Early Clinical Drug Development Research Articles

Use of patient-reported outcomes (PRO) data to complement exposure–response analysis in early clinical cancer drug development

BackgroundThis proof-of-concept retrospective case study investigated whether patient-reported outcomes (PRO) instruments, designed to capture symptomatic adverse event data, could identity a known exposure–response (ER) relationship for safety characterized in an original FDA analysis of an approved anti-cancer agent. PRO instruments have been designed to uniquely quantify the tolerability aspects of exposure-associated symptomatic adverse events. We explored whether standard ER analyses of clinician-reported safety data for symptomatic adverse events could be complemented by ER analysis using PRO data that capture and quantify the tolerability aspects of these same symptomatic adverse events.MethodsExposure-associated adverse event data for diarrhea were analyzed in parallel in 120 patients enrolled in a clinical trial using physician reported Common Terminology Criteria for Adverse Events (CTCAE) and patient-reported symptomatic adverse event data captured by the National Cancer Institute’s (NCI) PRO Common Terminology Criteria for Adverse Events (PRO-CTCAE) instrument. Comparative ER analyses of diarrhea were conducted using the same dataset. Results from the CTCAE and PRO-CTCAE ER analyses were assessed for consistency with the ER relationship for diarrhea established in the original NDA using a 750-patient dataset. The analysis was limited to the 120-patient subset with parallel CTCAE and PRO-CTCAE assessments.ResultsWithin the same 120-patient dataset, ER analysis using dense, longitudinal PRO-CTCAE-derived data was sensitive to identify the known ER relationship for diarrhea, whereas the standard CTCAE based ER analysis was not.ConclusionsER analysis using PRO assessed symptomatic adverse event data may be a sensitive tool to complement traditional ER analysis. Improved identification of relationships for safety, by including quantification of the tolerability aspect of symptomatic adverse events using PRO instruments, may be useful to improve the sensitivity of exposure response analysis to support early clinical trial dosage optimization strategies, where decision making occurs within limited small patient datasets.

Exploratory food effect assessment in patients in early clinical development of oncology drugs.

Instructions for administration with regard to food are a key aspect of how patients experience oral drugs. Through potential effects on pharmacokinetics, the food condition can influence safety and efficacy, and thereby is one of many dimensions of dose optimization. Regulatory guidance from major health authorities advocates for the early investigation of food effect (FE) in clinical development. In oncology, exploratory food effect (eFE) evaluation is often incorporated into the first-in-human (FIH) studies in patients to inform food condition of later clinical studies. However, the design aspects of such exploratory assessments are generally under-reported and barely described, and yet complex, due to uniqueness of FIH study design and drug development process in oncology. Herein, we review literature of eFE assessment study design in oncology in patients, and present the Novartis experience in the design, execution, and impact of eFE in FIH oncology studies from 2014 to 2021. Based on this, we propose a roadmap for eFE assessment in early clinical drug development for oncology drugs in patients, including a framework for common study design options with a focus on study- and patient-level timing for typical scenarios, and provide a broad spectrum of decision-making factors which should be evaluated to drive the design and implementation of eFE assessment, spanning from clinical development strategy, FIH study design, to compound specific features.

N-Doped Carbon Nanotubes Supported Fe-Mn Dual-Single-Atoms Nanozyme with Synergistically Enhanced Peroxidase Activity for Sensitive Colorimetric Detection of Acetylcholinesterase and Its Inhibitor.

