This document discusses detecting cardiac safety signals from drugs. Common drug-related safety issues can be detected in clinical trials by comparing rates to background. Rare but severe issues sometimes appear in trials or are detected by biomarkers or epidemiological studies. Spontaneous increased event rates with a drug usually require a large controlled trial or meta-analysis to interpret. QT prolongation is a safety biomarker and rare torsade de pointes requires alternative risk assessment methods. Diabetes drugs require evaluation of cardiovascular risk through clinical trial design. Acceptable risk bounds are defined to determine if post-marketing studies are needed. Groups like Cardio-Oncology and the Cardiac Safety Research Consortium conduct research on these issues.
This document discusses several case studies that illustrate potential proarrhythmic effects of antiarrhythmic drugs:
1) A man experienced recurrent dizzy spells after being started on metoprolol in addition to his long-term quinidine and digoxin treatment. Monitoring revealed drug interactions had caused excessive bradycardia.
2) A farmer's atrial flutter worsened when started on flecainide due to paradoxical acceleration of his ventricular rate.
3) An elderly woman developed sinus bradycardia and QT prolongation after starting sotalol, resulting in nonsustained ventricular tachycardia due to her underlying renal impairment.
The case studies demonstrate the importance of
Patient undergoing non-cardiac surgery represents an opportunity to assess cardiac risk both in the short and long term. A full evaluation should be performed to understand prognosis and any need for treatment of underlying cardiac conditions or risks. The referring physician should be informed of the evaluation results and their implications. Patients should not be described as simply "cleared for surgery".
This document discusses targeted temperature management (TTM) for patients after cardiac arrest. It provides an overview of post-cardiac arrest syndrome and complications. The goals of treatment are to identify and treat the cause of cardiac arrest, minimize brain damage, treat cardiovascular dysfunction, and manage complications from ischemia and reperfusion injury. Therapeutic hypothermia, including mild, moderate and deep hypothermia, aims to lower body temperature and involves several steps of induction, maintenance and rewarming. Clinical trials have studied TTM outcomes but more research is still needed. The document also covers seizure monitoring and control in post-cardiac arrest patients.
This document provides guidelines for the management of ST-elevation myocardial infarction (STEMI) from the 2017 European Society of Cardiology. It outlines recommendations for emergency care, reperfusion strategies including primary percutaneous coronary intervention (PCI) and pharmacoinvasive strategies. It also discusses adjunctive therapies, imaging, long-term drug therapies, and new concepts in the 2017 version compared to 2012, including the management of myocardial infarction with non-obstructive coronary arteries (MINOCA). The guidelines emphasize short timelines for reperfusion and emphasize radial access and new generation drug-eluting stents for primary PCI.
FDA 2013 Clinical Investigator Training Course: The Investigator as Collabora...MedicReS
FDA 2013 Clinical Investigator Training Course: The Investigator as Collaborator in Promoting the Clinical Research Enterprise
Neil J. Weissman, M.D., MedStar Health Research Institute
FDA 2013 Clinical Investigator Training Course: How to put together an Applic...MedicReS
This document provides an overview of a presentation by Dr. Donald Fink on preparing an Investigational New Drug (IND) application for submission to the Center for Biologics Evaluation and Research (CBER) at the FDA, focusing on the requirements for the Chemistry, Manufacturing and Controls (CMC) section of the application for cellular therapy products. The presentation outlines the key information to include in the CMC section regarding manufacturing processes, product characterization, release testing, and stability testing in order to demonstrate consistent production of the cellular therapy product. Contact information is also provided for individuals at CBER who can answer regulatory questions regarding IND submissions.
This document discusses detecting cardiac safety signals from drugs. Common drug-related safety issues can be detected in clinical trials by comparing rates to background. Rare but severe issues sometimes appear in trials or are detected by biomarkers or epidemiological studies. Spontaneous increased event rates with a drug usually require a large controlled trial or meta-analysis to interpret. QT prolongation is a safety biomarker and rare torsade de pointes requires alternative risk assessment methods. Diabetes drugs require evaluation of cardiovascular risk through clinical trial design. Acceptable risk bounds are defined to determine if post-marketing studies are needed. Groups like Cardio-Oncology and the Cardiac Safety Research Consortium conduct research on these issues.
