April 15,2008
April 15, 2008
Richard T. Clark
Chairman, President, and Chief Executive Officer
Merck & Co., Inc.
1 Merck Drive
Whitehouse Station, NJ 08889
Dear Mr. Clark:
The United States Senate Committee on Finance (Committee) has jurisdiction over theMedicare and Medicaid programs. As a senior member of the United States Senate and asRanking Member of the Committee, I have a special responsibility to protect the health ofMedicare and Medicaid beneficiaries and safeguard taxpayer dollars authorized by Congress forthese programs. This includes the responsibility to conduct oversight of the medical industry,including makers of pharmaceuticals and medical devices.
More than three years ago, on November 18, 2004, the Committee held a hearing titled,"FDA, Merck and VIOXX: Putting Patient Safety First?" At that hearing, I raised concerns notonly about the almost two-year delay in updating the VIOXX label with important informationabout cardiovascular risks, but also Merck & Co., Inc.'s (Merck) aggressive marketing ofVIOXX during that same timeframe when consumers and doctors were largely unaware of thoserisks.
I am writing today because additional findings regarding Merck's handling of VIOXXhave come to light. Several studies based on a review of documents from recent litigationagainst your company were published today in the Journal of the American Medical Association(JAMA). In particular, one study seems to show selective reporting by Merck of mortality datafrom clinical trials of VIOXX that were conducted in patients with Alzheimer disease orcognitive impairment.
I am deeply troubled by the findings of this study. According to the authors, Merckmisled the FDA by submitting initial mortality data from a trial called study 078 in July 2001that minimized the appearance of an increased risk of death. FDA was not provided with theintention-to-treat analyses that the company had conducted in April 2001. The intention-to-treatmortality data from Merck's study 078 were not submitted to the FDA until 2003-about twoyears later.
The article also reports that the FDA raised questions about the safety data submitted in2001 because of excess deaths seen in study 078, as well as in a separate study 091. Accordingthe JAMA authors, Merck responded that it did not report the excess in deaths from this 091study to the institutional review boards (IRBs) overseeing study 078. Thus, those individualswho enrolled in study 078 seem to have been left in the dark about a very serious risk. Thepeople in the study had Alzheimer disease or cognitive impairment, and they are a vulnerablepopulation who deserves special attention. Furthermore, Merck stated that there was no data andsafety monitoring board (DSMB) in place for study 078. The authors argue that the mortalityfindings might have led a DSMB to terminate study 078 before completion in the interest ofprotecting the human subjects that had volunteered.
It should be no surprise to you that VIOXX has been an interest of mine for several yearsnow. Besides incurring over $1 billion dollars in costs to our federal programs for this drug, itturned out that VIOXX was also causing heart attacks. Merck, with knowledge of the increasedrisk of heart attacks associated with VIOXX, proceeded to negotiate with FDA for label changes,while at the same time initiating an aggressive campaign to sell as much of the drug as possible.In fact, one FDA safety officer determined that VIOXX negatively affected tens of thousands ofpatients who took the drug.
Now we are learning that VIOXX not only increased the risk of heart attacks-it seemsthat it caused the death of certain patients. Had the federal government, namely the FDA knownof this risk in 2001, instead of 2003, I am confident that the federal government would not havepaid Merck $1billion dollars for the drug.
Another matter of concern that is also set forth in JAMA relates to allegations of ghostwriting. I have been looking at this issue for about a year now. As I understand it, the practice ofghost writing involves company employees, or marketing or medical education companies, whodraft review articles, editorials, and/or research papers. The companies then present the article toprominent doctors and scientists, particularly those affiliated with academic institutions, to signon as authors, who become "guest" authors. The doctors and scientists agree to be authors on thearticles even though they may not be intimately familiar with the underlying data and/or relevantdocumentation.
The 078 study, which was not published until 2005 (a year after VIOXX was withdrawn)appears to have employed several guest authors. According to another JAMA article entitled,"Guest Authorship and Ghostwriting in Publications Related to Rofecoxib," several courtdocuments show that Merck hired a medical publishing company, Scientific TherapeuticsInformation, Inc. (STI), to:
1) draft manuscripts for the company's VIOXX studies; and
2) seek academic investigators to sign on as the primary author(s).
