[ Diabetes Solutions ]

Cardiovascular Safety Evaluation in the Development of New Drugs for Diabetes Mellitus

On January 16, 2015, the U.S. The first (issued in August 2013) is the second edition of the May 2007 draft guidance document “Guidance for Industry: Frequently Asked Questions About Medical Foods”[1] and the other (issued in September 2013) is “Guidance for Clinical Investigators, Sponsors and IRBs: Investigational New Drug Applications (INDs) – Determining Whether Human Research Studies Can Be Conducted Without an IND.”[2]  Clearly, some guidance is necessary, due to the fact that the medical food category has expanded to include foods that might not meet the original intent of the category. A recent breakthrough has been a non-clinical testing strategy for assessing the QT interval prolongation liability: the single most important cause of drug withdrawals in recent years. Specifically, CDRH does not intend to examine low risk general wellness products to determine whether they are medical devices within the meaning of the Federal Food, Drug, and Cosmetic Act (FDCA), and if they are devices, whether they comply with the premarket review and post-market regulatory requirements for devices under the FDCA and implementing regulations (e.g., 21 CFR Part 807 (premarket notification); 21 CFR Part 801 and 21 CFR § 809.10 (labeling); 21 CFR Part 820 (good manufacturing practices/Quality Systems); and 21 CFR Part 803 (Medical Device Reporting (MDR) requirements)). For example, if a given condition gave rise to a potassium deficiency, a banana marketer could not brand his products as medical foods. Healthy weight and balanced diet may help living well with high blood pressure and type 2 diabetes. The devices are designed to work together, monitoring the body’s glucose levels and automatically pumping appropriate doses of insulin as determined by a computer algorithm.


The Draft Guidance eliminates these limitations to the exemption, and states that, “to the extent that these limitations apply, FDA does not intend to enforce compliance with regulatory controls for MDDS intended to be used in a system for assessing the risk of cardiovascular diseases (21 CFR 880.9(c)(4)) or for use in diabetes management (21 CFR 880.9(c)(5)).”  Draft Guidance, at 7. People older than 50, those with high blood pressure, diabetes and chronic kidney disease, and African-Americans should eat no more than 1,500 milligrams of sodium per day, according to the American Heart Association. What’s surprising is that draft guidance means that FDA believes there’s a market for a generic version of a brand-name drug that has failed. Moreover, when cardiovascular clinical end points were actually measured, end point definitions varied from 1 study to another, and independent ascertainment of events across a drug development program were usually inconsistent. Most of that sodium is hidden inside common processed foods and restaurant meals, making it harder for consumers to control how much they eat. These limitations inherent in previous diabetic drug development programs led the FDA to issue guidance for the development of drugs and therapeutic biologics regulated within the Center for Drug Evaluation. The central tenet of this guidance was that all effective agents in type 2 diabetes mellitus needed to prove cardiovascular neutrality or benefit before gaining full market approval.

Likewise computerized insulin dosing require a trained patient who is ready to override the software and take control of insulin dosing if the software instructions are not correct for that situation. The guidance accepts the reduction of hemoglobin A1c as an effective and meaningful primary end point for drugs seeking to treat hyperglycemia in diabetes mellitus, but emphasizes the importance of evaluating the impact of newer agents designed to treat type 2 diabetes mellitus on cardiovascular outcomes in a large well-powered data set. These proposed cardiovascular end points include a primary composite of relatively hard cardiovascular events, including cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, and hospitalization for unstable angina. When other cardiovascular events like hospitalization for heart failure or coronary revascularization are occasionally included in the composite end point, discussions with the FDA before trial conduct seek to ensure adequate core major adverse cardiovascular events like death, stroke, and nonfatal myocardial infarction. The guidance emphasizes that the study protocol and the statistical methods, as well, must be standardized and outlined before the initiation of the drug development program with new agents for type 2 diabetes mellitus. Indeed, Britain shows that the FDA plan can work, Frieden wrote. These subjects are at higher risk of cardiovascular events and will likely prove a better gauge of the drug’s performance postapproval in the real world.

In assessing whether a product is “low risk,” the FDA also recommends determining whether particular types of products that share common qualities with the product in question, are actively regulated by FDA, which may be helpful for the purposes of categorizing an item that is not explicitly addressed in the Final Guidance. The definitions for these outcomes, including cardiovascular mortality, myocardial infarction, stroke, hospitalization for acute coronary syndrome, urgent revascularization, and heart failure, have also been standardized and are currently being validated. There were concerns that the increased cost of drug development based on these requirements would discourage future innovation. Parts 73 and 74); a substance that is generally recognized, by qualified experts, to be safe under the conditions of its intended use (Generally Recognized As Safe (GRAS)) (see 21 C.F.R. These pathways include a 2-step option that provides drug developers the opportunity to potentially market a new agent during the ongoing conduct of adequately powered trials evaluating cardiovascular outcome.

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