This document discusses several case studies that illustrate potential proarrhythmic effects of antiarrhythmic drugs:
1) A man experienced recurrent dizzy spells after being started on metoprolol in addition to his long-term quinidine and digoxin treatment. Monitoring revealed drug interactions had caused excessive bradycardia.
2) A farmer's atrial flutter worsened when started on flecainide due to paradoxical acceleration of his ventricular rate.
3) An elderly woman developed sinus bradycardia and QT prolongation after starting sotalol, resulting in nonsustained ventricular tachycardia due to her underlying renal impairment.
The case studies demonstrate the importance of
Patient undergoing non-cardiac surgery represents an opportunity to assess cardiac risk both in the short and long term. A full evaluation should be performed to understand prognosis and any need for treatment of underlying cardiac conditions or risks. The referring physician should be informed of the evaluation results and their implications. Patients should not be described as simply "cleared for surgery".
This document discusses targeted temperature management (TTM) for patients after cardiac arrest. It provides an overview of post-cardiac arrest syndrome and complications. The goals of treatment are to identify and treat the cause of cardiac arrest, minimize brain damage, treat cardiovascular dysfunction, and manage complications from ischemia and reperfusion injury. Therapeutic hypothermia, including mild, moderate and deep hypothermia, aims to lower body temperature and involves several steps of induction, maintenance and rewarming. Clinical trials have studied TTM outcomes but more research is still needed. The document also covers seizure monitoring and control in post-cardiac arrest patients.
This document provides guidelines for the management of ST-elevation myocardial infarction (STEMI) from the 2017 European Society of Cardiology. It outlines recommendations for emergency care, reperfusion strategies including primary percutaneous coronary intervention (PCI) and pharmacoinvasive strategies. It also discusses adjunctive therapies, imaging, long-term drug therapies, and new concepts in the 2017 version compared to 2012, including the management of myocardial infarction with non-obstructive coronary arteries (MINOCA). The guidelines emphasize short timelines for reperfusion and emphasize radial access and new generation drug-eluting stents for primary PCI.
FDA 2013 Clinical Investigator Training Course: The Investigator as Collabora...MedicReS
FDA 2013 Clinical Investigator Training Course: The Investigator as Collaborator in Promoting the Clinical Research Enterprise
Neil J. Weissman, M.D., MedStar Health Research Institute
FDA 2013 Clinical Investigator Training Course: How to put together an Applic...MedicReS
This document provides an overview of a presentation by Dr. Donald Fink on preparing an Investigational New Drug (IND) application for submission to the Center for Biologics Evaluation and Research (CBER) at the FDA, focusing on the requirements for the Chemistry, Manufacturing and Controls (CMC) section of the application for cellular therapy products. The presentation outlines the key information to include in the CMC section regarding manufacturing processes, product characterization, release testing, and stability testing in order to demonstrate consistent production of the cellular therapy product. Contact information is also provided for individuals at CBER who can answer regulatory questions regarding IND submissions.
FDA 2013 Clinical Investigator Training Course: Clinical pharmacology 2: Clin...MedicReS
FDA 2013 Clinical Investigator Training Course: Clinical pharmacology 2: Clinical Considerations During Phase 2 and Phase 3 of Drug Development
Kellie Reynolds, Pharm.D.,(CDER)
FDA 2013 Clinical Investigator Training Course Preparing an IND Application: ...MedicReS
FDA 2013 Clinical Investigator Training Course Preparing an IND Application: Preclinical Considerations for Cell and Gene Therapy Products
Patrick Au, Ph.D., (CBER)
FDA 2013 Clinical Investigator Training Course: Clinical Investigator Inspect...MedicReS
FDA conducts two types of clinical investigator inspections: routine inspections and for-cause inspections directed at a specific issue or concern. During inspections, FDA issues Form FDA 482 to notify of the inspection and Form FDA 483 with any inspectional observations. After the inspection, investigators may respond to Form FDA 483 and FDA issues an Establishment Inspection Report and determines whether further action is indicated, which could include a warning letter or disqualification proceedings.
FDA 2013 Clinical Investigator Training Course: Biosimilar Biological ProductsMedicReS
This document provides an overview of biosimilar biological products from a presentation given by Dr. Sue Lim of the FDA. It defines biological products and biosimilars. Biosimilars are developed using a stepwise approach to demonstrate biosimilarity to a reference product through analytical, nonclinical and clinical studies. Clinical study design considerations for biosimilars include using endpoints sensitive to potential differences, assessing products at time points most likely to detect differences, using the same or similar patient populations and doses as the reference product, and evaluating safety including immunogenicity over a duration adequate to detect potential impacts.
