The spectre of ghostwriting: eroding public trust in physicians, clinical trial integrity and biomedical authorship.

The impact of medical ghostwriting, a violation of authorship ethics, remains unclear within the biomedical literature and among the public, potentially raising concerns about the integrity of the biomedical evidence base. Core texts in authorship and ghostwriting from the clinical literature and the 2010 Senate Minority Report on ghostwriting were reviewed as were uses of the term 'ghostwriting' in contemporary (2009-2011) and more recent (2015-2016) journalistic news coverage originally printed in English. Journalistic coverage oversimplified key concerns about ghostwriting identified by the medical community and the US government. More recent journalistic uses of the term 'ghostwriting' suggest confusion with topics such as financial disclosures or patient monitoring. Pharmaism in the medical literature, an expression of bias against pharmaceutical companies that casts doubt on the credibility of physicians and scientists, may be a source for confusion. The tendency for medical journal editors to discuss ghostwriting in the context of clinical trial transparency or data integrity is another possible source for misinterpretation via oversimplification. Journalistic descriptions of ghostwriting consistently downplay the critical reasoning abilities and competence of practising physicians and deflect attention away from patient concerns and back to pharmaceutical companies. Some uses of the term ghostwriting in news coverage may implicitly undercut belief in the competence of physicians, a troubling trend. Further work is needed to characterise the impact of ghostwriting in the medical literature and to reassure the public that their trust in medical practitioners is well placed.

Publication planning: promoting an ethics of transparency and integrity in biomedical research.

Biomedical research should include plans to communicate complete and accurate results to the scientific community and the public in a timely manner. All too often, however, such planning is lacking until after data have been generated. We developed a collaborative professional statement following review of the indexed biomedical literature and relevant professional society guidelines. Planning for publications before, during and after biomedical research studies are conducted promotes the timely dissemination of accurate and comprehensive results. Effective publication planning accounts for the work of all contributors, encourages full transparency and contributes to overall scientific integrity. Although the most obvious contribution of publication planning is to result dissemination, the best planning may also help improve the overall quality of research study design and the overall integrity of study conduct by keeping the final audience in the forefront of the investigators' attention. Publication planning can help biomedical researchers achieve and maintain high standards of transparency and integrity. Table 1 below highlights briefly some of the aspects to be included in a publication plan.

Correlation between serum bactericidal activity against Neisseria meningitidis serogroups A, C, W-135 and Y measured using human versus rabbit serum as the complement source.

The surrogate of protection against invasive meningococcal disease is the presence of serum bactericidal activity (SBA) at a titer ≥4 in an assay using human serum as the complement source (hSBA). However, for various practical and logistical reasons, many meningococcal vaccines in use today were licensed based on a modified SBA assay that used baby rabbit serum as the complement source (rSBA). To assess the strength of correlation between the two assay systems for serogroups A, C, W-135 and Y, we analyzed a subset of samples from adolescent subjects enrolled in a Phase II study of Novartis' MenACWY-CRM conjugate vaccine vs. an ACWY polysaccharide vaccine; samples were analyzed in parallel using hSBA and rSBA. We compared geometric mean titers (GMTs), calculated Pearson correlation coefficients between paired hSBA and rSBA results, and calculated sensitivity/specificity and likelihood ratios for an rSBA ≥8 or ≥128 for classifying hSBA ≥4, taking hSBA as the 'gold standard'. Correlations between hSBA and rSBA ranged from 0.46 to 0.78 for serogroup C, but were weaker for serogroups A, W-135 and Y (range -0.15 to 0.57). In post vaccination samples, nearly all subjects had rSBA titers ≥8, though up to 15% remained seronegative by hSBA. In post vaccination settings, rSBA titers at ≥8 or ≥128 was highly sensitive for an hSBA titer ≥4, but non-specific. In conclusion, results generated by rSBA did not accurately classify serostatus according to hSBA for serogroups A, W-135 and Y.

A placebo and active comparator-controlled trial of rofecoxib for the treatment of rheumatoid arthritis.

