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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. Here, we reviewed FDA recommendations on dose selection for efficacy trials at end‐of‐phase meetings between the FDA and drug developers for 76 new molecular entities approved between 2013 and 2017 that are considered amenable for an individualized dosing method, response‐guided titration. Forty FDA dosing recommendations were identified as specific to dose selection and design of the respective efficacy trials and subsequently: (i) characterized based on if they were supportive of individualized dosing and (ii) compared with dosing regimens used in efficacy trials and labeling at approval to evaluate if FDA recommendations were implemented. Of these 40 recommendations for efficacy trials, 35 (88%) were considered supportive of individualized dosing. Eighteen of these 40 recommendations (45%) were incorporated into efficacy trials and 11 (28%) were incorporated into labeling. This research suggests that early FDA‐sponsor interactions can support the study of doses in efficacy trials that may lead to individualized dosing strategies in labeling.
Dose-finding studies in drug development for rare genetic diseases
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. Recognizing the challenges of conducting dose finding studies in rare disease populations and the importance of dose selection and optimization for successful drug development, we assessed the dose-finding studies and analyses conducted for drugs recently approved for rare genetic diseases. Of the 40 marketing applications for new molecular entity (NME) drugs and biologics approved by the United States Food and Drug Administration for rare genetic diseases from 2015 to 2020, 21 (53%) of the development programs conducted at least one dedicated dose-finding study. In addition, the majority of drug development programs conducted clinical studies in healthy subjects and included population pharmacokinetic and exposure–response analyses; some programs also conducted clinical studies in patient populations other than the disease for which the drug was initially approved. The majority of primary endpoints utilized in dedicated dose-finding studies were biomarkers, and the primary endpoint of the safety and efficacy study matched the primary endpoint used in the dose finding study in 9 of 13 (69%) drug development programs where primary study endpoints were assessed. Our study showed that NME drug development programs for rare genetic diseases utilize multiple data sources for dosing information, including studies in healthy subjects, population pharmacokinetic analyses, and exposure–response analyses. In addition, our results indicate that biomarkers play a key role in dose-finding studies for rare genetic disease drug development programs. Our findings highlight the need to develop study designs and methods to allow adequate dose-finding efforts within rare disease drug development programs that help overcome the challenges presented by low patient prevalence and other factors. Furthermore, the frequent reliance on biomarkers as endpoints for dose-finding studies underscores the importance of biomarker development in rare diseases.
Di-22:6-bis(monoacylglycerol)phosphate: A clinical biomarker of drug-induced phospholipidosis for drug development and safety assessment
The inability to routinely monitor drug-induced phospholipidosis (DIPL) presents a challenge in pharmaceutical drug development and in the clinic. Several nonclinical studies have shown di-docosahexaenoyl (22:6) bis(monoacylglycerol) phosphate (di-22:6-BMP) to be a reliable biomarker of tissue DIPL that can be monitored in the plasma/serum and urine. The aim of this study was to show the relevance of di-22:6-BMP as a DIPL biomarker for drug development and safety assessment in humans. DIPL shares many similarities with the inherited lysosomal storage disorder Niemann–Pick type C (NPC) disease. DIPL and NPC result in similar changes in lysosomal function and cholesterol status that lead to the accumulation of multi-lamellar bodies (myeloid bodies) in cells and tissues. To validate di-22:6-BMP as a biomarker of DIPL for clinical studies, NPC patients and healthy donors were classified by receiver operator curve analysis based on urinary di-22:6-BMP concentrations. By showing 96.7-specificity and 100-sensitivity to identify NPC disease, di-22:6-BMP can be used to assess DIPL in human studies. The mean concentration of di-22:6-BMP in the urine of NPC patients was 51.4-fold (p ≤ 0.05) above the healthy baseline range. Additionally, baseline levels of di-22:6-BMP were assessed in healthy non-medicated laboratory animals (rats, mice, dogs, and monkeys) and human subjects to define normal reference ranges for nonclinical/clinical studies. The baseline ranges of di-22:6-BMP in the plasma, serum, and urine of humans and laboratory animals were species dependent. The results of this study support the role of di-22:6-BMP as a biomarker of DIPL for pharmaceutical drug development and health care settings. - Highlights: • A reliable biomarker of drug-induced phospholipidosis (DIPL) is needed for humans. • Di-22:6-BMP is specific/sensitive for DIPL in animals as published in literatures. • The di-22:6-BMP biomarker can be validated for humans via NPC patients. • DIPL shares morphologic/mechanistic similarities with Niemann–Pick type C disease. • Di-22:6-BMP is an effective DIPL biomarker in humans via NPC patient validation.