FDA 2013 Clinical Investigator Training Course: Preparing an IND Application:...MedicReS
FDA 2013 Clinical Investigator Training Course: Preparing an IND Application: Clinical Considerations for Cell and Gene Therapy Products
Rachel Witten, M.D., (CBER)
FDA 2013 Clinical Investigator Training Course: How do I put together an IND ...MedicReS
This document provides guidance on submitting an Investigational New Drug (IND) application to the FDA. It defines key terms related to INDs and clinical investigations. It outlines when an IND is required and exceptions. The major components of an IND are described, including a cover letter, forms, clinical and non-clinical sections with protocols, chemistry data, and pharmacology/toxicology information. Tips are provided on formatting, submitting, and the review process within the first 30 days. Resources for IND guidance and assistance are also listed.
Thalidomide was a sedative that was prescribed to pregnant women in the late 1950s to treat morning sickness. It was later found to cause severe birth defects in over 10,000 babies worldwide, with malformed limbs being the most common defect. Thalidomide was withdrawn from the market in 1961 after the link to birth defects was established. This tragedy highlighted the need for rigorous safety testing of drugs, especially for teratogenic effects, and led to the establishment of regulatory frameworks for drug approval and pharmacovigilance systems like the Yellow Card Scheme to monitor adverse drug reactions.
Drug-induced priapism is a persistent penile erection lasting more than four hours that is not associated with sexual stimulation. It most commonly occurs with antipsychotic medications and requires immediate medical attention to prevent long-term complications. Patients prescribed medications known to cause priapism should be advised of the signs and symptoms. Some medications should not be removed from their original packaging, as this may impact the medication's effectiveness and safety due to exposure to heat, air, light, or moisture. Medication storage and handling precautions are important to follow in order to maintain proper medication stability and avoid potential adverse effects.
Various forms of contrast media have been used to improve medical imaging.
• Their value has long been recognized, as attested to by their common daily use
in imaging departments worldwide.
• Like all other pharmaceuticals, however, these agents are not completely devoid
of risk.
• Adverse side effects from the administration of contrast media vary from minor
physiological disturbances to rare severe life-threatening situations.
• Preparation for prompt treatment of contrast media reactions must include
preparation for the entire spectrum of potential adverse events and include
prearranged response planning with availability of appropriately trained
personnel, equipment, and medications.
• Thorough familiarity with the presentation and emergency treatment of
contrast media reactions must be part of the environment in which all
intravascular contrast media are administered.
The document discusses the Yellow Card Scheme in the UK for reporting adverse drug reactions (ADRs). It defines an ADR and describes how common ADRs are, causing 6.5% of adult hospital admissions. It outlines how ADRs can be classified and factors that influence them. The Yellow Card Scheme acts as an early warning system to identify new ADRs and risks. Healthcare professionals, patients and the public can report suspected ADRs to the scheme to help continual drug safety monitoring.
Part of our assignment in which we have to make a paperwork and presentation of a few sub-topics (hepatotoxicity, renal toxicity, neurotoxicity, skeletal-muscle-toxicity) under the topic of Drug-induced Toxicity.
Paperwork can be found in: http://www.slideshare.net/annisahayatunnufus/druginduced-toxicity-liver-kidney-nervous-system-muscle-54844837
Students of Bachelor of Pharmacy
Management & Science University
This document discusses cardiovascular toxicity that can result from cancer treatments. It covers 9 main categories of cardiovascular complications and focuses on myocardial dysfunction and heart failure, which are among the most common side effects. Several chemotherapy agents, targeted therapies, and radiotherapy can cause heart failure by damaging heart tissue through oxidative stress or other mechanisms. Regular cardiac monitoring is important for early detection of issues so they can be managed to prevent further deterioration.
Anxiety disorder and medical comorbidityAndri Andri
This document discusses the relationship between anxiety disorders and medical comorbidities. It begins by outlining the talk and reviewing the epidemiology of anxiety disorders. It then examines how anxiety can be both primary or secondary to medical conditions and substance abuse. Several studies are cited showing links between anxiety and increased risks of heart disease, respiratory illness, and gastrointestinal problems. The document also reviews treatment approaches for anxiety disorders like SSRIs, SNRIs, benzodiazepines, and cognitive behavioral therapy. It provides efficacy evidence and tolerability profiles for sertraline and alprazolam in particular. Finally, it emphasizes that treating anxiety in medically ill patients can improve disease management and reduce risks.
