Failure to adhere to study plans is the most common research error among US investigators

BMJ 2014; 348 doi: (Published 26 June 2014) Cite this as: BMJ 2014;348:g4245
  1. Michael McCarthy
  1. 1Seattle

Warning letters issued by the US Food and Drug Administration (FDA) to clinical investigators commonly cite failure by the researchers to stick to their stated plans, to protect the safety of trial participants, and to maintain good records, according to a new study.

Under US law the FDA is charged with regulating clinical research and has developed a bioresearch monitoring programme to safeguard patient rights and safety and to ascertain the quality and integrity of data being submitted to the agency.

To assure compliance with FDA regulations, the programme’s staff conducts site visits to clinical trial investigators, study sponsors and monitors, institutional review boards (IRBs), and others entities involved in research.

In the new study, researchers reviewed 84 first warning letters issued between 2005 and 2012 by the FDA following such site visits. The study was published online on June 23 in the Journal of Medical Ethics.1

Coauthors Yashashri C Shetty and Aafreen A Saiyed, of the department of pharmacology and therapeutics at Seth GS Medical College in Mumbai, Maharashtra, India, reported that of the 20 warning letters issued to clinical investigators, the most common violation was deviation from the investigational plan, a problem cited in 19 of the 20 letters (95%). Failure to protect subject safety and report adverse events to the IRB was the next most common violation, cited in 11 of the 20 letters (55%). Eight of the 20 letters (40%) cited failures to maintain accurate and adequate case histories, failure to retain records, and inability to produce records for inspection and regulatory compliance.

Eighteen warning letters were issued to IRBs. The most common violation, cited in 11 (61%) of the letters, was failure to follow written procedures for continuing review. The next most common violations, cited in 10 of the letters (56%) were “failure to maintain minutes of meeting, inappropriate membership, quorum issues, misuse of expedited review and lack of a layperson in meetings,” the researchers reported.

Forty six warning letters were sent to trial sponsors during this time period. The most common violation, cited in 27 (59%) of the letters, was failure to follow the monitoring schedule. Other common violations were: failure to obtain investigator agreement stating the investigator will comply with the trial protocol, failure to maintain records of study data, and, in 13 (28.26%) of the letters, failure to submit an Investigational Device Exemption or Investigational New Drug application to the FDA, which are required to use the device or drug in a trial.

Compared with earlier reviews, the researchers noted a statistically significant rise in citations for failure to protect patient safety and failure to report adverse events to institutional review boards (P=0.001) and for failure to personally supervise the study (P=0.05).2 3

Nevertheless, by other measures, such as adherence to investigation plans, record keeping, and issues concerning informed consent, the conduct of clinical trials seemed to have improved, the researchers said.

The researchers recommended that the FDA practice of site inspections and the issuing of such warning letters should be “copied worldwide by regulatory agencies overseeing clinical trials.” But, they add, that despite the “stringent regulation in the USA” violations by clinical investigators, sponsors, and other stakeholders nevertheless continue. “A culture of research must be developed in order to retain public confidence and the link between public health and community trust,” they conclude.


Cite this as: BMJ 2014;348:g4245


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