Gastrointestinal Tolerability and Effectiveness of Rofecoxib versus Naproxen in the Treatment of Osteoarthritis: A Randomized, Controlled Trial

To the Editor,

In their recent letter to the editor, Braunstein and Polis address the omission of important cardiovascular safety results from an October 2003 article on the ADVANTAGE trial in the Annals of Internal Medicine (1,2). The 2003 article by Lisse and colleagues (including Polis) reported no statistically significant differences for any cardiovascular endpoints in comparisons of Vioxx (rofecoxib) and naproxen in ADVANTAGE, a 12-week clinical trial. In fact, almost three years earlier, Merck gave the FDA a data table showing a statistically significant relative risk of 7 for cardiac events amongst patients on Vioxx compared to naproxen in the ADVANTAGE trial. The Merck data table is included in a three-page January 19, 2001 letter responding to the FDA*s request for additional information on the ADVANTAGE trial; it shows 7 serious adverse cardiac events on Vioxx (6 events adjudicated as myocardial infarction and 1 event adjudicated as sudden/unknown death) and 1 cardiac event on naproxen (1 adjudicated MI) (3). Additionally, another event in the table "reported as hypertensive heart disease and death by Merck" was re-classified by the FDA in November 2001 as a sudden/unknown death, pushing the cardiac event relative risk for Vioxx to 8 (4).

Merck*s January 19, 2001 letter and the FDA*s re-classification are emphatic evidence of Merck*s knowledge that the ADVANTAGE trial showed that Vioxx use caused an important and statistically significant excess risk of cardiac events in patients on Vioxx, namely MI and sudden/unknown death. Merck*s omission of this important risk information from its 2003 article in the Annals presents a serious public health hazard because it misled the medical community. In their Annals letter, Braunstein and Polis say that Merck's pre-defined procedures kept the case of hypertensive heart disease and death from being externally adjudicated hence, its exclusion from the APTC "cardiac event" group. Since Merck defined an external adjudication events list that kept out relevant events such as hypertensive heart disease, it was fortunate that the FDA adjudicated the case. Merck still omitted this information when they published the trial.

Underlying this already egregious omission of safety data is more deeply disturbing evidence of medicine run amok. Internal Merck documents reveal that the ADVANTAGE trial did not have a medical purpose per se. Instead, it was a "seeding trial," meant to seed the medical community with Merck's new drug before it was approved for the market. Thus, the deaths of patients on Vioxx in the trial were deaths in an unnecessary trial. The real subjects of the trial were the physician "investigators" (non-participants served as controls) chosen to participate by Merck sales representatives (5). Merck intended to promote the drug to influential doctors and their patients and analyze the prescribing information of these physician-investigators for marketing purposes. A Merck public relations supervisor instructed employees to avoid revealing the true purpose of the trial, "I ELIMINATED THE REFERENCE TO SEEDING. IT MAY BE A SEEDING STUDY, BUT LET'S NOT CALL IT THAT IN OUR INTERNAL DOCUMENTS (6)." [emphasis in original]

Merck*s conduct in designing, conducting, analyzing, and publishing the ADVANTAGE trial is disturbing at best. The ethical ramifications of deaths-on-drug in a "seeding trial" deserve a more thorough examination than is possible here. The practice of selectively reporting drug safety data is evidence of the need for complete and public disclosure - perhaps on the internet - of clinical trial data for new drugs. If anything, ADVANTAGE teaches us we cannot rely on drug companies to honestly report all of the important data.

Some documents cited in this commentary were obtained in Vioxx litigation and were previously confidential but since have been entered as evidence at trial and have been unsealed.

David S. Egilman, M.D., M.P.H. Amos H. Presler, B.A. degilman@egilman.com Brown University

References (1)Braunstein N, Polis A, Report of Specific Cardiovascular Outcomes of the ADVANTAGE Trial. Ann Intern Med. 2005;143:158-159.

(2)Lisse et al., Gastrointestinal tolerability and effectiveness of rofecoxib versus naproxen in the treatment of osteoarthritis: a randomized, controlled trial. Ann Intern Med. 2003;139:539-546

(3)Silverman RE, Merck Research Laboratories, Letter to FDA, CDER: NDA 21-042/S-007: VIOXX* (rofecoxib tablets) Response to FDA Request for Information, January 19, 2001. MRK-AAF0003308-MRK-AAF0003310.

(4)Medical Officer Review, NDA 21-042 and NDA 21-052 (Rofecoxib tablets and rofecoxib oral solution) Re: Complete response to Approvable letter for 21-042/S 007 and 21-052/S 004 Submission date (letter): July 12, 2001 End of Review date: November 28, 2001, at page 10 ,, Reviewer: Maria Lourdes Villalba, M.

(5)Smith B, to Webb J. Communication: Re: Vioxx Seeding Study Selection. MRK-AFB0001598

(6)Higbee, Rebecca email to: Lindemann, Kyra; Fanelle, Christine; Weiner, Jan D, Subject: ADVANTAGE ideas, Friday, March 19, 1999 MRK-ACX0002969- MRK-ACX0002974.

Conflict of Interest:

Dr. Egilman has served as an expert witness in Vioxx Litigation. Mr. Presler is employed by Dr. Egilman.

We recently published a letter by Egilman and Presler (1) that cited a letter from a Merck & Co. Inc. official to the US Food and Drug Administration (FDA) (reference 3 in the Egilman and Presler letter). The cited letter reported patients that Merck & Co. Inc. had adjudicated as having had a myocardial infarction (6 patients) and sudden death (one patient) while on Vioxx during the ADVANTAGE trial (2). Dr. Braunstein, another Merck & Co. Inc official, reviewed the cited letter at our request and wrote to say that it contained an error. The correct numbers of adjudicated events were 5 myocardial infarctions and 2 sudden deaths, as documented by materials submitted by Merck & Co. Inc. to the FDA along with the letter that contained the error. Table 2 of a Letter to the Editor from Dr. Braunstein also contains the correct number of events (3).

Harold C. Sox, M.D. Editor

Cynthia Mulrow, M.D., MSc Deputy Editor

References

1. Egilman and Presler letter

2. Lisse JR, Perlman M, Johansson G, Shoemaker JR, Schechtman J, Skalky CS, Dixon ME, Polis AB, Mollen AJ, Geba GP for the ADVANTAGE Study Group. Gastrointestinal Tolerability and Effectiveness of Rofecoxib versus Naproxen in the Treatment of Osteoarthritis: A Randomized, Controlled Trial. Ann Intern Med, Oct 2003; 139: 539 - 546.

3. Braunstein N, Polis A. Report of Specific Cardiovascular Outcomes of the ADVANTAGE Trial. Ann Intern Med, Jul 2005; 143: 158 - 159.

Conflict of Interest:

None declared