080: Is it Time to Retire Cockcroft-Gault & “Original” Schwarz Formulas in Drug Development?

Statement of Purpose, Innovation or Hypothesis: Cockcroft-Gault and the “original” Schwartz formulas were used clinically to assess kidney function in adults and pediatrics, respectively, for several decades. Several new equations (CKD-EPI for adults, and Modified Schwartz for pediatric patients) have been released over the last 15 years that have attempted to overcome shortcomings in these original equations. The superiority of these new equations has been endorsed by various nephrology organizations worldwide and are widely accepted in clinical practice and clinical labs. The objective of this work was to evaluate the adaption of the contemporary equations by the pharmaceutical industry.

Description of Methods & Materials: FDA approved drug labelings, reviews of new molecular entities available at drugs@fda, and primary literature were reviewed for dedicated renal impairment trials (RIT) for the years 2020-2023. We focused on the following aspects during the review: 1. Which equations were used to define renal impairment that determined dose adjustment in the labels for adult/pediatric patients? 2. Was the equation used clearly indicated in the drug label?

Data & Results: Between 2020 and 2023, 117 systemic NME NDAs were approved, of which 96 and 2 NME labeling contained dosing information in adult and pediatric with renal impairment (RI), respectively. Five NME contained dosing information in both adults and pediatrics with RI. Of the drugs disclosing the formula used to assess renal function (RF) for either adults or pediatrics, equations were clearly mentioned in the label for 35 drugs. A look at the FDA review or associated dedicated RIT was needed to understand the formula used for 36 drugs. Adults: RF estimation was reported using estimated glomerular filtration rate (eGFR) for 44 drugs, creatinine clearance (CrCl) for 31 drugs, and using both CrCl and eGFR for 25 drugs. Whereas 1 drug used serum creatinine to assess RF. When GFR was used, it was based on the use of either MDRD equation (34 drugs), CKD-EPI equation (9 drugs), or CKD-EPI creatinine-cystatin C equation (1 drug) during drug development. For 25 drugs that referred to eGFR in labeling information or FDA review, an equation could not be identified from any source. When CrCl was used, it was based on the use of the Cockcroft-Gault equation (39 drugs) or measured CrCl (1 drug). For 16 drugs that referred to CrCl in labeling information or FDA review, an equation could not be identified. Pediatrics: For the pediatric parts of the labels, eGFR was reported using the Schwartz equation (2 drugs), Bedside Schwartz Equation (5 drugs). When the labels referred to the Schwartz equation, it is unclear from publicly available information as to which Schwartz equation was used.

Interpretation, Conclusion or Significance: Whilst the physicians receive GFR estimates from labs using more contemporary equations, many drug labels are based on older equations, such as Cockcroft-Gault, that are error prone. It is clear from our work that drug development has not kept up with developments in the field of nephrology and this is not ideal from a patient care perspective. To add to this, not all labelings indicate which equation was used during drug development to assess kidney function.

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