Monitoring acetylcholinesterase (AChE) and its inhibitors is of importance for early diagnosis and therapy of neurological diseases. Herein, N-doped carbon nanotubes supported Fe-Mn dual-single-atoms (FeMn DSAs/N-CNTs) were fabricated by a simple pyrolysis, as thoroughly figured out by a series of the characterization techniques. The peroxidase-like activity of FeMn DSAs/N-CNTs was investigated by catalytic oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) to generate rich hydroxyl radicals (·OH) in the H2O2 system, which effectively catalyzed colorless TMB oxidation to blue oxidized TMB (ox-TMB). Besides, the peroxidase-like activity was greatly weakened by thiocholine (derived from AChE), accompanied by making blue ox-TMB fade. Impressively, the highly improved peroxidase-like property is further evidenced by density functional theory (DFT) calculations, where the dual-single atoms show a lower energy barrier (0.079 eV) and their interactions with the N-CNTs played critical roles for producing the oxygen radicals. By virtue of the nanozyme, a low-cost, specific, and sensitive colorimetric sensor was built for detection of AChE with a broader linear range of 0.1-30 U L-1 and a lower limit of detection (LOD, 0.066 U L-1), combined with its feasible analysis in human serum samples. Also, this platform was applied for measuring huperzine A inhibitor with a wide linear scope of 5-500 nM and a LOD down to 4.17 nM. This strategy provides a low-cost and convenient approach for early clinical diagnosis and drug development.

International consortium for innovation and quality: An industry perspective on the nonclinical and early clinical development of intravitreal drugs.

The eye, which is under constant exposure to environmental pathogens, has evolved various anatomic and immunological barriers critical to the protection of tissues lacking regenerative capacity, and the maintenance of a clear optic pathway essential to vision. By bypassing the ocular barriers, intravitreal (IVT) injection has become the mainstay for the delivery of drugs to treat conditions that affect the back of the eye. Both small molecules and biotherapeutics have been successfully administered intravitreally, and several drugs have been approved for the treatment of (wet) age-related macular degeneration and diabetic macular edema. However, IVT injection is an invasive procedure, which requires sufficient technical expertise from the healthcare professional administering the drug. Potential side effects include bleeding, retinal tear, cataracts, infection, uveitis, loss of vision, and increased ocular pressure. Pharmaceutical companies often differ in their drug development plan, including drug administration techniques, collection of ocular tissues and fluids, ophthalmology monitoring, and overall conduct of nonclinical and clinical studies. The present effort, under the aegis of the Innovation & Quality Ophthalmic Working Group, aims at understanding these differences, identifying pros and cons of the various approaches, determining the gaps in knowledge, and suggesting feasible good practices for nonclinical and early clinical IVT drug development.

Towards 2-arachidonoylglycerol (2-AG) as a reliable pharmacodynamic in early phase clinical drug development: a validation study in healthy volunteers

Towards 2-arachidonoylglycerol (2-AG) as a reliable pharmacodynamic in early phase clinical drug development: a validation study in healthy volunteers

Potential Errors and Corrections in Early Phase Drug Development

Many foreign and small companies trying to enter the United States biopharmaceutical market make avoidable errors in their early clinical phase drug development and clinical trials. They need to first understand the risks that they must endure with patent law, regulatory hurdles, the complexity and duration of the necessary clinical trials, and the large cost of drug development, which often necessitates raising substantial capital from investors. If appropriate capital for these clinical studies must be raised, then the company must be able to clearly articulate a realistic expected return on investment to these individuals. So, they must also understand the market, its exclusivity, and the competition. This must all be put together in a sleek pitch deck. Early errors frequently begin with too few, inadequate, or poorly constructed patents. These and other risks and errors may be prevented by the use of an experienced product development team. Many of these errors could be avoided if companies used more experienced drug development professionals to assist them in selecting the optimum patent strategy, regulatory plan, budget, contract research organization (CRO), clinical investigators, and etc. It is hoped that this opinion piece will help make early clinical trials more effective and save time and money.

Aiding early clinical drug development by elucidation of the relationship between tumor growth inhibition and survival in relapsed/refractory multiple myeloma patients.

