Addressing Drug-Drug Interaction Knowledge Gaps at the Time of Approval: An Analysis of FDA Postmarketing Requirements and Commitments from 2009 to 2023.

It has become increasingly common for patients to rely on the use of multiple prescription medications. The management of polypharmacy requires careful consideration for how drugs are metabolized and their potential for interaction with other drugs. Drug-drug interaction (DDI) assessments are typically performed in a stepwise manner during drug development, though knowledge gaps can exist at the time of approval. The US Food and Drug Administration can establish postmarketing requirements (PMRs) or postmarketing commitments (PMCs) to address these knowledge gaps. In this study, we systematically evaluated PMRs and PMCs established to new molecular entities (NMEs) at the time of initial approval between 2009 and 2023, for the assessment of pharmacokinetics-based DDIs (i.e., drug metabolizing enzyme- and transporter-related DDIs). We found that 22% of NMEs had at least one DDI-related PMR or PMC, with a total of 263 that were pharmacokinetic based. Of these, 67% were for the assessment of drug metabolizing enzymes, which were established most frequently for their evaluation as a substrate, and 28% for transporters, which were established most frequently for their evaluation as an inhibitor. The 89% of PMRs and PMCs that were considered fulfilled had a revision to the United States prescribing information, the majority of which resulted in updated new instructions for use. This study highlights the value in conducting PMRs and PMCs early in the drug development process allowing broad patient inclusion at the time of initial drug approval.

The Potential of Disease Progression Modeling to Advance Clinical Development and Decision Making.

While some model-informed drug development frameworks are well recognized as enabling clinical trials, the value of disease progression modeling (DPM) in impacting medical product development has yet to be fully realized. The Clinical Trials Transformation Initiative assembled a diverse project team from across the patient, academic, regulatory, and industry sectors of practice to advance the use of DPM for decision making in clinical trials and medical product development. This team conducted a scoping review to explore current applications of DPM and convened a multi-stakeholder expert meeting to discuss its value in medical product development. In this article, we present the scoping review and expert meeting output and propose key questions that medical product developers and regulators may use to inform clinical development strategy, appreciate the therapeutic context and endpoint selection, and optimize trial design with disease progression models. By expanding awareness of the unique value of DPM, this article does not aim to be technical in nature but rather aims to highlight the potential of DPM to improve the quality and efficiency of medical product development.

Model-Informed Drug Development-Based Approval of Intravenous Secukinumab for the Treatment of Adult Patients with Active Psoriatic Arthritis, Active Ankylosing Spondylitis, and Active Non-Radiographic Axial Spondyloarthritis.

On October 6, 2023, the US Food and Drug Administration (FDA) approved an intravenous (IV) formulation and dosage of Cosentyx® (secukinumab), for the treatment of adult patients with active psoriatic arthritis (PsA), active ankylosing spondylitis (AS), and active non-radiographic axial spondyloarthritis (nr-axSpA) with objective signs of inflammation. Clinical pharmacokinetics (PK), efficacy, and short-term placebo-controlled safety data were available from clinical studies (NCT04156620 and NCT04209205) with the to-be-marketed IV formulation using a maintenance dosage 3 mg/kg every 4 weeks (q4w), which was different from the dose approved (1.75 mg/kg q4w). The IV dosage of 3 mg/kg utilized in these two trials resulted in exposures (Cmax,ss) significantly higher than those for the approved subcutaneous (SC) regimens. Further, there is limited long-term safety information available for this 3 mg/kg q4w IV dose. To address this important limitation, a model-informed drug development (MIDD) approach was employed to leverage available clinical PK, efficacy, and safety data from the secukinumab development program to identify a maintenance IV dosing regimen, 1.75 mg/kg IV q4w, that better approximated the relevant SC secukinumab exposures for which efficacy and safety have been established. The MIDD analyses were used to support approval of this IV dosing regimen not directly studied in the indications sought for licensure, PsA, AS, and nr-AxSpA.

Statin Drug-Drug Interactions: Pharmacokinetic Basis of FDA Labeling Recommendations and Comparison Across Common Tertiary Clinical Resources.

