Strategies and Practices in Off-Label Marketing of Pharmaceuticals: A Retrospective Analysis of Whistleblower Complaints

Aaron Kesselheim and colleagues analyzed unsealed whistleblower complaints against pharmaceutical companies filed in US federal fraud cases that contained allegations of off-label marketing, and develop a taxonomy of the various off-label practices

Placebo-only-controlled versus active-controlled trials of new drugs for nine common life-threatening diseases

Sarah Sorscher, Azza AbuDagga, Sammy Almashat, Michael A Carome, Sidney M Wolfe Health Research Group, Public Citizen, Washington, DC, USA Purpose: The Food and Drug Administration (FDA) permits investigators to withhold active interventions from human subjects randomly assigned to control groups in clinical trials. The scope of this practice in trials for life-threatening diseases is unknown. We assessed the frequency and characteristics of trials providing control group subjects with active interventions versus those providing only placebos to control group subjects in trials supporting FDA approvals of new drugs for nine life-threatening diseases. Materials and methods: We reviewed the FDA’s database of approved drug products and identified all new approvals from 2006 to 2011 for drugs or biological products indicated for asthma, bipolar disorder, chronic obstructive pulmonary disease (COPD), diabetes mellitus, hypertension, osteoporosis, Parkinson’s disease, partial seizures, and schizophrenia. Then, we identified all trials described in FDA medical review documents for these approvals and abstracted information on trial characteristics and the interventions provided to control group subjects. Results: Of 508 included trials, 201 (39.6%) were placebo-only-controlled, meaning subjects in at least one control group did not receive an active intervention, and 307 (60.4%) were active-controlled, meaning subjects in all control groups received an active intervention. The total recorded enrollments in control groups provided with placebos only and in control groups provided with active interventions were 19,361 and 93,093 subjects, respectively. The proportion of placebo-only-controlled trials varied across diseases (P<0.001), ranging from 75.5% for COPD to 0% for partial seizures and osteoporosis. Placebo-only controls were used in 76.9% of trials for severe COPD, 56.4% of trials for severe hypertension, 43.8% of trials for moderate or severe persistent asthma, and 6.7% of trials for severely uncontrolled diabetes. Logistic regression analysis showed that longer trials were associated with lower odds of being placebo-only-controlled compared with shorter trials.Conclusion: Providing only placebos to control groups in trials for life-threatening diseases is a common practice, potentially entailing varying degrees of risk to subjects. Further research is warranted to assess the impact of this practice, particularly in trials of long duration and those involving subjects with severe disease. Keywords: drug approval, bioethics, medical ethics, Food and Drug Administration, research ethic