Early prognosis of clinical efficacy is an urgent need for oncology drug development. Herein, we systemically examined the quantitative approach of tumor growth inhibition (TGI) and survival modeling in the space of relapsed and refractory multiple myeloma (MM), aiming to provide insights into clinical drug development. Longitudinal serum M‐protein and progression‐free survival (PFS) data from three phase III studies (N = 1367) across six treatment regimens and different patient populations were leveraged. The TGI model successfully described the longitudinal M‐protein data in patients with MM. The tumor inhibition and growth parameters were found to vary as per each study, likely due to the patient population and treatment regimen difference. Based on a parametric time‐to‐event model for PFS, M‐protein reduction at week 4 was identified as a significant prognostic factor for PFS across the three studies. Other factors, including Eastern Cooperative Oncology Group performance status, prior anti‐myeloma therapeutics, and baseline serum ß2‐microglobulin level, were correlated with PFS as well. In conclusion, patient disease characteristics (i.e., baseline tumor burden and treatment lines) were important determinants of tumor inhibition and PFS in MM patients. M‐protein change at week 4 was an early prognostic biomarker for PFS.

Clinical trial and translational research for cancer immunology in Asian countries: Understanding the new frontier.

e14510 Background: Among the major advances in cancer treatment is the progress in cancer immunotherapy; however, despite the strides, there is few information specific to the Asian population. It is unclear to what extent clinical trial and translational research in cancer immunology are conducted in Asian institutions. Methods: This questionnaire-based survey was conducted among researchers and healthcare professionals who are involved in cancer immunology research and therapeutics in Asia-Pacific countries. The study identified the involvement of respondents in various phases of clinical trials, and immunotherapy research. In addition, the current capabilities of the institutions to conduct translational research were surveyed. Results: We received a total of 122 responses from 20 Asia-Pacific countries. More than half (58%) of the responders are currently conducting clinical trials on cancer immunology with 25% having performed more than 10 Phase 3 trials in the last 3 years. In clinical trials and clinical practice, immune checkpoint inhibitors were performed in most countries (81.8% and 88.6%, respectively). Clinical trials and clinical practice of CAR-T and TCR-T were performed only in some countries (CAR-T; 22.7% and 15.9%, TCR-T; 2.3% and 0%, respectively). In the absence of novel therapeutics in their institution, 18% of the responders refer their patient to facilities that have ongoing clinical trials. Among the institutions that perform Hematopoietic stem cell transplant (55.1%), the most common type offered include autologous (81.3%) and allogenic (70.8%) peripheral blood stem-cell transplantation. About 51.7% of the respondents have institutions that can conduct early drug phase development studies with only 11.2% capable of utilizing their own immunotherapeutic agents. Less than half of the respondents (40.7%) belong to institutions that have conducted translational researches using patient-derived samples for the last three years. Furthermore, more than half of the respondent institutions have no personnel that is experienced to handle and/or run patient-derived fresh peripheral blood or fresh tumors. Collaboration among neighboring countries can allow send out of specimens to other institutions that have such capability, however, 56.9% of countries have regulations or restrictions in transporting lymphocytes or tumor tissues. Conclusions: Oncologists and researchers in Asia recognize the importance of cancer immunology researches for patients. There were institutional and inter-country differences particularly in the conduct of early phase clinical drug development and translational research.

Model-based dose selection to inform translational clinical oncology development of WNT974, a first-in-class Porcupine inhibitor.

WNT974 is a potent, selective, and orally bioavailable first‐in‐class inhibitor of Porcupine, a membrane‐bound O‐acyltransferase required for Wnt secretion, currently under clinical development in oncology. A phase I clinical trial is being conducted in patients with advanced solid tumors. During the dose‐escalation part, various dosing regimens, including once or twice daily continuous and intermittent dosing at a dose range of 5–45 mg WNT974 were studied, however, the protocol‐defined maximum tolerated dose (MTD) was not established based on dose‐limiting toxicity. To assist in the selection of the recommended dose for expansion (RDE), a model‐based approach was utilized. It integrated population pharmacokinetic (PK) modeling and exposure–response analyses of a target‐inhibition biomarker, skin AXIN2 mRNA expression, and the occurrence of the adverse event, dysgeusia. The target exposure range of WNT974 that would provide a balance between target inhibition and tolerability was estimated based on exposure–response analyses. The dose that was predicted to yield an exposure within the target exposure range was selected as RDE. This model‐based approach integrated PK, biomarker, and safety data to determine the RDE and represented an alternative as opposed to the conventional MTD approach for selecting an optimal biological dose. The strategy can be broadly applied to select doses in early oncology trials and inform translational clinical oncology drug development.