Statins are widely prescribed and highly susceptible to pharmacokinetic (PK)-based drug-drug interactions (DDIs). To date, there has not been a comprehensive analysis of the basis upon which statin DDI recommendations in US Food and Drug Administration (FDA) prescribing information (PI) are derived. We have conducted such an analysis. We also assessed the degree of concordance of statin DDI recommendations in FDA PI and those provided in common tertiary clinical resources. We catalogued statin DDI information, including PK data and management recommendations, for statin precipitant drugs approved from 2010 to 2021, available from FDA PI and tertiary clinical resource databases. Recommendations were categorized and mapped with associated PK data to assess consistency in the PK basis for labeling recommendations. From the 80 precipitant drugs evaluated, 180 statin DDIs were identified in FDA PI. Dedicated clinical DDI studies were conducted for 54% (n = 97) of these DDIs and 34% (n = 61) of DDI recommendations were extrapolated from clinical data with other statins. Overall, we found that PK-based statin recommendations were consistent across PI. These findings highlight regulatory precedence for translating information across statins without conducting dedicated clinical DDI studies, which may support future efforts toward streamlining the approach to investigation and labeling of statin DDIs. In addition, with the exception of some notable discrepancies, general concordance was observed between FDA and tertiary resources regarding "Dose Adjustment" and "Avoid Coadministration" recommendations. However, further analyses are warranted across other DDI pairs to determine whether discordance can routinely lead to different clinical recommendations depending on the drug information resource.

Clinical Pharmacology Approaches to Support Approval of New Routes of Administration for Therapeutic Proteins.

Intravenous or subcutaneous routes of administration (ROAs) are common dosing routes for therapeutic proteins. Eleven therapeutic proteins with approval for one ROA have subsequently received approval for a second ROA. The clinical programs supporting the second ROA consistently leveraged data from the first ROA and included studies that characterized the pharmacokinetics (PKs) of the drug administered by the new ROA to identify an appropriate dosage regimen. The selected dosing regimen was then further evaluated in clinical trials designed with various primary end points. All programs implemented model-informed drug development approaches to ensure that the selected regimens would achieve comparable systemic exposures (PK-based bridging) or pharmacodynamic (PD) responses (PD-based bridging) as the reference ROA. To support the approval of a second ROA, these programs either demonstrated noninferiority in PK, PD, and/or clinical end points for the second ROA, or established efficacy and safety through a comparison to a placebo treatment. The accumulative examples showed that clinical trials which provided the primary evidence to support approvals of the second ROA generally demonstrated noninferiority in the systemic exposures regardless of being specified as an end point or not in the study protocols. The experience to date supports the use of PK- and PD-based bridging approaches not only in the selection of dosing regimens for a second ROA to be tested in clinical studies, but also for providing evidence of effectiveness to support approval, when appropriate.

Inclusion of Subjects who are Obese in Drug Development: Current Status and Opportunities.

The prevalence of obesity has grown tremendously in recent years and this population has an increased risk of disease comorbidities. The presence of disease comorbidities requires treatment interventions and proper dosing guidelines. However, drug development programs often do not have adequate representation of individuals who are obese in clinical trials, leaving gaps in the understanding of treatment response leading to a lack of adequate individualization options. Based on a recent survey of approved drug product package inserts, very few approved products included specific dosing based on obesity, in both adults and pediatrics. Reasons for the limited information on patients who are obese may include the under-reporting of information regarding such patients and a lack of clinical trial diversity in enrolling patient groups in whom obesity or obesity-related comorbidities are more prevalent. An inadvertent impact of the practice of exclusion of subsets of patients with some comorbidities in clinical trials may play a role in the reduced enrollment of individuals who are obese. Recently, regulatory authorities have taken specific initiatives to promote clinical trial diversity, including engaging with stakeholders and publishing regulatory guidance. These guidance documents highlight the need to enroll diverse clinical trial populations and provide recommendations on concepts related to drug development for obese populations. Such efforts will help to address the gap in information regarding drug response and dosing in patients who are obese.

Need for Representation of Pediatric Patients with Obesity in Clinical Trials.