The JAMA authors published one email sent between STI and Merck that listed severalmanuscripts that STI was drafting on Merck's behalf. The email stated that, "At the request ofJohn Romankiewicz, I am providing you with an update on development and estimated deliverydates for various publications related to VIOXX that STI is working on." John Romankiewicz ispresident of STI. The JAMA authors also note that in a document entitled, "VIOXXPublications Status Report," STI representatives wrote that a study draft had been sent to Merckfor comments, but that an author for the publication still needed to be invited.
Articles published in medical and scientific journals are widely read and relied upon bypractitioners. The information in these articles can have a significant impact on doctors'prescribing behavior and, in turn, on the American taxpayer, because the Medicare and Medicaidprograms pay billions of dollars for prescription drugs. Thus, any attempt to manipulate thescientific literature, that can in turn mislead doctors to prescribe drugs that may not work and/orcause harm to their patients, is just plain offensive.
Accordingly, please respond to the following questions and request for documents.When responding to each question, please repeat the enumerated request and follow with theappropriate response.
1. Please describe in detail how Merck determines when a DSMB is appropriate. What wasthe basis for Merck's decision to not establish a DSMB for study 078? Please provide allrelated communications and other documentation supporting that decision.
2. Please provide copies of the original protocols for studies 078 and 091. What was theoriginal data analysis plan for the safety data in these studies? Please provide copies ofall amendments to the data analysis plans and a timeline for all changes made in the dataanalysis plans.
3. Please provide a copy of communications, including but not limited to memoranda andemail, and documentation of meetings and teleconferences related to Merck's decision tosubmit data to the FDA in July 2001 from study 078 based on an on-treatment analysisrather than an intention-to-treat analysis. Please explain why the intention-to-treat datawere not submitted to the FDA until 2003.
4. When Merck became aware of the excess deaths seen in study 091, did the companyinform IRBs overseeing any other VIOXX studies ongoing at the time? Was there aDSMB for 091? Please provide all communications about IRBs and DSMBs for study091.
5. Please list all of the IRBs that provided oversight for study 078 and their members.
6. Please provide the Committee with a list of all VIOXX-related manuscripts or reportsprepared by STI on behalf of Merck. For each study, research paper or article, pleaseprovide the following information
a) Title of study
b) Brief description
c) Period of time for which the work was done
d) Author who signed name onto study, research paper or article
e) Fees that were paid to author
f) Extent of involvement/participation of the author in the drafting of the final manuscript
g) Journal where study or article was published
h) Charge to Merck for completed work
7. Please provide all internal and external correspondence and communicationsregarding each of these STI-prepared studies.
8. Were the primary authors of the article on study 078, "A Randomized, Double-Blind,Study of Rofecoxib in Patients with Mild Cognitive Impairment," directly involved in theconduct and/or review of study 078? Which authors of the published version of 078 wereaware of the intention-to-treat analyses conducted in April 2001? Were theseintention-to-treat analyses provided to the "guest" academic authors? Please identify allindividuals and/or third party entities that contributed to the initial and final drafts of themanuscript. If a medical publishing company, such as STI, drafted the manuscript,please provide the following information:
a) Name of the company
b) Fees that were paid to each author listed on the published article
c) Extent of involvement/participation of each author in the drafting of the final manuscript.
In cooperating with the Committee's review, no documents, records, data, or otherinformation related to these matters, either directly or indirectly, shall be destroyed, modified,removed, or otherwise made inaccessible to the Committee.
Thank you in advance for your cooperation. Please provide the requested informationand documents by no later than May 2, 2008.
Sincerely,
Charles E. Grassley
United States Senator
Ranking Member of the Committee on Finance
April 15, 2008
John A. Romankiewicz
President and Chief Executive Officer
Scientific Therapeutics Information, Inc.
505 Morris Ave
Springfield, NJ 07081
Dear Mr. Romankiewicz:
The United States Senate Committee on Finance (Committee) has jurisdiction over theMedicare and Medicaid programs. As a senior member of the United States Senate and asRanking Member of the Committee, I have a special responsibility to the more than 80 millionAmericans who receive health care coverage under those programs to ensure that beneficiariesreceive drugs that are both safe and effective.