Improving Dose-Optimization Processes Used in Oncology Drug Development to Minimize Toxicity and Maximize Benefit to Patients
This review highlights strategies to integrate dose optimization into premarketing drug development and discusses the underlying statistical principles. Poor dose optimization can have negative consequences for patients, most commonly because of toxicity, including poor quality of life, reduced effectiveness because of inability of patients to stay on current therapy or receive subsequent therapy because of toxicities, and difficulty in developing combination regimens. We reviewed US Food and Drug Administration initial approvals (2019-2021) of small molecules and antibody-drug conjugates for oncologic indications to determine the proportion with a recommended dosage at the maximum tolerated dose or the maximal administered dose, to characterize the use of randomized evaluations of multiple dosages in dose selection, to describe the frequency of dose modifications at the recommended dosage, and to identify case examples that highlight key principles for premarket dose optimization during drug development. Herein, we highlight major principles for dose optimization and review examples of recent US Food and Drug Administration approvals that illustrate how investigation of dose- and exposure-response relationships and use of randomized dose trials can support dose optimization. Although there has been some progress, dose optimization through randomized dose evaluation in oncology trials is not routinely conducted. Dose optimization is essential to ensure that patients receive therapies which maximize efficacy while minimizing toxicity.
Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development
A number of drivers and developments suggest that microdosing and other phase 0 applications will experience increased utilization in the near-to-medium future. Increasing costs of drug development and ethical concerns about the risks of exposing humans and animals to novel chemical entities are important drivers in favor of these approaches, and can be expected only to increase in their relevance. An increasing body of research supports the validity of extrapolation from the limited drug exposure of phase 0 approaches to the full, therapeutic exposure, with modeling and simulations capable of extrapolating even non-linear scenarios. An increasing number of applications and design options demonstrate the versatility and flexibility these approaches offer to drug developers including the study of PK, bioavailability, DDI, and mechanistic PD effects. PET microdosing allows study of target localization, PK and receptor binding and occupancy, while Intra-Target Microdosing (ITM) allows study of local therapeutic-level acute PD coupled with systemic microdose-level exposure. Applications in vulnerable populations and extreme environments are attractive due to the unique risks of pharmacotherapy and increasing unmet healthcare needs. Lastly, all phase 0 approaches depend on the validity of extrapolation from the limited-exposure scenario to the full exposure of therapeutic intent, but in the final analysis the potential for controlled human data to reduce uncertainty about drug properties is bound to be a valuable addition to the drug development process.
Global harmonization of immediate‐release solid oral drug product bioequivalence recommendations and the impact on generic drug development
Immediate-release (IR) solid oral drug products constitute a significant portion of approved drug products and products under development. Bioequivalence (BE) assessment for these oral products is important for establishing therapeutic equivalence for generic products to their respective comparator products. In December 2022, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) published the first new draft guideline on BE for IR solid oral dosage forms (M13A). To support the development of ICH M13A, we comprehensively reviewed the landscape of oral IR products approved by the U.S. Food and Drug Administration (FDA) and compared BE recommendations for these products in the current U.S. FDA and European Medicines Agency (EMA) BE guidances. We utilized databases including Drugs@FDA, Orange Book, and product-specific guidances (PSGs) published on the U.S. FDA and EMA websites to collect information. Oral IR products account for 46% of all FDA-approved new drug applications currently listed in Orange Book with 82.5% solids, 0.9% semi-solids, and 16.6% liquids. For all published U.S. FDA PSGs for solid oral IR products, in vivo BE studies with pharmacokinetic (PK) endpoints account for 88% of BE approaches recommended. Of these PK BE studies, 86.5% recommended fasting and fed BE studies, while only 15.9% EMA PSGs recommended both fasting and fed BE studies. This review helps clarify the scope of U.S. solid oral IR products impacted by the new ICH M13A draft guideline and demonstrates how recommendations in draft ICH M13A could significantly harmonize BE recommendations for IR oral products to facilitate global drug development.
