“EU regulatory and clinical development framework for biosimilars”
Explains the current EU experience and practices relating to the submission and approval of biosimilars
Bruno Flamion, Professor of Physiology and Pharmacology, Molecular Physiology Research Unit, University of Namur
Presentation at EIPG – VAPI-UPIP Symposium “Biotech and Advanced Therapies: Challenges and Opportunities” at the Faculty of Medicine and Pharmacy, Campus Jette, Vrije Universiteit van Brussel, Brussels 2013
The Investigator's Brochure (IB) is a comprehensive document summarizing the body of information about an investigational product (IB) obtained during a drug trial.
Bruno Flamion, Professor of Physiology and Pharmacology, Molecular Physiology Research Unit, University of Namur
Presentation at EIPG – VAPI-UPIP Symposium “Biotech and Advanced Therapies: Challenges and Opportunities” at the Faculty of Medicine and Pharmacy, Campus Jette, Vrije Universiteit van Brussel, Brussels 2013
The Investigator's Brochure (IB) is a comprehensive document summarizing the body of information about an investigational product (IB) obtained during a drug trial.
Pharmacological Approach to Drug DiscoverySuhas Reddy C
For better understanding of students. This will give you a detailed explanation of Pharmacological approach. Contact me through comment section if you need any assistance in understating
Drug discovery and development is and always has been the most exciting part of clinical pharmacology. It is my attempt to compile the basic concepts from various books, articles and online journals. Feel free to comment.
Pharmacological Approach to Drug DiscoverySuhas Reddy C
For better understanding of students. This will give you a detailed explanation of Pharmacological approach. Contact me through comment section if you need any assistance in understating
Drug discovery and development is and always has been the most exciting part of clinical pharmacology. It is my attempt to compile the basic concepts from various books, articles and online journals. Feel free to comment.
“The Evolution of Pharmaceutical Biotechnology – Science, Strategies, Products, and Regulations”
Shows the latest developments in pharmaceutical biotechnology and provides a broad overview of biotherapeutic & biosimilar regulations globally and in the EU
This presentation mainly deals with clinical development of biosimilar products. It also gives enough on non-clinical development so that the audience is well oriented.
Turning up the Compen-DIAL: Rapid Test Methods for Cell & Gene TherapiesMerck Life Sciences
Watch the presentation of this webinar here: https://bit.ly/3aeCPNB
Find out how we turn up the dial on quality control testing for cell and gene therapies through rapid methods for sterility, mycoplasma, and replication competent virus. We will review the current regulatory expectations as well as the benefits and limitations that come with each method.
Two of the biggest challenges with applying traditional quality control (QC) test methods to cell and gene therapies, is time to results, due to short shelf-life, and availability of sufficient sample, due to small production volumes.
So how can these challenges be overcome while still meeting regulatory expectations?
In this webinar we will discuss and review suitable methods for rapid testing of short-life cell and gene therapies that may also help conserve limited production material. We will look at benefits, limitations, and regulatory expectations for various QC needs including current and future rapid methods for sterility, mycoplasma and replication competent virus.
In this webinar, you will learn:
• Why the shelf life of a cell or gene therapy product may impact your QC testing strategy
• Current regulatory expectations surrounding rapid methods for sterility, mycoplasma and replication competent virus
• Potential impacts of pursuing a non-optimal QC testing strategy
Turning up the Compen-DIAL: Rapid Test Methods for Cell & Gene TherapiesMilliporeSigma
Watch the presentation of this webinar here: https://bit.ly/3aeCPNB
Find out how we turn up the dial on quality control testing for cell and gene therapies through rapid methods for sterility, mycoplasma, and replication competent virus. We will review the current regulatory expectations as well as the benefits and limitations that come with each method.
Two of the biggest challenges with applying traditional quality control (QC) test methods to cell and gene therapies, is time to results, due to short shelf-life, and availability of sufficient sample, due to small production volumes.
So how can these challenges be overcome while still meeting regulatory expectations?
In this webinar we will discuss and review suitable methods for rapid testing of short-life cell and gene therapies that may also help conserve limited production material. We will look at benefits, limitations, and regulatory expectations for various QC needs including current and future rapid methods for sterility, mycoplasma and replication competent virus.
