As the diabetic epidemic grows, so does the prevalence of diabetic kidney disease (DKD), a frequent complication of both type 1 and 2 diabetes. Diabetic nephropathy is the leading cause of end-stage renal disease, and despite its global health burden and increased prevalence, no specific regulatory guidelines exist for developing drugs for diabetic renal disease.
Renal function and renal insufficiency are discussed in many different regulatory guidances. But when looking to develop a treatment specifically for DKD, none of these guidances directly relate to conducting a clinical trial in patients with diabetic nephropathy. One guidance that comes the closest to providing advice was issued from the EMA in 2015, but even this document notes that "Due to ongoing developments in this field, frequent revisions and amendments are foreseen."
Other examples of EMA and FDA guidances include general approaches for evaluating pharmacokinetics of drugs in patients with decreased renal function, but these are designated for drug development in general, and not specifically directed to drugs intended for diabetic nephropathy treatment.
While some drug developers may feel uneasy about the lack of regulatory guidance, this absence can be seen as a positive attribute. Drug developers can construct strategies tailored to the drug and design - an approach based on solid science and adapted to the molecule's unique mechanism of action.
Examining past studies can be helpful to map out a sensible regulatory approach. For DKD, safety is still a concern, but measuring efficacy is paramount. Proof of efficacy can be established with early models and, if successful, evaluated further in the clinic.
Studying a drug intended to treat DKD also presents challenges given the various stages of renal impairment. A well-planned regulatory strategy will consider these variables and how to evaluate the drug accordingly in patients with varying levels of renal function and/or urinary albumin excretion.
For example, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blocking (ARB) agents have been evaluated in trials of diabetic patients with substantially increased urinary albumin levels and impaired kidney function at baseline. Typically, these studies utilized a composite endpoint that included death, end-stage renal disease or a doubling of serum creatinine. The use of these composite endpoints in trials with the antihypertensive ACE inhibitors and ARBs have resulted in sponsors gaining a label claim for diabetic nephropathy such as: "Treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria in patients with type 2 diabetes and a history of hypertension." Clearly, as our knowledge of DKD evolves, composite endpoints in DKD will also change, as will the potential for a broader label claim. So while precedent is important in developing drugs for DKD, gaining up-to-date regulatory input will be equally, or perhaps more important.
Developing a Target Product Profile (TPP) will set the stage for development and help build a sound regulatory strategy. Establishment of a TPP early in the development process proactively identifies possible issues and looks at the registration path from multiple perspectives, such as market access and reimbursement.
Once key decision points are in place, the aims of the TPP can be discussed with regulatory agencies to get buy in prior to initiating an individual or multiple clinical trials. Given the lack of global guidance for DKD, a solid strategic development plan in one geographic region will likely apply to the global landscape. Of course, regulatory meetings across global agencies should also be conducted to ensure harmonization of the development path, and to maximize the value of the asset.
Without specific guidelines to follow for DKD, sponsors must be flexible in their regulatory approach. When you partner with Covance, we will help you to gain clarity for your development plan through meetings with global regulatory agencies and development of comprehensive clinical and preclinical development plans. Together, we can create a strategy that best addresses your molecule's unique mechanism of action to maximize the probability of success in the clinic.
Check out other DKD blogs in this series:
 EMA Guideline on the clinical investigation of medicinal products to prevent the development/slow progression of chronic renal insufficiency. January 2015.
 EMA Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with decreased renal function. July 2016; FDA Guidance on Pharmacokinetics in Patients with impaired hepatic function: Study design, data analysis, and impact on dosing and labeling. May 2003.