Signal detection and management activities are at the core of ensuring drug safety. A complex process of signal detection; through their validation and confirmation; analysis and prioritisation; and signal assessment to recommending action.
Find out more at out training: http://bit.ly/1W31NCF
What are some of the challenges in pharmacovigilance? This presentation offers you more information on signal detection, signal management and risk minimisation measures.
Introduction to Expectedness/Unexpectedness Assessment in Drug Safety & Pharmacovigilance of Pharmaceuticals, Bio-Pharmaceuticals, Medical Devices, Cosmeceuticals and Foods.
Contact:
"Katalyst Healthcares & Life Sciences"
South Plainfield, NJ, USA
info@KatalystHLS.com
FREQUENTLY ASKED QUESTIONS IN PHARMACOVIGILANCE INTERVIEWS & Its PREPARATIONSJonaid Ali
FREQUENTLY asked questions about pharmacovigilance in an interview. Pharmacovigilance is fastest growing career in these days in the healthcare sector specially for pharmacy students although some corporates allow non pharm candidates also
Signal detection and management activities are at the core of ensuring drug safety. A complex process of signal detection; through their validation and confirmation; analysis and prioritisation; and signal assessment to recommending action.
Find out more at out training: http://bit.ly/1W31NCF
What are some of the challenges in pharmacovigilance? This presentation offers you more information on signal detection, signal management and risk minimisation measures.
Introduction to Expectedness/Unexpectedness Assessment in Drug Safety & Pharmacovigilance of Pharmaceuticals, Bio-Pharmaceuticals, Medical Devices, Cosmeceuticals and Foods.
Contact:
"Katalyst Healthcares & Life Sciences"
South Plainfield, NJ, USA
info@KatalystHLS.com
FREQUENTLY ASKED QUESTIONS IN PHARMACOVIGILANCE INTERVIEWS & Its PREPARATIONSJonaid Ali
FREQUENTLY asked questions about pharmacovigilance in an interview. Pharmacovigilance is fastest growing career in these days in the healthcare sector specially for pharmacy students although some corporates allow non pharm candidates also
Literature Surveillance in Pharmacovigilance; Current Trends, Methods and Challenges
Please join Elizabeth E. Garrard, PharmD, founder and CEO of Garrard Safety Solutions, as she reviews key issues in literature surveillance for Pharmacovigilance.
Objectives:
• Understand the regulatory obligations, best sources and procedures for conducting literature surveillance.
• Appreciate some examples of when a safety signal was detected in the literature and its impact on the lifecycle of a drug.
• Understand when to start and where to look for emerging safety information.
• Setting up your search strategy, how to ensure your search strings are well balanced, recognizing the challenges between precision and sensitivity.
• What is the impact of the new literature monitoring by EMA of a number of substances in selected medical literature to identify suspected adverse reactions with medicines authorized in the European Union. Early insights into successes and issues.
• Discuss current methods that can increase the likelihood of early detection of a safety issue and minimize the issues surrounding.
• Realize the challenges we face including wide differences in quality, accuracy, and completeness in the scientific literature and how best to navigate these differences and maintain proper vigilance.
Safety reports rmp risk management plan pharmacovigilanceAzierta
A Risk management plan is a document based on safety profile of medicines that collects all pharmacovigilance activities and it is used to plan and implement measures in order to minimize risks.
This summary explains how to develop a Risk Management Plan according to European regulatory requirements.
Implementation dates and objectives of RMP module V of Good Pharmacovigilance Practices.
Development safety update report (dsur) pharmacovigilance and safetyAzierta
According to ICH guideline E2F (Step 5) on Development Safety Update Reports (DSURs) already implemented since 2011, companies must submit DSURs on a yearly basis for medicinal products involved in clinical trials. The focus of the DSUR is on data and findings from clinical trials of drugs and biologicals, whether they are authorized or not.
DSURs are internationally-harmonized, safety documents covering the safety summary of medicinal products during their development or clinical trial phase.