I am writing to follow up on a letter I sent to you last October regarding ghost writing ofmedical studies. For the last three years, the Committee has been examining various aspects ofthe medical industry. More recently, I began examining a practice used by drug and devicecompanies referred to as "medical ghostwriting." I have been informed that this practiceinvolves marketing or medical education companies that draft review articles, editorials, and/orresearch papers. This information is then presented to prominent doctors and scientists,particularly those affiliated with academic institutions, to sign on as authors, whether or not theyare intimately familiar with the underlying data and relevant documentation.
Specifically, I am a concerned about several allegations of ghostwriting that have cometo light in an article published today in the Journal of the American Medical Association(JAMA). This article points out that Scientific Therapeutics Information, Inc. (STI) draftedscientific studies on the painkiller VIOXX and then sought academics to sign on as the primaryauthor(s). As I am sure you are aware, any attempt to meddle in the scientific literature canmislead doctors to prescribe drugs that may not work, or that may even be harmful. Suchactivity is also a concern to the federal government which pays out billions every year for drugs.In addition, there is a concern that such activities will make medical literature nothing more thanan extension of drug or device marketing.
The JAMA authors published one email that was sent between STI and Merck, themakers of VIOXX. This email lists several manuscripts that STI was drafting on Merck's behalf.The email states that, "At the request of John Romankiewicz, I am providing you with an updateon development and estimated delivery dates for various publications related to VIOXX that STIis working on."
The JAMA authors also note that in a document titled, "VIOXX Publications StatusReport," STI representatives wrote that a study draft had been sent to Merck for comments, butthat an author for the publication still needed to be invited.
I would also like to mention that my investigators found an email sent to your companyby a professor at Northwestern University back in August 2000 (see attachment). In this email,the professor apparently declines payment for some type of work on a manuscript. He wrote, "Ireally do not feel it is appropriate to be paid for this type of work." This email was thenforwarded on to several STI employees. You were copied on the response where one of theemployees wrote, "We were offering him $2000. Should I offer to issue the check as a researchgrant?"
Accordingly, I would appreciate your response to the following request for documentsand responses to questions. When responding to each question, please repeat the enumeratedrequest followed by the appropriate response.
1. Please provide the Committee with a list of all VIOXX-related manuscripts or reportsprepared by STI on behalf of Merck for the period of January 1, 2000 through thepresent. For each study, please provide the following information
a. Title of study and/or report
b. Brief description
c. Period of time for which the work was done
d. Author who signed name onto study
e. Fees that were paid to author
f. Extent of involvement/participation of the author in the drafting of the final manuscript
g. Journal where study was published
h. Charge to Merck for completed work
2. Please provide all internal and external correspondence and communications regardingeach of these studies.
In cooperating with the Committee's review, no documents, records, data, or otherinformation related to these matters, either directly or indirectly, shall be destroyed, modified,removed, or otherwise made inaccessible to the Committee.
Thank you in advance for your continued cooperation. Please provide the requestedinformation and documents by no later than May 2, 2008.
Sincerely,
Charles E. Grassley
United States Senator
Ranking Member of the Committee on Finance
Attachment
Grassley says new reports buttress effort for greater transparency from drug makers
WASHINGTON — Senator Chuck Grassley is asking the drug maker Merck to respondto accounts in today’s Journal of the American Medical Association about the selectivepresentation of data to federal regulators and manipulation of scientific literature through ghostwriters concerning the painkiller Vioxx, which was removed from the market in 2004 because ofcardiovascular risks.
Grassley held a hearing of the Senate Committee on Finance more than three years ago,in the wake of the Vioxx scandal, to examine the relationship between the drug industry and theFood and Drug Administration and expose shortcomings in the drug safety system.
