The deception and fallacies of sponsored randomized prospective double-blinded clinical trials: the bisphosphonate research example.
The randomized prospective double-blinded clinical trial (RCT) is accepted as Level I evidence and is highly regarded. However, RCTs that gained FDA approval of drugs such as Vioxx, Fen-Phen, and oral and intravenous bisphosphonates have proven to generate misleading results and have not adequately identified serious adverse reactions. The development, research, and clinical marketing of the oral and intravenous bisphosphonates can serve as a representative example for the deteriorated value of many of today's RCTs. The expected high value of RCTs is jeopardized by: (1) sponsorship that incorporates bias; (2) randomization that can select out an expected improved result or eliminate higher-risk individuals; (3) experimental design that can avoid recognition of serious adverse reactions; (4) blinding that can easily become unblinded by the color, shape, odor, or administration requirements of a drug; (5) definitions that can define an observation as something other than what it actually represents, or fail to define it as an adverse reaction; (6) labeling of retrospective data as a prospective trial by using adjudicators prospectively to look at retrospective data; (7) change of the length of study to avoid the longer-term adverse reaction from accumulation of drug or treatment effects; (8) ghost writing, as when drug company physicians or a hired corporation either edit or write the entire protocol and/or manuscript for publication. Such corruption of the well-intended properly conducted RCT should be viewed with a sense of outrage by practitioners and requires a restructuring of the levels of evidence accepted today.
Robert E
RE
Marx
D019386:Alendronate / Q000009:adverse effects; D001067:Appetite Depressants / Q000009:adverse effects; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000209:etiology*; D050071:Bone Density Conservation Agents / Q000009:adverse effects*; D008192:Deception; D004164:Diphosphonates / Q000009:adverse effects*; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D005264:Femoral Fractures / Q000139:chemically induced; D049673:History, 20th Century; D006801:Humans; D007783:Lactones / Q000009:adverse effects; D008297:Male; D060735:Pharmacovigilance; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic / Q000941:ethics / Q000266:history / Q000379:methods / Q000592:standards*; D012015:Reference Standards; D015203:Reproducibility of Results; D012107:Research Design; D058028:Research Report / Q000592:standards; D012109:Research Support as Topic / Q000592:standards*; D012189:Retrospective Studies; D013450:Sulfones / Q000009:adverse effects; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000266:history; D014481:United States; D014486:United States Food and Drug Administration
D001067:Appetite Depressants; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D004338:Drug Combinations; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib; D019386:Alendronate