Clinical Pharmacology Guidances Advancing Drug Development and Regulatory Assessment: Role and Opportunities

Abstract

Clear and pragmatic scientific recommendations from regulators promote consistent and timely generation of quality data during drug development leading to more efficient regulatory review. To provide these scientific recommendations, the Office of Clinical Pharmacology (OCP) within the US Food and Drug Administration (FDA) has adopted a lifecycle approach to guidance and policy development.¹ This end-to-end process provides a structured approach for identification, development, clearance, implementation, and evaluation of guidances and policies, and facilitates modernization of existing guidances and policies or development of de novo guidances and policies in an informed manner in an ever-changing scientific landscape (Figure 1). In the multidisciplinary field of clinical pharmacology, such an approach is important to ensure that guidances and policies are relevant, contemporary, and informed by accumulated scientific and regulatory experience. The goals are to enable innovation in drug development, ensure consistency in decision-making, and protect health and safety of real-world patients and research participants.

Developing and updating clinical pharmacology guidances benefits from proactive engagement of all the interested parties within the ecosystem of drug development, regulatory assessment, and patient care. As part of engagement efforts, OCP published a federal register notice and conducted a public workshop to identify emerging scientific topics that might benefit from further scientific research and best practice development.^{2, 3} Herein, we highlight the discussions from the “Clinical Pharmacology Guidances Advancing Drug Development and Regulatory Assessment: Role and Opportunities” workshop conducted as part of a collaboration between OCP and the University of Maryland Center for Excellence in Regulatory Science and Innovation (MCERSI) on May 8–9, 2024. The discussions focused on five areas: specific patient populations, rare diseases, drug lifecycle management, application of quantitative approaches, and value of globally harmonized clinical pharmacology guidelines. The workshop highlighted current guidances relevant to the field of clinical pharmacology, discussed the challenges and gaps in applying clinical pharmacology principles during drug development, and identified potential opportunities for further regulatory research and best practice development. Outlined below and in Figure 2 are some of the challenges and opportunities identified by the discussants.

“Specific patient populations” typically refers to subgroups of patients who may require additional considerations to optimize therapy based on potential differences in drug disposition or response, and may include subpopulations such as older adults, children, those with organ impairment, and pregnant or lactating females. While several regulatory guidances are dedicated to generating data and prescribing recommendations for some specific populations, dedicated guidances are not available for all subpopulations for which there may be differences in exposure or response based on specific intrinsic or extrinsic factors.^4-7 Additionally, some specific patient populations are more routinely included and evaluated in the drug development program and labeling (e.g., renal or hepatic impairment) compared to other populations (e.g., patients with comorbidities). Even within specific patient populations that are more frequently evaluated, data may still be scarce for some subgroups of these specific populations (e.g., patients with severe hepatic or severe renal impairment or end stage renal disease).⁸ In addition, an individual can have multiple conditions or comorbidities that result in (patho)physiological changes (e.g., older adult with reduced renal function and comorbid diseases taking multiple drugs), but generally studies and product labeling address the impact of only one factor at a time (e.g., age or drug–drug interaction). Discussions highlighted the need to use quantitative approaches rooted in mechanistic understanding to inform the drug development program (e.g., identify eligibility criteria for clinical trials and identify the need for standalone studies) and promote therapeutic optimization and individualization for a broader range of specific patient populations.

Some challenges associated with rare disease drug development include small patient population size, limited understanding of natural history, suboptimal dose exploration, lack of validated endpoints or established biomarkers, and ability to meaningfully integrate patient and caregiver input. Several guidances are available to support rare disease drug development that attempt to address some of these challenges.⁹ However, opportunities to support patient-centric drug development remain, including proactive partnerships with patients and caregivers and utilization of innovative and patient-friendly trial designs such as those incorporating decentralized elements. Opportunities for clinical pharmacology investigations include informing the development of relevant disease-specific outcome measures, developing translational models of drug disposition and response, guiding drug use in certain subpopulations not studied in clinical trials, and integrating comprehensive biomarker approaches utilizing validated analytical methods. It is important to prospectively plan informative translational and clinical pharmacology studies to support dose optimization and evidence of effectiveness. In addition, novel therapeutic modalities (e.g., antisense oligonucleotides) that are targeted to specific rare diseases may require special consideration given their targeted mechanisms and pharmacological properties may be distinct from small molecules and biologics.

