Data Fraud in Medical Research – Part I – Blog Post #323 by Asrar Qureshi

Dear Colleagues!  This is Pharma Veterans Blog Post #323. Pharma Veterans welcomes sharing of knowledge and wisdom by Veterans for the benefit of Community at large. Pharma Veterans Blog is published by Asrar Qureshi on WordPress, the top blog site. Please email to asrar@asrarqureshi.com for publishing your contributions here.

Clin Investig (Lond). 2015; 5(2): 161–173.

doi: 10.4155/cli.14.116   Authors. Stephen L George^*,1 and Marc Buyse²

“The US Public Health Service defines research misconduct more narrowly, restricting it to the most egregious practices [4]:

• “Research misconduct means fabrication, falsification, or plagiarism in proposing, performing, or reviewing research, or in reporting research results;
• Fabrication is making up data or results and recording or reporting them;
• Falsification is manipulating research materials, equipment, or processes, or changing or omitting data or results such that the research is not accurately represented in the research record;
• Plagiarism is the appropriation of another person’s ideas, processes, results, or words without giving appropriate credit;
• Research misconduct does not include honest error or differences of opinion.”

The last point in the definition is crucial; the key distinction between misconduct or fraud and honest error is intent (fraud is ‘intent to cheat’).”

This paper particularly deals with a specific type of scientific fraud, i.e. deliberate fabrication or falsification of data in clinical trials. The authors suggest that it is difficult to estimate the exact incidence of data fraud in clinical research and it may be assumed it is low. This, however, is just an assumption.

“Overall, the available evidence is rather unreliable but seems to suggest that the incidence of certain types of misconduct may be quite high, but the incidence of data fabrication or falsification is low – but perhaps not as low as might be suggested by the frequency of confirmed and publicized cases. Given the large number of investigators involved, approximately 535,000 US scientists in 2012 [23], even low percentages yield a large number of perpetrators.”

The authors have reported some high-profile cases where data was fabricated and manipulated in order to get desirable results. The detail is so relevant that it is hard to edit it.

[Quote]

Robert Fiddes

In the 1990’s Dr. Robert Fiddes was the director of the Southern California Research Institute, a for-profit institution, and was the lead clinical investigator for a large number of clinical trials conducted for pharmaceutical company sponsors… Unfortunately, to maintain his highly successful business Dr. Fiddes had been conducting scientific fraud on an impressive scale for over a decade [40]. Ineligible patients were enrolled on trials; fictitious patients were also enrolled; some patients were pressured to enter trials; laboratory data were altered; blood pressure, EKGs and other results were fabricated; blood and urine samples were submitted that did not come from the patient enrolled (in one instance, an employee with proteinuria, a necessary eligibility criterion for some trials, was paid $25 per urine sample to be submitted as if it were a sample from an actual patient.). Dr. Fiddes was able to maintain his fraud over a long period of time despite audits and other checks until a concerned whistleblower contacted the FDA about the misconduct. After an exhaustive investigation, Dr. Fiddes pled guilty to fraud in 1997, and was sentenced to 15 months in prison [41].

Harry W Snyder Jr & Renee Peugot

In 1994, Dr. Harry W Snyder Jr, a prominent dermatologist and scientist at BioCryst Pharmaceuticals, a biotech company founded in 1986 in Birmingham, Alabama, was overseeing a clinical trial sponsored by BioCryst at the University of Alabama at Birmingham (UAB), where his wife, Renee Peugot, a registered nurse at the University, was the study coordinator responsible for the day-to-day conduct of the trial. Both had considerable financial interests in BioCryst and a vested interest in the outcome of the trial. The product being tested was BCX-34, a purine nucleoside phosphorylase agent, used as a topical ointment in the treatment of psoriasis and in the treatment of cutaneous T-cell lymphoma (CTCL)….. In February 1995 a BioCryst press release claimed highly favorable results for BCX-34 for both psoriasis and CTCL patients, particularly noteworthy for CTCL. A subsequent internal re-analysis of the data by the new Medical Director of BioCryst raised serious questions about the initial results and led eventually to a retraction in June 1995 of the results claimed in the earlier press release, now with ‘no statistically significant drug effect’ noted. Further inquiry and audits by the company and by the FDA led to charges against Snyder and Peugot of falsification of data, including the randomization assignments, to make the results more favorable for BCX-34. Felony convictions followed for both Snyder and Peugot, with prison sentences of 3 years and 2.5 years respectively, payment of financial restitution and permanent debarment by the FDA. The University also had all clinical trials stopped for a period of time while the investigation was underway for failure to properly oversee the trials. [42,43]

