Determination of five positive control drugs in hERG external solution (buffer) by LC-MS/MS to support in vitro hERG assay as recommended by ICH S7B.

ICH S7B recommends screening for hERG channel block using patch clamp recordings to assess a drug's proarrhythmic risk. Block of the hERG channel has been associated with clinical QTC prolongation as well as the rare, but potentially fatal ventricular tachyarrhythmia Torsade de Pointes (TdP). During recording, drug concentrations perfused to the cells can deviate from nominal concentrations due to molecule-specific properties (such as non-specific binding), thereby introducing error when assessing drug potency. To account for this potential source of error, both the original ICH S7B and the newly released ICH E14/S7B Q&As guidelines call for verifying drug solutions' concentrations. Dofetilide, cisapride, terfenadine, sotalol and E-4031 are hERG blockers commonly used as positive controls to illustrate hERG assay sensitivity. The first four compounds are also clinical drugs associated with high TdP risk; therefore, their safety margins may be useful comparators to better understand an investigational product's TdP risk. Having analytical methods to quantify these five compounds in the hERG external solution that will be used for patch clamp recordings is important from a regulatory science research perspective. However, a literature search revealed no analytical methods or stability information for these molecules in the high salt, serum-free matrix that constitutes the hERG external solution. This study was conducted to develop and validate LC-MS/MS methods to quantify these 5 molecules in hERG external solution. The bioanalytical methods for these positive controls were validated as per the FDA's bioanalytical method validation guidance along with various stabilities.

New science, drug regulation, and emergent public health issues: The work of FDA's division of applied regulatory science.

The U.S. Food and Drug Administration (FDA) Division of Applied Regulatory Science (DARS) moves new science into the drug review process and addresses emergent regulatory and public health questions for the Agency. By forming interdisciplinary teams, DARS conducts mission-critical research to provide answers to scientific questions and solutions to regulatory challenges. Staffed by experts across the translational research spectrum, DARS forms synergies by pulling together scientists and experts from diverse backgrounds to collaborate in tackling some of the most complex challenges facing FDA. This includes (but is not limited to) assessing the systemic absorption of sunscreens, evaluating whether certain drugs can convert to carcinogens in people, studying drug interactions with opioids, optimizing opioid antagonist dosing in community settings, removing barriers to biosimilar and generic drug development, and advancing therapeutic development for rare diseases. FDA tasks DARS with wide ranging issues that encompass regulatory science; DARS, in turn, helps the Agency solve these challenges. The impact of DARS research is felt by patients, the pharmaceutical industry, and fellow regulators. This article reviews applied research projects and initiatives led by DARS and conducts a deeper dive into select examples illustrating the impactful work of the Division.

Piloting social engagement on a federal agency-administered Facebook page.

OBJECTIVES: To evaluate the impact of a Federal drug information center initiating engagement with stakeholders on a Facebook Page administered by a Federal Agency. SETTING: The U.S. Food and Drug Administration (FDA) Facebook page from July 21, 2014, to October 18, 2014. PRACTICE INNOVATION: FDA's Division of Drug Information (DDI) in the Center for Drug Evaluation and Research (CDER) Office of Communications serves as a federal drug information center providing timely, accurate, and useful information on CDER initiatives and CDER-regulated products. We report a 90-day (July 21 to October 18, 2014) pilot during which DDI pharmacists monitored and moderated comments received on FDA's Facebook page to identify those warranting a reply. Once identified, DDI pharmacists replied within 2 business days. EVALUATION: Impact was measured by comparing the average number of Likes, Shares, and Reach for Facebook posts before and after the pilot. Additional metrics collected include the number of DDI replies provided to stakeholders' comments and the number of DDI replies provided on time (within 2 business days). RESULTS: During the pilot, DDI contributed 14 posts. On average, each post reached 23,582 more individuals (an increase of 187% compared with pre-pilot posts). On average, each post also received 463 more Likes (450% increase) and 130 more Shares (271% increase). DDI pharmacists replied to 3% (121/3994) and hid 0.58% (23/3994) of Facebook comments received during the 90-day period. All actions were taken within 2 business days. CONCLUSION: Initiating social engagement had a positive impact on FDA's Facebook page.