ICES Report: The Changing Landscape for COX-2 Inhibitors: A Summary of Recent Events
Bibliographic record
Abstract
The announcement on September 30, 2004 of the withdrawal of Merck & Co.’s Vioxx® (rofecoxib) from the international market sent shock waves throughout the medical community and instigated a public outcry over the current regulatory approach to monitoring drug safety (Horton 2004). The events leading up to the largest drug withdrawal in history certainly warrant discussion. Vioxx® belongs to a relatively new type of non-steroidal anti inflammatory drugs (NSAIDs) known as cyclooxygenase (COX)-2 inhibitors. NSAIDs are commonly used to manage pain and inflammation associated with acute conditions, such as sports injuries, and chronic conditions, such as arthritis. Approximately one in four elderly people use these drugs. While COX-2 inhibitors offer similar levels of pain relief relative to older, traditional NSAIDs, they are marketed as possessing lower rates of adverse gastrointestinal effects. The publication of a large randomized controlled trial in November 2000 convincingly demonstrated a favourable gastrointestinal adverse event profile associated with Vioxx® compared to a commonly used traditional NSAID, Naprosyn® (naproxen). A 50% relative risk reduction in serious gastrointestinal outcomes was observed among Vioxx® users relative to Naprosyn (Bombardier et al. 2000). However, in a secondary analysis of general safety, the same clinical trial also suggested a five fold increased risk of heart attack associated with Vioxx® relative to Naprosyn. Consequently, this prompted numerous systematic reviews and observational studies, the results of which further supported a possible adverse cardiovascular effect of Vioxx®, and were published long before Vioxx’s® withdrawal from the market. Despite this mounting evidence, Vioxx® was not withdrawn until the interim results of a second large randomized controlled trial demonstrated an associated increased cardiovascular risk with the drug; this withdrawal of Vioxx® occurred about four years after the first clinical trial suggested cardiovascular risk. Allegations that the cardiovascular risks associated with Vioxx® were suspected by Merck scientists well before the launch of Vioxx® – as early as 1996 (Lenzer 2004) – have cast serious doubts on the ethical conduct of the pharmaceutical industry and its relationship with the Food and Drug Administration (FDA) of the United States, the federal drug regulatory body. The Vioxx® withdrawal created a common state of confusion about alternative treatments for frustrated patients and prescribing physicians. At this point, the evidence supporting the use of alternative treatments to Vioxx® varies significantly. Alternatives to Vioxx® include treatment with other drugs marketed as COX-2 inhibitors in Canada, such as Celebrex® (celecoxib), BextraTM (valdecoxib) and Mobic® (meloxicam); traditional NSAIDs, such as Naprosyn® and Advil® (ibuprofen); topical NSAIDs, such as Pennsaid® (topical diclofenac) for limited joint pain; alternative therapies, such as Lakota®; and non-drug therapies, such as weight-bearing exercise, knee taping and acupuncture. A first choice for many physicians was to switch patients to Celebrex®, as the overwhelming majority of evidence from large comparative studies suggested no excess cardiovascular risk with exposure to commonly used doses.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.014 | 0.023 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.003 |
| Bibliometrics | 0.011 | 0.018 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.007 | 0.006 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.004 | 0.004 |
| Insufficient payload (model declined to judge) | 0.010 | 0.005 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".