Doppler ultrasound to assess the pharmacodynamic effects of splanchnic vasoactive compounds.

In search of noninvasive biomarkers to assess the pharmacodynamic effects of portal pressure-lowering drugs, the reproducibility of flow measurements in the superior mesenteric artery was evaluated using Doppler ultrasound. A reproducibility study was conducted in 15 healthy male volunteers (18-50 y). Eight ultrasound measurements were performed for each subject: 2 observers each conducted 2 measurements during 2 separate visits. The following flow parameters were captured: peak systolic velocity (PSV), end diastolic velocity (EDV), pulsatility index (PI), volume flow (VF) and vessel diameter. Reproducibility was assessed by the intraclass correlation coefficient. Results are presented as intraclass correlation coefficient [95% confidence interval]. The flow parameters PSV, EDV, PI and VF correlated excellently within observer during visit 1 (0.888 [0.748-0.953], 0.910 [0.793-0.962], 0.844 [0.656-0.933] and 0.916 [0.857-0.951], respectively) and visit 2 (0.925 [0.829-0.968], 0.942 [0.863-0.976], 0.883 [0.719-0.954] and 0.915 [0.855-0.951], respectively). Measurements conducted during 2 separate visits by 1 observer correlated well to excellently for PSV, EDV, PI and VF (0.756 [0.552-0.875], 0.836 [0.694-0.916], 0.807 [0.631-0.904] and 0.839 [0.783-0.882], respectively). Measurements conducted by 2 distinct observers correlated well to excellently for PSV, EDV and VF during visit 1 (0.813 [0.584-0.922], 0.884 [0.597-0.945] and 0.786 [0.575-0.899], respectively) and visit 2 (0.779 [0.498-0.912], 0.861 [0.672-0.945], 0.810 [0.553-0.926], respectively). Vessel diameter measurements were poorly reproducible. Doppler ultrasound is a reproducible method for flow measurements in the superior mesenteric artery in a standardized group of healthy volunteers. Therefore, it is a promising technique to assess pharmacodynamic effects of splanchnic vasoactive compounds in early clinical drug development.

Application of Clinical Pharmacology in Early Clinical Drug Development: PK/PD studies of a new proton pump inhibitor

Clinical pharmacology is critical in drug development. This presentation introduces the current status of its application in China, and then presents a PK/PD model for proton-pump inhibitor (PPI) drugs. This mechanism-based model is established using ilaprazole as a case drug in which food effect and circadian rhythm are taken into account, and it provides a potential strategy to accelerate the development of novel PPIs.

A Clinical Study To Assess The Magnitude, Time‐course And Variability Of CYP3A4 Induction By Rifampin In Healthy Volunteers

