Clinical pharmacology's next stage

Providing Expert Support for Your Needs in
Drug Development

AzureDelta Consulting Inc.

My company is devoted to consulting in clinical research and the name represents multiple meanings related to Clinical Pharmacology.
Azure is a color of dreams, helping pharmaceutical companies to bring better medicine to patients faster and safer to save lives and make families happier.

Azure is A to Z of clinical support encompassing impact of adjacent areas such as CMC and nonclinical research on Clinical Pharmacology.
Delta is a difference that streamlined clinical programs can make in patients’ journeys and in the success of pharmaceutical companies.
Delta is fertile land where the river tributaries meet the ocean for merging creative ideas and collaboration.

Similar to multiple meanings of the name AzureDelta, the goal of my consulting is to maximize the use of clinical data and supporting preclinical programs to gain as much knowledge about the drug as possible in an efficient and economical way. 
 
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About AzureDelta Consultant Galina Bernstein, PhD

Galina Bernstein has over 20 years of experience in the Preclinical Research and Pharmaceutical and Medical Devices Industry. Galina Bernstein received her PhD degree in Biochemistry from Moscow State University and a Certificate of postdoctoral training in Medicinal Chemistry from the University of Michigan College Of Pharmacy. 

She received formal PK training during her postdoctoral tenure with the Pharmacokinetics, Dynamics and Metabolism Department of Pfizer GRD (former Parke-Davis/Warner-Lambert). 

She has conducted non-compartmental PK, compartmental PK and advanced PK/PD modelling including exposure-response, population PK and  PK/PD analyses, biomarkers selection and  correlation analysis.

Galina Bernstein has provided preclinical, clinical pharmacology, pharmacometrics and analytical support for multiple clinical programs for over 300 studies including over 30 studies for the pediatric population. She was involved in a large number of studies for rare diseases as well as advanced therapy medicinal products (ATMP) such as gene therapy. She has been involved in the development and characterization of medical devices and clinical programs in the therapeutic areas of oncology, CNS, vaccines, dermatology, diabetes, cardiovascular, immunology, infectious diseases, renal impairment and others.

Galina Bernstein charted clinical development plans for a wide variety of drugs and indications, represented multiple pharmaceutical companies at FDA meetings, wrote clinical pharmacology and nonclinical sections in IND, NDA and other regulatory documents, responded to information requests with the unique solutions accepted by the Agency and other Health Authorities.

The main accomplishments included integrated data presentation for clinical and preclinical results to maximize the impact of the analysis on the approval of the complete program.

Services Offered

Pharmacometrics

Regulatory support of clinical programs

Strategic support for regulatory approaches to clinical programs; IND/NDA/MAA/PDCO submissions, PSP/PIP; responses to regulatory questions, IRB requests, investigator meetings, justification of study design and dose selection.

Experience with the regional agencies: Japan, China, Australia, New Zealand, European countries, South America

Clinical Pharmacology

Clinical Pharmacology

Design of Clinical Pharmacology studies based on totality of available information, first in human studies, DDI including rare interactions without clinically validated probe, relative bioavailability, studies in special populations – renal and hepatic impairment, pediatric, geriatric; proof of concept or mechanism; small molecules, biologics, gene and RNA therapy

Development and regulatory support of complete clinical development programs for an asset, innovative design of clinical studies, gap analysis of preclinical and clinical programs, selection of appropriate populations for the studies;

Support of late phase studies from concept development to implementation in diverse therapeutic areas, vendor and site selection support and communication with KOLs.

Synthetic approach to the results of complete program to streamline the development of the drug

Modeling skills

Molecular Pharmacology

Mechanism of drug action, interaction with other drugs, diseases and patient characteristics, pharmacogenomics and pharmacogenetics, personalized medicine, rare diseases and innovative therapeutics, biologics and gene therapies.

