ABSTRACT:
Background: Seeding trials, clinical studies conducted by pharmaceutical companies that are designed
to seem as if they answer a scientific question but primarily fulfill marketing objectives, have not been
described in detail.
Purpose: To describe a known seeding trial, ADVANTAGE (Assessment of Differences between Vioxx and Naproxen
To Ascertain Gastrointestinal Tolerability and Effectiveness), through documents of the trial sponsor,
Merck & Co. (Whitehouse Station, New Jersey).
Data Sources: Merck internal and external correspondence, reports, and presentations elicited to inform
legal proceedings of Cona v Merck and Co., Inc., and McDarby v Merck and Co., Inc. The documents
were created between 1998 and 2006.
Data Extraction: An iterative case-study process of review, discussion, and re-review of documents to
identify themes relevant to the design and conduct of ADVANTAGE. To supplement the case-study review,
the authors did a systematic review of the literature to identify published manuscripts focused on seeding trials
and their conduct.
Data Synthesis: Review of the documents revealed 3 key themes: The trial was designed by
Merck's marketing division to fulfill a marketing objective; Merck's marketing division handled both the
scientific and the marketing data, including collection, analysis, and dissemination; and Merck hid the marketing
nature of the trial from participants, physician investigators, and institutional review board members.
Although the systematic review of the literature identified 6 articles that focused on the practice
of seeding trials, none provided documentary evidence of their existence or conduct.
Limitations: The legal documents in these cases provide useful, but limited, information about the
practices of the pharmaceutical industry. This description of 1 company's actions is incomplete and
may have limited generalizability.
Conclusion: Documentary evidence shows that ADVANTAGE is an
example of marketing framed as science. The
documents indicate that ADVANTAGE was a seeding trial developed by Merck's marketing division to promote
prescription of Vioxx (rofecoxib) when it became available on the market in 1999.
EXTRACTS OF THE EVIDENCE FROM THE FULL ARTICLE:
The Merck
marketing division designed and executed the ADVANTAGE trial. Figure 1 shows an internal award nomination memo from Charlotte McKines, Executive Director of Marketing
Communications at Merck, and Louis Sherwood, Senior Vice President for Medical and Scientific Affairs,
that describes the influence of the marketing division (17).
The memo outlines 4 key Merck marketing principles:
target the trial to a select group of customers—in this case, primary care physicians; use the
trial to demonstrate the value of Vioxx to these physicians; integrate the marketing division and those responsible
for trial-related operations in the field with the highest level of precision; and carefully track marketing-related
results, that is, rates of Vioxx prescriptions written by study physicians.
According to an internal presentation on 16 March
1999 by Jan Weiner, Executive Director of Public Affairs at Merck, the responsibilities of the marketing
division were to "[s]et objectives" and "[d]esign [the] protocol and oversee execution of [the] trial" (18) (Figure 2). In a memo, Merck explained why the company targeted primary care physicians (17) (Figure 1):
First,
the trial was targeted to a select group of critical customers. The clinical trial program for VIOXX focused primarily
on specialists. While they would be critical to the early uptake and advocacy for VIOXX, the large majority
of prescriptions in the A&A [arthritis and analgesia] market (
60%) come from primary
care physicians. The ADVANTAGE trial utilized this important group of prescribers as investigators. In addition
to gaining experience with VIOXX, many of these physicians gained a highly coveted introduction to clinical
research. Second, the design of the trial focused on demonstrating the value of VIOXX to this important
audience.
The internal memo also noted the importance of ADVANTAGE
in creating positive perceptions of Vioxx and Merck among primary care physicians (17) (Figure 1):
Feedback
from the field has been overwhelmingly positive about their ability to access key customers and the influence that
being involved in the trial has had on their perceptions of VIOXX and Merck.
We did not identify documents describing participation
of the research division in the planning or implementation of ADVANTAGE from the database search. However,
Dr. Edward Scolnick, the head of the research division at Merck Research Laboratories, wrote that ADVANTAGE
and other "large marketing clinical studies" are "intellectually redundant" (19). In an e-mail on 4 April 2001 to a colleague about the impact of ADVANTAGE's cardiovascular safety data on Vioxx's
status with the FDA, Scolnick wrote (typographical errors corrected and explanations of acronyms provided) (19):
[T]he
reason we have resisted doing large marketing clinical studies is just this. It opens a lot of data to FDA that
compromises the large clinically meaningful trials. Small marketing studies which are intellectually
redundant are extremely dangerous and the PAC [Products Advisory Committee] system with the marketing emphasis
in CDP [Clinical Development Program, a part of Merck's Marketing Division] on all their studies opens Pandora's
box which we have urged against from the beginning of time. Their budget is now 179 million for CDP—as
much as our phase 2/3 new chemical entities used to be. I have told [another Merck colleague] I think
it is wasteful.
Marketing Division Handles Scientific and
Marketing Data
Merck's marketing division, as illustrated by Jan
Weiner's internal presentation, handled the scientific and marketing data, including collection, analysis,
and dissemination (18) (Figure 2). The first author of the primary publication resulting from ADVANTAGE, Dr. Jeffrey
R. Lisse, an academic physician not employed by Merck, told The New York Times that he did not have a role
in data collection or analysis (20):
Merck
designed the trial, paid for the trial, ran the trial. Merck came to me after the study was completed and said,
"We want your help to work on the paper." The initial paper was written at Merck, and then it was sent
to me for editing. {AN EXAMPLE OF GHOST WRITING ARTICLES, AND THEN PUTTING AN INDEPENDENT PHYSICAN’S
NAME UPON THE PUBLISHED ARTICLE—JK}
Merck collected detailed information about the prescribing
habits of participating physicians, including the numbers of prescriptions written for Vioxx versus
those written for a competing drug during the portion of the ADVANTAGE trial that took place after approval
of Vioxx (21) (Figure 3). Merck summarized changes in prescribing habits that it believed to have occurred as a
result of ADVANTAGE (17) (Figure 1):
FROM CONCLUSION:
Failure to disclose the primary purpose of a trial
has ethical ramifications for patients, physicians, and the design of clinical trials. Seeding trials
like ADVANTAGE, in which the study medication has yet to receive FDA approval, may cause patient injury for
marketing purposes. Such trials may provide incremental scientific benefit: ADVANTAGE affirmed the increased
cardiac risk for Vioxx compared with naproxen (29), which was originally seen in the VIGOR trial (30), although the number of cardiovascular events was misreported in the original publication
(31).
Here it should be noted that the risk of cardiac
risk—which has been estimated at 55.000 deaths and 125,000 MI and strokes as of 2006—when VIOXX was pulled. (A number that is still growing since VIOXX accelerates atherosclerosis. Merck not
only hid the risk in the ADVANTAGE study by under reporting events, they also failed to do a long-term study to confirm this
fatal risk.