Application of electroretinography (ERG) in early drug development for assessing retinal toxicity in rats
Retinal ocular toxicity is among the leading causes of drug development attrition in the pharmaceutical industry. Electroretinography (ERG) is a non-invasive functional assay used to assess neuro-retinal physiological integrity by measuring the electrical responses. To directly assess the utility of ERG, a series of studies was conducted following intravitreal and/or iv administration of pan-cyclin-dependent kinase inhibitors: AG-012,986 and AG-024,322 in rats. Both compounds have previously shown to induce retinal toxicity. Retinal injury was evaluated by ERG, histopathology and TUNEL staining. Intravitreal injection of AG-012,986 at ≥ 10 μg/eye resulted in decreases (60%) in ERG b-wave and microscopic changes of mild to moderate retinal degeneration, and at 30 μg/eye led to additional ophthalmic findings. Intravenous administration of AG-012,986 daily at ≥ 5 mg/kg resulted in dose-related decreases (25 to 40%) in b-wave and sporadic to intense positive TUNEL staining. Intravitreal injection of AG-024,322 at 30 μg/eye also resulted in decreases (50 to 60%) in b-wave, mild to marked retinal degeneration and mild vitreous debris. These experiments demonstrate that ERG can be used as a sensitive and reliable functional tool to evaluate retinal toxicity induced by test compounds in rats complementing other classical ocular safety measurements. - Highlights: • There were strong correlations of ERG readouts to in vivo ophthalmic exams, TUNEL assay, and histopathology. • ERG appears to be more sensitive and can detect retinal functional changes at a very early stage of pathogenesis. • ERG can be incorporated into routine exploratory toxicity study to identify compound ocular safety issues. • In drug discovery, ERG is a quick, non-invasive, sensitive and reliable tool in retinal toxicity de-risking.
Recent Drug Development and Medicinal Chemistry Approaches for the Treatment of SARS‐CoV‐2 Infection and COVID‐19
Abstract COVID‐19, caused by SARS‐CoV‐2 infection, continues to be a major public health crisis around the globe. Development of vaccines and the first cluster of antiviral drugs has brought promise and hope for prevention and treatment of severe coronavirus disease. However, continued development of newer, safer, and more effective antiviral drugs are critically important to combat COVID‐19 and counter the looming pathogenic variants. Studies of the coronavirus life cycle revealed several important biochemical targets for drug development. In the present review, we focus on recent drug design and medicinal chemistry efforts in small molecule drug discovery, including the development of nirmatrelvir that targets viral protein synthesis and remdesivir and molnupiravir that target viral RdRp. These are recent FDA approved drugs for the treatment of COVID‐19.
Inhibition of CRM1-mediated nuclear export of influenza A nucleoprotein and nuclear export protein as a novel target for antiviral drug development
An anti-influenza compound, DP2392-E10 based on inhibition of the nuclear export function of the viral nucleoprotein-nuclear export signal 3 (NP-NES3) domain was successfully identified by our previous high-throughput screening system. Here, we demonstrated that DP2392-E10 exerts its antiviral effect by inhibiting replication of a broad range of influenza A subtypes. In regard to the molecular mechanism, we revealed that DP2392-E10 inhibits nuclear export of both viral NP and nuclear export protein (NEP). More specifically, in vitro pull-down assays revealed that DP2392-E10 directly binds cellular CRM1, which mediates nuclear export of NP and NEP. In silico docking suggested that DP2392-E10 binds at a region close to the HEAT9 and HEAT10 domains of CRM1. Together, these results indicate that the CRM1-mediated nuclear export function of influenza virus represents a new potential target for antiviral drug development, and also provide a core structure for a novel class of inhibitors that target this function. - Highlights: •DP2392-E10 inhibits replication of a broad range of influenza A subtypes. •DP2392-E10 inhibits nuclear exports of NP and NEP via their NP-NES3 and NEP-NES2 domains, respectively. •DP2392-E10 is predicted to directly bind CRM1 in the region near the HEAT9 and HEAT10 repeats.
Identification of and Structural Insights into Hit Compounds Targeting N -Myristoyltransferase for Cryptosporidium Drug Development
Each year, approximately 50,000 children under 5 die as a result of diarrhea caused by Cryptosporidium parvum, a protozoan parasite. There are currently no effective drugs or vaccines available to cure or prevent Cryptosporidium infection, and there are limited tools for identifying and validating targets for drug or vaccine development. We previously reported a high throughput screening (HTS) of a large compound library against Plasmodium N-myristoyltransferase (NMT), a validated drug target in multiple protozoan parasite species. To identify molecules that could be effective against Cryptosporidium, we counter-screened hits from the Plasmodium NMT HTS against Cryptosporidium NMT. We identified two potential hit compounds and validated them against CpNMT to determine if NMT might be an attractive drug target also for Cryptosporidium. We tested the compounds against Cryptosporidium using both cell-based and NMT enzymatic assays. We then determined the crystal structure of CpNMT bound to Myristoyl-Coenzyme A (MyrCoA) and structures of ternary complexes with MyrCoA and the hit compounds to identify the ligand binding modes. The binding site architectures display different conformational states in the presence of the two inhibitors and provide a basis for rational design of selective inhibitors.