This document describes a case of streptokinase-induced anaphylaxis in a 40-year-old male patient admitted for sudden severe chest pain. After being pre-medicated, the patient was given streptokinase which is a thrombolytic agent. After 30 minutes, the patient developed hypotension and vomiting. Epinephrine was administered and the patient was diagnosed with anaphylaxis from streptokinase. The patient was treated with antihistamines and steroids and recovered without further issues. The document then discusses anaphylaxis, streptokinase reactions, Kounis syndrome which is a condition where allergic reactions can induce myocardial infarction, and treatment approaches.
This document discusses the toxicities of targeted cancer therapies. It begins by defining targeted therapy and describing the ideal features of an anticancer target. It then outlines several common toxicities of targeted therapies including cardiovascular issues like hypertension and ventricular dysfunction, QTc prolongation, thromboembolic complications, and various skin toxicities. Specific mechanisms, risk factors, management strategies, and monitoring approaches are described for each toxicity.
FDA 2013 Clinical Investigator Training Course: Clinical pharmacology 2: Clin...MedicReS
FDA 2013 Clinical Investigator Training Course: Clinical pharmacology 2: Clinical Considerations During Phase 2 and Phase 3 of Drug Development
Kellie Reynolds, Pharm.D.,(CDER)
FDA 2013 Clinical Investigator Training Course Preparing an IND Application: ...MedicReS
FDA 2013 Clinical Investigator Training Course Preparing an IND Application: Preclinical Considerations for Cell and Gene Therapy Products
Patrick Au, Ph.D., (CBER)
FDA 2013 Clinical Investigator Training Course: Clinical Investigator Inspect...MedicReS
FDA conducts two types of clinical investigator inspections: routine inspections and for-cause inspections directed at a specific issue or concern. During inspections, FDA issues Form FDA 482 to notify of the inspection and Form FDA 483 with any inspectional observations. After the inspection, investigators may respond to Form FDA 483 and FDA issues an Establishment Inspection Report and determines whether further action is indicated, which could include a warning letter or disqualification proceedings.
FDA 2013 Clinical Investigator Training Course: Biosimilar Biological ProductsMedicReS
This document provides an overview of biosimilar biological products from a presentation given by Dr. Sue Lim of the FDA. It defines biological products and biosimilars. Biosimilars are developed using a stepwise approach to demonstrate biosimilarity to a reference product through analytical, nonclinical and clinical studies. Clinical study design considerations for biosimilars include using endpoints sensitive to potential differences, assessing products at time points most likely to detect differences, using the same or similar patient populations and doses as the reference product, and evaluating safety including immunogenicity over a duration adequate to detect potential impacts.
FDA 2013 Clinical Investigator Training Course: Preparing an IND Application:...MedicReS
FDA 2013 Clinical Investigator Training Course: Preparing an IND Application: Clinical Considerations for Cell and Gene Therapy Products
Rachel Witten, M.D., (CBER)
FDA 2013 Clinical Investigator Training Course: How do I put together an IND ...MedicReS
This document provides guidance on submitting an Investigational New Drug (IND) application to the FDA. It defines key terms related to INDs and clinical investigations. It outlines when an IND is required and exceptions. The major components of an IND are described, including a cover letter, forms, clinical and non-clinical sections with protocols, chemistry data, and pharmacology/toxicology information. Tips are provided on formatting, submitting, and the review process within the first 30 days. Resources for IND guidance and assistance are also listed.
Thalidomide was a sedative that was prescribed to pregnant women in the late 1950s to treat morning sickness. It was later found to cause severe birth defects in over 10,000 babies worldwide, with malformed limbs being the most common defect. Thalidomide was withdrawn from the market in 1961 after the link to birth defects was established. This tragedy highlighted the need for rigorous safety testing of drugs, especially for teratogenic effects, and led to the establishment of regulatory frameworks for drug approval and pharmacovigilance systems like the Yellow Card Scheme to monitor adverse drug reactions.