They are based heavily on the PSUR format already used for updating the safety record of drugs in their marketing phase.
A DSUR should be prepared after the first authorization of a clinical trial worldwide. A copy of the DSUR should be submitted to each concerned European Member State (MS) if a clinical trial is authorized in this MS for this investigational drug (still using the DIBD). Therefore, the first DSUR can be submitted to a concerned MS earlier than 1 year, but the covered reporting period should not be longer than 1 year.
The DSUR presents an annual review & evaluation of safety information:
• Information reported during the current review period and analysis based on previous knowledge of the products’ safety
• Description of new issues that may impact the overall program or specific clinical trials.
• Summarization of current understanding and management of known and potential safety risks to exposed patients.
• Provide an update on the status of the clinical development program.
In Azierta, scientific and healthcare consulting, we are experts in Pharmacovigilance and we have a team of highly qualified drug safety experts who support our clients to manage pharmacovigilance in an optimal way. Our work covers all areas of pharmacovigilance, both at the level of medicines, as well as medical devices and cosmetic products.
If you are interested in the contents of the good practices of pharmacovigilance (GVPs), as well as in other products related to pharmacovigilance visit our safety reports website for more details and feel free to contact us, we will be pleased to help you.
Introduction to Aggregate Reporting in Drug Safety & Pharmacovigilance in Pharmaceuticals, Bio-Pharmaceuticals, Medical Devices, Cosmeceuticals and Foods.
Contact:
"Katalyst Healthcares & Life Sciences"
South Plainfield, NJ, USA
info@KatalystHLS.com
MedDRA - the Medical Dictionary for Regulatory Activities - is a medical terminology used to classify adverse event information associated with the use of biopharmaceuticals and other medical products (e.g., medical devices and vaccines). Coding these data to a standard set of MedDRA terms allows health authorities and the biopharmaceutical industry to more readily exchange and analyze data related to the safe use of medical products.
Importance of aggregate reporting in pharmacovigilanceSollers College
Pharmacovigilance is the science which deals with the activities related to the detection, assessment, understanding, and prevention of ADRs. The scope of Pharmacovigilance has evolved.
Reconciliation and Literature Review and Signal Detection_Katalyst HLSKatalyst HLS
Introduction Reconciliation and Literature Review and Signal Detection in Drug Safety & Pharmacovigilance in Pharmaceuticals, Bio-Pharmaceuticals, Medical Devices, Cosmeceuticals and Foods.
Contact:
"Katalyst Healthcares & Life Sciences"
South Plainfield, NJ, USA
info@KatalystHLS.com
Literature Surveillance in Pharmacovigilance; Current Trends, Methods and Challenges
Please join Elizabeth E. Garrard, PharmD, founder and CEO of Garrard Safety Solutions, as she reviews key issues in literature surveillance for Pharmacovigilance.
Objectives:
• Understand the regulatory obligations, best sources and procedures for conducting literature surveillance.
• Appreciate some examples of when a safety signal was detected in the literature and its impact on the lifecycle of a drug.
• Understand when to start and where to look for emerging safety information.
• Setting up your search strategy, how to ensure your search strings are well balanced, recognizing the challenges between precision and sensitivity.
• What is the impact of the new literature monitoring by EMA of a number of substances in selected medical literature to identify suspected adverse reactions with medicines authorized in the European Union. Early insights into successes and issues.
• Discuss current methods that can increase the likelihood of early detection of a safety issue and minimize the issues surrounding.
• Realize the challenges we face including wide differences in quality, accuracy, and completeness in the scientific literature and how best to navigate these differences and maintain proper vigilance.
Safety reports rmp risk management plan pharmacovigilanceAzierta
A Risk management plan is a document based on safety profile of medicines that collects all pharmacovigilance activities and it is used to plan and implement measures in order to minimize risks.
This summary explains how to develop a Risk Management Plan according to European regulatory requirements.
