Raising Suspicions with the Food and Drug Administration: Detecting Misconduct

Abstract

The clinical Bioresearch Monitoring (BIMO) oversight program of the US Food and Drug Administration (FDA) assesses the quality and integrity of data submitted to the FDA for new product approvals and human subjects protection during clinical studies. A comprehensive program of on-site inspections and data verification, the BIMO program routinely performs random inspections to verify studies submitted to the FDA to support a marketing application. On occasion the FDA will conduct a directed inspection of a specific site or study to look for problems that may have previously been identified. The inspection of a clinical study sometimes uncovers evidence of research fraud or misconduct and it must be decided how to deal with the investigator and the suspect data. The prevention of [or] decreasing the incidence of fraud and misconduct through monitoring by the sponsor is one way to manage compliance issues and can help prevent misconduct. A training program is another way to manage compliance issues in clinical research. While training does not guarantee quality, it does help to ensure that all individuals involved understand the rules and the consequences of research misconduct.

Detecting Data Quality Issues in Clinical Trials: Current Practices and Recommendations

“…Misconduct and fraud (a severe type of misconduct) have generally been viewed to include a level of deception, 5,6 perpetrated to gain profit or an unfair or dishonest advantage, 5 at odds with what is agreed to be a sound scientific method, and/or generally falling short of good ethical and scientific standards. 6,7 Although fraudulent activity implies intent to deceive, 5,6 unintentional noncompliance is commonly associated with carelessness, misunderstanding of or lack of clarity in the protocol, or the inability to perform assigned tasks. In clinical trials, examples of fraud and misconduct may include activities such as fabricating patients, falsifying eligibility data to enroll otherwise unqualified patients, and knowingly fabricating data when a study procedure was inadvertently missed instead of documenting that the procedure was not done.…”

Good Clinical Practice Training: Identifying Key Elements and Strategies for Increasing Training Efficiency

“…We identified 31 articles related to GCP training and classified them into the following 5 categories: qualitative and survey, 8 – 17 investigator and site staff training, 18 – 24 research networks, 25 – 30 policy and guidance, 31 – 34 and online training modules. 35 – 38 GCP training programs referenced in the literature range from departmental-based training for researchers to centralized GCP training programs offered at the university or organizational level (eg, training offered by government agencies).…”

The FDA Outlook of Events Reporting after Ticagrelor or Clopidogrel in the PLATO Trial: Impact of Sponsor Censoring Dates, Drug Discontinuation, and Withdrawal of Consent

“…The site monitoring and censoring of clinical events by study sponsors in randomized controlled trials is controversial but at present is still acceptable to regulatory authorities. Delegating such a pivotal task to pharmaceutical industry representatives, rather than to blinded investigators or to independent adjudicators, may introduce a bias that impacts trial results in favor of experimental agents; this outcome would be especially harmful in indication-seeking studies later submitted for regulatory approval [1,2,3]. Importantly, though still undertaken, sponsor involvement in endpoint censoring has been demonstrated to be time- and cost-inefficient [1,4,5].…”

“…Delegating such a pivotal task to pharmaceutical industry representatives, rather than to blinded investigators or to independent adjudicators, may introduce a bias that impacts trial results in favor of experimental agents; this outcome would be especially harmful in indication-seeking studies later submitted for regulatory approval [1,2,3]. Importantly, though still undertaken, sponsor involvement in endpoint censoring has been demonstrated to be time- and cost-inefficient [1,4,5]. Sponsor involvement in the censoring of site-reported outcome events has come into question once again as a result of the recent US Food and Drug Administration (FDA) review [6] of the Platelet Inhibition and Clinical Outcomes (PLATO) trial.…”