Jon Sudbø

In October 2005, The Lancet published a paper by Jon Sudbø, a Norwegian physician and researcher, and co-authors on non-steroidal anti-inflammatory drugs and the risk of oral cancer [44]. The paper reported the analysis of a case–control study of 908 subjects from a population based cohort in Norway. Cases were patients with oral cancer (N = 454) with an equal number of matched controls. Based on detailed statistical analyses, the authors concluded, among other things, that “Long-term use of NSAIDs is associated with a reduced incidence of oral cancer (including in active smokers), but also with an increased risk of death due to cardiovascular disease. These findings highlight the need for a careful risk-benefit analysis when the long-term use of NSAIDs is considered.” [44]. However, soon after publication, in January 2006, the editors of The Lancet received correspondence from officials in the hospital where Sudbø worked, that they had uncovered “ information that strongly indicates that material published … has not been based upon data from our national databases, but on manipulated data… it was not manipulation of real data…it was … complete fabrication.” [45]. This was followed quickly by a retraction of the article [46]. A subsequent investigation by an independent commission of inquiry found that all 908 subjects in the Lancet paper and all data were fictitious (250 subjects had the same birthday!) and, furthermore, that many of Sudbø’s previous publications contained fabricated data, including his doctoral dissertation. Many of these other papers have now also been retracted. Sudbø’s dissertation was rescinded and he is no longer allowed to practice medicine or work in medical research.

Yoshitaka Fujii

A letter to the editor of the journal Anesthesia and Analgesia in April 2000 called attention to some unusual results in the clinical trials reported in papers published by Yoshitaka Fujii, an anesthesiologist and researcher who had published extensively on his clinical trials involving agents used to treat postoperative nausea and vomiting (PONV) [47]. Specifically, the authors of the letter noted that in 21 papers reporting postoperative headache rates in randomized clinical trials of antiemetic agents, the numbers of headaches was exactly equal in all treatment groups in 13 papers and the numbers differed by at most one in the remaining eight papers. The probability of such a chance occurrence in one trial is quite small; the probability that it occurred in all 21 trials is so small that it strains credulity. The authors, in an ironic understatement, concluded that “…there must be an underlying influence causing such incredibly nice data reported by Fujii et al.” [47]. In his brief reply, Fujii failed to address the key issue of how such unusual results might have occurred, noting “…an incidence of headache seems to be identical, but it was true.” [48]. Remarkably, despite the suspicions this must have raised and the lack of a satisfactory explanation for the findings, other than this brief exchange of letters, there does not seem to have been any other official follow-up or repercussions at that time. Dr. Fujii continued to publish the results of his clinical trials over the next 12 years.

In 2012, JB Carlisle, a UK anesthesiologist, published an exhaustive analysis of the statistical distributions of variables from 168 randomized clinical trials conducted and published by Fujii over the previous 20 years, an extraordinary number of trials for any investigator [49]. For most of the categorical and continuous variables reported in these papers, the frequency distributions were much less variable than would be expected by chance alone, echoing and markedly extending the earlier findings on a single variable from a smaller number of studies. Carlisle’s cautiously worded conclusion was “Whether the raw data from any of these studies can be analysed, and whether this might provide an innocent explanation of such results…is beyond the scope of this paper.” [49]. In his letter replying to this paper, Fujii, as in his previous letter in 2000, again failed to address the key question raised by the statistics (i.e., what is the explanation for these remarkably implausible results?), but stated “…this article by Carlisle can obviously be very damaging to me and I want to answer it seriously, but I am not a statistician. I can only offer a few elements of rebuttal at this point…analyses of data obtained from the experiments were performed by myself and colleagues (co-authors), and this can be proved by them…The only thing I can say is that we performed the tests over years with full honesty and integrity. Additionally, I did not write these articles alone, and some of data were collected by others as well.” [50]. But this time the evidence would not be ignored. The editors of 23 journals formally requested a review by the seven institutions in Japan at which Fujii had worked [51]. Shortly thereafter, the Japanese Society of Anesthesiologists (JSA) also began an extensive investigation of 212 papers published by Fujii, including a review of lab records and interviews with other investigators whenever possible. Their findings were astonishing: Out of the 212 papers reviewed, 172 were fraudulent, including 126 ‘totally fabricated’ papers reporting the results of [52]. Meanwhile, as the investigations got underway, Dr. Fujii was no longer involved in research, having been dismissed from the university where he worked for failure to obtain ethical review board approval for his studies. [Unquote]

Continued……

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340084/