Caveat Medicus: Clinician experiences in publishing reports of serious oncology-associated adverse drug reactions

Abstract

Oncology-associated adverse drug/device reactions can be fatal. Some clinicians who treat single patients with severe oncology-associated toxicities have researched case series and published this information. We investigated motivations and experiences of select individuals leading such efforts. Clinicians treating individual patients who developed oncology-associated serious adverse drug events were asked to participate. Inclusion criteria included having index patient information, reporting case series, and being collaborative with investigators from two National Institutes of Health funded pharmacovigilance networks. Thirty-minute interviews addressed investigational motivation, feedback from pharmaceutical manufacturers, FDA personnel, and academic leadership, and recommendations for improving pharmacovigilance. Responses were analyzed using constant comparative methods of qualitative analysis. Overall, 18 clinicians met inclusion criteria and 14 interviewees are included. Primary motivations were scientific curiosity, expressed by six clinicians. A less common theme was public health related (three clinicians). Six clinicians received feedback characterized as supportive from academic leaders, while four clinicians received feedback characterized as negative. Three clinicians reported that following the case series publication they were invited to speak at academic institutions worldwide. Responses from pharmaceutical manufacturers were characterized as negative by 12 clinicians. One clinician’s wife called the post-reporting time the “Maalox month,” while another clinician reported that the manufacturer collaboratively offered to identify additional cases of the toxicity. Responses from FDA employees were characterized as collaborative for two clinicians, neutral for five clinicians, unresponsive for negative by six clinicians. Three clinicians endorsed developing improved reporting mechanisms for individual physicians, while 11 clinicians endorsed safety activities that should be undertaken by persons other than a motivated clinician who personally treats a patient with a severe adverse drug/device reaction. Our study provides some of the first reports of clinician motivations and experiences with reporting serious or potentially fatal oncology-associated adverse drug or device reactions. Overall, it appears that negative feedback from pharmaceutical manufacturers and mixed feedback from the academic community and/or the FDA were reported. Big data, registries, Data Safety Monitoring Boards, and pharmacogenetic studies may facilitate improved pharmacovigilance efforts for oncology-associated adverse drug reactions. These initiatives overcome concerns related to complacency, indifference, ignorance, and system-level problems as barriers to documenting and reporting adverse drug events- barriers that have been previously reported for clinician reporting of serious adverse drug reactions.

Consequences to patients, clinicians, and manufacturers when very serious adverse drug reactions are identified (1997–2019): A qualitative analysis from the Southern Network on Adverse Reactions (SONAR)

“…Finally, the identified drug and very serious ADRs were not identified by a systematic search, but were based on input from a large number of clinicians who have been collaborative with this National Institutes of Health funded pharmacovigilance initiative for over two decades. While a systematic search may have identified more drugs associated with other very serious ADRs, the current study has been conceptualized as a qualitative study that parallels in design our recent qualitative analysis of events that occurred to clinicians who reported serious hematologic and oncologyic ADRs [2] . Input from senior qualitative researchers who had published studies of “whistle-blowers” in health care recommended that between 15 and 25 clinicians would be optimal for such a qualitative study.…”

“…We identified clinician first authors of the first and second publications describing each very serious ADR by reviewing PubMed lists of publications for the two years following the related FDA Advisory Committee meetings. As with the earlier study [2] , co-investigators felt that physicians who had either treated patients with implicated drugs or devices or who treated the related toxicity were in the best position to conduct clinical ADR studies. We excluded case reports and ADR reports if reporting physicians were regulatory agency employees who did not provide patient care or if the first or last authors had not personally treated individuals with the implicated drugs/devices or individuals with the identified toxicity.…”

“…Outcomes were selected by co-investigators and included purported effects of reporting very serious ADRs on clinicians (reputational or professional harms), pharmaceutical manufacturers (loss of sales, removal of implicated drug or device from marketing, hearings with the pharmaceutical manufacturer conducted by the FDA and/or the US Congress, and criminal fines and civil settlements), and patients (publicly reported numbers of persons who were injured or who died from the very serious ADR and publicly reported financial payments related to patient injury). These outcomes were included in our study of effects of reporting serious hematologic and oncologic associated ADRs on patients, clinicians, and pharmaceutical manufacturers [2] .…”

“…Similar information was abstracted from transcripts of FDA Advisory Committee meetings or Congressional hearings (keywords: “identified drug,” “identified toxicity,” “identified manufacturer,” “FDA meeting,” “Congressional meeting”) and inclusion dates within two years of very serious ADR publications. These key words were used in our prior publication [2] .…”

“…As the relevant ADR had not been published previously in the literature, these clinicians were felt to be the persons most responsible for ADR identification. The study found that 83% of the fourteen clinicians reported experiencing negative feedback from manufacturers, half reported receiving negative feedback from universities or colleagues, and a third received negative feedback from regulatory officials [2] .…”