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.

EMA: New gene therapy treatment for haemophilia B

EMA has recommended granting a conditional marketing authorisation in the European Union (EU) for Durveqtix (fidanacogene elaparvovec) to treat severe and moderately severe haemophilia B in adults who do not have factor IX inhibitors (auto-antibodies produced by the immune system against factor IX replacement medicines) and who have no detectable antibodies to variant adeno-associated virus serotype Rh74 (AAVRh74var).

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EMA: First vaccine to protect adults from Chikungunya

EMA has recommended granting a marketing authorisation in the European Union (EU) for Ixchiq, the first vaccine in the EU to protect adults 18 years and older against ChikungunyaIt is given as a single dose. Chikungunya (also called CHIK fever) is a viral disease caused by Chikungunya virus (CHIKV), a virus transmitted to humans by infected mosquitoes (primarily Aedes aegypti and Aedes albopictus).

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FDA approves lisocabtagene maraleucel for relapsed or refractory mantle cell lymphoma

On May 30, 2024, the Food and Drug Administration approved lisocabtagene maraleucel (Breyanzi, Juno Therapeutics, Inc.) for adult patients with relapsed or refractory mantle cell lymphoma (MCL) who have received at least two prior lines of systemic therapy, including a Bruton tyrosine kinase inhibitor (BTKi).

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ICH Announces the Availability of a Final Guideline and Questions and Answers Document on Drug Interaction Studies (M12)

On May 22, 2024, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) announced the availability of a final guideline on Drug Interaction Studies (M12) as well as an M12 Question and Answers document (M12 Q&A). The guideline provides recommendations to promote a consistent approach in designing, conducting, and interpreting enzyme- or transporter-mediated in vitro and clinical drug-drug interaction (DDI) studies during the development of a therapeutic product. In response to questions posted during the ICH M12 comment period, the M12 Q&A was developed to provide clarity around some of the concepts related to evaluation of drug interaction covered in the M12 guideline.

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FDA grants accelerated approval to selpercatinib for pediatric patients two years and older with RET-altered metastatic thyroid cancer or solid tumors

On May 29, 2024, the Food and Drug Administration granted accelerated approval to selpercatinib (Retevmo, Eli Lilly and Company) for pediatric patients two years of age and older with the following:

  • advanced or metastatic medullary thyroid cancer (MTC) with a RET mutation, as detected by an FDA-approved test, who require systemic therapy;
  • advanced or metastatic thyroid cancer with a RET gene fusion, as detected by an FDA-approved test, who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate); and
  • locally advanced or metastatic solid tumors with a RET gene fusion, as detected by an FDA-approved test, that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.

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FDA Approves First Interchangeable Biosimilar for Two Rare Diseases

The U.S. Food and Drug Administration approved Bkemv (eculizumab-aeeb) as the first interchangeable biosimilar to Soliris (eculizumab) to treat certain rare diseases. Bkemv is approved for the following treatment indications, which are also currently approved for Soliris:

  • the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis; and
  • the treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy.
Bkemv is a monoclonal antibody that binds to the complement C5 protein and inhibits activation of the complement system, a part of the body’s immune system. This binding prevents the breakdown of red blood cells in the bloodstream (intravascular hemolysis) in patients with PNH and aHUS.

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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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