Implementation dates and objectives of RMP module V of Good Pharmacovigilance Practices.
Development safety update report (dsur) pharmacovigilance and safetyAzierta
According to ICH guideline E2F (Step 5) on Development Safety Update Reports (DSURs) already implemented since 2011, companies must submit DSURs on a yearly basis for medicinal products involved in clinical trials. The focus of the DSUR is on data and findings from clinical trials of drugs and biologicals, whether they are authorized or not.
DSURs are internationally-harmonized, safety documents covering the safety summary of medicinal products during their development or clinical trial phase.
They are based heavily on the PSUR format already used for updating the safety record of drugs in their marketing phase.
A DSUR should be prepared after the first authorization of a clinical trial worldwide. A copy of the DSUR should be submitted to each concerned European Member State (MS) if a clinical trial is authorized in this MS for this investigational drug (still using the DIBD). Therefore, the first DSUR can be submitted to a concerned MS earlier than 1 year, but the covered reporting period should not be longer than 1 year.
The DSUR presents an annual review & evaluation of safety information:
• Information reported during the current review period and analysis based on previous knowledge of the products’ safety
• Description of new issues that may impact the overall program or specific clinical trials.
• Summarization of current understanding and management of known and potential safety risks to exposed patients.
• Provide an update on the status of the clinical development program.
In Azierta, scientific and healthcare consulting, we are experts in Pharmacovigilance and we have a team of highly qualified drug safety experts who support our clients to manage pharmacovigilance in an optimal way. Our work covers all areas of pharmacovigilance, both at the level of medicines, as well as medical devices and cosmetic products.
If you are interested in the contents of the good practices of pharmacovigilance (GVPs), as well as in other products related to pharmacovigilance visit our safety reports website for more details and feel free to contact us, we will be pleased to help you.
Introduction to Aggregate Reporting in Drug Safety & Pharmacovigilance in Pharmaceuticals, Bio-Pharmaceuticals, Medical Devices, Cosmeceuticals and Foods.
Contact:
"Katalyst Healthcares & Life Sciences"
South Plainfield, NJ, USA
info@KatalystHLS.com
MedDRA - the Medical Dictionary for Regulatory Activities - is a medical terminology used to classify adverse event information associated with the use of biopharmaceuticals and other medical products (e.g., medical devices and vaccines). Coding these data to a standard set of MedDRA terms allows health authorities and the biopharmaceutical industry to more readily exchange and analyze data related to the safe use of medical products.
Importance of aggregate reporting in pharmacovigilanceSollers College
Pharmacovigilance is the science which deals with the activities related to the detection, assessment, understanding, and prevention of ADRs. The scope of Pharmacovigilance has evolved.
Reconciliation and Literature Review and Signal Detection_Katalyst HLSKatalyst HLS
Introduction Reconciliation and Literature Review and Signal Detection in Drug Safety & Pharmacovigilance in Pharmaceuticals, Bio-Pharmaceuticals, Medical Devices, Cosmeceuticals and Foods.
Contact:
"Katalyst Healthcares & Life Sciences"
South Plainfield, NJ, USA
info@KatalystHLS.com
The masking effect of measures of Disproportionality AnalysisFrancois MAIGNEN
Presentation on the three studies conducted on the masking effect of measures of disproportionality analysis (point estimates and confidence intervals).
Bertrand de Meulder-El impacto de las ciencias ómicas en la medicina, la nutr...Fundación Ramón Areces
El 29 de marzo de 2016 celebramos un Simposio Internacional sobre el 'Impacto de las ciencias ómicas en la medicina, nutrición y biotecnología'. Organizado por la Fundación Ramón Areces en colaboración con la Real Academia Nacional de Medicina y BioEuroLatina, abordó cómo un mejor conocimiento del genoma humano está permitiendo notables avances hacia una medicina de precisión.
This presentation is aimed at presenting the issues associated with subgroup analyses in clinical trials: the different types of subgroup analyses and the statistical issues associated with the conduct of subgroup analyses.