Across the lifecycle of a drug, clinical pharmacology concepts are applied extensively to bridge new formulations, develop new dosage forms, change the route of administration, and extend the indication to new patient populations. Many clinical pharmacology guidances provide recommendations that become relevant over the lifecycle of a drug.^{10, 11} Additionally, bioequivalence, biopharmaceutic, and quality-related guidances are also important to demonstrate product performance control and consistency. Some challenges discussed were the multitude of changes that happen during the drug lifecycle and the lack of systematic knowledge management to share case examples. The opportunities identified included the need to increase patient-centric considerations throughout drug lifecycle, encourage multidisciplinary partnerships (e.g., clinical pharmacology, biopharmaceutics, chemists, and statisticians), and leverage modeling and simulation tools to address product and process changes.

Over the past few decades, quantitative medicine approaches have been increasingly used to answer questions related to disease progression, dose finding, dose selection and optimization, study design, and evidence generation. Several existing guidances provide recommendations to facilitate the consistent utilization of the model informed drug development (MIDD) approaches by highlighting the foundational principles and applications.^12-14 Challenges discussed focused on the need to take advantage of the rapid advances in methodologies and technologies and the need for the development of best practices that can foster broader acceptance of emerging technologies (e.g., artificial intelligence and machine learning) and use of real-world data. It was acknowledged that using the MIDD Paired Meeting Program to obtain real-time feedback during drug development and the Fit-for-Purpose Initiative to gain regulatory acceptance of drug development tools (DDTs) are some of the avenues for regulatory engagement on the development and application of quantitative medicine approaches.

Clinical pharmacology guidances and policies provide a structure for drug development and also provide an opportunity to spur innovation on emerging topics. The discussants highlighted the need to strike a balance by not being overly prescriptive (i.e., allowing for the flexibility to adapt to the evolving science) while not being very high level (i.e., lacking meaningful and actionable recommendations).

From conceptualization to final guidance publication, developing guidances is a resource intensive, repetitive, and lengthy process. Once published, guidances may be inconsistently implemented or be at risk of becoming obsolete if the tools, technologies, and approaches rapidly evolve. These challenges could be overcome by increased focus on education and regular evaluation of the effectiveness of final guidances. Additional suggestions to increase agility included publishing addendums to guidances (e.g., Q&A documents) and developing less prescriptive lean guidances that provide a framework for rapidly evolving topics.

Globally harmonized guidelines that are developed via consensus among global regulators and stakeholders can help reduce uncertainty during global drug development. Many clinical pharmacology relevant guidelines have been published under the aegis of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), including the recent drug interaction guideline.¹⁵ Some of the challenges identified in developing harmonized guidelines include the time and resources needed to develop or update a harmonized guideline as well as anecdotal reports of inconsistent implementation of recommendations across global regulatory authorities. As with FDA guidances, a focus on education, training, and evaluation are needed to support successful implementation of global guidelines. Due to time and resource intensive nature, topic selection for future harmonization needs to balance impact with amenability to global alignment.

The landscape of drug development is evolving, powered by advancing science as well as tools and technologies. In such an environment, guidances and policies must be nimble while ensuring consistency in decision-making. Cutting edge regulatory research and multistakeholder engagements are crucial to ensure that we can navigate the tension between consistency and innovation. Patient-centric regulatory research is valuable in filling knowledge gaps in drug discovery, development, regulation, and utilization, and can inform the scientific recommendations provided in guidances. However, to be effective, regulatory science should start at drug discovery and continue even after approval of the drug, with research adapting to identified knowledge gaps and needs. To ensure continuity, stakeholder input becomes crucial. Discussions with stakeholders from other government agencies, international regulators, industry, academia, professional societies, healthcare providers, patient advocates, and patients become important to learn about their experiences, challenges, and potential future opportunities. This can lead to the development of clear, pragmatic, contemporary, and patient-centered guidances and best practices that increase efficiency of the drug development process.

The authors declare that they have no conflicts of interest to disclose.

None.

This manuscript reflects the views of the author and should not be construed to represent FDA's views or policies.