Drug-induced priapism is a persistent penile erection lasting more than four hours that is not associated with sexual stimulation. It most commonly occurs with antipsychotic medications and requires immediate medical attention to prevent long-term complications. Patients prescribed medications known to cause priapism should be advised of the signs and symptoms. Some medications should not be removed from their original packaging, as this may impact the medication's effectiveness and safety due to exposure to heat, air, light, or moisture. Medication storage and handling precautions are important to follow in order to maintain proper medication stability and avoid potential adverse effects.
Various forms of contrast media have been used to improve medical imaging.
• Their value has long been recognized, as attested to by their common daily use
in imaging departments worldwide.
• Like all other pharmaceuticals, however, these agents are not completely devoid
of risk.
• Adverse side effects from the administration of contrast media vary from minor
physiological disturbances to rare severe life-threatening situations.
• Preparation for prompt treatment of contrast media reactions must include
preparation for the entire spectrum of potential adverse events and include
prearranged response planning with availability of appropriately trained
personnel, equipment, and medications.
• Thorough familiarity with the presentation and emergency treatment of
contrast media reactions must be part of the environment in which all
intravascular contrast media are administered.
The document discusses the Yellow Card Scheme in the UK for reporting adverse drug reactions (ADRs). It defines an ADR and describes how common ADRs are, causing 6.5% of adult hospital admissions. It outlines how ADRs can be classified and factors that influence them. The Yellow Card Scheme acts as an early warning system to identify new ADRs and risks. Healthcare professionals, patients and the public can report suspected ADRs to the scheme to help continual drug safety monitoring.
Part of our assignment in which we have to make a paperwork and presentation of a few sub-topics (hepatotoxicity, renal toxicity, neurotoxicity, skeletal-muscle-toxicity) under the topic of Drug-induced Toxicity.
Paperwork can be found in: http://www.slideshare.net/annisahayatunnufus/druginduced-toxicity-liver-kidney-nervous-system-muscle-54844837
Students of Bachelor of Pharmacy
Management & Science University
This document discusses cardiovascular toxicity that can result from cancer treatments. It covers 9 main categories of cardiovascular complications and focuses on myocardial dysfunction and heart failure, which are among the most common side effects. Several chemotherapy agents, targeted therapies, and radiotherapy can cause heart failure by damaging heart tissue through oxidative stress or other mechanisms. Regular cardiac monitoring is important for early detection of issues so they can be managed to prevent further deterioration.
Anxiety disorder and medical comorbidityAndri Andri
This document discusses the relationship between anxiety disorders and medical comorbidities. It begins by outlining the talk and reviewing the epidemiology of anxiety disorders. It then examines how anxiety can be both primary or secondary to medical conditions and substance abuse. Several studies are cited showing links between anxiety and increased risks of heart disease, respiratory illness, and gastrointestinal problems. The document also reviews treatment approaches for anxiety disorders like SSRIs, SNRIs, benzodiazepines, and cognitive behavioral therapy. It provides efficacy evidence and tolerability profiles for sertraline and alprazolam in particular. Finally, it emphasizes that treating anxiety in medically ill patients can improve disease management and reduce risks.
This document describes a case of streptokinase-induced anaphylaxis in a 40-year-old male patient admitted for sudden severe chest pain. After being pre-medicated, the patient was given streptokinase which is a thrombolytic agent. After 30 minutes, the patient developed hypotension and vomiting. Epinephrine was administered and the patient was diagnosed with anaphylaxis from streptokinase. The patient was treated with antihistamines and steroids and recovered without further issues. The document then discusses anaphylaxis, streptokinase reactions, Kounis syndrome which is a condition where allergic reactions can induce myocardial infarction, and treatment approaches.
This document discusses the toxicities of targeted cancer therapies. It begins by defining targeted therapy and describing the ideal features of an anticancer target. It then outlines several common toxicities of targeted therapies including cardiovascular issues like hypertension and ventricular dysfunction, QTc prolongation, thromboembolic complications, and various skin toxicities. Specific mechanisms, risk factors, management strategies, and monitoring approaches are described for each toxicity.
This document discusses the management of hypertensive crises. It defines hypertensive crises as acute elevations in blood pressure associated with end-organ damage, requiring immediate blood pressure reduction. Hypertensive urgencies involve severely elevated blood pressure without acute end-organ damage, allowing more gradual blood pressure lowering. The document reviews the epidemiology, etiology, clinical manifestations, and initial therapeutic approach for hypertensive crises and urgencies.