Regulatory Support of Clinical Programs

Pharmacokinetics and statistical analysis

PK analysis of clinical studies data for drug concentrations in plasma, serum, whole blood, urine and other matrices;

PD parameters derivation for biomarkers and clinical endpoints; statistical analysis for dissolution comparison and stability in support of CMC; comparison and correlation statistical analyses; dose proportionality, exposure-response correlation analysis

Statistical analysis documentation: Statistical Analysis Plan (SAP), mock Tables-Figures-Listings (TLFs), Data analysis plan for biomarkers and exposure-response, meta-analysis and cross-study analysis plans and reports, review of TLFs and analysis reports, writing of analysis reports

statistic data analyst

Modeling & Simulation and Pharmacometrics

Population PK, statistics, kinetics and pharmacokinetics data analysis and non-linear mixed effects modeling with Phoenix WinNonLin/NLME, conversion of published NONMEM models and coding, Quantitative Structure-Activity Relationship

Pharmacokinetic/pharmacodynamic and exposure-response correlation analysis; developing modeling and simulation strategy for clinical programs; use of simulation methods to support dose and dosing regimen selection, trial design, and Go/No-Go decisions, dosing in pediatric studies; simulation of multiple options for the selection of best approach in drug development.

Toxicology

Non-clinical toxicology

Support of clinical programs through in vitro characterization and animal studies, gap analysis for regulatory requirements, in vitro drug-drug interaction, cardiac effect, genotoxicity/carcinogenicity, toxicology in multiple species, toxicokinetics, statistical modeling of safety events to support NOAEL;

Target validation, biophysical characterization of drug candidates, protein biochemistry, microbiology and cell culture, CMC, Molecular biology and recombinant DNA technique

Molecular Parmac

Biomarker analysis and validation, bioanalysis

Selection of biomarkers, support of assay development for PK and biomarkers, review of bioanalytical validation plans and reports; help in selection of bioanalytical methods, laboratories and vendors

Data analysis plans for biomarkers, correlation to dose, PK metrics, depending on the type of biomarkers and frequency of sampling from intense sampling to sparse data, planning and presentation of PK/PD data to regulatory agencies – FDA, EMA, other

Medical Equipment

Medical devices

In vitro diagnostics, risk management, design control, process and product validation, clinical validation, submissions, technology transfer.

News from FDA and EMA

Augmented Reality
Augmented Reality and Virtual Reality (AR/VR) have the potential to transform health care, delivering altogether new types of treatments and diagnostics, and changing how and where care is delivered. Central to their potential in diagnosis and treatment is their ability to deliver both standard and entirely new types of content in highly immersive and realistic ways, remotely, and tailored to a variety of clinical contexts.

European decentralised CAR T manufacturing consortium launched

A European project to develop an automated, modular point-of-care manufacturing platform for chimeric antigen receptor T-cell (CAR T) therapy has launched. EASYGEN aims to increase treatment access by improving hospital workflows and is backed by €8 million in EU funding from the Innovative Health Initiative (IHI).

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FDA tightens use of Pfizer, Moderna and Novavax COVID-19 vaccines

The US Food and Drug Administration (FDA) has revoked its emergency COVID-19 vaccine approvals, handing out three revised mandates that mainly restrict use to those deemed ‘high risk’.

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MHRA pilot to prepare sponsors for clinical trial regulation changes

The Medicines and Healthcare products Regulatory Agency (MHRA) has launched a pilot scheme to streamline the approval process for certain changes to clinical trials.

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FDA Accepts Proposal for Reasonably Likely Surrogate Endpoint for ‘MASH’ All-Cause Mortality or Liver-Related Events

FDA's Center for Drug Evaluation and Research, Office of New Drugs has accepted a Letter of Intent for the qualification of Liver Stiffness Measurement by Vibration-Controlled Transient Elastography as a reasonably likely surrogate endpoint for clinical trials in adults with non-cirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with moderate-to-advanced liver fibrosis (scarring).

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FDA to recommend additional, earlier MRI monitoring for patients with Alzheimer’s disease taking Leqembi (lecanemab)

The U.S. Food and Drug Administration (FDA) is recommending an additional, earlier magnetic resonance imaging (MRI) monitoring prior to the 3rd infusion for patients with Alzheimer’s disease taking Leqembi (lecanemab). The earlier monitoring can identify individuals with amyloid-related imaging abnormalities with edema (ARIA-E), which is characterized by brain swelling or fluid buildup. ARIA-E is usually asymptomatic, although serious and life-threatening events, including seizure and status epilepticus, can occur and there have been deaths.