Clinical trials are the gold standard of evidence-based medicine. Properly designed clinical trials can lead to chance findings and potentially lead to erroneous conclusions.
Importantly, clinical trials can also be badly designed on purpose to increase the risk of false or chance findings leading to support misleading claims. Such techniques are frequently used by bad researchers and charlatans to substantiate their claims with biased clinical trials. It is therefore important to be weary of the limitations of clinical trials and understand how causal inference should be approach. In that presentation, I discuss the situations under which the risk of erroneous conclusions from clinical trials is increased and I discuss ways to identify and prevent bad clinical research.
The views expressed and presented in that presentation are my own views and may not represent the views of the National Institute for Health and Care Excellence.
Complex innovative trial designs are becoming increasingly used to improve the efficiency of the clinical development of new technologies. There is no agreed taxonomy of CID trials, these studies encompass a range of different approaches with some advantages but also some major drawbacks. This presentation discusses the issues associated with the conduct of complex innovative trial designs and the potential impact of CID trials on HTA methodological requirements and decisions.
The role of health technology assessment bodies in the value of cancer care i...Francois MAIGNEN
This presentation details the role of European HTA bodies in the value of new cancer therapies in Europe. The presentation also describes the NICE scientific advice activities and the activities of the HTA / regulatory parallel advice.
Clinical developments of medicines based on biomarkersFrancois MAIGNEN
The presentation provides an overview of the clinical development of new medicines based on biomarkers including basket, umbrella and platform trials. This is mostly relevant to oncology products.
This presentation explains the main features of medicines which will be developed and authorised via the adaptive pathways. It provides a definition of real world evidence and the caveats associated with the use and analysis of real world evidence in drug development.
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.
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
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
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.
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
HOT NEW PRODUCT! BIG SALES FAST SHIPPING NOW FROM CHINA!! EU KU DB BK substit...GL Anaacs
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We specializes in exporting high quality Research chemical, medical intermediate, Pharmaceutical chemicals and so on. Products are exported to USA, Canada, France, Korea, Japan,Russia, Southeast Asia and other countries.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
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!
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
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.
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.
Title: Sense of Taste
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 structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
Quantitative methods of Signal detection on spontaneous reporting systems - Seminar Paris V
1. An agency of the European Union
Signal detection: le point de vue
de l’EMA (EudraVigilance, CIOMS,
nouvelle legislation)
Ne soyez pas dupes … je vais vous donner MON point de
vue
Presented by: François MAIGNEN
Principal scientific administrator (PhvRM)
2. Presentation title (to edit, click View > Header and Footer)2
Introduction & Disclaimers
- Background (main objective of seminar)
- Conflicts of interests & disclaimer
- Apologies for the lack of French
- Learning objectives:
- Fundamentals Disproportionality analysis
- Evaluation / Comparison of the methods (limitations, stats vs
clinical)
- Fundamental issues included in CIOMS VIII / EudraVigilance
guideline on the use of signal detection methods in EudraVigilance
DAS: DMEs/TMEs/Medical confirmation/Prioritisation/Impact
analysis
- PITFALLS +++
4. Before we start … Let’s bet on horse racing …
Presentation title (to edit, click View > Header and Footer)4
5. Signal detection = horse racing
• You might want to bet on the horse which will win the race.
• You might want to find the top three / five horses which will
win the race.
• You might want to read a specialised newspaper to find out
about each of the horse which will enter the race (pedigree,
jockey, owner, previous records, track, form, …).
• You will possibly use the odds to help you to decide (4:1 what
is % of bets backing a win of this horse?). An outsider might
win the race (more money).
• It is always easier to comment once the race is over than
finding the correct combination BEFORE the race starts.
5
7. 7
7
Measures of disproportionate reporting
Most of the methods routinely used in pharmacovigilance
(spontaneous reporting systems) databases are based on
measures of disproportionate reporting (i.e. ROR, PRR, BCPNN,
MGPS, etc …).