IntroductionConsistent with its important role in human drug metabolism, CYP3A4 has an exceptionally broad substrate specificity. Consequently, CYP3A4 is highly susceptible to metabolic‐drug drug interactions (mDDI’s) that induce activity, which are an important source of between‐subject variability (BSV) in drug exposure. Failure to account for BSV is a common underlying cause of attrition in early clinical drug development. An understanding of CYP3A4 induction will hence improve the accuracy of clinical mDDI prediction. No prescriptive dosing guidance exists for clinical DDI studies that use the prototypical CYP3A4 inducer rifampin to assess the clinical mDDI victim risk of drugs metabolised by CYP3A4. Recent simulation data indicate dosing rifampin for less than 10 days is likely to underestimate the magnitude of induction.AimsThis study sought to assess CYP3A4 activity at baseline (Day 1) and following 7 and 14 days administration of rifampin (600 mg PO/daily) in a cohort of healthy males and females and to assess CYP3A4 activity at baseline and following 7 days administration of rifampin (300 mg PO/daily) in a cohort of healthy males. The impact of rifampin dose (mg) was assessed as a trial characteristic effecting the magnitude of CYP3A4 induction. The performance of a personalised PBPK model with respect to estimating exposure to oral midazolam was also evaluated.MethodsThe study was a single centre, open label, single sequence metabolic phenotyping clinical trial. Healthy volunteers were dosed with midazolam (1 mg PO on Day 1, 8, 15) and timed blood samples (8mL) were collected pre‐dose, and up to 6 hr post‐dose. Participants self‐administered up to a 14‐day course of rifampin (300 or 600 mg PO daily). Midazolam exposure was measured prior the first rifampin dose (Day 1), following seven doses of rifampin (Day 8) and 16 hours after completing the 14‐day course rifampin (Day 15). Baseline CYP3A4 activity was compared with activity following administration of rifampin for 7 and 14 days. A verified Simcyp® model describing rifampin‐mediated CYP3A4 induction was used to compare personalised PBPK simulations to observed oral midazolam exposure at baseline and following rifampin administration.ResultsThe mean observed midazolam AUC ratio following dosing of rifampin (300 mg) for 7 days was 0.32, the mean midazolam AUC ratio following dosing of rifampin (600 mg) for 7 days was 0.21. No significant difference in AUC ratio was observed between 7 and 14 days rifampin dosing (600 mg). Simulated midazolam PK parameters for Day 1 (baseline) was within 2‐fold of the observed parameter (i.e. MFE 0.62 to 1.61) for all participants. Simulated parameters for Day 7 and Day 14 ranged from 3‐fold lower to 6.5‐fold higher than the observed parameter (i.e. MFE 0.33 to 6.40).DiscussionConsistent with prior studies greater CYP3A4 induction was achieved using 600 mg rifampin. Contrary to simulations suggesting a minimum of 10 days rifampin dosing is required to achieve maximal induction of hepatic CYP3A4, data indicate 7 days dosing is sufficient to produce maximal change in midazolam exposure. Robust concordance of individual participant simulated and observed oral midazolam PK parameters at baseline (Day 1) was observed, however concordance was variable and typically poor following rifampicin administration.Support or Funding InformationNHMRC

Lessons learned from using fMRI in the early clinical development of a mu-opioid receptor antagonist for disorders of compulsive consumption.

Functional magnetic resonance imaging (fMRI) has been widely used to gain a greater understanding of brain circuitry abnormalities in CNS disorders. fMRI has also been used to examine pharmacological modulation of brain circuity and is increasingly being used in early clinical drug development as functional pharmacodynamic index of target engagement, and to provide early indication of clinical efficacy. In this short review, we summarize data from experimental medicine and early clinical development studies of a mu-opioid receptor antagonist, GSK1521498 developed fordisorders of compulsive consumption including binge eating in obesity. We demonstrate how fMRI can be used to answer important questions of early clinical drug development relating to; (1) target engagement, (2) dose response relationships, (3) differential efficacy and (4) prediction of behavioural and clinically relevant outcomes. We also highlight important methodological factors that need to be considered when conducting fMRI studies in drug development given the challenges faced with small sample sizes in Phase 1 and early proof of mechanism studies. While these data highlight the value of fMRI as a biomarker in drug development, its use for making Go/No-go decisions is still faced with challenges given the variability of responses, interpretation of brain activation changes and the limited data linking drug induced changes in brain activity to clinical or behavioural outcome. These challenges need to be addressed to fulfil the promise of fMRI as a tool in clinical drug development.

The Case for an Unblinded Modeler in Early Clinical Development.

The current trend for clinical pharmacology is toward more complex studies (eg, umbrella protocols covering single and multiple ascending doses, food effect, metabolism pathways), requiring many decisions to be made during their conduct. This article discusses guidance of such early clinical studies by modeling and simulation. The ability to make use of all available information each time new data become available during the study requires the modeling scientist to be unblinded. This must of course not jeopardize the blinding of the clinical team, and this article discusses how unblinding can be prevented. Although modeling and simulation are established for guidance of the drug development process overall, they are not frequently used for guidance on a small scale, that is, during studies with the largest uncertainty, the first-in-human studies. Application of a quantitative model backbone makes early clinical drug development a more efficient process and provides additional safety for healthy subjects and patients. Real clinical impact is illustrated by 3 case studies that show different contributions from unblinded modeling: dose escalation based on safety data, modeling and predicting with explicit incorporation of in vitro data, and dose escalation supported by unblinded analysis of adverse event data, which resulted in new insights of the clinical team without being unblinded and made it possible to proceed with dose escalation and to extend the study with an up-titration group.