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Clinical Pharmacology Corner: New CDER Research on the Effect of Cannabidiol on Liver Enzymes and Endocrine Measures Highlighted in CDER Impact Story

Despite limited and inconsistent human safety data, unregulated cannabidiol (CBD) products are widely available to consumers. In this CDER Impact Story, CDER experts describe a randomized, double-blinded, placebo-controlled study demonstrating that CBD use at doses representative of consumer products is associated with liver enzyme elevations in 5.6% of healthy adults.  The study findings have important regulatory implications that can inform discussions about appropriate safeguards and underscore the need for further investigation of the long-term effects of CBD use, its effects on various populations, and the safety of lower doses commonly used by consumers.

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Nature

Affiliations and Volunteering

Reviewer and member of the Editorial board for Elsevier publisher’s European Journal for Pharmaceutical Sciences
AAPS – abstract reviewer, member Scientific programming committee for AAPS360
ASCPT – past member, presenter and abstract reviewer
DIA – Past member of the DIA Clinical Pharmacology Core Committee and presenter

Representative Publications

Ambrosy AP, Bensimhon D, Bernstein G, Kolski B, Neutel J, Esque B, Adler E. Randomized Study Comparing a Novel Intranasal Formulation of Bumetanide to Oral and Intravenous Formulations. Circulation. 2024 Nov 18. doi: 10.1161/CIRCULATIONAHA.124.072949. Epub ahead of print. PMID: 39555978. https://pubmed.ncbi.nlm.nih.gov/39555978/

E-J van Hoogdalem, G Bernstein. Special issue: Innovations in Early Clinical Drug Evaluation. Curr Rev Clin Exp Pharmacol. 2022;17(1):3. https://www.eurekaselect.com/article/119643 

M Tatipalli, VK Siripuram, T Long, D Shuster, G Bernstein, P Martineau, KA Cook, R Cristofoletti, S Schmidt, V Vozmediano. Informed Optimization of a Pediatric Clinical Pharmacokinetic Trial of a New Spironolactone Liquid Formulation. Pharmaceutics. 2021 Jun 8;13(6):849. Model-https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228864/pdf/pharmaceutics-13-00849.pdf 

G Bernstein, K Davis, C Mills, L Wang, M McDonnell, J Oldenhof, C Inturrisi, PL Manfredi, OV Vitolo. Characterization of the Safety and Pharmacokinetic Profile of D-Methadone, a Novel N-Methyl-D-Aspartate Receptor Antagonist in Healthy, Opioid-Naive Subjects: Results of Two Phase 1 Studies. J Clin Psychopharmacol. 2019 May/Jun;39(3):226-237. https://journals.lww.com/psychopharmacology/Abstract/2019/05000/Characterization_of_the_Safety_and_Pharmacokinetic.8.aspx 

G Bernstein, J Palatka, S Schmidt. Biomarkers for Personalized Medicine in Oncology: a Work in Progress AAPS Newsmagazine, Jan’19: pp. 10-17, 2019.https://www.aapsnewsmagazine.org/aapsnewsmagazine/articles/2019/jan19/cover-story-jan19

G Bernstein, J Oldenhof. Practical considerations for pharmacokinetic and pharmacodynamic analysis of antibody-drug conjugates in clinical studies. AAPS CROFG Newsletter. October 2017.

TL Davis, JR Walker, V Campagna-Slater, PJ Finerty, R Paramanathan, G Bernstein, F MacKenzie, W Tempel, H Ouyang, WH Lee, EZ Eisenmesser, S Dhe-Paganon. Structural and biochemical characterization of the human cyclophilin family of peptidyl-prolyl isomerases. PLoS Biol. 2010 Jul 27;8(7):e1000439. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911226/pdf/pbio.1000439.pdf

A Schuetz, G Bernstein, A Dong, T Antoshenko, H Wu, P Loppnau, A Bochkarev, AN Plotnikov. Crystal structure of a binary complex between human GCN5 histone acetyltransferase domain and acetyl coenzyme A Proteins. 2007 Jul 1;68(1):403-7. https://onlinelibrary.wiley.com/doi/epdf/10.1002/prot.21407