Clinical trials are an integral aspect of drug development. Tremendous progress has been made in ensuring drug products are effective and safe for use in the intended pediatric population, but there remains a paucity of information to guide drug dosages in pediatric patients with obesity. This is concerning because obesity may influence the disposition of drug products. When pediatric patients with obesity are not enrolled in clinical trials, dosing options for use in this subpopulation may be suboptimal. Reliance on physiological-based dosing strategies that are not informed by evaluation of the pharmacokinetics of the drug product could lead to under- or over-dosing with ensuing therapeutic failure or toxicity consequences. Thus, representation of pediatric patients with obesity in clinical trials is crucial to understand the benefit-risk profile of drug products in this subpopulation. It is important to acknowledge that this is a challenging endeavor, but not one that is insurmountable. Collective efforts from multiple stakeholders including drug developers and regulators to enhance diversity in clinical trials can help fill critical gaps in knowledge related to the influence of obesity on drug disposition.

Pediatric dosing for locally acting drugs in submissions to the U.S. Food and Drug Administration between 2002 and 2020.

Deriving pediatric doses for locally acting drugs (LADs) presents a unique challenge because limited systemic exposure hinders commonly used approaches such as pharmacokinetic matching to adults. This study systematically evaluated drug development practices used for pediatric dose selection of LADs approved by the U.S. Food and Drug Administration from 2002 to 2020. The three study objectives were: (1) to determine the dose selection approach for the labeled pediatric dose, (2) to examine the studied pediatric dose(s), and (3) to evaluate the characteristics of the pediatric clinical programs used to support the labeled pediatric dose. A total of 187 pediatric submissions were characterized for the labeled and studied pediatric doses of LADs. The pediatric dose was predominantly labeled as a flat dose (91%) and at a single-dose level (67%) similar to adults. The majority (68.4%) of the submissions had the same labeled dose for pediatrics and adults. Independent pharmacodynamic/efficacy studies in pediatric patients commonly (64.2%) provided supportive evidence for the labeled pediatric dose. Inhalation, nasal, and injectable submissions had the highest number of clinical trials, lowest usage of an extrapolation of efficacy approach, and utilized diverse approaches in selecting the studied pediatric doses. This article highlights approaches for LAD dosing in pediatric patients and can be used to inform drug development of these products in the pediatric population.

Informing a Comprehensive Risk Assessment of Infant Drug Exposure From Human Milk: Application of a Physiologically Based Pharmacokinetic Lactation Model for Sotalol.

Characterization of infant drug exposure through human milk is important and underexplored. Because infant plasma concentrations are not frequently collected in clinical lactation studies, modeling and simulation approaches can integrate physiology, available milk concentrations, and pediatric data to inform exposure in breastfeeding infants. A physiologically based pharmacokinetic model was built for sotalol, a renally eliminated drug, to simulate infant drug exposure from human milk. Intravenous and oral adult models were built, optimized, and scaled to an oral pediatric model for a breastfeeding-relevant age group (<2 years). Model simulations captured the data that were put aside for verification. The resulting pediatric model was applied to predict the impacts of sex, infant body size, breastfeeding frequency, age, and maternal dose (240 and 433 mg) on drug exposure during breastfeeding. Simulations suggest a minimal effect of sex or frequency on total sotalol exposure. Infants in the 90th percentile in height and weight have predicted exposures ≈20% higher than infants of the same age in the 10th percentile due to increased milk intake. The simulated infant exposures increase throughout the first 2 weeks of life and are maintained at the highest concentrations in weeks 2-4, with a consistent decrease observed as infants age. Simulations suggest that breastfeeding infants will have plasma concentrations in the lower range observed in infants administered sotalol. With further validation on additional drugs, physiologically based pharmacokinetic modeling approaches could use lactation data to a greater extent and provide comprehensive information to support decisions regarding medication use during breastfeeding.

Predicting Food Effects on Oral Extended-Release Drug Products: A Retrospective Evaluation.

Theoretically, the risk of food effects for extended-release (ER) products compared to IR products may be less because: (1) postprandial physiological changes are usually transient and last for 2-3 h only; and (2) the percentage of drug release from an ER product within the first 2-3 h post dose is usually small under both fasted and fed states. The major postprandial physiological changes that can affect oral absorption of ER drugs are delayed gastric emptying and prolonged intestinal transit. Oral absorption of ER drugs under fasted state mainly occurs in large intestine (colon and rectum) while the absorption of ER drugs under fed state occurs in both small and large intestines. We hypothesized that food effects for ER products are mainly caused by intestinal region-dependent absorption and food intake is more likely to increase rather than decrease the exposure of ER products due to a longer transit time and improved absorption in small intestine. For drugs with good absorption from large intestine, food effects on the area under the curve (AUC) of ER products are usually not expected. Our survey of oral drugs approved by the US FDA between 1998-2021 identified 136 oral ER drug products. Among the 136 ER drug products, 31, 6 and 99 products exhibited increased, decreased, and unchanged AUC under fed conditions, respectively. In general, when an ER product exhibits a fasted bioavailability (BA) relative to its corresponding immediate-release (IR) product between 80-125%, regardless the solubility or permeability of drug substances, substantial food effects on the AUC of ER product are generally not expected. If the fasted relative BA data are not available, a high in vitro permeability (i.e., Caco-2 or MDCK cell permeability comparable or higher than that of metoprolol) may inform no food effect on the AUC of an ER product of high-solubility (BCS class I and III) drug.

US FDA Postmarketing Requirements and Commitments: A Systematic Assessment of Clinical Pharmacology Studies and Their Impact on US FDA Prescribing Information.

Many of the conditions for the safe and effective use of new molecular entities (NMEs) are understood at the time of initial drug approval. However, some remaining knowledge gaps can be addressed after drug approval through postmarketing requirements (PMRs) or commitments (PMCs) established by the US Food and Drug Administration (FDA). Our objective was to conduct an assessment of clinical pharmacology-related PMRs and PMCs established at the time of approval and evaluate the impact of fulfilled PMRs and PMCs on prescription information (PI). This analysis included clinical pharmacology-related PMRs and PMCs established for NMEs approved between 2009 and 2020. Of the 1171 PMRs and PMCs, over one-third were clinical pharmacology-related. Of these, 46% were to evaluate drug interactions, 16% were to evaluate drug dosing in patients with hepatic impairment, and 10% were related to dose. The majority (57%) of PMRs and PMCs were fulfilled at the time of analysis, with a median time to fulfillment of approximately 2.3 years. The majority (94%) of the fulfilled PMRs and PMCs, either with or without a PI revision, resulted in new or modified instructions for use or supported existing instructions for use. This is the first time that clinical pharmacology-related PMRs and PMCs have been catalogued and analyzed to understand their impact on PI. An understanding of the knowledge gaps that exist at the time of drug approval could inform the most effective and efficient methods for evidence generation prior to and after new drug approval.

Promoting Clinical Trial Diversity: A Highlight of Select US FDA Initiatives.

Although the population in the United States is diverse, there are disparities in healthcare outcomes in some populations, for example, based on characteristics such as race, ethnicity, sex, gender, age, socioeconomic status, and geographic location. Despite disproportionate healthcare outcomes, certain populations are frequently under-represented in clinical trials intended to support applications requesting US Food and Drug Administration (FDA) approval to market a drug or biologic. Additionally, safety and efficacy of therapeutic products may vary based on intrinsic (e.g., sex, age, race, and ethnicity) and/or extrinsic (e.g., drug interactions and medical practice) factors. Enrolling diverse populations in clinical trials can aid in addressing disparities and better inform the use of medical products in all patients who will use them upon approval. Herein, we outline a few initiatives and activities, such as policy development, regulatory review, regulatory research, and stakeholder engagement, that the FDA has undertaken to promote diversity in clinical trials, to support submission of such information in marketing applications for subgroup analyses, and to communicate information to the public.

Clinical pharmacology information in regulatory submissions and labeling: A comparative analysis of orphan and non-orphan drugs approved by the FDA.