The studies and editorial appearing in today’s Journal of the American MedicalAssociation describe documents made public in lawsuits against Vioxx where the company wasnot forthcoming about drug risks in its communication with the Food and Drug Administration.The Journal of the American Medical Association articles also detail how the drug maker soughtout academic ghost writers to put their names on manufacturer-drafted studies about Vioxx.“These reports reveal just how far a drug maker might go to market its product and try tobury information that might hurt sales even when that information directly affected the healthand safety of the people taking their medicine,” Grassley said. “Revealing this kind of activity isvery important in building pressure on the Food and Drug Administration to regulate, notaccommodate drug makers. These new reports also underscore the value of transparency inmaking industry more accountable to the public.”
Grassley has sponsored legislation to require manufacturers of pharmaceutical drugs,devices and biologics to report payments to doctors for consulting, speeches and other services.He issued a report last year about the drug industry’s financial support of continuing medicaleducation. Grassley also has pressed for greater transparency from the Food and DrugAdministration through legislative and oversight initiatives.
The text of letters sent today from Grassley to Merck & Co., Inc. and ScientificTherapeutics Information, Inc. follows here.
April 15, 2008
Richard T. Clark
Chairman, President, and Chief Executive Officer
Merck & Co., Inc.
1 Merck Drive
Whitehouse Station, NJ 08889
Dear Mr. Clark:
The United States Senate Committee on Finance (Committee) has jurisdiction over theMedicare and Medicaid programs. As a senior member of the United States Senate and asRanking Member of the Committee, I have a special responsibility to protect the health ofMedicare and Medicaid beneficiaries and safeguard taxpayer dollars authorized by Congress forthese programs. This includes the responsibility to conduct oversight of the medical industry,including makers of pharmaceuticals and medical devices.
More than three years ago, on November 18, 2004, the Committee held a hearing titled,"FDA, Merck and VIOXX: Putting Patient Safety First?" At that hearing, I raised concerns notonly about the almost two-year delay in updating the VIOXX label with important informationabout cardiovascular risks, but also Merck & Co., Inc.'s (Merck) aggressive marketing ofVIOXX during that same timeframe when consumers and doctors were largely unaware of thoserisks.
I am writing today because additional findings regarding Merck's handling of VIOXXhave come to light. Several studies based on a review of documents from recent litigationagainst your company were published today in the Journal of the American Medical Association(JAMA). In particular, one study seems to show selective reporting by Merck of mortality datafrom clinical trials of VIOXX that were conducted in patients with Alzheimer disease orcognitive impairment.
I am deeply troubled by the findings of this study. According to the authors, Merckmisled the FDA by submitting initial mortality data from a trial called study 078 in July 2001that minimized the appearance of an increased risk of death. FDA was not provided with theintention-to-treat analyses that the company had conducted in April 2001. The intention-to-treatmortality data from Merck's study 078 were not submitted to the FDA until 2003-about twoyears later.
The article also reports that the FDA raised questions about the safety data submitted in2001 because of excess deaths seen in study 078, as well as in a separate study 091. Accordingthe JAMA authors, Merck responded that it did not report the excess in deaths from this 091study to the institutional review boards (IRBs) overseeing study 078. Thus, those individualswho enrolled in study 078 seem to have been left in the dark about a very serious risk. Thepeople in the study had Alzheimer disease or cognitive impairment, and they are a vulnerablepopulation who deserves special attention. Furthermore, Merck stated that there was no data andsafety monitoring board (DSMB) in place for study 078. The authors argue that the mortalityfindings might have led a DSMB to terminate study 078 before completion in the interest ofprotecting the human subjects that had volunteered.
It should be no surprise to you that VIOXX has been an interest of mine for several yearsnow. Besides incurring over $1 billion dollars in costs to our federal programs for this drug, itturned out that VIOXX was also causing heart attacks. Merck, with knowledge of the increasedrisk of heart attacks associated with VIOXX, proceeded to negotiate with FDA for label changes,while at the same time initiating an aggressive campaign to sell as much of the drug as possible.In fact, one FDA safety officer determined that VIOXX negatively affected tens of thousands ofpatients who took the drug.
Now we are learning that VIOXX not only increased the risk of heart attacks-it seemsthat it caused the death of certain patients. Had the federal government, namely the FDA knownof this risk in 2001, instead of 2003, I am confident that the federal government would not havepaid Merck $1billion dollars for the drug.
