Plaintiffs in personal injury lawsuits will undoubtedly cite the FDA’s recent black box warning as evidence that the anti-malarial agent mefloquine causes adverse health effects.
This post was drafted by David H. Schwartz, a principle at Innovative Science Solutions, and John Clark, MD, MSPH, who provides expertise to ISS in litigation involving pharmacovigilence and adverse event reporting. Dr. Clark has consulted with corporations and defense counsel on mass tort and complex litigation for the past three decades. He has worked with individual clients and industry groups on management of some of the country’s largest and most prominent pharmaceutical issues. Dr. Clark is the president and chief medical officer at PCSglobal, a pharmaceutical, biotechnology and medical device industries consulting company specializing in risk-reduction services.
Plaintiffs in personal injury lawsuits will undoubtedly cite the FDA’s recent black box warning as evidence that the anti-malarial agent mefloquine causes adverse health effects. However, the FDA’s warning about the possibility of neurological and psychiatric side effects from mefloquine, and the associated label change, are based solely on case reports. Scientists consider case reports to be among the least reliable forms of evidence.
Scientists have developed specific methods for evaluating the reliability of evidence, and case reports/case series consistently fall at the bottom of the list. For example, in its “Levels of Evidence” ranking, the Oxford Centre for Evidence-Based Medicine lists “case series” second to last – just above “expert opinion.”
The “Message from the Editor” segment titled “The Value of a Case Report” in the Annals of Neurology adroitly sums up the scientific community’s view of case reports:
“No matter how compelling a vignette may seem, one must always be concerned about the reliability of inference based on an “n of one.” No statistics are possible in case reports. Inference is entirely dependent, then, on subjective judgment.”
Organizations have developed broad consensus statements devaluing case reports. Following is a quote from IARC’s statement on case reports:
“The uncertainties that surround the interpretation of case reports, case series and correlation studies make them inadequate, except in rare instances, to form the sole basis for inferring a causal relationship.”
So why do regulators rely on case reports to make decisions? If appropriate scientific evidence is unavailable, regulators are forced to rely on case reports when the public’s health is at stake.
The problem is that plaintiffs will use the same level of evidence to establish causation in a courtroom. Another concern is that regulators’ actions tend to influence the court of public opinion. For example, a recent editorial in The New York Times on mefloquine cites case report evidence linking psychiatric symptoms and behaviors to mefloquine exposure, even though a causal relationship may or may not exist. The author refers to uncontrolled, anecdotal evidence and presents it as incontrovertible proof that the drug caused the symptoms.
The FDA is also reviewing safety data related to acetaminophen and its alleged link to serious skin reactions. Like the situation with mefloquine, the purported relationship between acetaminophen and skin diseases is based on case report data, but plaintiffs will likely present it as evidence of causation in the courtroom.
The recent controversies surrounding mefloquine and acetaminophen are nothing new. Case report evidence has been used to impugn a slew of drugs and medical devices over the years:
Each and every one of the relationships posited above have turned out to be exaggerated or even false, based on more rigorous, controlled scientific evidence. Unlike evidence from controlled scientific studies, case reports are based on anecdotal observsations lacking a protocol-driven approach. Therefore, they are affected by the author’s bias, cherry picking of data, the role of chance, and a host of other factors that make them unreliable.
So what specific steps can be taken by the defense team and by pharmaceutical and device manufacturers when the plaintiff’s allegations are based substantially on evidence from case reports? We’ll address this question in our next blog post. Stay tuned.
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Dr. David Schwartz of Innovative Science Solutions will be presenting at the IADC 2020 Virtual Annual Meeting on a panel titled The Use of Genetic Testing in the Courtroom. Read more
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