The document discusses hypertension, noting that its prevalence is increasing worldwide and discusses its classification, treatment options including various classes of antihypertensive drugs and their mechanisms of action, experimental models used to study hypertension, and approaches to it in Ayurveda.
Hello friends. In this PPT I am talking about adverse drug effects. If you like it, please do let me know in the comments section. A single word of appreciation from you will encourage me to make more of such videos. Thanks. Enjoy and welcome to the beautiful world of pharmacology where pharmacology comes to life. This video is intended for MBBS, BDS, paramedical and any person who wishes to have a basic understanding of the subject in the simplest way.
This document summarizes a study examining medical and neurological complications in 279 patients with acute ischemic stroke. The study found that 95% of patients experienced at least one complication. The most common serious medical complication was pneumonia (5%) and the most common serious neurological complication was new or extended cerebral infarction (5%). Medical complications contributed to 51% of deaths within 3 months. Patients with serious medical complications had significantly worse outcomes on functional scales even after accounting for baseline differences.
The Effect of Long Term Smoking as an Independent Coronary Risk
Factor on Myocardial Perfusion Detected by Thallium 201 or Tc99m Sestamibi Spect Study. Samir Rafla*, Ahmed Ibrahim Abdel-Aaty, Mohammed Ibrahim Lotfy and Riham Gamal
This presentation discusses adverse drug reactions (ADRs). It defines ADRs and outlines methods for classifying, identifying, and reporting ADRs. It also discusses epidemiology of medication errors and ADRs, provides examples of important ADRs, and explains how to manage and find further information on ADRs. The presentation is intended to inform healthcare professionals about ADRs.
This document discusses hypertensive crises, including definitions, epidemiology, pathophysiology, assessment, diagnosis, and management. It defines hypertensive emergencies as elevated blood pressure with acute end-organ damage, while hypertensive urgencies involve impending end-organ damage. The typical patient presenting with crisis is middle-aged, noncompliant with medications, and may use substances. Treatment of emergencies requires immediate blood pressure reduction in the ICU to prevent further damage, while urgencies can be treated gradually as uncontrolled hypertension. Nitroprusside is very effective but has limitations like toxicity risks with prolonged use.
1. The document provides guidelines for categorizing TB cases and treatment regimens under the Revised National Tuberculosis Control Programme (RNTCP) in India. It describes 5 categories of TB cases and their standard treatment regimens.
2. The document also summarizes various adverse drug reactions associated with anti-TB medications, their causative agents, clinical presentations, and management guidelines. It provides treatment guidelines for special groups including children, pregnant women, HIV patients, and those with comorbidities.
3. Guidelines are given for diagnosis and treatment of MDR-TB and XDR-TB cases. Standardized treatment regimens are recommended depending on drug susceptibility testing results and previous treatment history. Strict treatment
Approach to the severe hypertension (3)AnjaniJha10
This document discusses the management of severe hypertension. It defines severe hypertension as blood pressure above 180/110 mmHg that can cause acute organ damage, termed a hypertensive emergency. The main points are:
1. Severe hypertension requires immediate treatment to prevent progressive organ injury, while less severe high blood pressure without organ damage can be managed in an outpatient setting.
2. Intravenous drugs like nicardipine and labetalol are used to lower blood pressure by no more than 25% in the first hour and to 160/100 mmHg in the next 2-6 hours to avoid hypotension.
3. Oral antihypertensives should be started 6-12 hours after intravenous
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Co-Chairs, Val J. Lowe, MD, and Cyrus A. Raji, MD, PhD, prepared useful Practice Aids pertaining to Alzheimer’s disease for this CME/AAPA activity titled “Alzheimer’s Disease Case Conference: Gearing Up for the Expanding Role of Neuroradiology in Diagnosis and Treatment.” For the full presentation, downloadable Practice Aids, and complete CME/AAPA information, and to apply for credit, please visit us at https://bit.ly/3PvVY25. CME/AAPA credit will be available until June 28, 2025.
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Breast cancer in postmenopausal women with hormone receptor-positive (HR+) status is a common and complex condition that necessitates a multifaceted approach to management. HR+ breast cancer means that the cancer cells grow in response to hormones such as estrogen and progesterone. This subtype is prevalent among postmenopausal women and typically exhibits a more indolent course compared to other forms of breast cancer, which allows for a variety of treatment options.
