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Is a Renal Impairment Study Needed for NDA or BLA Approval?

Renal Impairment Studies for FDA Approval – Common Questions and Answers

Is a renal impairment study needed for your drug development program and NDA/BLA? The answer depends on a lot of factors and understanding your options can mean big savings in both time and money. Like the strategies we discussed in our recent post on avoiding a hepatic impairment clinical study, it may be possible to pursue a reduced study design for your renal impairment assessment. With proper study design and population PK modeling approaches, it may be possible to avoid a study altogether.

Why Are Renal Impairment Assessments Important?

Because of the critical role that the kidneys play in eliminating many drugs from the body (as well as in other PK processes like renal metabolism), renal impairment can impact dosing recommendations compared to patients with normal renal function. For example, renal impairment can decrease the renal excretion of a drug and/or its metabolites, can cause detrimental effects on certain hepatic and intestinal metabolism pathways (e.g., biliary excretion), and may result in changes in drug absorption and distribution. In such cases, doses must often be adjusted in renally impaired patients to ensure that appropriate drug exposures and patient safety are maintained.

The FDA has provided some helpful guidance on study design and data analysis for these studies in their Guidance for Industry: Pharmacokinetics in Patients with Impaired Renal Function — Study Design, Data Analysis, and Impact on Dosing and Labeling.

Below, we provide some additional insight into renal impairment studies by answering some of the most common questions that we have received from our clients on the topic.

Study-Related Questions

Q: Do I have to investigate the effect of renal impairment on my drug?
A: Yes and No. It depends on your drug. The FDA generally recommends renal impairment studies for products that include one or more of the following characteristics:

  • Intended for chronic use
  • Likely to be used in patients with impaired renal function
  • Primarily eliminated renally (i.e., ≥ 30% of the dose is excreted unchanged in urine)
  • Primarily metabolized or secreted in bile
  • Belongs to a certain class of therapeutic proteins (e.g., some cytokines and cytokine modulators)
  • Otherwise of particular clinical concern in renally impaired patients (e.g., antibiotics)

The FDA notes that a renal impairment study is not typically required for the following:

  • Drugs that are gaseous or volatile and primarily eliminated via the lungs
  • Drugs that are intended to be administered only once (unless there is a safety/efficacy concern about a particular drug product)
  • Monoclonal antibodies

Q: Do I have to conduct a separate, standalone renal impairment study to understand how renal impairment impacts the dosing recommendations in the product label/package insert?
A: No. Although assessing the effects of renal impairment is commonly done via a separate, standalone renal impairment study, there are other less expensive options to consider, such as using population PK modeling with Phase 2 and Phase 3 clinical data from patients with varying degrees of renal impairment (even if you excluded patients with renal impairment).

Q: My drug is still early in development. Can I avoid conducting a renal impairment study?
A: Yes. Planning can help ensure that the patient population includes varying degrees of renal impairment in future Phase 2 and Phase 3 studies. Using population PK modeling techniques, potential inclusion/exclusion criteria adjustments, and collection of laboratory parameters that determine renal function, it may be possible to avoid a standalone renal impairment study entirely.

Q: What if we can’t include patients with renal impairment in our Phase 2 or Phase 3 clinical studies?
A: This is a common question. Drift in renal function may occur and enrolled patients could experience decreases in renal function over time during the study. By the end of the study, you may have patients with mild or possibly moderate renal impairment and these data may be useful to address dose adjustments in a renal impairment population. The success of this strategy depends on the indication, drug, and ongoing discussions with the FDA as well as prospectively collecting the right clinical data and developing an overall modeling strategy.

Q: My drug is in late phase development. Can I still use previously collected data from my Phase 2 or Phase 3 safety/efficacy clinical studies to provide recommendations for dose adjustment in patients with renal impairment for the product label/package insert?
A: Yes. There may still be enough range in renal function within your Phase 2 or Phase 3 patient population to use population PK modeling (even if you specifically excluded subjects with renal impairment). The FDA noted this in their Guidance for Industry.