M Kahraman, S Sinishtaj, PM Dolan, TW Kensler, S Peleg, U Saha, SS Chuang, G Bernstein, B Korczak, GH Posner. Potent, selective and low-calcemic inhibitors of CYP24 hydroxylase: 24-sulfoximine analogues of the hormone 1alpha,25-dihydroxyvitamin D(3).J Med Chem. 2004 Dec 30;47(27):6854-63. https://pubs.acs.org/doi/10.1021/jm040129%2B

 

Presentations and Posters

G Bernstein, E Kendig, MM Goodwin, JF Mohr. Furosemide pharmacokinetic and pharmacodynamic model to describe urine output in heart failure patients following different routes of administration. European Society of Cardiology – Heart Failure 2022. Madrid, Spain. May 21-24 2022.

A Chimalakonda, S Singhal, R Dockens, G Bernstein, D Marchisin, IG Girgis, S Banerjee, J Throup, U Aras, W Li, B Murthy Deucravacitinib (BMS-986165), an Oral, Selective Tyrosine Kinase 2 Inhibitor: Overview of Pharmacokinetics in Healthy Volunteers Including ADME, Food and pH Effects, and Drug-Drug Interactions, EADV 2020: European Academy of Dermatology and Venereology. Vienna, Austria. Oct 29–31, 2020

Bernstein. Lectures in Clinical Pharmacokinetics and Clinical Pharmacodynamics, TOPRA (The Organizations for Professionals in Regulatory Affairs). Continuing Regulatory Education and Development (CRED) Programme. London, UK, Jun 2018, 2020 (virtual). https://www.topra.org/topra/topra_member/pdfs/Clinical_Development_Programme_2020_without%20speakers.pdf

H Mehta, G Bernstein, J He, J Oldenhof, C Mills, D Milovan, B Setnik, S Schmidt, N Hakim, C Dick. Insights from structural model delineate PK associated with abuse potential following intranasal administration in recreational drug users. ACoP8 Annual Meeting, Ft. Lauderdale, FL, USA, Oct 15-18, 2017

G Bernstein, J Steyn, H Mehta, J He, A Andrion, J Oldenhof. Data Listing and the Analysis for Immunogenicity of Biologic Agents; Correlation with Efficacy and Pharmacokinetics. ACCP Annual Meeting, San Diego, CA, USA, Sep 17-19, 2017.

G Bernstein, Chair. Title:  Exploration of PK/PD in NDA Enabling or Early Proof of Concept Studies. Core Interest Area: Translational Science: Preclinical/Clinical and Product Development. Presentation: Proof of Concept in Early Phase Studies Through PK/PD Modeling: Clinical CRO Perspective. DIA Annual Meeting, Chicago, IL, USA, Jun 18-22, 2017.

G Bernstein, J. Oldenhof. Planning of Dosing Regimen and Schedule of Assessments for First in Human Oncology Clinical Trials for Therapeutic Monoclonal Antibodies. ASCO-SITC Clinical Immuno-Oncology Symposium. Orlando, FL, USA, Feb 23-35, 2017.

G Bernstein. A Quantitative Approach to Understanding the Dynamic Interplay between Pain and Concomitant Medications, and Genetics. Oral presentation at symposium “Evolving methods in clinical pain studies: strategies to evaluate abuse deterrence, drug interaction and appropriate patient selection” DIA Annual Meeting, Philadelphia, PA, USA, Aug 28-30, 2016.

Bernstein, Mills C, Davis K, Oldenhof J. Drug PK-ECG correlation in the Dynamic Clinical Study Environment – Evaluation of contributing factors. DIA/FDA Statistics Forum, North Bethesda, MD, April 25-27, 2016.

Software Packages Used

Professional latest supported version 8.4.0 of Phoenix WinNonLin/NLME for PK analysis and modeling
JMP 17.2.0 for statistical analysis
Collaboration with Biostatistical CRO Resolutum Global to enhance statistical analysis offerings https://rgcro.health/

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