Basically: “Observed vs Expected” analysis in a given database
i.e. % of reports involving a given reaction for a given medicine
compared to the % of reports involving this reaction on the
whole database
8. 8
8
A spontaneous reporting system database
SRS Drug 1 Drug 2 Drug 3 Drug 4 Drug 5 Drug 6 Drug 7 … Drug N
Event 1 n11 n12 n13 n14 n15 n16 n17 … n1N
Event 2 n21 n22 n23 n24 n25 n26 n27 … n2N
Event 3 n31 n32 … … … … … … n3N
Event 4 n41 n42 … … … … … … n4N
Event 5 n51 n52 … … … … … … n5N
Event 6 n61 n62 … … … … … … n6N
… … … … … … … … … …
Event P nP1 nP2 nP3 nP4 nP5 nP6 nP7 … nPN
9. Proportional Reporting Ratio
9
Drug 1 All other
medicinal
products
Total
Event 1 a c
All other
reaction
terms
b d
Total
N = a +
b + c + d
c + d
a + c
a + b
10. 1010
Proportional Reporting Ratio
PRR = a/(a+b) / c/(c+d) WHAT DOES THAT MEAN IN
PRACTICAL TERMS?
a/(a+b) = Proportion of reports involving a specific adverse
event among all the reports involving DRUG A
c/(c+d) = Proportion of reports involving THE SAME adverse
event among all the reports of your database but DRUG A
11. 1111
Proportional Reporting Ratio
If the rate of reporting of AE for drug 1 is similar to the rate of
reporting of this AE for all the other products of the database,
the PRR will be equal to 1 (same proportion of reports involving
the reaction for drug A than for the other drugs) …
BUT … If the reaction is proportionately MORE reported with
drug A than for the other products, the PRR will be increased
(typically > 1).
DIS-PROPORTIONALITY of reporting
12. 1212
Disproportionality analysis (example)
. CNS drug for which the total No of reports is 400, of these 20
reports of diarrhoea
. All other products in the database (1 million reports excluding
reports involving drug A), of these 50,000 reports of diarrhoea.
PRR = [20/400] / [50,000/1,000,000] = 1 (no SDR)
13. 1313
Disproportionality analysis (example)
CNS drug for which the total No of reports is 400, of these 40
reports of drowsiness
. All other products in the database (1 million reports excluding
reports involving drug A), of these 25,000 reports of diarrhoea.
PRR = [40/400] / [25,000/1,000,000] = 4 (presence of a SDR)
14. Strong underlying assumptions
- Association between a true risk and reporting of this risk (not
always true i.e. notoriety bias)
- Similar under-reporting for products across the database (not
true)
- Role of the confounding (indication, underlying disease)
14
15. 15
Improvements of these methods
•Considering possible confounding factors:
stratification and log-linear models (ROR – see work
from E. Van Puijenbroek)
•Trying to circumvent low expected values or low
case counts: Bayesian models (A. Bate & W.
DuMouchel)
•Other regression methods: LASSO and Bayesian
logistic regressions (N. Noren, D. Madigan)
•Public Health relevance not always clear or
demonstrated
•Some methods can be computationally demanding
16. 16
Bayesian methods
BCPNN and MGPS rely on the same principle of conjugate prior
distributions:
•These methods will shrink the value of the measure of
disproportionality using a Bayesian approach (prior based on
existing dataset)
•BCPNN: cell counts ~ Binomial dist., conjugate prior = beta
•MGPS: cell counts ~ Poisson, conjugate prior = Gamma
(mixture of Gammas).