New designs in early clinical drug development.

The availability of an unprecedented massive amount of data has provided a magnificent window of opportunity for the development of new drugs. There are currently more drugs in development targeting cancer than any other disease. While this has brought us new waves of drugs, the counterpart is that with these new molecules we have different mechanisms of action, drug kinetics and dynamics, response types and toxicity profiles, which impair classical early clinical trial designs from being effective and efficient. What we once treated as a 'one-size-fits-all' homogeneous disease, has now been uncovered to be a rather heterogeneous condition with multiple targetable mutations. As this generates endless scenarios, it will be impossible to design single 'me-too' trials for every different disease, target, biomarker and agent. To overcome this, we must focus on improving early phase studies, undoubtedly the most critical step from bench to bedside. Goals include decreasing clinical development times, lowering research and development costs and optimizing decisions in advancing through the several phases with a higher degree of certainty in exchange for less failed attempts. We need more informative and, really, transformative early phase designs that seek to obtain the typical late phase objectives in a time continuum and to allow for more robust and efficient go/no-go decisions. With this in mind, different classes of drugs seem to fit with different designs, which present solutions to the different challenges that they pose after finding the maximum tolerated dose/optimum biological dose. This article reviews these concepts and designs and how they can adapt to this new reality in early phase investigation.

Reproducibility of a battery of human evoked pain models to detect pharmacological effects of analgesic drugs.

BackgroundAlthough reproducibility is considered essential for any method used in scientific research, it is investigated only rarely; thus, strikingly little has been published regarding the reproducibility of evoked pain models involving human subjects. Here, we studied the reproducibility of a battery of evoked pain models for demonstrating the analgesic effects of two analgesic compounds.MethodsA total of 81 healthy subjects participated in four studies involving a battery of evoked pain tests in which mechanical, thermal and electrical stimuli were used to measure pain detection and tolerance thresholds. Pharmacodynamic outcome variables were analysed using a mixed model analysis of variance, and a coefficient of variation was calculated by dividing the standard deviation by the least squares means.ResultsA total of 76 subjects completed the studies. After being administered pregabalin, the subjects’ pain tolerance thresholds in the cold pressor and pressure stimulation tests were significantly increased compared to the placebo group. Moreover, the heat pain detection threshold in UVB‐irradiated skin was significantly increased in subjects who were administered ibuprofen compared to the placebo group. Variation among all evoked pain tests ranged from 2.2% to 30.6%.ConclusionsFour studies using a similar design showed reproducibility with respect to the included evoked pain models. The relatively high consistency and reproducibility of two analgesics at doses known to be effective in treating clinically relevant pain supports the validity of using this pain test battery to investigate the analgesic activity and determine the active dosage of putative analgesic compounds in early clinical development.SignificanceThe consistency and reproducibility of measuring the profile of an analgesic at clinically relevant doses illustrates that this pain test battery is a valid tool for demonstrating the analgesic activity of a test compound and for determining the optimal active dose in early clinical drug development.

Dose translation between laboratory animals and human in preclinical and clinical phases of drug development.

