October 10, 2023
We appreciate the opportunity to comment on FDA’s proposed guidance regarding: “QTc Information in Human Prescription Drug and Biological Product Labeling; Draft Guidance for Industry; Availability.”
The National Center for Health Research (NCHR) is a nonprofit think tank that conducts, analyzes, and scrutinizes research on a range of health issues, with a particular focus on which prevention strategies and treatments are most effective for which patients and consumers. We do not accept funding from companies that make products that are the subject of our work, so we have no conflicts of interest.
We agree that an FDA guidance is needed to assist sponsors in developing labeling that includes clinically relevant information regarding the QTc interval. However, the guidance that FDA has drafted is too vague to be clinically useful or to meaningfully inform patient care. Here are our recommendations to improve the FDA’s draft guidance to better inform patient care.
- The FDA should provide more information regarding the conduction of thorough QT (TQT) studies as the proposed guidance will allow for inconsistency and limited interpretability among healthcare professionals. For example, the QT interval is a physiologic measurement captured by an electrocardiogram (EKG), while the corrected QT interval (QTc) is a calculation intended to correct for the impact of heart rate on the QT interval. However, there are several different formulas available to calculate the QTc and the accuracy and application of each formula has been widely debated in medical literature. Therefore, for the draft guidance to be clinically meaningful for patient care, the FDA should include information regarding different QTc calculations as well as identify a formula of preference to standardized sponsor data. In addition, the FDA should require sponsors to include information on the label and in the package inserts regarding which of the QTc formulas they used in the development of their product. This will help avoid uncertainty and create consistency in data interpretation among sponsors, reviewers, and healthcare professionals.
- The FDA recommends using TQT studies in the proposed guidance, but the guidance fails to explicitly describe the preferred methods of design, analysis, or interpretation of these studies in detail. The guidance also includes limited information regarding the circumstances in which exposure-response modeling or pharmacokinetic-pharmacodynamic modeling would be appropriate alternative study designs. This information should be made clearer for sponsors. Providing more detailed and comprehensive information on superior TQT study designs, circumstances for alternative study designs, preferred methods of data analysis, and guidance for data interpretation will lead to higher quality results that are readily interpretable across different sectors of medicine.
- Medications that effect the QT interval are rarely taken in isolation or under normal physiologic conditions. Most patients take more than one medication and can be on multiple medications that affect the QT interval while in a pathologic disease state. Yet, the guidance does not provide any information for sponsors to examine drug-drug interactions or drug-disease interactions on the physiologic QT interval or corrected QT interval. The guidance should recommend that sponsors to examine drug-drug interactions and drug-disease interactions on the physiologic QT interval or corrected QT interval. This is of critical importance as many common disease processes affect the QT interval (e.g., thyroid disease, cardiac arrythmias, and electrolyte imbalances) and being able to correctly monitor the QT interval has dire consequences on patient care, as unrecognized QT prolongation can lead to sudden cardiac death.
While the draft guidance is intended to make QTc labeling information available for healthcare professionals, the NCHR encourages the FDA to also make QTc labeling information accessible and understandable for patients. We recommend that similar QTc labeling, package inserts, and medication leaflets be prepared for patients in clear, plain language to better inform them of their medication’s risks and adverse effects. Providing specific guidance on QTc information in patient labeling and medication leaflets will help to ensure that patients make well-informed medical decisions with their medical provider.
In conclusion, NCHR appreciates the opportunity to comment on the FDA’s draft guidance in developing clinically relevant labeling information regarding QTc interval prolongation. To improve patient outcomes, the FDA should provide more detailed recommendations regarding a preferred method of QTc calculation, optimal TQT study design and data analysis, and the effect of drug-drug and drug-disease interactions on the QTc interval. This will help achieve the FDA’s goal for the guidance to provide meaningful results that inform patient care. We recommend that the FDA extend labeling and product information to patients, so they are empowered to make well-informed decisions regarding their medical care with their medical team.