FDA’s final guidance on renal impairment: Assessment of the regulatory approach to inform clinical development planning

This blog is part of The Regulatory Navigator series, where we explore the evolving regulatory landscape with actionable insight from Parexel's experts, sharing their experience to maximize success for clinical development and patient access.

After nearly 14 years of draft guidance, the FDA published the final guidance for industry on Pharmacokinetics in Patients with Impaired Renal Function.¹ First released in 2010 and revised in 2020, the document’s long history shows the evolution of the Agency’s approach in this field. While assisting sponsors in the design, analysis, and reporting of studies that evaluate the influence of renal impairment on the PK of an investigational drug remains its primary purpose, there are specific areas to consider in the assessment of draft to final guidance: 

1.    Patient-focus

There is greater emphasis on the importance of pharmacodynamic evaluations (besides PK assessment) and on potential dose adjustment recommendations relevant for patients with reduced kidney function. Sponsors are encouraged to include patients with renal impairment in drug development programs as early as possible. To ensure patient safety, appropriate information must be gathered early to make informed decisions. An important question in this context is whether patients with renal impairment can be given the same dose as other patients when included in a phase III trial. 

Our recommendation: Investigate the effect of impaired renal function on a drug’s PK in earlier trials, so patients can be included and appropriately dosed in late-phase confirmatory trials. This allows for a more inclusive phase III study population and enables the generation of more data on the effectiveness of a drug in such participants.

2.    Modelling and simulation within innovative study designs

There is an increased focus on modelling and simulation, which recognizes the increased emphasis on modelling techniques and the progress made in practical applications since the initial draft guidance was issued. With more widespread use of modelling and simulation tools, for example physiologically based pharmacokinetic (PBPK) modelling and simulation, sponsors have alternatives to clinical studies available and can obtain the information they need via those tools.

Our recommendation: When sponsors include patients with renal impairment in phase II/III studies they should include sufficient participants over a wide range of renal function to fully understand the impact of renal impairment on the PK of a product and for the model to operate well. The more accurate the dosing and sample collection times records are, the higher the quality of the data. This approach, if well-planned and supported by quality data, can even serve as a substitute for a dedicated PK study. Acceptance should be clarified with the FDA prior to study conduct, e.g. at an EOP2 meeting.

Sponsors should consider implementing innovative study designs, such as adaptive enrollment or sequential evaluation, that can facilitate the inclusion of patients with impaired renal function in phase II and III studies. For example, patients with mild renal impairment can be included before patients with more severe impairment, preceded by an interim safety assessment.

3.    Assessing requirements for dedicated renal PK study

With more biologic therapeutics being developed than ever before, there is a broader cutoff value of the drug’s molecular size when no dedicated renal PK study is required (although this previously could have been argued). This stems from a time when monoclonal antibodies were the leading therapeutic protein class, weighing around 150 kDa. Other macromolecules with a molecular weight of greater than 69 KDa should be considered in the same category warranting waiving of a PK study, since macromolecules of that size undergo little to no glomerular filtration. 

Further, the FDA is now less prescriptive in using formulas to calculate the estimated glomerular filtration rate and has also slightly adapted the definition of severity groups.

Our recommendation: For PK studies, estimation of renal function using a contemporary and widely accepted equation, is usually sufficient. We generally recommend using the Cockcroft-Gault² formula or the CKD-EPI^3,4 equation. When these formulas are used in special populations, such as the obese and particularly for the Cockcroft-Gault formula, there should be additional focus to ensure accurate results are collected (use of ideal body weight or adjusted body weight): labs often still provide the eGFR referenced to a body surface value (BSA) of 1.73 m² but the values should not be normalized to BSA in an individual patient, which should be clarified with the reporting lab upfront. Noteworthy to sponsors is that patients with kidney failure not receiving dialysis can be grouped into the severe impairment group. This subgroup previously belonged to the End-Stage Renal Disease group, which was distinct from the severe impairment group. This somewhat broadens the patient group's accessibility for this kind of research.

4.    Sample size 

Most sponsors have taken a practical (or feasible) approach for an adequate sample size. Typically group sizes were in the range of 6 to 8 participants per severity group. For drugs with a large variability in PK data, this may no longer be sufficient. The sample size must be justified on the grounds of statistical precision. Although the agency allows for a wide 95% confidence interval of 60-140% associated with the ratio of PK parameters, drugs with a large PK variability may result in a higher sample size than historically used.
 
Our recommendation: A consistent PK strategy for your molecule including non-clinical studies in any considerations. Also, a human mass balance study, which should be part of every clinical development program (with few exceptions only), provides very meaningful information on excretion pathways and can be an important pillar for a biowaiver justification of a renal PK study. A biowaiver is an informal, relatively uncomplicated process (processed in any milestone meeting with the FDA) and generally is accepted if well justified by data.

5.    Dosing recommendations 

Dosage recommendations are important and most relevant for patient safety and effectiveness. Exposure-response relationships are critical to the overall understanding of the relationship between renal function, drug exposure, and a drug’s safety and efficacy. 

Our recommendation: Sponsors should consider that matching the exposure to a reference group is not necessarily done to the population with a normal renal function, but it should be rather to the group with an acceptable benefit-risk profile for the drug, i.e. the relevant reference population in the phase III study.  

The FDA has recently released a Q&A podcast discussing the key components of the final guidance which is available here: https://www.fda.gov/drugs/guidances-drugs/guidance-recap-podcast-pharmacokinetics-study-design-considerations-patients-impaired-renal-function).

As a leading global phase I-IV clinical research organization, we leverage the breadth of our clinical, regulatory and therapeutic expertise to optimize clinical development programs. Our team of ex-regulators is always available to help you navigate the regulatory requirements of the major regulatory agencies, including FDA’s final guidance on renal impairment. Parexel’s Regulatory Consulting group interprets evolving regulatory requirements, prepares robust submissions, and effectively manages interactions with regulatory agencies, ultimately helping to bring innovative therapies to patients more efficiently and effectively. Please contact us.

References

1. U.S Food & Drug Administration (2024, March). Pharmacokinetics in Patients with Impaired Renal Function — Study Design, Data Analysis, and Impact on Dosing: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/pharmacokinetics-patients-impaired-renal-function-study-design-data-analysis-and-impact-dosing [accessed July 2024] 
2. Cockcroft DW and MH Gault, 1976, Prediction of Creatinine Clearance from Serum Creatinine, Nephron, 16(1):31-41 
3. CKD-EPI: Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. May 5 2009; 150(9): 604-612 
4. Titan S, S Miao, H Tighiouart, N Chen, H Shi, L Zhang, Z Li, M Froissart, P Rossing, A Grubb, L Fan, M Mauer, O Bakoush, C Wyatt, MG Shlipak, T Shafi, LA Inker, and AS Levey, 2020, Performance of Indexed and Nonindexed Estimated GFR, Am J Kidney Dis, 76(3):446-9

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