Comparing probabilistic and descriptive analyses of time–dose–toxicity relationship for determining no-observed-adverse-effect level in drug development
The no-observed-adverse-effect level (NOAEL) of a drug defined from animal studies is important for inferring a maximal safe dose in human. However, several issues are associated with its concept, determination and application. It is confined to the actual doses used in the study; becomes lower with increasing sample size or dose levels; and reflects the risk level seen in the experiment rather than what may be relevant for human. We explored a pharmacometric approach in an attempt to address these issues. We first used simulation to examine the behaviour of the NOAEL values as determined by current common practice; and then fitted the probability of toxicity as a function of treatment duration and dose to data collected from all applicable toxicology studies of a test compound. Our investigation was in the context of an irreversible toxicity that is detected at the end of the study. Simulations illustrated NOAEL's dependency on experimental factors such as dose and sample size, as well as the underlying uncertainty. Modelling the probability as a continuous function of treatment duration and dose simultaneously to data from multiple studies allowed the estimation of the dose, along with its confidence interval, for a maximal risk level that might be deemed as acceptable for human. The model-based data integration also reconciled between-study inconsistency and explicitly provided maximised estimation confidence. Such alternative NOAEL determination method should be explored for its more efficient data use, more quantifiable insight to toxic doses, and the potential for more relevant animal-to-human translation. - Highlights: • Simulations revealed issues with NOAEL concept, determination and application. • Probabilistic modelling was used to address these issues. • The model integrated time-dose-toxicity data from multiple studies. • The approach uses data efficiently and may allow more meaningful human translation.
Analysis of the first ten years of FDA’s rare pediatric disease priority review voucher program: designations, diseases, and drug development
Abstract Background The Rare Pediatric Disease (RPD) Priority Review Voucher (PRV) Program was enacted in 2012 to support the development of new products for children. Prior to requesting a voucher, applicants can request RPD designation, which confirms their product treats or prevents a rare disease in which the serious manifestations primarily affect children. This study describes the trends and characteristics of these designations. Details of RPD designations are not publicly disclosable; this research represents the first analysis of the RPD designation component of the program. Results We used an internal US Food and Drug Administration database to analyze all RPD designations between 2013 and 2022. Multiple characteristics were analyzed, including the diseases targeted by RPD designation, whether the product targeted a neonatal disease, product type (drug/biologic), and the level of evidence (preclinical/clinical) to support designation. There were 569 RPD designations during the study period. The top therapeutic areas were neurology (26%, n = 149), metabolism (23%, n = 131), oncology (18%, n = 105). The top diseases targeted by RPD designation were Duchenne muscular dystrophy, neuroblastoma, and sickle cell disease. Neonatology products represented 6% (n = 33), over half were for drug products and 38% were supported by clinical data. Conclusions The RPD PRV program was created to encourage development of new products for children. The results of this study establish that a wide range of diseases have seen development—from rare pediatric cancers to rare genetic disorders. Continued support of product development for children with rare diseases is needed to find treatments for all children with unmet needs.
Advanced drug development and manufacturing
X-ray fluorescence (XRF) spectrometry has been used for detecting binding events and measuring binding selectivities between chemicals and receptors. XRF may also be used for estimating the therapeutic index of a chemical. For estimating the binding selectivities of a chemical versus chemical analogs, for measuring post translational modification of proteins, and for drug manufacturing.
Drug development and manufacturing
X-ray fluorescence (XRF) spectrometry has been used for detecting binding events and measuring binding selectivities between chemicals and receptors. XRF may also be used for estimating the therapeutic index of a chemical, for estimating the binding selectivity of a chemical versus chemical analogs, for measuring post-translational modifications of proteins, and for drug manufacturing.
Structural basis of HIV inhibition by L-nucleosides: Opportunities for drug development and repurpos
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Structural insights into drug development strategy targeting EGFR T790M/C797S
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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. We identified 134 programs (73 unique drug targets) and 147 clinical trials. Less than 1% ( n = 1/147) trials used a genomic biomarker prospectively for in‐trial enrichment despite 32% ( n = 23/73) of the drug targets having evidence of genetic variations. Additionally, 46% ( n = 68/147) of the trials specified exploratory biomarker use. The results highlight an opportunity for more targeted CVD drug development by leveraging genomic biomarker knowledge.