John R. Senior, MD
Authors: Mark Avigan, Paul B. Watkins
Journal: Hepatology (2022)

The hepatology community mourns the loss of John R. Senior, MD, who passed away January 25th at the age of 94, after a lengthy illness and testing positive for COVID-19. He is survived by his dear wife Sara, with whom he was married for 69 years, three children, six grandchildren, and five great-grandchildren. "Since he was an ensign in the navy, John Senior has never been one to shy away from obstacles thrown in his path, adhering to Admiral Farragut's pronouncement in the Battle of Mobile Bay - 'damn the torpedoes, full steam ahead'." Tribute by Mark Avigan included in the AASLD Distinguished Service Award presentation, 2017. John was elected to the Council of the AASLD in 1969 and became the organization's 25th President in 1974. During that period, he initiated an expansion of the annual meeting's course on liver disease. Determined to secure the course, John contributed his own personal money which might never have been reimbursed had it not turned out to be the success that it was. Over subsequent years, the liver disease course has become a major draw as well as an important source of revenue for the society. In the same year as he served as AASLD president, John became director of the Clinical Research Center at the Graduate Hospital, then part of University of Pennsylvania's Medical training programs. He oversaw the opening of a special treatment unit for serious medical complications of alcoholism which, between 1974 and 1979, cared for 3500 patients referred from the Philadelphia metropolitan area and surrounding region in Pennsylvania and New Jersey. In 1981, John changed course to become Vice President for Worldwide Clinical Affairs at the Squibb and Sterling-Winthrop Research Institute. From 1984 to 1995 he was an independent consultant to pharmaceutical companies in Europe, Japan, and North America specializing in regulatory standards for clinical trial data and new drug applications. John then joined the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration as a medical reviewer for gastrointestinal drugs. During his first few years as a reviewer, he helped bring to light a number of treatment-related safety issues, including an apparent association between certain 5-HT3 antagonists used to treat IBS, and an increased risk for ischemic colitis. John's growing interest in drug safety led to his appointment to the FDA's Office of Drug Safety. This was a time of rising concern for liver safety as two newly approved drugs, troglitazone and bromfenac, were withdrawn from the market due to serious liver toxicity. John focused his activities on hepatotoxic drugs and was a highly respected consultant for medical officers on liver safety issues. Beginning in 1999, John arranged annual meetings near the FDA White Oak Campus focused on understanding, assessing and managing the liver safety of pharmaceuticals and biological agents. These meetings comprised two full days of highly interactive, in-person presentations by invited scientists and analysts with regulatory, academic, and industry backgrounds. He insisted that the entire contents of each meeting be made accessible in the public domain. For this purpose, all the presentations and interactive discussions were recorded and transcribed, and together with each of the PowerPoint presentations placed on a public website. To ensure accuracy of translation, John meticulously reviewed each transcript with a fine-tooth comb, checking back with the speakers to ensure their accuracy prior to their posting. Not surprisingly, among many of the attendees these meetings were informally known as the 'John Senior Meetings.' It is hard to overestimate the impact that the gatherings have had in the development of a broad-based, multi-disciplinary international community with an interest in drug-induced liver injury. The DILI meetings continue to flourish as a bi-annual event sponsored by FDA in partnership with the AASLD. Together with a core group of other FDA colleagues including Ruyi He, Ross Pierce, Mark Avigan and Bob Temple, John played a central role in the development of a landmark FDA guidance entitled 'Drug-Induced Liver Injury: Premarketing Clinical Evaluation' issued by the FDA in 2009. This guidance has set a lasting standard for manufacturers of pharmaceuticals and biological products, regarding DILI risk assessment and risk management during drug development. A major contribution of this guidance was the identification of simultaneous elevations in serum ALT and total bilirubin as a gold standard signal of liability for serious liver injury. Cases with these elevations, in the absence of cholestasis, caused by a study drug were dubbed by Bob Temple as fulfilling 'Hy's Law', acknowledging a seminal observation made decades earlier by the late Hyman Zimmerman that patients who develop drug-induced hepatocellular jaundice have at least a 10% chance of developing liver failure. It is important to note that since issuance of the FDA guidance, no newly approved drugs have been removed from the U.S. market due to life-threatening liver toxicity. During this period, together with Ted Guo PhD, a mathematician in CDER's Office of Biostatistics, John developed a software platform that has had an enormous impact on how the liver safety of new drug candidates is assessed in clinical trials. Termed 'eDISH' (Evaluation of Drug-Induced Serious Hepatoxicity), this graphic tool displays the peak serum ALT and total bilirubin levels observed in each study subject in a clinical trial population, with different symbols for those exposed to the active treatment and comparator. The two-dimensional display of these test results permits the immediate identification of any imbalance in hepatocellular liver events, as well as the identification of potential Hy's Law Cases. By clicking on any symbol with abnormal peak liver test results, the corresponding patients' serial liver chemistries are displayed on a time-line graph, along with additional case-level clinical and diagnostic information. eDISH, or some modification of this software platform, are now universally employed as essential tools in the evaluation of liver safety concerns that arise during clinical drug development. For developing eDISH, John and Dr. Guo were recognized by their FDA colleagues with an award in 2017. John also received the Distinguished Service Award from the AASLD in 2017. He retired from the FDA in 2019, at the age of 92. John will be remembered as an extraordinarily energetic and creative clinician-scientist who maintained a quick wit and somewhat crusty sense of humor to the end. He has left a long-lasting legacy in improving the safety of new medications and will be missed by many.