Quality Lessons from Humira Lawsuit

A suit was filed against Abbott Laboratories regarding its top-selling arthritis drug, Humira. The plaintiff, a patient with Rheumatoid Arthritis (RA), alleges the drug caused a life-threatening fungal infection, histoplasmosis. A rough chronology of the case as described by Bloomberg's report of the patient's complaint:

1. The FDA orders Abbott to "warn patients and doctors of an increased risk of potentially fatal Humira-induced histoplasmosis"


2. About a month later, the patient is prescribed Humira, as therapy for RA, allegedly without any notification of the risk of histoplasmosis


3. Months later the patient is diagnosed with disseminated histoplasmosis


4. Over a year after originally receiving notice to send a warning, Abbott finally does so

Specifically, the FDA identified patients living in the Mississippi or Ohio River valleys (endemic areas) and taking methotrexate as having the greatest risk of infection. The lawsuit was filed in Memphis, where the patient was diagnosed. Additionally, reports state that the patient was taking methotrexate, which is a common component of RA therapy. The patient appears to fit the full risk profile of geographic region and use of methotrexate.

A systemic fault. While casual reporting would make this appear to be a clear case, key facts point to the need to improve the timeliness of the Risk Evaluation and Mitigation Strategy (REMS). The FDA approved the Humira REMS in April of 2010, over a year after the patient was diagnosed with disseminated histoplasmosis. By comparison, Abbott was speedy, and seems to have required a little over a month to distribute letters. A REMS for Enbrel, Pfizer's competing TNF-alpha inhibitor, was approved nearly 3 months before the original FDA notice. Piecing together how that document fits into the timeline of this case was obscured when the Enbrel REMS was updated shortly after the debut of the Humira REMS. Regardless, the process for releasing the REMS was inadequate to help this patient.

The information finally provided by the REMS was also inadequate. To treat RA, Humira calms an immune system that is attacking the patient's joints. Therefore, physicians would expect a person taking the drug to have an increased risk of acquiring a disease which non-immunosuppressed people easily shake off. The key consideration to determine whether Humira is the appropriate treatment for a patient requires weighing benefits against risk. To properly assess those trade-offs requires data. The REMS reads as if it was pieced together from my medical school syllabus and lacks clinical data which would allow a practicing physican to reconsider risk. A separate notice on the FDA's site reports case numbers of those who developed histoplasmosis while prescribed various TNF-alpha inhibitors. However, missing are the respective histoplasmosis case rates which would allow comparison between those RA patients who are prescribed a TNF-alpha inhibitor and those RA patients who receive other therapy.

These shortcomings fail to meet the objectives that data be timely, transparent, comparable and understandable. By these standards the REMS developed by Abbott Labs and approved by the FDA was a failure for physicians and patients.

Missed Diagnosis? The immune system responds to histoplasmosis by sending macrophages to engulf the fungus-its common histological presentation is described as clusters of small yeast within macrophages. TNF-alpha, which Humira inhibits, is released primarily by macrophages with the effect of coordinating and enhancing their ability to consume pathogens. T-cells are believed to release a chemical which amplifies the macrophage's ability to digest the pathogens it has consumed.

Current microbiology and immunology could have led a physician to theorize that patients taking TNF-alpha inhibitors may be more susceptible to histoplasmosis. With a heightened suspicion, the physician's gut may have connected the dots even before post-marketing surveillance of TNF-alpha inhibitors provided data to corroborate the theory. However, the Veterans Affairs medical team, as alleged by the compliant, failed to make an earlier diagnosis. Does a need to justify costs, when pursuing a diagnosis, lower a physician's index of suspicion? As a result, are important diagnoses being missed? Among many measures, Evidence Based Medicine (EBM) considers the sensitivity of a diagnostic test. Has an over reliance on data lowered the sensitivity of the physician's gut, which is now weary to act in the absence of data?

This patient’s health seems to have grown worse in the absence of timely and useful data. If the REMS had been made available earlier, the VA physicians may have made the diagnosis. However, EBM will likely never reach its full potential and instead forever remain in a pubescent phase, always a bit ungainly. Therefore, when EBM fails to place sufficient data at clinicians’ fingertips, clinicians must remain prepared to heighten their own index of suspicion and fill the gaps with their expertise and consultations.

Possibly the VA team requested a consultation, as reports indicate an infectious disease specialist later successfully diagnosed and treated the patient. The current chatter within health policy generally demands and applauds greater reliance on primary care. It is regarded as more affordable by many pundits. However, the forward march of scientific discovery continues to require experts in specific fields. Generalists will continue to rely on those specialists for their valuable knowledge. Improving quality requires better teamwork amongst clinicians; maximizing quality continues to require individual excellence.

A certainty of this case is that REMS system is flawed-from the development of its content to the timeliness of its delivery. We hope physicians and other healthcare professionals will join 2directions in discussing its improvement.