The European Medicines Agency (EMA) has released a new guideline aimed at assisting sponsors in the development of products to treat or prevent diabetes mellitus. The guideline makes important changes to how the agency plans to assess the cardiovascular risk of diabetes products and its "high-level" approach to emerging diabetes products.
The new guideline, On Clinical Investigation of Medicinal Products in the Treatment or Prevention of Diabetes Mellitus, updates a previous version of the same document that went into effect in November 2002. Revisions to the current guideline have been underway since January 2010, and are scheduled to come into effect on 15 November 2012.
Focus on Cardiovascular Safety
"The main change to the guideline involves revision of the information on the long-term safety of anti-diabetes medicines, particularly the addition of a new section on cardiovascular safety," EMA explained. "The update also involved inclusion of more specific and up-to-date information on studies in children."
In section 4.4.3 of the document, Long-term Safety and Cardiovascular Safety, the agency explains safety studies are made more complicated by the co-morbidities and concomitant medications taken by patients with diabetes. EMA said it is "essential to, as far as possible, exclude that the new drug increases the risk of macrovascular complications" including cardiovascular disease.
While it has not been possible to assess the cardiovascular safety of glucose-lowering agents in the past, EMA said it will expect sponsors to conduct them "for future developments." Sponsors will be required to collect non-clinical data using "relevant animal models" and clinical data using either a meta-analysis or a long-term controlled outcome study.
Section 4.4.3 also outlines the study populations that sponsors should enroll in clinical studies, as well as the expected outcomes.
Sponsors should look to enroll "an adequate number of high risk patients including those with long duration of the disease (e.g. > 8-10 years), elderly patients, subjects with microvascular disease (e.g. renal dysfunction), subjects with cardiovascular risk factors (e.g hypertension, hyperlipidemia), high risk for cardiovascular complications and confirmed history of ischemic heart disease and/or congestive heart failure."
EMA did not offer any concrete insight as to whether they have a threshold for cardiovascular risk above which they will refuse to approve a drug, though it did mention it will take a risk-based approach for postmarketing studies. "If a benefit or at least absence of harm in terms of CV risk has been shown with the other agents in the class and product specific differences in the off target effects between agents are unlikely this may reduce the need for a specific outcome study," the agency wrote.
Preventing the Onset of Diabetes
EMA's guidance also looks to the emergence of new classes of drugs capable of preventing diabetes. Section 6 of the guidance describes a "high-level" approach to diabetes product development due to "limited" experience in the development area, wrote EMA.
While "lifestyle measures" remain the preferred first-line defense against the onset of diabetes, EMA noted "additional drug therapy may be beneficial in individuals with particularly high risk of developing diabetes."
Clinical trials on products to prevent diabetes will represent unique risks to patients, and sponsors will need to be mindful of the ethical implications of enrollment, wrote EMA.
"Unless the test agent has an absolutely benign safety profile, pharmacological intervention studies that aim to delay or prevent the onset of type 1 diabetes should only enroll patients who are at high risk of developing the disease," EMA explained. "The validity for the choice of antibodies and other criteria should be properly justified prior to study start; notably the positive predictive values of such antibodies for development of T1DM should be sufficiently documented."
EMA - European Medicines Agency finalises update to diabetes guideline
EMA - Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus