Evaluation of the landscape of pharmacodynamic biomarkers in Niemann-Pick Disease Type C (NPC).

Niemann-Pick disease type C (NPC) is an autosomal recessive, progressive disorder resulting from variants in NPC1 or NPC2 that leads to the accumulation of cholesterol and other lipids in late endosomes and lysosomes. The clinical manifestations of the disease vary by age of onset, and severity is often characterized by neurological involvement. To date, no disease-modifying therapy has been approved by the United States Food and Drug Administration (FDA) and treatment is typically supportive.

Clinical pharmacology considerations for first-in-human clinical trials for enzyme replacement therapy.

Inborn errors of metabolism (IEM) such as lysosomal storage disorders (LSDs) are conditions caused by deficiency of one or more key enzymes, cofactors, or transporters involved in a specific metabolic pathway. Enzyme replacement therapy (ERT) provides an exogenous source of the affected enzyme and is one of the most effective treatment options for IEMs. In this paper, we review the first-in-human (FIH) protocols for ERT drug development programs supporting 20 Biologic License Applications (BLA) approved by the Center for Drug Evaluation and Research (CDER) at the US Food and Drug Administration (FDA) in the period of May 1994 to September 2023.

Assessment of Dosing Strategies for Pediatric Drug Products.

Pediatric drug dosing is challenged by the heterogeneity of developing physiology and ethical considerations surrounding a vulnerable population. Often, pediatric drug dosing leverages findings from the adult population; however, recent regulatory efforts have motivated drug sponsors to pursue pediatric-specific programs to meet an unmet medical need and improve pediatric drug labeling. This paradigm is further complicated by the pathophysiological implications of obesity on drug distribution and metabolism and the roles that body composition and body size play in drug dosing.

Leveraging in Vitro Models for Clinically Relevant Rare Variants in Pharmacogenomics.

Cytochrome P450 2D6 (CYP2D6) is responsible for the metabolism of up to 20% of small-molecule drugs and therefore, may impact the safety and efficacy of medicines in broad therapeutic areas. is highly polymorphic, and the frequency of variants can differ across racial and ethnic populations, significantly affecting enzymatic function and drug metabolism. However, rare variants of present a unique challenge for academia, industry, and regulatory agencies alike due to the lack of feasibility of characterizing their clinical relevance in clinical trials, particularly in variants that exhibit population-specific frequencies in racial and ethnic groups that are poorly represented in clinical trials.

Creating a Roadmap to Quantitative Systems Pharmacology-Informed Rare Disease Drug Development: A Workshop Report.

One of the goals of the Accelerating Rare Disease Cures (ARC) program in the Center for Drug Evaluation and Research (CDER) at the US Food and Drug Administration (FDA) is the development and use of regulatory and scientific tools, including drug/disease modeling, dose selection, and translational medicine tools. To facilitate achieving this goal, the FDA in collaboration with the University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI) hosted a virtual public workshop on May 11, 2023, entitled "Creating a Roadmap to Quantitative Systems Pharmacology-Informed Rare Disease Drug Development." This workshop engaged scientists from pharmaceutical companies, academic institutes, and the FDA to discuss the potential utility of quantitative systems pharmacology (QSP) in rare disease drug development and identify potential challenges and solutions to facilitate its use.

Model-Informed Approach Supporting Drug Development and Regulatory Evaluation for Rare Diseases.

A rare disease is defined as a condition affecting fewer than 200 000 people in the United States by the Orphan Drug Act. For rare diseases, it is challenging to enroll a large number of patients and obtain all critical information to support drug approval through traditional clinical trial approaches. In addition, over half of the population affected by rare diseases are children, which presents additional drug development challenges.

FDA Approval Summary: Pemigatinib for Previously Treated, Unresectable Locally Advanced or Metastatic Cholangiocarcinoma with FGFR2 Fusion or Other Rearrangement.

On April 17, 2020, the FDA granted accelerated approval to pemigatinib (PEMAZYRE, Incyte Corporation) for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement as detected by an FDA-approved test. Approval was based on FIGHT-202 (NCT02924376), a multicenter open-label single-arm trial. Efficacy was based on 107 patients with locally advanced unresectable or metastatic cholangiocarcinoma whose disease had progressed on or after at least one prior therapy and had an FGFR2 gene fusion or rearrangement.

Premarket assessment of molecular alterations in drug targets: a case study of 2020 drug approvals.

Molecular alterations in drug targets may result in differential drug activity. Therefore, the authors aimed to characterize how molecular alterations in drug targets were assessed during drug development. The authors analyzed nonclinical and clinical study reports submitted to the US FDA for novel drugs approved in 2020 to determine if studies, animal models or clinical studies assessed molecular alterations in the drug target.

Dose-finding studies in drug development for rare genetic diseases.

Background: The small patient populations inherent to rare genetic diseases present many challenges to the traditional drug development paradigm. One major challenge is generating sufficient data in early phase studies to inform dose selection for later phase studies and dose optimization for clinical use of the drug. However, optimizing the benefit-risk profile of drugs through appropriate dose selection during drug development is critical for all drugs, including those being developed to treat rare diseases.

Evaluating Patients With Impaired Renal Function During Drug Development: Highlights From the 2019 US FDA Pharmaceutical Science and Clinical Pharmacology Advisory Committee Meeting.

Patients with multiple chronic conditions, including more advanced chronic kidney disease (CKD), are often excluded from clinical trials, creating challenges in deriving appropriate dosing information and labeling. This article summarizes the May 7, 2019, US Food and Drug Administration Pharmaceutical Science and Clinical Pharmacology Advisory Committee Meeting, which solicited expert opinions on how to enroll patients with more advanced CKD into clinical trials as well as the assumptions behind and different approaches of exposure-matching.

A Systematic Assessment of US Food and Drug Administration Dosing Recommendations For Drug Development Programs Amenable to Response-Guided Titration.

A key goal in drug development is optimized dosing for patients. Interactions between drug developers and regulatory scientists throughout development are important for the optimization of dosing and serve as a forum to discuss approaches for optimal dosing, such as precision or individualized dosing. To date, there has not been a systematic assessment of the advice provided by the US Food and Drug Administration (FDA) to drug developers from an individualized dosing perspective.

New directions in clinical trials for frontotemporal lobar degeneration: Methods and outcome measures.

Introduction: Frontotemporal lobar degeneration (FTLD) is the most common form of dementia for those under 60 years of age. Increasing numbers of therapeutics targeting FTLD syndromes are being developed.

Methods: In March 2018, the Association for Frontotemporal Degeneration convened the Frontotemporal Degeneration Study Group meeting in Washington, DC, to discuss advances in the clinical science of FTLD.

An Overview of Genomic Biomarker Use in Cardiovascular Disease Clinical Trials.

Clinical trial designs targeting patient subgroups with certain genetic characteristics may enhance the efficiency of developing drugs for cardiovascular disease (CVD). To evaluate the extent to which genetic knowledge translates to the CVD pipeline, we analyzed how genomic biomarkers are utilized in trials. Phase II and III trial protocols for investigational new drugs for CVD and risk factors were evaluated for prospective and exploratory genomic biomarker use; drug targets were evaluated for the presence of evidence that genetic variations can impact CVD risk or drug response.

Weighing the Evidence: Variant Classification and Interpretation in Precision Oncology, US Food and Drug Administration Public Workshop-Workshop Proceedings.

Purpose: Next-generation sequencing (NGS) oncology panels are becoming integral in hospital and academic settings to guide patient treatment and enrollment in clinical trials. Although NGS technologies have revolutionized decision-making for cancer therapeutics, physicians may face many challenges in parsing and prioritizing NGS-based test results to determine the best course of treatment for individual patients. On January 29, 2018, the US Food and Drug Administration held a public workshop entitled, "Weighing the Evidence: Variant Classification and Interpretation in Precision Oncology.

Use of Titration as a Therapeutic Individualization Strategy: An Analysis of Food and Drug Administration-Approved Drugs.

Selecting a dose regimen that is both safe and effective for patients is one of the most critical elements of a successful drug development program. Titrating the dose regimen of a drug based on patient response may help to identify safe and effective dosages at the individual patient level. Therefore, we quantified and characterized the use of response-guided titration for drugs recently approved by the US Food and Drug Administration (FDA) to assess how frequently this dosing strategy is used and how titration regimens are evaluated during drug development.

Considerations for Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease.

Advances in our understanding of the molecular underpinnings of disease have spurred the development of targeted therapies and the use of precision medicine approaches in patient care. While targeted therapies have improved our capability to provide effective treatments to patients, they also present additional challenges to drug development and benefit-risk assessment such as identifying the subset(s) of patients likely to respond to the drug, assessing heterogeneity in response across molecular subsets of a disease, and developing diagnostic tests to identify patients for treatment. These challenges are particularly difficult to address when targeted therapies are developed to treat diseases with multiple molecular subtypes that occur at low frequencies.

Enrichment Strategies in Pediatric Drug Development: An Analysis of Trials Submitted to the US Food and Drug Administration.

Clinical trial enrichment involves prospectively incorporating trial design elements that increase the probability of detecting a treatment effect. The use of enrichment strategies in pediatric drug development has not been systematically assessed. We analyzed the use of enrichment strategies in pediatric trials submitted to the US Food and Drug Administration from 2012-2016.

Urinary 11-dehydro-thromboxane B2 levels are associated with vascular inflammation and prognosis in atherosclerotic cardiovascular disease.

Cyclooxygenase-derived thromboxane (TxA2) and prostacyclin (PGI2) regulate atherogenesis in preclinical models. However, the relationship between TxA2 and PGI2 biosynthesis, vascular inflammation, and atherosclerotic cardiovascular disease (ASCVD) progression in humans remains unclear. The association between stable urine metabolites of thromboxane (TxA2-M) and prostacyclin (PGI2-M), circulating levels of cellular adhesion molecules (CAMs: E-selectin, P-selectin), chemokines and C-reactive protein, and the incidence of major adverse cardiovascular events (MACE) were evaluated in 120 patients with stable ASCVD on aspirin therapy.

Clinical Evidence Supports a Protective Role for CXCL5 in Coronary Artery Disease.

Our goal was to measure the association of CXCL5 and molecular phenotypes associated with coronary atherosclerosis severity in patients at least 65 years old. CXCL5 is classically defined as a proinflammatory chemokine, but its role in chronic inflammatory diseases, such as coronary atherosclerosis, is not well defined. We enrolled individuals who were at least 65 years old and undergoing diagnostic cardiac catheterization.

FDA Approval Summary: Rucaparib for the Treatment of Patients with Deleterious Mutation-Associated Advanced Ovarian Cancer.

On December 19, 2016, the FDA granted accelerated approval to rucaparib (RUBRACA; Clovis Oncology, Inc.) for the treatment of patients with deleterious mutation (germline and/or somatic)-associated advanced ovarian cancer who have been treated with two or more chemotherapies. The FDA also approved the FoundationFocus CDx test (Foundation Medicine, Inc.

Clinical and regulatory considerations in pharmacogenetic testing.

Purpose: Both regulatory science and clinical practice rely on best available scientific data to guide decision-making. However, changes in clinical practice may be driven by numerous other factors such as cost. In this review, we reexamine noteworthy examples where pharmacogenetic testing information was added to drug labeling to explore how the available evidence, potential public health impact, and predictive utility of each pharmacogenetic biomarker impacts clinical uptake.

Pharmacogenomic Biomarkers: an FDA Perspective on Utilization in Biological Product Labeling.

Precision medicine promises to improve both the efficacy and safety of therapeutic products by better informing why some patients respond well to a drug, and some experience adverse reactions, while others do not. Pharmacogenomics is a key component of precision medicine and can be utilized to select optimal doses for patients, more precisely identify individuals who will respond to a treatment and avoid serious drug-related toxicities. Since pharmacogenomic biomarker information can help inform drug dosing, efficacy, and safety, pharmacogenomic data are critically reviewed by FDA staff to ensure effective use of pharmacogenomic strategies in drug development and appropriate incorporation into product labels.