FUNDAMENTALLY SAME PRINCIPLE AS DA +++
18. 1818
Thresholds - ARBITRARY
All these methods provide a ranking …
Thresholds = arbitrary
Trade-off between
•Reviewing too many drug-event pairs
(loss of operational benefit)
•Missing some signals
No ADR ADR
19. Limitations of the quantitative methods
19
The concept of threshold implies that not all the
reports will be reviewed and the quantitative
methods will not detect all the signals (for which
the data have been reported to the database on
which the DMA is used)
See Importance of reporting negative findings in
data mining – the example of exenatide and
pancreatitis Pharm Med 2008; 22(4): 215-219).
20. 2020
Comparison of the methods
Methodological difficulties
No gold standard / no standardised reference method (in many
instances “traditional methods of PhV”)
Imprecision of what constitutes a signal
Retrospective vs prospective evaluation
Importance of clinical judgement. The added value of clinical
evaluation is currently unknown (if any).
22. 2222
Performances of these methods
Operational benefit (screening of large databases)
Anecdotal evidence (in opposition to structured) of signals
discovered thanks to the quantitative methods (recent
examples incl. D:A:D and MI)
Time benefit in some cases (Hochberg & EV study)
NND ~ 7/15 (depending whether the study is retrospective or
prospective)
Idea: Quant. Methods + DMEs/TMEs
23. 2323
New approaches to signal detection
Deviation of Obs. vs Expect. distr. from a fitted distribution
(Jim)
Modelling of the hazard function of the time to onset (DSRU /
François) hazard # mechanism
Use of longitudinal databases (record linkage and electronic
health records – OMOP / Noren / Callreus) ~ incidence rate
ratio
• Same patients different time windows (A. Bate)
• Hospital records of different patients (T. Callreus)
25. 25
Hazard fcts of parametric survival dist.
Kalbfleisch and Prentice. The statistical analysis of failure time
data. Second ed. Wiley and sons.
26. Reported hazard of occurrence: a phenomenon
involving several mechanisms
26
P(occur.)*P(diag./occur.)*P(rep./diag.)(1)
P = prob. failure conditional on survival until
time t.
Lim f(x)*g(x) = Lim f(x)*Lim g(x)
Then when we take Lim t -> 0 (1) becomes.
h(occur.)*h(diag./occur.)*h(rep./diag.)
PD
Toxicology profile
Efficacy / duration tt
Monitoring and
“RM” activities
Awareness
Awareness
Reporting mechanisms
27. 27Presentation title (to edit, click View > Header and Footer)
Liver injuries reported with bosentan (KM)
29. Bosentan – liver injuries
29
Logical course of events some occurrences need
careful interpretation (blood bilirubin inc. and
[hyper]bilirubinemia)
Pattern AST/ALT unusual for liver injuries (but
not for mitochondrial injuries from hepatocytes)
but consistent with clinical safety data
Residual and constant risk of liver failure
Consistent with the putative mechanism of
toxicity (dose-dpt)
Consistent with the safety profile of bosentan
(lack of independence)
Influence of the risk minimisation activities
32. The fundamental difference between a SDR
and a signal +++
32
•PRR is a measure of disproportionality of reporting in a specific
database (observed vs expected value computed on the whole
database)
•The disproportionality analysis is not an inferential exercise (i.e.
the method is not aimed at drawing conclusions about a parent
population on the basis of evidence obtained from a random
sample from this population).
•These “REPORTED statistical associations” detected by
the quantitative methods do not imply any kind of causal
relationship between the administration of the drug and
the occurrence of the adverse event.
33. Different concepts / different definitions
33
SDR (signal of disproportionate reporting): refer to drug-
event pairs highlighted by DMAs. (see EMEA guideline)
NOTE: The term SIGNAL in SDR will not be retained by the
CIOMS VIII.
Signal: A signal is information on an adverse event that is
new or incompletely documented that may have causal
relationship to treatment and is recognized as being
worthy of further explorations (see CIOMS VIII). The SDRs
must be systematically medically confirmed.
(Identified) Risk: An untoward occurrence for which there
is adequate evidence of an association with the medicinal
product of interest (see Guideline on risk management
systems for medicinal products for human use
EMEA/CHMP/96268/2005).