Preclinical Research & Development Appropriate translation and determination of the maximum recommended starting dose in human is a vital task in new drug development and research. Allometric scaling is the most frequently used approach for dose extrapolation based on normalization of dose-to-body surface area. Misinterpretation of allometric dose conversion and safety factor application can lead to major problems in calculating maximum recommended safe starting dose in first-in-human clinical trials. Therefore, dose translation always necessitates careful consideration of body surface area, pharmacological, physiological and anatomical factors, pharmacokinetic parameters, metabolic function, receptor, and life span. The concept of estimating the first-in-human dose, interspecies scaling between species and the factors influencing the dose escalation were reviewed. The pros and cons of various approaches to determine first-in-human dose including allometric scaling, pharmacokinetically guided approach, minimal anticipated biological effect level, pharmacokinetic-pharmacodynamic modeling, similar drug approach, and microdosing were explained. The five steps to estimate maximum recommended starting dose for human studies by scaling factor were elaborated. Few examples, illustrating the application of different approaches were also demonstrated along with concerns that may be considered while applying such methods. Furthermore, typical considerations in dose administration, dosing through diet, maximum absorbable dose, blood sampling, and anesthesia in animal species were discussed. In summary, this review may serve as a concise guide for predicting human equivalent dose from animal species for researchers involved in various phases of preclinical and early clinical drug development.

Evaluating cardiac risk: exposure response analysis in early clinical drug development.

The assessment of a drug’s cardiac liability has undergone considerable metamorphosis by regulators since International Council for Harmonization of Technical Requirement for Pharmaceuticals for Human Use E14 guideline was introduced in 2005. Drug developers now have a choice in how proarrhythmia risk can be evaluated; the options include a dedicated thorough QT (TQT) study or exposure response (ER) modeling of intensive electrocardiogram (ECG) captured in early clinical development. The alternative approach of ER modeling was incorporated into a guidance document in 2015 as a primary analysis tool which could be utilized in early phase dose escalation studies as an option to perform a dedicated TQT trial. This review will describe the current state of ER modeling of intensive ECG data collected during early clinical drug development; the requirements with regard to the use of a positive control; and address the challenges and opportunities of this alternative approach to assessing QT liability.

Tracking the Sugar Rush: Incorporating Continuous Glucose Monitoring Into Multisite Early Clinical Research With Type 2 Diabetes Subjects.

Continuous glucose monitoring (CGM) systems allow patients with diabetes mellitus to closely track glucose concentrations over several days, identify trends in glucose levels, and avoid glucose excursions. This technology has not only advanced diabetes mellitus management but has increased patient safety through greater glycemic awareness. Due to these attributes, CGM is now being applied in therapeutic research as a pharmacodynamic tool to support early clinical drug development programs. However, to date only a handful of studies have utilized CGM in type 2 diabetes mellitus (T2DM) drug development. A potential barrier from fostering greater use of CGM in clinical development may be related to concerns over subject variability. Therefore, we investigated a key consideration when implementing CGM into early clinical research studies: daily variation within patients with T2DM from multiple clinical research units. From 24 patients with T2DM, we observed strong daily reproducibility (Pearson R = 0.86, P < .0001) in CGM results and found that this technique is practical for multisite studies. Altogether, with low daily variability, CGM is a powerful pharmacodynamic tool for drug efficacy and safety monitoring.

EUFEMED London Conference 2017: Exploratory Medicines Development: Innovation and Risk Management

The first formal conference of the EUropean Federation for Exploratory MEdicines Development (EUFEMED) held in London was the result of a collaborative effort of its founding associations: the Association for Applied Human Pharmacology (AGAH; Germany), the Association for Human Pharmacology in the Pharmaceutical Industry (AHPPI; UK), the Belgian Association of Phase-I Units (BAPU; Belgium), and Club Phase-I (France). The conference focused on innovation and risk management in early clinical drug development. Among other innovations, immunotherapy in oncology and inflammatory diseases were discussed as well as the importance of adaptive trial designs in early clinical drug development. Consideration was given to assessing and mitigating risk in early clinical drug development, and included a preconference workshop. Different measures to minimize risks in healthy volunteers and patients in first-in-human trials were discussed in addition to the importance of non-clinical data, the need for reliable biomarkers, improved communication on adverse events (AEs) and well-trained study sites with ready access to intensive care units and clinical specialists. The need for a European-wide system for prevention of over-volunteering was also discussed. The conference provided opportunity to discuss these developments and concerns and the changing regulatory environment with stakeholders from academia, industry, and regulatory agencies including the European Medicines Agency (EMA). Presentations given by invited speakers are published on http://www.eufemed.eu/london-conference-2017/.