Another matter of concern that is also set forth in JAMA relates to allegations of ghostwriting. I have been looking at this issue for about a year now. As I understand it, the practice ofghost writing involves company employees, or marketing or medical education companies, whodraft review articles, editorials, and/or research papers. The companies then present the article toprominent doctors and scientists, particularly those affiliated with academic institutions, to signon as authors, who become "guest" authors. The doctors and scientists agree to be authors on thearticles even though they may not be intimately familiar with the underlying data and/or relevantdocumentation.
The 078 study, which was not published until 2005 (a year after VIOXX was withdrawn)appears to have employed several guest authors. According to another JAMA article entitled,"Guest Authorship and Ghostwriting in Publications Related to Rofecoxib," several courtdocuments show that Merck hired a medical publishing company, Scientific TherapeuticsInformation, Inc. (STI), to:
1) draft manuscripts for the company's VIOXX studies; and
2) seek academic investigators to sign on as the primary author(s).
The JAMA authors published one email sent between STI and Merck that listed severalmanuscripts that STI was drafting on Merck's behalf. The email stated that, "At the request ofJohn Romankiewicz, I am providing you with an update on development and estimated deliverydates for various publications related to VIOXX that STI is working on." John Romankiewicz ispresident of STI. The JAMA authors also note that in a document entitled, "VIOXXPublications Status Report," STI representatives wrote that a study draft had been sent to Merckfor comments, but that an author for the publication still needed to be invited.
Articles published in medical and scientific journals are widely read and relied upon bypractitioners. The information in these articles can have a significant impact on doctors'prescribing behavior and, in turn, on the American taxpayer, because the Medicare and Medicaidprograms pay billions of dollars for prescription drugs. Thus, any attempt to manipulate thescientific literature, that can in turn mislead doctors to prescribe drugs that may not work and/orcause harm to their patients, is just plain offensive.
Accordingly, please respond to the following questions and request for documents.When responding to each question, please repeat the enumerated request and follow with theappropriate response.
1. Please describe in detail how Merck determines when a DSMB is appropriate. What wasthe basis for Merck's decision to not establish a DSMB for study 078? Please provide allrelated communications and other documentation supporting that decision.
2. Please provide copies of the original protocols for studies 078 and 091. What was theoriginal data analysis plan for the safety data in these studies? Please provide copies ofall amendments to the data analysis plans and a timeline for all changes made in the dataanalysis plans.
3. Please provide a copy of communications, including but not limited to memoranda andemail, and documentation of meetings and teleconferences related to Merck's decision tosubmit data to the FDA in July 2001 from study 078 based on an on-treatment analysisrather than an intention-to-treat analysis. Please explain why the intention-to-treat datawere not submitted to the FDA until 2003.
4. When Merck became aware of the excess deaths seen in study 091, did the companyinform IRBs overseeing any other VIOXX studies ongoing at the time? Was there aDSMB for 091? Please provide all communications about IRBs and DSMBs for study091.
5. Please list all of the IRBs that provided oversight for study 078 and their members.
6. Please provide the Committee with a list of all VIOXX-related manuscripts or reportsprepared by STI on behalf of Merck. For each study, research paper or article, pleaseprovide the following information
a) Title of study
b) Brief description
c) Period of time for which the work was done
d) Author who signed name onto study, research paper or article
e) Fees that were paid to author
f) Extent of involvement/participation of the author in the drafting of the final manuscript
g) Journal where study or article was published
h) Charge to Merck for completed work
7. Please provide all internal and external correspondence and communicationsregarding each of these STI-prepared studies.
8. Were the primary authors of the article on study 078, "A Randomized, Double-Blind,Study of Rofecoxib in Patients with Mild Cognitive Impairment," directly involved in theconduct and/or review of study 078? Which authors of the published version of 078 wereaware of the intention-to-treat analyses conducted in April 2001? Were theseintention-to-treat analyses provided to the "guest" academic authors? Please identify allindividuals and/or third party entities that contributed to the initial and final drafts of themanuscript. If a medical publishing company, such as STI, drafted the manuscript,please provide the following information:
a) Name of the company
b) Fees that were paid to each author listed on the published article
c) Extent of involvement/participation of each author in the drafting of the final manuscript.