34. 34Presentation title (to edit, click View > Header and Footer)
DMA
Database (drug-events
pairs)
SDRs
SIGNALS
SIGNALS
(other data sources)
Medical judgement
RISKS
Further evaluation / characterisation
Regulatory
action
NO
35. 35
Process flow included in the
EMEA guideline on the use of
statistical methods implemented
in the EV data analysis system
(EMEA/106464/06) July 2008.
39. Data capture and data management (1)
39
Fundamental but not in the scope of CIOMS VIII
IT infrastructure and software
The volume of information hence the data
management activities (data coding, entry,
recoding, data quality) is extremely resource
demanding.
Data management will have a critical influence
on the signal detection activities incl.
• Medicinal product information: creation and maintenance
of dictionaries, lack of international standard, absence of
INN or standards in some instances e.g. vaccines
• Medical terminology: criteria for the use of terms,
conversion of legacy data encoded with a different
terminology, …
• Data quality: FUp, duplicates
45. Signal management
45
• Similarly the CIOMS has identified a signal
management step which includes:
• Triage
• Prioritisation and impact analysis
• Evaluation
• Decision
• Communication (broad sense)
• Follow-up
• Link with risk management
46. FUNDAMENTAL QUESTION OF IMPACT
ANALYSIS
NO VALIDATED METHOD. Assess the Public Health impact of the
signal:
Usually:
-Seriousness
-Frequency of occurrence (absence of evidence is NOT evidence
of absence)
-Particular population at risk
-“worst case scenario” (what would happen if … ?)
-Preventability, reversibility, etc …
46
48. 48
Signal prioritisation and serious medical
events: reported rate of fatality as a
prioritisation variable
About the EV-EWG IME list and lists of IMEs in general (e.g.
CIOMS V)
Useful but purpose not always clear (early signal detection?
Focus the detection? Signal prioritisation?)
Based on expert’s judgment
Has not been formally “validated” / tested (no standards)
Probably situation dependant
49. 49
Concept of seriousness # linked to the
outcome # surrogate for grading the severity
of the reactions hence prioritisation
Grading in seriousness: death >> disability (permanent) >>>
life-threatening >>> disability (temp.) >> prolongation hosp.
Variable linked to fatal outcome = reported rate of fatality
For each drug-event pair = No of reported fatal cases / total
number of reported cases
Computed for the intensively monitored products
Reaction 1 Reaction 2 Reaction 3 Outcome (incl. fatal)
Surrogate to predict the outcome
50. 50
Hazardous identification of serious events a
priori
Some examples of reactions not usually considered to be
serious per se which can be linked to most dramatic outcomes
(e.g. dramatic increases of liver aminotransferases e.g. >100
ULN leading to liver failure, liver transplant and death)
Exhaustion/
tiredness
Jaundice
incr. aminotransferases 500ULN
hyperbilirubinemia
Liver transplant Death
Prioritise these events on the associated reported outcome (here death)
51. 51
Reported rate of fatality
Some reactions may be consistently linked to a high reported
mortality rate
Some reactions are serious but do not lead to a fatal outcome
Some reactions are situation dependent (the reported rate of
fatality may be highly variable)
For each of the MedDRA PT involved in a DEC in EudraVigilance,
the following variables were computed across all the products
involved in the reported combinations:
• Mean, min., max., range: max. – min., SD
52. 52
How does it relate to IME status?
Reported rate of fatality for
IMEs > non-IMEs
Number of events for which the
reported rate is high which are
non-IMEs
Very high number of IMEs for
which the reported rate of
fatality is zero.
IMEs useful for prioritisation?