OBJECTIVE: To evaluate the efficacy and tolerability of rofecoxib 25 mg and 50 mg once daily versus placebo and naproxen 500 mg twice daily in patients with RA. METHODS: Eligible patients were randomized (double-blind) to placebo (n = 289), rofecoxib 25 mg (n = 306), 50 mg (n = 286) once daily, or naproxen (n = 142) for 12 weeks. Efficacy assessments included the ACR core set, with prespecified primary endpoints: patient and investigator global assessments of disease activity, tender and swollen joint counts. Investigator-reported adverse experiences, routine laboratory and vital sign measurements were monitored. RESULTS: Rofecoxib 25 mg, 50 mg, and naproxen provided similar treatment effects, significantly different from placebo, consistent with improvement, for all primary endpoints. Effects were evident at the earliest assessment (week 2) and sustained for 12 weeks. All treatments were generally well-tolerated. CONCLUSIONS: Rofecoxib 25 mg once daily had similar efficacy to naproxen 500 mg twice daily (a standard dose). No additional benefit was seen with 50 mg rofecoxib.

Results of a randomized, dose-ranging trial of etoricoxib in patients with osteoarthritis.

OBJECTIVES: To evaluate the clinical efficacy and tolerability of etoricoxib in the treatment of osteoarthritis (OA) of the knee and define the clinically active dose range for further clinical trials. METHODS: This two-part, randomized, double-blind, placebo- and active comparator-controlled trial was conducted in 617 adults with knee OA. In Part 1 (6 weeks), patients received placebo, etoricoxib 5, 10, 30, 60 or 90 mg q.d. In Part 2 (8 weeks), patients received etoricoxib 30, 60 or 90 mg q.d. or diclofenac 50 mg t.i.d., predetermined at Part 1 allocation. Efficacy and safety were evaluated. Primary efficacy end-points were the Western Ontario and McMaster's University Osteoarthritis Index (WOMAC) Pain subscale, Patient Global Assessment of Response to Therapy, and Investigator Global Assessment of Disease Status. RESULTS: At 6 weeks, etoricoxib 5, 10, 30, 60 and 90 mg each demonstrated clinical efficacy superior to placebo. Maximal efficacy was seen with 60 mg. In Part 2, etoricoxib 30, 60 and 90 mg were generally similar to diclofenac. Patients receiving etoricoxib 30, 60 or 90 mg in Parts I and II had sustained effects over 14 weeks. All treatments were well tolerated. CONCLUSIONS: Etoricoxib 60 mg once daily showed maximal efficacy in treating OA in this study. Etoricoxib 5-90 mg once daily was generally well tolerated in OA patients for up to 14 weeks.

Rofecoxib shows consistent efficacy in osteoarthritis clinical trials, regardless of specific patient demographic and disease factors.

OBJECTIVE: To evaluate the efficacy of rofecoxib (Vioxx) in subpopulations of patients with osteoarthritis (OA) identified by demographic or baseline disease characteristics, or varied OA involvement. METHODS: Data were combined from three 6-week double blind trials in patients with OA of the knee or hip. All trials contained placebo, 12.5 mg rofecoxib, and 25 mg rofecoxib arms (the only trials to date containing all 3 treatments). Analyses were performed on subgroups categorized according to the following baseline demographics and disease characteristics [age, sex, height, weight, body mass index, American Rheumatism Association (ARA) functional class, joint tenderness, joint stiffness, Western Ontario-McMaster University OA Index (WOMAC) functional subscale, unilateral/bilateral joint involvement, number of joint groups involved]. Three primary endpoints--Pain Walking on Flat Surface (WOMAC), Patient Global Assessment of Response to Therapy, and Investigator Global Assessment of Disease Status--were analyzed. The global assessments, which provided data on overall aspects of OA, regardless of affected joint, were used to assess effects among patients with one, 2, 3, or 4 joint groups affected (from among the following: interphalangeal/first carpal-metacarpal joint, spine, hip, or knee). RESULTS: Data from 1501 patients were included. No consistent treatment-by-subgroup interaction was observed with all 3 primary endpoints for patients taking placebo or 12.5 or 25 mg rofecoxib. Rofecoxib showed generally consistent efficacy across subgroups of patients identified by sex, race, age, OA location(s), prior OA therapy, baseline study joint tenderness or swelling (patients with knee OA only), and ARA functional class level. CONCLUSION: In this combined analysis, no specific factor predicted a differential treatment effect to rofecoxib.

