Interdisciplinary Safety Evaluation for Learning and Decision-Making.

The FDA IND safety reporting Final Rule (21CFR 312.32) applies to all human drugs and biological products being studied under an Investigational New Drug (IND). A sponsor must file an IND safety report for any serious unexpected suspected adverse reaction (SUSAR) of a medicinal product being investigated. Some events may be obviously drug-related (e.g., agranulocytosis, anaphylactic reaction, drug-induced hepatic injury, Stevens-Johnson Syndrome). For serious adverse events that are not interpretable as individual occurrences, additional processes and procedures need to be employed for identifying and assessing risks in the accumulating safety data. The approaches shared in this manuscript apply principally to safety reporting of events that are anticipated to occur in the patient population-regardless of study participation. For these events, the study sponsor should periodically review the data in the aggregate and make a judgment as to whether there is a reasonable possibility of an event having been caused by the study drug rather than the underlying condition of the patient or a concomitant therapy. Factors cited for consideration are the size and consistency of the difference in event frequency between the test and control groups, supportive preclinical findings, evidence of a dose response relationship, plausible mechanism of action, known class effect and occurrence of other related adverse events. Examples are provided that demonstrate the flexibility sponsors have in meeting the spirit of the Final Rule; some combination and variation of methods from the examples could be employed. The important thing, as expressed by Jacqueline Corrigan-Curay (Director of the Office of Medical Policy, Center for Drug Evaluation and Research, FDA), is to have a thoughtful process; a system in place to look for clinically important imbalances, applying the best clinical and quantitative judgment, while maintaining trial integrity (Ball et al. in Interdisciplinary aggregate assessments for IND safety reporting: a dialogue among colleagues from industry, Academia and the FDA. ASA biopharmaceutical section regulatory-industry statistics workshop, 2018).

Effects of reconcile (fluoxetine) chewable tablets plus behavior management for canine separation anxiety.

Canine separation anxiety is a common behavioral problem presented to veterinarians. Associated behaviors are distressing to both dog and owner, have the potential to disrupt the human-companion animal bond, and may lead to euthanasia. The results of this study demonstrate the clinical efficacy and safety of Reconcile (fluoxetine, 1 to 2 mg/kg/day [0.45 to 0.91 mg/lb/day]), in conjunction with behavior management, for the treatment of canine separation anxiety. The beef flavored chewable formulation was palatable to treated dogs and easy to administer. This study provides to veterinarians and owners valuable information about an effective separation anxiety treatment plan that combines use of Reconcile with behavior modification.

Analysis of reports of human exposure to Micotil 300 (tilmicosin injection).

OBJECTIVE: To identify clinical signs associated with and outcome of human exposure to Micotil 300 (tilmicosin injection). DESIGN: Retrospective case series. STUDY POPULATION: Reports of 3,168 human exposures to Micotil 300. PROCEDURES: Reports of human exposure to Micotil 300 submitted to the Elanco Animal Health Pharmacovigilance Unit between March 1992 and March 2005 were reviewed. RESULTS: At least 1 clinical sign was described in 1,404 (44%) reports, whereas the remaining 1,764 (56%) exposures were presumably asymptomatic. Eighty percent of exposures involved males; mean age was 38 years. Sixty-one percent of exposures were a result of accidental injection, with injection site pain, bleeding, swelling, or inflammation being the most common signs, followed by nausea, tachycardia, dizziness, anxiety, an abnormal taste, headache, lightheadedness, limb pain, paresthesia, chest pain, and soreness. Only 156 (5%) reports involved serious adverse effects (ie, tachycardia, bradycardia, hypertension, hypotension, heart disorder, chest pain, tachypnea, or death). There were reports of 13 deaths following tilmicosin exposure, but only 2 of those deaths were related to accidental exposure. Time to onset of clinical signs was < or = 60 minutes in 63 of the 156 (40%) reports involving serious adverse effects. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that the overall risk of accidental human exposure to tilmicosin resulting in serious adverse effects is low (approx 2 people for every 1 million doses administered). Nevertheless, safe handling and proper use should be emphasized.