Clinical pharmacology is an integral discipline supporting the development, regulatory evaluation, and clinical use of drugs for the treatment of both common and rare diseases. Here, we evaluated the recommendations and information available from select clinical pharmacology studies in the therapeutic product labeling of new molecular entities (NMEs) approved from 2017 to 2019 for both common and rare diseases. A total of 151 NMEs, including 72 orphan and 79 non-orphan drugs, were analyzed for recommendations and information available related to food-drug interaction, drug-drug interaction, renal impairment, hepatic impairment, QT assessment, and human radiolabeled mass balance studies using data collected from the original labeling and other regulatory documents. The analysis showed no statistically significant difference in the recommendations between orphan and non-orphan drugs except for renal impairment related recommendations in section 8 of the labeling. Although not significant, fewer hepatic impairment labeling recommendations were available for orphan drugs when compared with non-orphan drugs. At the time of initial approval, 79 postmarketing requirements (PMRs) and postmarketing commitments (PMCs) for 33 orphan drugs and 39 PMRs and PMCs for 19 non-orphan drugs were established; with most difference observed for drug-drug interaction, hepatic impairment, and QT assessment. Overall, although there was a trend for more labeling recommendations and fewer postmarketing studies and clinical trials for non-orphan drugs, there appeared to be no substantial differences in how these select clinical pharmacology studies are leveraged during the development and approval of orphan and non-orphan drugs.

Current Perspective on Residual Knowledge Gaps in the Assessment of Transporter-Mediated Drug Interactions.

Assessment of transporter-mediated drug-drug interaction (DDI) is integral to drug development. A risk-based approach leveraging in vitro, in vivo, and in silico information is used to evaluate the DDI liability of drugs and inform the instructions of use. While tremendous advances have been made in recent decades, there are knowledge gaps warranting further research. Herein, we focus on select areas to advance assessment of DDI potential for drugs as substrates, inhibitors, or inducers of certain transporters.

Review: Role of Model-Informed Drug Development Approaches in the Lifecycle of Drug Development and Regulatory Decision-Making.

Model-informed drug development (MIDD) is a powerful approach to support drug development and regulatory review. There is a rich history of MIDD applications at the U.S. Food and Drug Administration (FDA). MIDD applications span across the life cycle of the development of new drugs, generics, and biologic products. In new drug development, MIDD approaches are often applied to inform clinical trial design including dose selection/optimization, aid in the evaluation of critical regulatory review questions such as evidence of effectiveness, and development of policy. In the biopharmaceutics space, we see a trend for increasing role of computational modeling to inform formulation development and help strategize future in vivo studies or lifecycle plans in the post approval setting. As more information and knowledge becomes available pre-approval, quantitative mathematical models are becoming indispensable in supporting generic drug development and approval including complex generic drug products and are expected to help reduce overall time and cost. While the application of MIDD to inform the development of cell and gene therapy products is at an early stage, the potential for future application of MIDD include understanding and quantitative evaluation of information related to biological activity/pharmacodynamics, cell expansion/persistence, transgene expression, immune response, safety, and efficacy. With exciting innovations on the horizon, broader adoption of MIDD is poised to revolutionize drug development for greater patient and societal benefit.

Roadmap to 2030 for Drug Evaluation in Older Adults.

Changes that accompany older age can alter the pharmacokinetics (PK), pharmacodynamics (PD), and likelihood of adverse effects (AEs) of a drug. However, older adults, especially the oldest or those with multiple chronic health conditions, polypharmacy, or frailty, are often under-represented in clinical trials of new drugs. Deficits in the current conduct of clinical evaluation of drugs for older adults and potential steps to fill those knowledge gaps are presented in this communication. The most important step is to increase clinical trial enrollment of older adults who are representative of the target treatment population. Unnecessary eligibility criteria should be eliminated. Physical and financial barriers to participation should be removed. Incentives could be created for inclusion of older adults. Enrollment goals should be established based on intended treatment indications, prevalence of the condition, and feasibility. Relevant clinical pharmacology data need to be obtained early enough to guide dosing and reduce risk for participation of older adults. Relevant PK and PD data as well as patient-centered outcomes should be measured during trials. Trial data should be analyzed for differences in PK, PD, effectiveness, and safety arising from differences in age or from the presence of conditions common in older adults. Postmarket evaluations with real-world evidence and drug labeling updates throughout the product lifecycle reflecting new knowledge are also needed. A comprehensive plan is needed to ensure adequate evaluation of the safety and effectiveness of drugs in older adults.