Most drugs are eliminated from the body through some combination of vital organs, such as the small intestine, liver and/or kidneys. The impaired function of either the liver or the kidney can significantly impact a drug’s pharmacokinetics (PK), influencing its absorption, distribution, metabolism and excretion. If a patient has impaired kidney and or liver function, the prescribed dose for a patient with normal function may need to be reduced to avoid adverse reactions/overdose.
For example, impaired kidney function can lead to notable alterations in drug PK, potentially affecting both therapeutic efficacy and safety (1,2). Therefore, it becomes imperative to evaluate the impact of varying degrees of kidney function by performing renal impairment studies. Similarly, impairment in hepatic function can impact a drug’s safety and efficacy profile by leading to the accumulation of the drug or its metabolites at toxic levels or affecting the drug’s safety and therapeutic effectiveness (3). Consequently, in order to establish a safe and effective dosing regimen, it is essential to assess the impairment of varying degrees of liver function on a new drug’s PK and metabolites in a hepatic impairment study.
Per the FDA, most traditional drug development will require either a renal or hepatic impairment study. In some cases, both renal and hepatic studies will be required due to their critical implications for patient safety and therapeutic efficacy.
Dr. Vince Clinical Research (DVCR) spoke with Harry Alcorn, PharmD, the chief scientific officer at Elixia, to gather greater insight into the design, recruitment and conduct of these complex studies. Dr. Alcorn is a recognized leader in both renal and hepatic impairment studies, having written over 50 renal protocols, presented and defended multiple protocols to the FDA and presented at DIA on these studies. Dr. Alcorn has served as Principal or Sub-Investigator on over 350 renal and/or hepatic protocols. He and his team at Elixia are partnering with Dr. Vince Clinical Research on renal and hepatic impairment studies.
Dr. Alcorn offered the following recommendations, best practices and key considerations for conducting hepatic and renal impairment studies.
1) Selecting the Right Site
“When conducting complex studies within specialty populations, you need a research site and clinical team that have specialty knowledge and expertise.”
There are a limited number of sites that can adequately conduct renal or hepatic impairment studies. These patients have complex medical issues and polypharmacy that require detailed understanding and knowledge. Research centers devoted to these populations are essential for ensuring the success of any clinical study. An experienced team will understand the day-to-day needs, limitations and challenges faced by these specialty populations. This translates into a more patient-centric approach, ensuring that the patient’s needs are met and clearly addressed from consent to the end of the study. They are also equipped to recognize and address the chronic metabolic and laboratory abnormalities typical in these populations. This knowledge improves study enrollment and completion rates for the clinical trial.
2) Recruitment Relies on Collaboration
Recruitment success starts with protocol development. Obtaining feedback from subject matter experts is critical for developing a study that can be enrolled and completed. In a real-world healthcare environment, particularly in specialty populations, the realities of the patient’s condition can make studies difficult. Open dialogue between sponsors and an experienced research site can ensure a successful study.
Patients with liver disease and chronic kidney disease have predictable abnormalities in laboratory values that deviate from a healthy population, variable weights and lengthy concomitant medication lists. An experienced team who understands this population can provide tailored inclusion and exclusion criteria that maximizes the ability for recruitment while maintaining patient safety and reaching study goals. Dialysis patients pose a further challenge. Variations in dialysis standard operating procedures (SOPs) across different providers can significantly impact study data and participant retention. Failure to account for these differences or not understanding Federal guidelines that control dialysis, can reduce enrollment, cause unnecessary adverse events and lead to spurious data. Specialized research sites have well-established collaborations with clinics and dialysis units and are prepared to offer procedural guidance beyond the study protocol. This may include guidance on standardizing dialysis, recommending medication changes to assure patient stability while not interfering with pharmacokinetic data and current FDA guidelines for studies in specialty populations.
Sponsors must engage in open dialogue with sites regarding the study protocol and the I/E criteria. For example, in renal impairment studies that enroll end-stage renal disease (ESRD) patients, variations in dialysis standard operating procedures (SOPs) across different providers can significantly impact study data. Sponsors can mitigate these variances by aligning SOPs across sites, offering procedural guidance beyond the study protocol and identifying potential risks associated with different dialysis procedures and equipment. For example, a patient’s dialysis is typically three times a week on Monday, Wednesday and Friday or Tuesday, Thursday and Saturday. As the sponsor may want to maximize time off between dialysis schedules in a dosing study drug, the dosing should occur on a Friday or Saturday, as the next dialysis session would be in three days, not two.