In this webinar, you will learn:
• Why the shelf life of a cell or gene therapy product may impact your QC testing strategy
• Current regulatory expectations surrounding rapid methods for sterility, mycoplasma and replication competent virus
• Potential impacts of pursuing a non-optimal QC testing strategy
“Approaches to evaluation of various groups of biological products in Russia”
Provides an overview of the current assessment approaches applicable to biotherapeutics in the Russian Federation
“Immunogenicity testing of Biotechnology Products and the Impact to Biosimilars”
Illustrates procedures and potential outcomes of immunogenicity testing for biotherapeutics
The regulation of medicines in AustraliaTGA Australia
View this presentation for information on:
*the different categories of medicines
* registered (higher risk) medicines and how they are regulated
* listed (lower risk) medicines and how they are regulated
* accessing unauthorised medicines
* medicines advertising
* changing medicine technologies
Bioequivalence studies for various pharmaceutical drug formulations manufactured and released into the market is outlined in this presentation. The various studies used to establish bioequivalency with the original formulation is also mentioned.
Bio similar and innovators - the battle of the two is a long story . In this presentation am trying to explain the merits nd demerits of each with available evidence
Similar to 10. Dr. Alex Kudrin - Medicines and Healthcare Products Regulatory Agency (UK) (20)
IFPMA-TFDA Workshop on Couterfeit Medicines
‘Integrated Approach Against Fake Medicines’
Session 1: Current Regulatory Landscape & Initiatives Against Fake Medicines
On 6th February 2015
At Taipei International Convention Center
Taipei, Taiwan
IFPMA-TFDA Workshop on Couterfeit Medicines
‘Integrated Approach Against Fake Medicines’
Session4: Collaboration within and between countries
On 6th February 2015
At Taipei International Convention Center
Taipei, Taiwan
IFPMA-TFDA Workshop on Couterfeit Medicines
‘Integrated Approach Against Fake Medicines’
Session 4: Collaboration within and between countries
On 6th February 2015
At Taipei International Convention Center
Taipei, Taiwan
IFPMA-TFDA Workshop on Couterfeit Medicines
‘Integrated Approach Against Fake Medicines’
Session 4: Collaboration within and between countries
On 6th February 2015
At Taipei International Convention Center
Taipei, Taiwan
IFPMA-TFDA Workshop on Couterfeit Medicines
‘Integrated Approach Against Fake Medicines’
On 6th February 2015
At Taipei International Convention Center
Taipei, Taiwan
IFPMA-TFDA Workshop on Couterfeit Medicines
‘Integrated Approach Against Fake Medicines’
Session 3: Practices and Technologies for Prevention, Detection, Control and Monitoring of Fake Medicines.
On 6th February 2015
At Taipei International Convention Center
Taipei, Taiwan
IFPMA-TFDA Workshop on Couterfeit Medicines
‘Integrated Approach Against Fake Medicines’
On 6th February 2015
At Taipei International Convention Center
Taipei, Taiwan
IFPMA-TFDA Workshop on Couterfeit Medicines
‘Integrated Approach Against Fake Medicines’
Session 3: Practices and Technologies for Prevention, Detection, Control and Monitoring of Fake Medicines
On 6th February 2015
At Taipei International Convention Center
Taipei, Taiwan
IFPMA-TFDA Workshop on Couterfeit Medicines
‘Integrated Approach Against Fake Medicines’
On 6th February 2015
At Taipei International Convention Center
Taipei, Taiwan
IFPMA-TFDA Workshop on Couterfeit Medicines
‘Integrated Approach Against Fake Medicines’
Session 2: Supply Chain Integrity
On 6th February 2015
At Taipei International Convention Center
Taipei, Taiwan
IFPMA-TFDA Workshop on Couterfeit Medicines
‘Integrated Approach Against Fake Medicines’
Session 2: Supply Chain Integrity
On 6th February 2015
At Taipei International Convention Center
Taipei, Taiwan
IFPMA-TFDA Workshop on Couterfeit Medicines
‘Integrated Approach Against Fake Medicines’
On 6th February 2015
At Taipei International Convention Center
Taipei, Taiwan
IFPMA-TFDA Workshop on Couterfeit Medicines
‘Integrated Approach Against Fake Medicines’
Session 1: Current Regulatorz Landscape & Initiatives Against Fake Medicines
On 6th February 2015
At Taipei International Convention Center
Taipei, Taiwan
IFPMA Geneva Pharma Forum on 9 May 2014
Bringing Psoriasis into the Light
Presentation of Kim kjoeller, Senior Vice President
Global Development, Leo Pharma
IFPMA Geneva Pharma Forum on 9 May 2014
Bringing Psoriasis into the Light
Presentation of Professor Mahira Hamdy El Sayed
Dermatology and Venereology, Ain Shams University
David K. Robinson, Ph. D.Vice President, BiologicsHead and Executive Director, Biologics and Vaccines CMC RegulatoryMerck & Co, Inc.