In cooperating with the Committee's review, no documents, records, data, or otherinformation related to these matters, either directly or indirectly, shall be destroyed, modified,removed, or otherwise made inaccessible to the Committee.
Thank you in advance for your cooperation. Please provide the requested informationand documents by no later than May 2, 2008.
Sincerely,
Charles E. Grassley
United States Senator
Ranking Member of the Committee on Finance
April 15, 2008
John A. Romankiewicz
President and Chief Executive Officer
Scientific Therapeutics Information, Inc.
505 Morris Ave
Springfield, NJ 07081
Dear Mr. Romankiewicz:
The United States Senate Committee on Finance (Committee) has jurisdiction over theMedicare and Medicaid programs. As a senior member of the United States Senate and asRanking Member of the Committee, I have a special responsibility to the more than 80 millionAmericans who receive health care coverage under those programs to ensure that beneficiariesreceive drugs that are both safe and effective.
I am writing to follow up on a letter I sent to you last October regarding ghost writing ofmedical studies. For the last three years, the Committee has been examining various aspects ofthe medical industry. More recently, I began examining a practice used by drug and devicecompanies referred to as "medical ghostwriting." I have been informed that this practiceinvolves marketing or medical education companies that draft review articles, editorials, and/orresearch papers. This information is then presented to prominent doctors and scientists,particularly those affiliated with academic institutions, to sign on as authors, whether or not theyare intimately familiar with the underlying data and relevant documentation.
Specifically, I am a concerned about several allegations of ghostwriting that have cometo light in an article published today in the Journal of the American Medical Association(JAMA). This article points out that Scientific Therapeutics Information, Inc. (STI) draftedscientific studies on the painkiller VIOXX and then sought academics to sign on as the primaryauthor(s). As I am sure you are aware, any attempt to meddle in the scientific literature canmislead doctors to prescribe drugs that may not work, or that may even be harmful. Suchactivity is also a concern to the federal government which pays out billions every year for drugs.In addition, there is a concern that such activities will make medical literature nothing more thanan extension of drug or device marketing.
The JAMA authors published one email that was sent between STI and Merck, themakers of VIOXX. This email lists several manuscripts that STI was drafting on Merck's behalf.The email states that, "At the request of John Romankiewicz, I am providing you with an updateon development and estimated delivery dates for various publications related to VIOXX that STIis working on."
The JAMA authors also note that in a document titled, "VIOXX Publications StatusReport," STI representatives wrote that a study draft had been sent to Merck for comments, butthat an author for the publication still needed to be invited.
I would also like to mention that my investigators found an email sent to your companyby a professor at Northwestern University back in August 2000 (see attachment). In this email,the professor apparently declines payment for some type of work on a manuscript. He wrote, "Ireally do not feel it is appropriate to be paid for this type of work." This email was thenforwarded on to several STI employees. You were copied on the response where one of theemployees wrote, "We were offering him $2000. Should I offer to issue the check as a researchgrant?"
Accordingly, I would appreciate your response to the following request for documentsand responses to questions. When responding to each question, please repeat the enumeratedrequest followed by the appropriate response.
1. Please provide the Committee with a list of all VIOXX-related manuscripts or reportsprepared by STI on behalf of Merck for the period of January 1, 2000 through thepresent. For each study, please provide the following information
a. Title of study and/or report
b. Brief description
c. Period of time for which the work was done
d. Author who signed name onto study
e. Fees that were paid to author
f. Extent of involvement/participation of the author in the drafting of the final manuscript
g. Journal where study was published
h. Charge to Merck for completed work
2. Please provide all internal and external correspondence and communications regardingeach of these studies.
In cooperating with the Committee's review, no documents, records, data, or otherinformation related to these matters, either directly or indirectly, shall be destroyed, modified,removed, or otherwise made inaccessible to the Committee.
Thank you in advance for your continued cooperation. Please provide the requestedinformation and documents by no later than May 2, 2008.
Sincerely,
Charles E. Grassley
United States Senator
Ranking Member of the Committee on Finance
Attachment
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