The Role of Model Master Files for Sharing, Acceptance, and Communication with FDA.

With the evolving role of Model Integrated Evidence (MIE) in generic drug development and regulatory applications, the need for improving Model Sharing, Acceptance, and Communication with the FDA is warranted. Model Master File (MMF) refers to a quantitative model or a modeling platform that has undergone sufficient model Verification & Validation to be recognized as sharable intellectual property that is acceptable for regulatory purposes. MMF provides a framework for regulatorily acceptable modeling practice, which can be used with confidence to support MIE by both the industry and the U.S. Food and Drug Administration (FDA). In 2022, the FDA and the Center for Research on Complex Generics (CRCG) hosted a virtual public workshop to discuss the best practices for utilizing modeling approaches to support generic product development. This report summarizes the presentations and panel discussions of the workshop symposium entitled "Model Sharing, Acceptance, and Communication with the FDA". The symposium and this report serve as a kick-off discussion for further utilities of MMF and best practices of utilizing MMF in drug development and regulatory submissions. The potential advantages of MMFs have garnered acknowledgment from model developers, industries, and the FDA throughout the workshop. To foster a unified comprehension of MMFs and establish best practices for their application, further dialogue and cooperation among stakeholders are imperative. To this end, a subsequent workshop is scheduled for May 2-3, 2024, in Rockville, Maryland, aiming to delve into the practical facets and best practices of MMFs pertinent to regulatory submissions involving modeling and simulation methodologies.

Comparing a Bayesian Approach (BEST) with the Two One-Sided t-Tests (TOSTs) for Bioequivalence Studies.

The two one-sided t-tests (TOST) procedure has been used to evaluate average bioequivalence (BE). As a regulatory standard, it is crucial that TOST distinguish BE from not-BE (NBE) when BE data are not lognormal. TOST was compared with a Bayesian procedure (BEST by Kruschke) in simulated datasets of test/reference ratios (T/R) which were BE and NBE, wherein (1) log(T/R) or T-R were normally distributed, (2) sample sizes ranged 10-50, and (3) extreme log(T/R) or T-R values were randomly included in datasets. The 90% "credible interval" (CrI) from BEST is a Bayesian alternative of the 90% confidence interval (CI) of TOST and it can be derived from a posterior distribution that is more reflective of the observed mean log(T/R) distribution that often deviates from normality. In the absence of extreme T/R values, both methods agreed BE when observed T/R were lognormal. BEST more accurately concluded BE or NBE, while requiring fewer subjects, when observed log(T/R) or T-R were normal in the presence of extreme values. Overall, TOST and BEST perform comparably on lognormal T/R, while BEST is more accurate, requiring fewer subjects when datasets are normal for T-R or contain extreme values. Of note, the normally distributed datasets only rarely contain extreme values. Our results imply that when BEST and TOST yield different BE assessment results from bioequivalent products, TOST may disadvantage applicants when T/R are not lognormal and/or include extreme T/R values. Application of BEST can address the situation when T/R are not lognormal or include extreme data values. Application of BEST to BE data can be considered a useful alternative to TOST for evaluation of BE and for efficient development of BE formulations.

Scientific considerations for global drug development.

Requiring regional or in-country confirmatory clinical trials before approval of drugs already approved elsewhere delays access to medicines in low- and middle-income countries and raises drug costs. Here, we discuss the scientific and technological advances that may reduce the need for in-country or in-region clinical trials for drugs approved in other countries and limitations of these advances that could necessitate in-region clinical studies.

Author Correction: At the end of the beginning: immunotherapies as living drugs.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Report on the current status of the use of real-world data (RWD) and real-world evidence (RWE) in drug development and regulation.

Radically expanding use of real-world data (RWD) and real-world evidence (RWE) holds the potential to substantially impact drug development, pharmaceutical regulation, and payment within health care systems. Central to this is the reconfiguration of data gathering and transformation of data to information, which can be used as evidence for decision making. We discuss applications of this paradigm in the light of recent developments in both the United States and Europe on RWD and RWE.

Individualized treatment strategies for hyperuricemia informed by a semi-mechanistic exposure-response model of uric acid dynamics.