Presenting on behalf of the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA)WCBP CASS, Washington DC, USAJanuary 2014
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
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Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
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Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...
10. Dr. Alex Kudrin - Medicines and Healthcare Products Regulatory Agency (UK)
1. IFPMA/AIPM Biotherapeutics Workshop, Moscow
EU regulatory and clinical development
framework for biosimilars
15-16th
May 2013
Dr Alex Kudrin, Medical Assessor in Biologicals, MHRA, London, UK
2. Disclaimer
• This presentation is given in personal capacity and
represents only the author’s personal views and does not
represent policies or recommendations of MHRA, EMA,
FDA, any other companies and regulatory bodies
mentioned in this presentation.
• No confidential data is disclosed.
• All relevant references and links are from public domain.
3. Biosimilars’ adoption will expand, but will
remain modest to 2016
• Market of biologics will
continue to expand due
to new, superior products
and earlier access;
• Spending on biosimilars
will increase but will
constitute only 2% of total
biologic spending;
• Biosimilar adoption is
expected to be modest
due to remaining patent,
market exclusivity and
lack of substitution
4. Lessons learned from first wave of biosimilars in EU
• Current EU biosimilar market:
- EPOs – 60%
- GSFs – 20%
- GHs – 20%
• Uptake of EPOs, filgrastims and GHs was highly variable
between EU countries (EPOs - 90% in Norway; <7% in Italy)
• Discounting of both reference and biosimilar products is
considerable: e.g. Eprex – 82% discount
• The dynamics is affected by pricing and extent of decision
making by physicians (e.g. GHs)
10. Definitions
Biological substance: produced by or extracted from a
biological source and for which a combination of physico-
chemical-biological testing and the production process and
its control is needed for its characterisation and the
determination of its quality
Similar biological medicinal product (SBMP or “biosimilar”):
a new biological medicinal product claimed to be similar to
a reference medicinal product authorised in the EU
Does not meet the definition of a generic product “owing to,
in particular, differences relating to raw materials or
differences in manufacturing processes” (Directive
2004/27/EC)
11. Biosimilar: Definition
• Reference is approved in EU or at least in one of EU countries
• Biosimilarity development pathway involving relevant orthogonal analytical
comparability methods, non-clinical and clinical models utilised from the
outset rather than in opportunistic fashion
• Quality TTP should be achieved (atypical glycosylation profile and presence
of impurities should be justified)
• An authorised biosimilar is generally administered via the same route of
administration
• The same dose (posology) as the reference products in indications approved
for a reference medicinal products
• Primary structure identical to the reference biological product
• Like the reference medicine, the biosimilar has a degree of natural variability
• Biosimilar and reference products have independent life cycle fate
• Quality, non-clinical, and clinical attributes are sufficiently similar yet might
not be identical between the biosimilar and the reference product
• More data is required as ‘essential similarity’ cannot be met
12. Biosimilars and “biobetters”
Attributes Biosimilars “Biobetters”
Experience Number of precedents No cases described so
far
Quality Similar TPP Different or atypical TPP
PK / PD Similar to reference Exaggerated or atypical
Efficacy Similar to reference Enhanced efficacy
Safety Similar to reference Similar / improved
Immunogenicity Similar to reference Similar / improved
Route of administration The same as for
reference
The same or different
Additional indications Potentially new
indications
Different or new
indications