A multicenter, randomized, controlled trial to evaluate the safety profile, tolerability, and efficacy of rofecoxib in advanced elderly patients with osteoarthritis.

This 6-week study was conducted to test the efficacy, safety, and tolerability of rofecoxib (a selective COX-2 inhibitor) compared to nabumetone (a non-selective NSAID) and placebo in osteoarthritis (OA) patients aged 80 and older. Three hundred forty-one patients, mean age 83 years, were randomized. Allocations were made in an approximately 1:2:1:2 ratio (placebo: 12.5 mg rofecoxib: 25 mg rofecoxib: 1500 mg nabumetone). Least square mean changes from baseline in the primary efficacy endpoint, Patient Global Assessment of Disease Status, were as follows (with negative numbers indicating improvement): -14.85 mm for placebo; -25.34 mm for 12.5 mg rofecoxib; -25.40 mm for 25 mg of rofecoxib; and -25.95 mm for nabumetone (p<0.001 for all active treatments vs placebo.) Results from secondary endpoints, including the 3 WOMAC sub-scales (pain, stiffness, and disability) and the Investigator Global Assessment of Disease Status, were consistent with those for the primary endpoint. No significant between-group differences were observed in the proportions of patients who discontinued treatment due to either clinical or laboratory adverse experiences. Renal safety (edema and hypertension adverse experiences) was similar for rofecoxib and nabumetone. No gastroduodenal ulcers occurred; however, the demonstration of gastrointestinal risk with rofecoxib or nabumetone was beyond the scope of this trial. We conclude that in patients 80 years and older, rofecoxib, 12.5 mg and 25 mg once daily, demonstrated clinical efficacy for the treatment for OA as did 1500 mg of nabumetone. Rofecoxib and nabumetone were generally well tolerated in this elderly population.

Rofecoxib, a new cyclooxygenase 2 inhibitor, shows sustained efficacy, comparable with other nonsteroidal anti-inflammatory drugs: a 6-week and a 1-year trial in patients with osteoarthritis. Osteoarthritis Studies Group.

INTRODUCTION: Rofecoxib, a cyclooxygenase 2 inhibitor (sometimes known as a specific cyclooxygenase 2 inhibitor or Coxib), is used in osteoarthritis (OA). Published information indicates rofecoxib's improved gastrointestinal safety profile over nonselective nonsteroidal anti-inflammatory agents (NSAIDs). OBJECTIVE: To evaluate the efficacy and safety of rofecoxib in treating OA in 2 studies. METHODS: Two randomized, double-blind, parallel-group studies in patients with OA of the knee or hip were conducted using identical entry criteria and end points. A 6-week placebo-controlled trial in 736 patients compared 12.5 and 25 mg of rofecoxib once daily with 800 mg of ibuprofen 3 times daily, and a 1-year study compared 12.5 and 25 mg of rofecoxib once daily with 50 mg of diclofenac 3 times daily in 693 patients. RESULTS: Rofecoxib, at 12.5 and 25 mg, demonstrated efficacy clinically comparable with ibuprofen, assessed by 3 primary end points according to predefined comparability criteria. Both rofecoxib doses and ibuprofen provided significantly greater efficacy than placebo on all primary end points at 6 weeks. Both rofecoxib doses and diclofenac showed similar efficacy over 1 year. All treatments were well tolerated. CONCLUSIONS: Rofecoxib is effective in treating OA with once-daily dosing for 6 weeks and 1 year. Rofecoxib was generally safe and well-tolerated in OA patients for 6 weeks and 1 year. Arch Fam Med. 2000;9:1124-1134