A trawl of internal documents held by the US Food and Drug Administration (FDA) has revealed official action due to “significant departures from good clinical practice” against a total of 57 clinical trials, including 22 affected by “falsification” – yet a parallel search of the published study reports finds no mention of these grave concerns being made public.
The documents about FDA action triggered by bad practice at clinical trial sites were uncovered by freedom of information requests to the US regulator made by Charles Seife, a professor at the Arthur L. Carter Institute of Journalism at New York University.
The researcher and his students cross-referenced the FDA official actions against all the available peer-reviewed studies on the clinical trials affected, and the results are collated in a journal of the American Medical Association, the latest online issue of JAMA Internal Medicine.
“Official action indicated” (OAI) is reserved by the FDA for the most severe forms of clinical trial violation found during the regulator’s site inspections: “objectionable conditions or practices” that warrant compulsory regulatory action, as opposed to “voluntary action indicated” for lesser violations.
The bad practices ranged from falsification of results to poor record-keeping in the 57 trials found to have received action between 1998 and 2013.
In the 2013 fiscal year alone, the author says, about 2% of the 644 inspections by the FDA at trial sites were classified for OAI.
One of the studies, published in 2012, gives positive claims about a stem cell treatment for all the 26 patients with severe loss of blood circulation to their legs, stating “major clinical improvements” for all – while making no mention that one of the patients in fact needed amputation of their leg 2 weeks after having the treatment for severe limb ischemia.
The FDA had to take action over this omission, yet no correction or retraction of the published results was found by Prof. Seife’s search of the medical literature.
An editorial article by Dr. Robert Steinbrook and Dr. Rita Redberg accompanying the findings says such examples are “disturbing” – and that another such case was an “entire study deemed unreliable by the FDA but published without mention of the issue.”
In diplomatic language, they comment on inadequate disclosure by medical researchers and a lack of transparency from the FDA, adding that a “central responsibility of medical journals is maintaining and improving trust in the medical literature.” The editorial says:
“Journals should expect that investigators and sponsors of clinical trials would promptly notify them of substantial findings from FDA and other regulatory agency inspections, and modify their reports of clinical trials as needed, either before or after publication.”
“We look forward to continued progress on transparency from the FDA” and from others, the editorial concludes.
Prof. Seife’s investigation uncovered the following serious violations among the 57 clinical trials – yet only 3 of the 78 published reports for these research studies gave any mention of the misconduct identified by the FDA:
- Fraudulent (“falsification or submission of false information”) – 39% (22 trials)
- Problems with the reporting of adverse events – 25% (14 trials)
- Protocol violations – 74% (42 trials)
- “Inadequate or inaccurate” recordkeeping – 61% (35 trials)
- “Failure to protect the safety of patients” and/or issues with oversight or informed consent – 53% (30 trials)
- Other violations not categorized – 35% (20 trials).
Prof. Seife gives the following conclusion: “When the FDA finds significant departures from good clinical practice, those findings are seldom reflected in the peer-reviewed literature, even when there is evidence of data fabrication or other forms of research misconduct.”
In addition to this failure of the people reporting their clinical trial results to reveal serious violations, there is no public disclosure by the FDA either, he notes:
“The FDA does not typically notify journals when a site participating in a published clinical trial receives an OAI inspection, nor does it generally make any announcement intended to alert the public about the research misconduct that it finds.”
Prof. Seife’s study also concludes that, even when the regulator is forced to reveal details after freedom-of-information requests, it hides details:
“The documents the agency discloses tend to be heavily redacted.
“As a result, it is usually very difficult, or even impossible, to determine which published clinical trials are implicated by the FDA’s allegations of research misconduct.”
The editorial article notes that even the FDA’s more recent efforts toward transparency fail to identify the clinical trials about which concerns are disclosed.
For example, the authors cite the FDA’s “inspections classifications database search,” which covers inspections from March 2008 March 2014 and lists “113,005 records, 4,143 (3.7%) of which are classified as official action indicated.”
They write: “Given the FDA’s missions to protect research subjects and the public health, it should be made possible to link the agency’s inspection documents to specific trials and publications.
“At present, many FDA documents that discuss or refer to clinical trials, including inspection reports, medical reviews, statistical reviews and even the public drug label, do not include the ClinicalTrials.gov identifier.”