Regulatory path Biosimilar New Active Substance
13. The biosimilar concept
Stepwise development approach
sufficient evidence of comparability at each stage
quality
non-clinical
PK/PD
efficacy/safety
14. Comparability tools
High
Low Probable clinical relevance
of differences found
Sensitivity to product
differences
Reference Biosimilar
Reference Biosimilar
Reference
Reference
Biosimilar
Biosimilar
A
B
15. The biosimilar concept
Holistic review process
biosimilarity
conclusion based on
all parts of the dossier
taken together
16. EMA Guidelines for Biosimilar Products
Overarching Guidance (CHMP/437/04)
Under revision: EMA/CHMP/BMWP/572643/2011
Concept and basic principles for biosimilar development
Product Specific Annexes to Non-/Clinical Guidelines
Quality Guideline (Draft)
EMA/CHMP/BWP/247713/2012
Non-/Clinical
Guidelines
(Under revision)
EMA/CHMP/BMWP/572828/2011
Insulins
EMEA/CHMP/BMWP/32775/2005
(Under revision)
(2011)
IFN-beta
Beta (draft)
CHMP/BMWP/652000/2010
IFN-alpha
EMEA/CHMP/BMWP/1
02046/2006
LMWH
EMA/CHMP/
BMWP/86572/2010
Somatotropins
EMEA/CHMP/BMWP/94528/2005
GM-CSF
EMEA/CHMP/BMWP/31329/2005
FSH
CHMP/BMWP/671292/2010
mAB
EMA/CHMP/BMWP/
403543/2010
(Draft)
Epoietin
EMEA/CHMP/
BMWP/301636/08
17. EMA and FDA differences in evaluation of the
biosimilarity
EMA FDA
Similar TTP Highly similar TTP
Risk driven non-clinical package NHP data still needed for biosimilar MABs
PK/PD study PK/PD study (address any differences
between US and EU commercialized
batches of the reference product)
Therapeutic equivalence study Might be waived in some cases
RMP in all cases REMS in exceptional circumstances
Not appropriate Switching data
18. Stepwise process
• Step 1: Orthogonal in vitro functional assays
• Step 2: Determination of the need for animal studies
• Step 3: Conduct of the relevant animal studies
20. Step 2: Determination of the need for in vivo
studies
Relevant in vivo model:
• Species (NHP, transgenic or transplant model)
• Design: sensitivity and variability
Factors to consider if relevant in vivo models available:
• Presence of quality attributes not detected in reference (e.g.
PTMs);
• Presence of quality attributes in higher amounts than those in
the reference (e.g. impurities)
• Relevant differences in formulation (excipients etc.)
21. Scenarios in step-wise decision making in non-
clinical development of biosimilars
Step 1 is OK
Step 2 is OK
Step 1 is OK
Step 2 some concerns
(e.g. new formulation,
relevant sensitive
models exist)
Step 1: differences found
Step 2: risks and concerns
Clinical
development
Step 3: in vivo
models and
additional data
Differences between
requirements from FDA, EMA,
PMDA and Indian Agency
22. Clinical requirements
The clinical comparability exercise:
a stepwise approach
1. PK/PD studies: in all cases
2. Clinical efficacy/safety trial(s)
o PK/PD may be sufficient to establish clinical comparability
regarding efficacy if PD marker is an accepted surrogate marker
for efficacy (e.g. insulin)
o efficacy in an appropriate model (assay sensitivity)
o safety & immunogenicity always necessary
23. Clinical requirements
Pharmacokinetics
not a standard bioequivalence study!
comparison of absorption and elimination (Cl, T1/2)
choice of the design and equivalence margins to be justified
Pharmacodynamics
to be justified!
relevance of the PD marker
choice of the population (re assay sensitivity)
choice of the study design, duration, dose (in the steep part of
the dose response curve, preferably several doses)
24. Example of PK or PD failure
PK soluble
insulin
test
PD isophane
insulin
test
EPAR, EMA
website
26. PK studies in healthy normal volunteers
• Ethical challenges
• Provide with lesser variability and greater sensitivity
• Immunocompetent host
• Preferred in single dose settings
• Optimal to gain initial clinical insight into PK/PD similarity
• Should be avoided in situations when subjects are likely to
develop immunogenicity but may require product in the future
• Avoid when high risk of immunogenicity or serious AEs (e.g.
PML).