Medications and laboratory results will be different for patients with renal or liver disease and not align with healthy volunteers’ laboratory values. For example, renal patients will run higher potassium levels and have a prolonged QTc interval. In addition, the sponsor must use the appropriate equation for assessing renal function, as there are several and the standard is only an estimate (eGFR). To ensure the use of accurate and up-to-date equations that align with the most current FDA guidance for renal stratification and maintain the highest standards of scientific rigor, sponsors must engage in continuous communication with CROs, investigators and subject matter experts in the industry.
“What comorbidities and concomitant medications should the protocol allow? If one can establish this criterion up front, that is a huge barrier removed for patient enrollment.”
Impaired patients with comorbidities are often prescribed multiple medications, which may require a change or stopping a medication (based on the I/E criteria) while maintaining an appropriate treatment regimen. Specialized sites understand this ask, and the PI will make recommendations to the primary care physician where appropriate to maintain the patient’s medical condition to maximize enrollment. In meeting the needs of specialty populations, sponsors must understand not working with specialty research sites puts their studies at risk for participant safety, along with limited to no enrollment and/or poor data.
A common temptation for sponsors in both renal impairment and hepatic impairment studies is to enroll all impaired patients and average the demographics before enrolling healthy matches. However, experienced sites and CROs understand the potential drawbacks of this approach: significant delays in study timelines and higher costs because it requires a fully enrolled impaired patient cohort before enrollment of the healthy cohort can begin. Recruiting impaired and healthy participants concurrently, in a one-to-one ratio, often proves more efficient and cost-effective and provides data sooner.
“Many sponsors take the approach of completing enrollment of all impaired subjects prior to the healthy control group because their perception is that this is less costly as it enrolls fewer subjects. However, this strategy often increases the study timelines, which results in an increase in direct and indirect costs.”
Finally, the concern of competition or patient prioritization with a site that conducts more than one renal or hepatic study is misguided. Well-designed protocols with clear I/E criteria are inherently distinct, as are the study designs. Furthermore, CROs and sites generally only accept protocols where the I/E are not in competition because they do not exactly know what lab values any given patients will have at screening, and if a patient doesn’t meet one protocol’s I/E, they may meet another. Renal and hepatic patients are difficult to identify, screen and enroll. Having multiple protocols with non-competing I/E criteria benefits the patient and sponsor. After all, patients who volunteer for research want to be in a study, and when they don’t qualify, they may feel rejected and not consider research in the future.
“Experienced sites with long-standing relationships with sponsors and CROs are adept at managing simultaneous yet unique protocols tailored to their patient populations. Effective communication and collaboration are the keys to nurturing such relationships, ultimately optimizing research as a care option for patients.”
3) Relationships With Sites Are Vital
“You have to make sure you have the right site and team with a robust patient database.”
Successful specialty population studies begin with strategic partnerships.
Among these partners, Dr. Vince Clinical Research (DVCR) stands out as a key player, offering a well-established network of highly regarded sites that specialize in renal and hepatic impairment studies as well as end-to-end solutions that support trial conduct. DVCR’s extensive network comprises strategically selected, highly desirable sites that cater to the unique demands of these trials. But what sets us apart is our trusted relationships with these specialized sites. We take a hands-on approach to managing sites for renal and hepatic impairment research, ensuring streamlined operations and optimal performance.
Reimagine Hepatic and Renal Impairment Research
“Conducting these disease trials right while ensuring the safety of the patients and obtaining quality data demands a long-term relationship today and in the future.”
Dr. Alcorn stresses that, in the world of renal and hepatic impairment studies, success boils down to having direct access to renal and hepatic patients, along with the right experience, the right team and a solid operational process. Dr. Vince Clinical Research is the ideal partner for these studies as our involvement goes beyond mere collaboration; it’s a holistic approach that results in effective communication and transparency throughout the study, optimizing study timelines, efficient patient recruitment and the delivery of high-quality data.
With partners such as Dr. Vince Clinical Research and the expertise provided by Dr. Alcorn at Elixia, you can confidently navigate the intricate landscape of renal and hepatic impairment studies, ensuring that your research endeavors yield meaningful outcomes and give patients the peace of mind they deserve. Contact us today to get started.
- Guidance for Industry Pharmacokinetics in Patients with Impaired Renal Function – Study Design, Data Analysis, and Impact on Dosing. U.S. Food and Drug Administration. Published Sept. 2020.
- Ravenstijn, P., et al. Design and conduct considerations for studies in patients with impaired renal function. Clinical and Translational Science. Published 2021 June 25.
- Ravenstijn, P., et al. Design and conduct considerations for studies in patients with hepatic impairment. Clinical and Translational Science. Published 2022 Oct. 9.