February 12,2008

Grassley asks additional questions about the Vytorin ENHANCE clinical trial


Senator Grassley is continuing his inquiries related to Schering-Plough’s drug Vytorinand has asked for documents and a list of all company statisticians who had access to theENHANCE trial data. The ENHANCE trial was an attempt to determine if Vytorin, acombination pill of Zetia and a statin, performed better than a generic statin alone. SenatorGrassley has expressed concern that individuals who had early access to this data could havelearned that Vytorin did not offer more value than an inexpensive statin. The ENHANCE trialended in April 2006, but the results were not released until almost two years later on January 14,2008.

Here is the text of his February 11 letter to the Schering-Plough Corporation.

February 11, 2008

Via Electronic Transmission

Mr. Fred HassanChairman of the Board, Chief Executive OfficerSchering-Plough Corporation2000 Galloping Hill RoadKenilworth, NJ 07033

Dear Mr. Hassan:

As the Ranking Member of the United States Senate Committee on Finance (Committee),I have an obligation to the more than 80 million Americans who receive health care coverageunder Medicare and Medicaid to ensure that taxpayer and beneficiary dollars are spent in afiscally sound manner. This also includes the responsibility to conduct oversight of the medicaland pharmaceutical industries to ensure that Medicare and Medicaid dollars are spentappropriately on safe and effective drugs and devices.

I am following up on my prior letter to you regarding the delayed release of theENHANCE trial by Schering-Plough and Merck.[1] This study examines whether Vytorinprovides better health benefits than generic simvastatin. Vytorin is a pill that combines thestatin, simvastatin, with a drug called ezetimibe that decreases absorption of cholesterol by thedigestive tract.

It has come to my attention that Schering Plough and Merck would not need to unblindthe data to understand that Vytorin performed no better than generic simvastatin. TheENHANCE trial is a non-inferiority study. These studies try to detect a statistically significantdifference between treatment groups on the primary endpoint. Once the results are recorded, thestudy is then unblinded to determine which drug is the better performer. However, if the drugsperformed the same, meaning there is no statistically significant difference in the treatments,then this information is apparent before the study has been unblinded.

According to your own press release on the ENHANCE results, "There was nostatistically significant difference between treatment groups on the primary endpoint."[2] Myconcern is that anyone who had access to the blinded data could have run simulations andlearned that Vytorin performed just the same as simvastatin.

My Committee investigators have learned that the ENHANCE trial data were routedfrom all of the trial centers to Dr. John J.P. Kastelein of the University of the Netherlands. Dr.Kastelein then transmitted the data to the Schering-Plough Research Institute in Kenilworth,New Jersey.

Accordingly, please respond to the following questions and request for documents. Foreach response, first repeat the enumerated question followed by the appropriate answer.

1. Please explain how the ENHANCE carotid ultrasound data was transferred from the corelaboratory to the Schering-Plough Research Institute.

2. Please name all Schering-Plough employees who had access to the ENHANCE dataduring or after completion of the trial. For each individual, please provide

a. Name;

b. Title;

c. Technical expertise (lawyer, statistician, medical doctor, etc.)

3. Please provide the names of all statisticians at the Schering-Plough Institute. Pleaseindicate which of these employees were involved in any analysis of the ENHANCE trialanalysis.

4. Please provide all emails, documents and communications discussing the results of theENHANCE trial, including any simulations regarding the results. The scope of this requestcovers employees at the Schering-Plough Institute or elsewhere within the company, from theperiod of July 2005 to the present.

5. Please provide any and all e-mails and communications between Dr. John Kastelein andSchering-Plough employees from July 2005 until the present.

In cooperating with the Committee's review, no documents, records, data, or other informationrelated to these matters, either directly or indirectly, shall be destroyed, modified, removed, orotherwise made inaccessible to the Committee.

I look forward to hearing from you by no later than February 22, 2008.


Chuck GrassleyUnited States SenatorRanking Member, Committee on Finance


[1] Alex Berenson, "Cardiologists Question Delay of Data on 2 Drugs," The New York Times,November 21, 2007.[2] Schering-Plough News Release, "Merck/Schering-Plough Pharmaceuticals Provides Resultsof EHANCE Trial," released on company Website on January 14, 2008.