27. PK study design
• Preferred: single dose in HV with full characterisation of PK
profile including late elimination phase (e.g. 5 half-lives)
• Non-mediated clearance
• Parallel / crossover (e.g. etanercept)
- If not possible:
• Single dose in patients
• Multiple dose in patients
28. Sampling times
• In SD studies: should cover whole PK profile,
including late elimination phase
• Sufficient sampling time-points around predicted Cmax
• In MD studies:
- Ideally, first dose (most sensitive comparability) and
last dose (for elimination)
- Otherwise, first dose and steady state (e.g. during 4-8
cycle NHL treatment with rituximab – after 6 cycle or
in CLL: cycles 2-6 after 4 cycle).
29. PK parameters
• In SD studies:
- Primary: AUC(0-∞)
- Secondary: Cmax, Tmax, Vd, T1/2
- For subcutaneous route: Cmax should be co-primary; partial AUCs
as secondary
• In MD studies:
- Primary: truncated AUC(0-t) after first dose and AUC(0-T) over
a dosage interval at steady state;
- Secondary: Cmax and Ctrough at steady state
30. Statistical tests
• Primary
- Equivalence margins of 80-125%
- Justification of any widening (including the impact on safety
and efficacy) – if slightly outside without any impact on efficacy
might be accepted.
• Secondary
- Descriptive statistics with ratio / difference and 90%CIs –
discussion of results
31. Clinical efficacy
Adequately powered randomised (double-blind) parallel
group equivalence trial in the most sensitive and
preferably well-known model
choice of the equivalence margin to be justified!
Example : Adalimumab or infliximab biosimilar
Primary endpoint: equivalence of ACR20 or DAS28
Both include some indices which are subjective, e.g. number of tender joints
(DAS28, ACR20), patient assessment of pain, and physician and patient
global assessments of disease activity (ACR20)
ACR20 represents the change in activity over time (20% improvement)
New
1 efficacy/safety study with one route
1 bridging multiple-dose PK/PD study with the other route
32. Patient population and dose selection
• Homogenous and most sensitive to reduce variability
attributed to disease, target expression, concomitant
therapies
• No requirement to test all approved dose regimens
• Most sensitive dose should be chosen
• Low dose is more sensitive to study target-mediated
clearance (because the mechanism is less likely to be
saturated)
• High dose more appropriate in general to study non
specific clearance and address safety differences
33. Justification for the margin size
Placebo Reference product
18% 42%
∆24%
Margin for equivalence 12%
Prior knowledge: EPAR, literature and symposia
34. General principles in immunogenicity
• The assay should be in place from Phase I study
• Sensitive and specific assay: for both reference and biosimilar
• Validated screening, confirmation and neutralisation assays
• Justification of periodicity and timing of sampling
• Sensitive patient population and subgroup analyses (exposure
related, immunosuppression status related, across indications,
AE-related, loss of efficacy, PK/PD modelling)
• Monitoring of immunogenicity without switching up 12 month
• Switch-associated immunogenicity data (not required in EU)
• EU: descriptive evaluation of immunogenicity
• US: one-sided margin for immunogenicity (larger study)
35. Extrapolation of indications
• It is possible to extrapolate therapeutic similarity
• Justification will depend on MOA, own clinical experience, and
available literature data
• Depends on the strength of knowledge around MOA (e.g. poor
understanding of Fc-receptor binding pattern and functionality)
• MABs with both immunomodulatory and anti-tumour MOA:
quality, non-clinical database, potency assay(s) and in-vitro
assays that cover the functionality of the molecule
• In some cases extrapolation is more challenging: e.g. rituximab
36.
37. Extrapolation: Outcomes
• Reliant on the totality of biosimilarity exercise and
satisfactory results of clinical studies and functional
cellular assays
• The preferred option is to grant all indications rather
than just few core indications with shared MoA
• Scenario with rituximab is the most complex
38. Pharmacovigilance of biosimilars: principles
• Reference and biosimilar have independent from each other life cycles
• No need to reiterate reference safety profile but safety burden
associated with reference products is still attached
• Pre-approval PV database will be limited and rarely exceed 500-700
patients
• RMPs for all new products including biosimilars are mandatory
• RMP / Postmarketing PV activities will be expected in all cases
• Risk management is closely linked with education of patients and
prescribers
• Biosimilar companies will have to deal with poor education around use
of reference products
• Closer monitoring of patients following the switch: 0-6 months and up
to 1 year for the adequacy of response, AEs / complications, and
immunogenicity
• Postmarketing observational studies / registries will be expected in
some cases
39. Pharmacovigilance Plan
Important identified and potential risks based on the reference
product – especially rare ADRs
Planned activities outside routine PV
• Traceability of batches
• Monitoring of safety and risks in sub-populations (pregnancy, paediatric etc.)