Q: Should I use the Cockcroft-Gault equation for determining renal impairment?
A: No. While this equation has been used extensively in the past, it has proven to be inaccurate and often over-estimates kidney function, which could result in overdosing a patient. There is also no version of the Cockcroft-Gault equation for use with standardized creatinine results. For these reasons, this equation is no longer recommended for clinical use. The two most common equations for calculating estimated glomerular filtration rate (eGFR) in adults 18 years of age and older are the Modification of Diet in Renal Disease (MDRD) Study equation and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (note: the CKD-EPI equation is the more accurate of the two for eGFR values > 60 mL/min/1.73 m2). For individuals younger than 18 years, the Bedside Schwartz equation should be used.

Patient Population-Related Questions

Q: I excluded patients with renal impairment from my Phase 2 and Phase 3 clinical program. Can I still use population PK to fulfill the requirements for assessing renal impairment for the NDA/BLA?
A: Yes (it depends). There is sometimes a wide enough range of renal function within a Phase 2/Phase 3 patient pool to allow for population PK approaches to be used to draw conclusions about renal impairment effects.

Q: Are End Stage Renal Disease (ESRD) patients not yet on dialysis readily available to enroll in a study as recommended by the FDA guidance for the “reduced” PK study?
A: No. ESRD patients are usually placed on dialysis quickly and not available for clinical studies. This makes enrollment of ESRD patients according to the guidance extremely challenging, if not impossible.

Q: What alternative strategies are available to enrolling ESRD patients not yet on dialysis in renal impairment studies?
A: One successful strategy has been to conduct a reduced PK design study involving severe renal impairment patients (eGFR ≤ 30 mL/min/1.73 m2) instead of ESRD patients. If there is no pharmacokinetic effect between the severe population and matched controls, then the study is complete. If there is an effect, then the study would enroll mild and moderate renal impairment subjects and matched controls, as per the guidance.

Q: How many subjects are enrolled in renal impairment studies?
A: Typically, cohorts of approximately 6 to 8 subjects are enrolled. For example, a reduced design PK study could have N=6 patients with severe renal impairment and N=6 matched controls. Additional cohorts of mild and moderate renal impairment could be N=6 each.

Q: Should I seek the FDA’s input on my renal impairment strategy if I choose an alternative approach to assessing renal impairment effects?
A: Yes. Whenever an alternative approach is being considered, we advise our clients to seek the FDA’s opinion to ensure that there are no surprises when it comes time to file the marketing application. See our blog on Communicating with the FDA.

Reduced Renal Impairment PK Study

Q: Should I consider a “Reduced” PK study design for renal impairment studies?
A: Yes. A reduced PK study design may be appropriate as a first step (as per FDA guidance) for many drugs. In general, a “reduced” design study commonly will evaluate the drug in patients with severe renal impairment (eGFR ≤ 30 mL/min/1.73 m2) instead of ERSD patients who are usually placed on dialysis quickly and not available for clinical studies. These severe patients are compared to individuals with normal renal function. Note also that depending upon the outcome of the reduced renal impairment PK study, a “full” study may be required.

Full Renal Impairment PK Study

Q: When is a full renal impairment PK study required?
A: If the reduced PK study design indicates a substantial increase in exposure (AUC) in renally impaired patients, then a full renal impairment study is recommended.

Q: How does a full renal impairment PK study differ from a reduced study design?
A: Unlike the reduced renal impairment PK study design, which compares PK parameters only for patients with ESRD or severe renal disease compared to normal matched controls, the full renal impairment study design may include mild, moderate, and severe renal impaired patients compared to normal matched controls.

Conclusions

Assessment of the effect of renal impairment on drug pharmacokinetics can provide valuable insights into appropriate dosing regimens to help ensure safety and effectiveness in renally impaired individuals.

While standalone renal impairment studies may be required in some cases, at least in a reduced format, population pharmacokinetic analysis on pooled data from multiple studies may offer a way to avoid a separate renal study altogether.

Both study design and analytical considerations are central to an efficient and cohesive clinical pharmacology strategy.

Our scientists may be able to help you streamline your development program and reduce your time to market. To learn more about strategies for assessing the effects of renal impairment on your product connect with one of our senior consultants today.

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