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.

Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 24-27 June 2024

EMA’s human medicines committee (CHMP) recommended ten medicines for approval at its June 2024 meeting. Balversa (erdafitinib), for the treatment of adult patients with unresectable or metastatic urothelial carcinoma, a cancer of the bladder and urinary system. Eurneffy (epinephrine), the first emergency treatment against allergic reactions that is administered as a nasal spray, not as an injection. mResvia (Respiratory Syncytial Virus (RSV) mRNA vaccine) Ordspono* (odronextamab), for the treatment of follicular lymphoma and diffuse large B-cell lymphoma Piasky (crovalimab) for the treatment of paroxysmal nocturnal haemoglobinuria Tauvid (flortaucipir (18F)), for positron emission tomography (PET) imaging of the brain in adult patients with cognitive impairmen Winrevair* (sotatercept), to treat adult patients with pulmonary arterial hypertension Steqeyma (ustekinumab), a biosimilar medicine and two generic medicines: Enzalutamide Viatris (enzalutamide) for the treatment of prostate cancer. Nilotinib Accord (nilotinib) for the treatment of Philadelphia chromosome positive chronic myelogenous leukaemia.

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FDA Issues Revised Draft Guidance on Addressing Misinformation About Prescription Drugs and Medical Devices

This revised draft guidance would apply only to approved/cleared medical products, which include medical devices for human use (including biological products), prescription human drugs (including biological products), and prescription animal drugs.

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Positive CHMP opinion on first-in-class medicine to treat pulmonary arterial hypertension

EMA has recommended granting a marketing authorisation in the European Union (EU) for Winrevair (sotatercept) to treat adult patients with pulmonary arterial hypertension (PAH), in combination with other specific PAH therapies, to improve exercise capacity.

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First nasal adrenaline spray for emergency treatment against allergic reactions

EMA’s human medicines committee (CHMP) has recommended granting a marketing authorisation in the European Union for Eurneffy (epinephrine), the first medicine to be taken through the nose for the emergency treatment of allergic reactions (anaphylaxis).

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EMA recommends revoking conditional marketing authorisation for Ocaliva

EMA’s human medicines committee (CHMP) has concluded its review of the medicine Ocaliva (obeticholic acid) and has recommended that the medicine’s marketing authorisation be revoked, because its benefits are no longer considered to outweigh its risks. Ocaliva is used to treat adults with primary biliary cholangitis (PBC), an autoimmune condition that causes gradual destruction of the bile ducts in the liver, which can lead to liver failure and increase the risk of liver cancer.

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EMA recommends non-renewal of authorisation of Duchenne muscular dystrophy medicine Translarna

EMA’s human medicines committee (CHMP) has recommended not renewing the conditional marketing authorisation for Translarna (ataluren), a medicine for treating patients with Duchenne muscular dystrophy. Translarna is used in patients whose disease is caused by a type of genetic defect called a ‘nonsense mutation’ in the dystrophin gene and who are able to walk. The CHMP issued an initial negative opinion on the renewal of the marketing authorisation for Translarna in September 2023, which was confirmed in January 2024 following a re-examination requested by the company marketing the medicine. Both rounds of assessment concluded that the effectiveness of Translarna had not been confirmed following a re-evaluation of the medicine’s benefits and risks.

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FDA Approves Treatment for Adults with Alzheimer’s Disease

The U.S. Food and Drug Administration has approved Kisunla (donanemab-azbt) injection for the treatment of Alzheimer’s disease. Treatment with Kisunla should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was studied in the clinical trials.

Kisunla is administered as an intravenous infusion every four weeks.

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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

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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