• Enhanced safety monitoring in indications based on extrapolation
• Immunogenicity and switcheability
• Risk for off-label use
Post-authorisation safety/efficacy studies
interventional
• long-term or repeated treatment (e.g. continuation of pivotal
trial)
• systematic antibody testing
• other (extrapolated) indication, route of administration
non interventional (registries)
drug utilisation surveys
Clinical requirements: Risk Management Plan
40. Product labelling
Same as the reference product, including
same ADRs
same PK/clinical efficacy study results
However, a few additional wording possible, e.g. description of
study results
“During clinical studies 541 cancer patients and 188 healthy volunteers were
exposed to Filgrastim ratiopharm. The safety profile of Filgrastim ratiopharm
observed in these clinical studies was consistent with that reported with the
reference product used in these studies”.
Specific statement in section 5.1 (Pharmacodynamic properties)
<(Invented) Name> is a biosimilar medicinal product. Detailed information is
available on the European Medicines Agency website; www.emea.europa.eu
41. “Changing one medicine for another that is
equivalent” (WHO)
Interchangeability: medical practice in a clinical
setting, on the initiative or with the agreement of
the prescriber
Substitutability: dispensing at the pharmacy level
without requiring consultation with the prescriber
Automatic substitution: obligation of substitution
due to national or local requirements
42. Switching / interchangeability data
• FDA: no precise study design, might be waived if high
level of biosimilarity is declared
• EMA: no pre-approval requirements but post-
marketing PV monitoring of switch-associated
phenomena
43. Substitutability
The rules for substitution are within the
remit of the EU national authorities
Most EU member states have already taken action.
In the UK, MHRA recommendation (Feb-2008)
“When prescribing biological products, it is good practice to
use the brand name. This will ensure that automatic
substitution of a biosimilar product does not occur when the
medicine is dispensed by the pharmacist.”
44. Substitutability
At EU level, same labelling for all erythropoietins
(2010):
SmPC (Special warnings): “In order to improve
the traceability of ESAs, the trade name of the
administered ESA should be clearly recorded (or
stated) in the patient file” .
Patient leaflet: “<Brand name> is one of a group
of products that stimulate the production of red
blood cells like the human protein erythropoietin
does. Your healthcare professional will always
record the exact product you are using.”
45. Substitutability
New EU pharmacovogilance directive (2010/84/EU)
Some medicinal products are authorised subject to additional
monitoring. This includes all medicinal products with a new
active substance and biological medicinal products, including
biosimilars, which are priorities for pharmacovigilance.
Member states shall ensure, through the methods for
collecting information and where necessary through the follow-
up of suspected adverse reaction reports, that all appropriate
measures are taken to identify clearly any biological medicinal
product prescribed, dispensed, or sold in their territory which is
the subject of a suspected adverse reaction report, with due
regard to the name of the medicinal product, and the batch
number.
[Key dialogue] Business opportunities in the global vaccine market has been growing. As suggested in the previous TGAB meeting in the last summer, Takeda has opportunities to be captured through global expansion of vaccine business leveraging our assets, including sIPV We have initiated 4 initiatives to assess potential opportunities to "Go global" 1. Reinforcement of Japan strategy to establish unique position in our core market 2. Assessment of opportunities for strategic partnering to enter emerging markets 3. Screening and evaluation of potential in-licensing targets for "innovation" to build competitive advantage 4. Formulation of roadmap to build required capability for sustained growth After introducing our initiatives, we would like to receive inputs from you about current direction of our global vaccine strategy Our key questions are; Whether our strategic concept and approach make sense Which actions are key for achieving successful expansion into emerging markets What other types of pipeline and technology would be in our focus Based on today's discussion, we will refine our strategy towards the MOC presentation in March