To provide insight into pharmacological treatment of hyperuricemia we developed a semi-mechanistic, dynamical model of uric acid (UA) disposition in human. Our model represents the hyperuricemic state in terms of production of UA (rate, PUA), its renal filtration (glomerular filtration rate, GFR) and proximal tubular reabsorption (fractional excretion coefficient, FE). Model parameters were estimated using data from 9 Phase I studies of xanthine oxidase inhibitors (XOI) allopurinol and febuxostat and a novel uricosuric, the selective UA reabsorption inhibitor lesinurad, approved for use in combination with a XOI. The model was qualified for prediction of the effect of patients' GFR and FE on concentration of UA in serum (sUA) and UA excretion in urine and their response to drug treatment, using data from 2 Phase I and 4 Phase III studies of lesinurad. Percent reduction in sUA from baseline by a XOI is predicted to be independent of GFR, FE or PUA. Uricosurics are more effective in underexcreters of UA or patients with normal GFR. Co-administration of a XOI and an uricosuric agent should be considered for patients with high sUA first in the treatment algorithm of gout before uptitration of XOI. The XOI dose in combination with a uricosuric can be reduced compared to XOI alone for the same target sUA to the degree dependent on patient's GFR and FE. This exposure-response model of UA can be used to rationally select the best drug treatment option to lower elevated sUA in gout patients under differing pathophysiological situations.

Poor medication adherence in clinical trials: consequences and solutions.

Poor adherence to medicines in clinical trials can undermine the value of the trials; for example, by compromising estimates of the benefits and risks of a medicine. In this article, we highlight such consequences and also discuss approaches to tackle this problem.

Determination of the starting dose in the first-in-human clinical trials with monoclonal antibodies: a systematic review of papers published between 1990 and 2013.

A systematic review was performed to evaluate how the maximum recommended starting dose (MRSD) was determined in first-in-human (FIH) studies with monoclonal antibodies (mAbs). Factors associated with the choice of each MRSD determination method were also identified. PubMed was searched for FIH studies with mAbs published in English between January 1, 1990 and December 31, 2013, and the following information was extracted: MRSD determination method, publication year, therapeutic area, antibody type, safety factor, safety assessment results after the first dose, and number of dose escalation steps. Seventy-nine FIH studies with mAbs were identified, 49 of which clearly reported the MRSD determination method. The no observed adverse effects level (NOAEL)-based approach was the most frequently used method, whereas the model-based approach was the least commonly used method (34.7% vs 16.3%). The minimal anticipated biological effect level (MABEL)- or minimum effective dose (MED)-based approach was used more frequently in 2011-2013 than in 1990-2007 (31.6% vs 6.3%, P=0.036), reflecting a slow, but steady acceptance of the European Medicines Agency's guidance on mitigating risks for FIH clinical trials (2007). The median safety factor was much lower for the MABEL- or MED-based approach than for the other MRSD determination methods (10 vs 32.2-53). The number of dose escalation steps was not significantly different among the different MRSD determination methods. The MABEL-based approach appears to be safer and as efficient as the other MRSD determination methods for achieving the objectives of FIH studies with mAbs faster.

17α-Ethynylestradiol-3-sulfate treatment of severe blood loss in rats.

BACKGROUND: From 2001-2011, >80% of potentially survivable United States battlefield deaths were due to severe hemorrhage. We subjected male rats to acute severe blood loss, administered a single dose of 17α-ethynylestradiol-3-sulfate (EE-3-SO4) without resuscitative fluids, and measured survival and also mean arterial pressures (MAP). METHODS: After controlled removal of 60% circulating blood volume (10-11 mL) over approximately 45 min, rats received EE-3-SO4 at 0 (vehicle controls), 0.1, 0.3, 1.0, or 3.0 mg/kg in 40 µL/100 g BW saline intravenously. MAP was recorded for 40 min after drug administration and survival was recorded for 6 h. RESULTS: The dose response curve was bell shaped with optimum survival at 1 mg/kg EE-3-SO4. Median survival times of rats receiving 1 mg/kg (360 min) were approximately 6 times that of the control group (57 min): P = 0.0001. The number of animals alive at 6 h was 16 of 20 (80%) in the 1 mg/kg group versus 0 of 20 (0%) in the control group. Early increases in MAP correlated with longer survival times. CONCLUSIONS: Administration of a single dose of 1 mg/kg EE-3-SO4 in 0.4 mL/kg of saline after controlled severe hemorrhage increased survival in rats by 6-fold. Partial recovery of blood pressure values correlated with longer survival time. These results, coupled with similar findings in a companion study in minipigs, support the further product development of EE-3-SO4 for: (1) severe hemorrhage when standard resuscitative fluids are not available, and (2) situations in which prolonged transportation periods are required for definitive treatment of the injured.

Efficacy of 17α-ethynylestradiol-3-sulfate for severe hemorrhage in minipigs in the absence of fluid resuscitation.

