In a recent FDA Drug Safety Communication, the Agency announced that the Celexa (citalopram hydrobromide) label now has revised dosing recommendations based on evaluations of post-marketing reports related to QTc prolongation and thorough QTC studies. The label reasonably stresses the importance of routine ECG monitoring and provides an upper level of prolongation that would necessitate discontinuation of the drug due to cardiac risk of arrhythmia.
In our opinion, somewhat lost in all the good intention is the notion that measurement of QTc, and identification of prolongation that rises to the level of requiring action, is not all that simple. Big pharma, in support of clinical trials, may send out ECGs to accredited cardiovascular consultants and specialist CROs for evaluation, programs that have high level training and quality control programs; this is not always the case for a typical general practitioner. Numerous known confounding variables (Barbey JT. 2012. Clin Pharm Therapeut 91:580) and technical issues related to measurement of the QTc can introduce considerable uncertainty in the final result.
Drug treatment decisions, based on label-designated blood test abnormalities, are generally supported by the high quality of accredited diagnostics laboratories. Similarly, required genomics screening for selection of candidate patients, now a common component of many approved drug labels, by default takes place in qualified settings outside the doctor’s office. We wonder if FDA’s appropriate focus on drug risks of arrhythmia may not be fully addressing the problems inherent in the way in which patients at risk are now being identified. Specifically, FDA may not fully be taking into account the extent to which the benefit of a medically appropriate decision may be counterbalanced by erroneous data driving that decision.
Posted by Bob Roth, Vice President and Worldwide Medical Director. For more information, please contact Bob at email@example.com.
In March 2011, the Tobacco Products Scientific Advisory Committee released a report on the impact of menthol on public health. Based on the committee’s review of all available evidence, they recommended the ban of menthol. Following the release of TPSAC’s report, the FDA began a thorough review of their findings and also considered a report on the issue prepared by the tobacco industry. Stakeholders continue to await the FDA’s final determination and it is unclear when this information will be available.
In the report, TPSAC concluded that the evidence is insufficient to conclude that smokers of menthol cigarettes face a different risk of tobacco‐caused diseases than smokers of non‐menthol cigarettes, but did note that epidemiologic data do not demonstrate increased disease risk in people. Adding to this body of evidence is a study recently released by a scientist from FDA’s Center for Tobacco Products. The study used 20 years of data from the large nationally representative household health survey, the National Health Interview Survey (NHIS). Included in the analysis were 6,074 smokers, including 1,417 who smoked only menthol cigarettes. Not only did the author report no difference in lung cancer mortality or all cause mortality between all menthol smokers and nonmenthol smokers, menthol smokers at ages 50 and over had a lower risk of lung cancer mortality compared with nonmenthol smokers.
This latest FDA study adds to a growing body of evidence that suggests modest to statistically significant reduced risks for lung cancer among menthol smokers. In the face of a potentially lower risk of lung cancer associated with menthol cigarettes, it will be even more difficult for the FDA to ban them from the market.
Posted by Marla Scarola, Senior Consultant. For more information, please contact Marla at firstname.lastname@example.org.
If your company has used Cetero Research’s Houston facility to conduct bioanalytical studies between April 1, 2005 and June 15, 2010, your marketing applications may need to be repeated or confirmed. By now, you should have received a letter from FDA asking that new bioequivalence studies be conducted, or if there is supporting stability of the analyte throughout the entire frozen storage period, that samples from the original BE studies be re-assayed.
The week, FDA further clarified their requirements regarding studies conducted at Cetero during the aforementioned time frame as follows:
- April 1, 2005, to February 29, 2008: Studies that were previously submitted as part of an approved or pending application, or studies that will be submitted as part of a new application, will need complete reanalysis (if adequate stability data exist) or repeat of the study.
- March 1, 2008, to August 31, 2009: The Agency will accept studies for submission and review if the sponsor performs an independent third-party data integrity audit using the Bioanalytical Electronic Raw Data Audit Plan (provided by FDA). Further, studies that were previously submitted as part of an approved or pending application will also need verification of data integrity by an independent third-party audit.
- September 1, 2009, to June 15, 2010: The Agency will accept studies for submission and review without reanalysis, repeating, or further audit by Cetero or a third party.
The Weinberg Group, a globally recognized regulatory and scientific consulting firm headquartered in Washington DC, has experience helping pharma companies in these matters. We were, in fact, a key player in remediating the similar MDS Pharma Services crisis at their Montreal facility in 2007, helping our clients prevail with minimal disruption to their organizations and supply chains.
If you are in need of our assistance, please do not hesitate to contact Jeff Antos (202.280.0815) immediately.