoting Drugs for Unapproved Uses,'' Bloomberg, November 9, 2009.

⁹² Id. ⁹³ Id.

The full 342 pages can be read via this link: http://finance.senate.gov/press/Gpress/2010/prg022010a.pdf.

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