BACKGROUND: Of the potentially survivable US battlefield deaths from 2001 to 2011, 80% to 91% were caused by severe hemorrhage. We subjected minipigs to acute severe blood loss, administered a single dose of 17α-ethynylestradiol-3-sulfate (EE-3-SO4) without resuscitative fluids, and determined survival as well as cardiovascular, biochemical, and physiologic response parameters. METHODS: Following controlled removal of 60% circulating blood volume over 1 hour, minipigs received EE-3-SO4 at 0, 1, 3, or 5-mg/mL saline per kilogram of body weight in Experiment 1 (n = 25) and 0-, 0.1-, 0.3-, or 1-mg/mL saline per kilogram in Experiment 2 (n = 23). Survival times and response parameters were recorded for the next 6 hours. RESULTS: Median survival times of the minipigs receiving 1 mg/kg (257 minutes and 360 minutes) were 1.8 times and 5 times those of the control group (140 minutes and 65 minutes) in Experiments 1 and 2, respectively. For both experiments combined, the log-rank p value was 0.0002, and the number of animals alive at 6 hours was 6 (50%) of 12 in the 1-mg/kg groups versus 0 (0%) of 12 in the control groups. Early increases in glucose, lactate, potassium, and phosphate as well as decreases in bicarbonate and mean arterial pressure correlated with shorter survival times. CONCLUSION: Administration of a single dose of 1-mg/kg EE-3-SO4 in 1-mL/kg of saline following severe hemorrhage increased survival in 60% acutely bled minipigs by 3.5-fold. Slightly elevated blood pressure values, more physiologic values of oxidative phosphorylation parameters, and lower elevations of possible tissue necrosis parameters correlated with longer survival time. These results support the further product development of EE-3-SO4 for the indication of severe hemorrhage when standard resuscitative fluids are not available.

Impact of the pharmaceutical sciences on health care: a reflection over the past 50 years.

During the last century, particularly the latter half, spectacular progress has been made in improving the health and longevity of people. The reasons are many, but the development of medicines has played a critical role. This report documents and reflects on the impressive contribution that those working in the pharmaceutical sciences have made to healthcare over the past 50 years. It is divided into six sections (drug discovery; absorption, distribution, metabolism, and excretion; pharmacokinetics and pharmacodynamics; drug formulation; drug regulation; and drug utilization), each describing key contributions that have been made in the progression of medicines, from conception to use. A common thread throughout is the application of translational science to the improvement of drug discovery, development, and therapeutic application. Each section has been coordinated by a leading scientist who was asked, after consulting widely with many colleagues across the globe, to identify "The five most influential ideas/concepts/developments introduced by 'pharmaceutical scientists' (in their field) over the past 50 years?" Although one cannot predict where the important breakthroughs will come in the future to meet the unmet medical needs, the evidence presented in this report should leave no doubt that those engaged in the pharmaceutical sciences will continue to make their contributions heavily felt.

Physiologically-based pharmacokinetics in drug development and regulatory science.

The application of physiologically-based pharmacokinetic (PBPK) modeling is coming of age in drug development and regulation, reflecting significant advances over the past 10 years in the predictability of key pharmacokinetic (PK) parameters from human in vitro data and in the availability of dedicated software platforms and associated databases. Specific advances and contemporary challenges with respect to predicting the processes of drug clearance, distribution, and absorption are reviewed, together with the ability to anticipate the quantitative extent of PK-based drug-drug interactions and the impact of age, genetics, disease, and formulation. The value of this capability in selecting and designing appropriate clinical studies, its implications for resource-sparing techniques, and a more holistic view of the application of PK across the preclinical/clinical divide are considered. Finally, some attention is given to the positioning of PBPK within the drug development and approval paradigm and its future application in truly personalized medicine.

Quantitative clinical pharmacology is transforming drug regulation.

Prior to 1970s, development and regulation of new drugs was devoid of a fully quantitative, pathophysiological conceptual foundation. Malcolm Rowland pioneered, in collaboration with colleagues and friends, our modern understanding of drug clearance concepts, and equipped drug development and regulatory scientists with key investigative tools such as physiologically-based pharmacokinetic (PBPK) modeling, standardized approaches to characterizing drug metabolism, and microdosing. From the 1970s to the present, Malcolm Rowland has contributed to key advances in pharmacokinetics that have had transformational impacts on drug regulatory science. These advances include concepts that have led to the fundamental understanding that mechanistically derived, quantitative variations in drug concentrations, rather than assigned dosage alone, drive pharmacodynamic effects (PKPD)-including disease biomarkers and clinical outcomes. This body of knowledge has transformed drug development and regulatory science theory and practice from naïve empiricism to a mechanism/model-based, quantitative scientific discipline. As a result, it is now possible to incorporate pre-clinical in vitro data on drug physico-chemical properties, metabolizing enzymes, transporters and permeability properties into PBPK-based simulations of expected PK distributions and drug-drug interactions in human populations. The most comprehensive application of PK-PD is in the modeling and simulation of clinical trials in the context of model-based drug development and regulation, imbedded in the "learn-confirm paradigm". Regulatory agencies have embraced these advances and incorporated them into regulatory requirements, approval acceleration pathways and regulatory decisions. These developments are reviewed here, with emphasis on key contributions of Malcolm Rowland that facilitated this transformation.