Drug Safety Oversight Board Meeting, October 15, 2009
The Executive Director updated the Drug Safety Oversight Board (DSB or Board) on risk communications [Public Health Advisories (PHAs), Early Communications about Ongoing Safety Reviews (ECs), and Information for Healthcare Professionals (HCP)] posted and in development since the September 17, 2009 meeting. The following is a list of the posted risk communications:
- September 25, 2009: Deferasirox and increased risk of death or serious and rarely fatal adverse reactions (e.g. fatal GI bleeds and renal and liver failure) in patients over age 60 with myelodysplastic syndromes
- September 25. 2009: Sitagliptin (Januvia) and sitagliptin/metformin (Janumet) and reports of acute pancreatitis, including hemorrhagic and necrotizing pancreatitis
- October 1, 2009: Change in Heparin USP Monograph
- October 2, 2009: Oseltamivir (Tamiflu)
The DSB heard presentations and discussed two topics: systems biology modeling and its relationship to drug safety planning and evaluation and the practice of tablet splitting and how it may relate to drug safety.
Systems Biology Modeling and Drug Safety Planning and Evaluation
Systems biology modeling involves the use of computer modeling and simulations to analyze and visualize complex interactions in biological systems. Modeling and simulation use available data (e.g. clinical, laboratory) to form a mathematical model in the computer. It shows promise to create a knowledge base for a deeper mechanistic understanding of drug toxicity and organ response in health and disease. It shows promise in predicting efficacy and safety outcomes for novel therapies; optimizing trial design and drug dosing to balance efficacy and safety; and predicting which patients are at risk and which drugs and drug combinations to avoid.
The Board discussed how FDA might study, develop, and use systems biology modeling as a tool in drug development with an emphasis on post market drug safety. In particular the Board discussed two FDA contracts using systems biology modeling to study drug-related liver and cardiovascular toxicities.
The Practice of Tablet Splitting
Insurance companies and doctors are increasingly recommending that patients split tablets, either to adjust their dose or as a cost saving measure. FDA’s Office of Pharmaceutical Sciences conducted internal research on tablet splitting and concluded that in some cases, there are possible safety issues, especially when tablets are not scored or evaluated for splitting. The FDA’s concerns with splitting a tablet include variations in the tablet content, weight, disintegration, or dissolution, which can affect how much drug is present in a split tablet and available for absorption. In addition, there may be stability issues with splitting tablets. The FDA, American Medical Association, National Association of Boards of Pharmacy, American Pharmaceutical Association and other medical organizations do not recommend splitting tablets unless specified in the FDA-approved product labeling.
FDA posted an article for consumers Tablet splitting: A Risky Practice in July 2009. FDA received letters from various organizations regarding their concerns about the article. FDA subsequently posted a follow-up article in October 2009 Best Practices for Tablet Splitting.
The Board discussed the following:
- The impact of the two recent FDA consumer articles on other federal agencies and the public
- Safety issues associated with splitting tablets that are scored or appear to be scored but are not labeled to be scored and split in the FDA-approved drug label
- Situations where it is safe to split tablets
- Patient considerations when recommending tablet splitting: scoring of the tablet; the ability of the patient to split the tablet (cognition, dexterity, and visual acuity); characteristics of the tablet (e.g. shape and coating); and the dose response curve of the drug and the likelihood that small differences in the tablet half may have a clinical impact
- How to examine content uniformity and equivalence of tablet halves and relate it to clinical outcomes
- How FDA can do a better job of capturing adverse event information associated with tablet splitting
A representative from the Division of Formulary and Benefit Operations from the Center for Medicare and Medicaid Services joined the DSB for its discussion on tablet splitting.