The figure displays the boxplot of the average reported rate of fatality for non-IMEs (left)
compared to IMEs (right) (red and blue line = mean rate for non-IMEs (red) vs IMEs (blue))
55. Liver injuries
Clear relation between Reported rate # seriousness of injury
and the severity of the outcome
Highest mean rate around 30% (1/3 fatal reports) with a max.
at 75% (3/4)
Some inconsistencies (bilirubin disorders: hyperbilirubinaemia
18.7%, blood bilirubin increased 16.2%, blood bilirubin
unconjugated increased 6.7% and bilirubin conjugated
increased 6.3%)
Unclear or undefined concepts (liver disorders [?]) linked to a
fairly high mean reported rate 18.9%, hepatic function
abnormal 8.5% and liver function test (singular) abnormal
9.1%.
57. 57
Discussion
Three set of events used for signal detection: mild reported rate
of mortality, moderate and high
Reported rate of fatality can be useful (and should be used) for
signal prioritisation
Needs to be considered with caution (events with rate of zero
include e.g. Torsade de pointes, autism, Breast cancer in situ,
Breast cancer stage I, Dermatitis exfoliative)
Does not replace DMEs
Death is not the only criterion which could be used
EudraVigilance = only serious reactions(!)
Some events are consistently associated either with low rate or
conversely with very high rate
59. 59
Masking effect of measures of
disproportionality (here = PRR)
The masking effect has first been described and identified by Gould in
spontaneous reporting system databases (pharmacoepidemiology and
drug safety in 2003 – 8 years ago).
The masking is a statistical artefact by which true signals are hidden by
the presence of information reported with other medicines in the
database. Therefore, the masking involves one given reaction and two
products (the product for which the DA is conducted) and a possible
masking drug.
The masking effect is a potentially important issue for Public Health
which is not perfectly understood or perfectly quantified: some signals
might be missed or identified with delay because of the presence (or a
suspicion on the presence) of masking effect.
60. 60
Masking effect of measures of
disproportionality
In particular, there is no algorithm to identify the potential
masking drugs to remove them from subsequent analyses
aimed at identifying new signals using the statistical methods of
signal detection based on disproportionality analysis.
We have developed an algorithm based on the computation of a
simple The masking ratio has been developed to be intuitive.
The highest masking drugs have the highest masking ratio.
From an underlying mathematical framework, we have
developed a simple expression of the masking ratio (which can
be easily computed on a database incl. No of computations and
IT resources) which allow a fairly rapid identification of the main
culprits.
62. 62
Masking effect of measures of
disproportionality
Recent studies have shown effects which were suspected from
the article by Gould, that masking products are usually products
for which the given reaction is known (i.e. listed in the SPC),
therefore likely to have a high PRR (in the database in which
the analysis is conducted) for the adverse drug event / reaction
which is included in the disproportionality analysis.
Unfortunately, the authors could not conclude on any algorithm
considering that this association is not systematically present
(not all products with high PRR will induce a significant masking
even if he masking generally involves products with a high
PRR).
63. 63
Masking effect of measures of
disproportionality (RRR)
Respective proportion of reports in
the database influences the extent
of the masking
The higher the proportion of reports
involving a product for a given
reaction the higher the masking
The lower the proportion involving a
given product over the total number
of reports in the database, the
higher the masking
65. 65
Relation between the masking effect and the
PRR (of the masking medicinal product for the
given event)
MR > 1
PRR > 2
66. 66
The highest masking is
induced by products known
to induce the given reaction
(and for which the PRR is
likely to be increased)
Products of the same class
induce the highest masking
for similar reactions
(gambling – ropinirole and
pathological gambling –
cabergoline, Fanconi
syndromes, role of drug-
drug interactions –
rifampicin)
68. FUNDAMENTAL ISSUES: take home messages
- Image of horse racing
-Most of the methods rely on disproportionality analysis: strong
underlying assumptions
-SDRs: statistical association : needs to be systematically
medically confirmed
-Process flow: PRIORITISATION & IMPACT ANALYSIS
-PITFALLS: METHOD (e.g. masking), prioritisation (e.g. IMEs)
-Importance of strategy incl. DMEs / TMEs
-PRIOR MEDICAL KNOWLEDGE (Prepared mind)
68