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Aromatase Inhibitors (AIs): These drugs, including anastrozole, letrozole, and exemestane, lower estrogen levels by inhibiting the aromatase enzyme, which converts androgens to estrogen in peripheral tissues. AIs are generally preferred in postmenopausal women due to their efficacy and safety profile compared to tamoxifen.
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Endocrine Therapy with mTOR Inhibitors: Everolimus, an mTOR inhibitor, can be added to endocrine therapy for patients who have developed resistance to aromatase inhibitors.
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FDA 2013 Clinical Investigator Training Course: Special Cardiac Safety Concerns
1. Special cardiac safety concerns
Shari L. Targum, MD, FACC,
FACP
Medical Team Leader
Division of Cardiovascular and
Renal Products, CDER, FDA
2. 2
Detecting safety signals in clinical trials
– Common, drug-related: can detect in controlled,
clinical trials
– Rare, severe, drug-related: sometimes detected in clinical trials
(e.g., Stevens-Johnson) or via
• risk biomarkers (e.g., QT prolongation) or
• epidemiologic studies (e.g., case-control)
– Spontaneous events ↑ rate with drug: single event usually not
interpretable; detect via
• large enough controlled trial
• epidemiologic study (large hazard ratio)
This talk will focus on latter two scenarios.
5. 5
QT interval
• Varies with heart rate, autonomic tone,
time of day
• Can be prolonged due to:
– heart disease (e.g., congestive heart failure)
– electrolyte abnormalities (e.g., hypokalemia)
– drugs (e.g., quinidine).
6. 6
Torsade de pointes: polymorphic
ventricular tachycardia
Rare, but life-threatening. Might not be detected
in a drug development program.
8. 8
Current QT policy
• Most systemically available drugs need a
“thorough QT” (TQT) study
• Threshold for potential clinical importance
set very low (10 msec)
• “Negative study” → routine phase 3
monitoring
• Failure to rule out 10 ms → heightened
phase 3 monitoring
9. 9
TQT Study Characteristics
• Includes placebo and positive control
• Characterize QT effects of the drug under
near “worst case” scenario
– Exposure at supratherapeutic concentrations
– ECG sampling at peak concentrations
(drug/metabolites)
– Sufficient duration of dosing/sampling to
characterize effects
10. 10
What if the study is positive?
• More intensive Phase 3 monitoring
• Might alter development (different
dose, different target population, etc.)
• Look for benefits that might offset risk
11. 11
Concerns about TQT studies
• QT studies difficult and expensive
• Relationship to risk (arrhythmia) not
constant
• Unknown public health consequences of
compounds removed from pharmaceutical
pipeline
• Interest in alternative approaches to
assess proarrhythmic risk.
14. 14
Appetite suppressants
• Fenfluramine (1973): approved for short-
term use
– racemic mixture*- increased serotonin,
associated with depression
• Dexfenfluramine (1996)* thought to be
“safer”
• Fen-Phen: never approved, widely used
off-label for long-term management
*withdrawn in 1997
19. 19
Rofecoxib (Vioxx)
• Originally approved (1999) for acute pain
(up to 5 days), dysmenorrhea, and
osteoarthritis (12.5 mg and 25 mg/day).
• Dose-related increase in hypertension and
edema were observed
• No cardiovascular signal observed at
approval.
20. 20
COX-2 inhibition
• Cyclooxygenase (COX): metabolize
arachidonic acid to produce
prostaglandins (PG)
• Promise of Cox 2 inhibition: analgesia with
less gastrointestinal toxicity.
21. 21
VIGOR study
• Randomized, large double-blind trial
• Vioxx 50 mg/day or Naproxen 500 mg
twice/day –no placebo arm
• Primary endpoint was GI events
• Rheumatoid arthritis, mostly < 65 years
23. 23
APPROVe study
• Three-year, placebo-controlled study
• Primary endpoint prevention of colorectal
polyps
• Terminated early—increased incidence of
MI and stroke after 18 months of Vioxx.
• Vioxx withdrawn (2004)
24. 24
Further evaluation of
cardiovascular outcomes
• Guidance evaluating cardiovascular risk in
new antidiabetic therapies to treat type 2
diabetes (2008)
– Integrated analyses of events in phase 2/3
– Prespecified upper bound
• Adequately powered cardiovascular safety
study (either pre- or post-approval).
• Expect further evolution in future
25. 25
Detecting safety signals in clinical trials
– Common, drug-related: detect in controlled,
clinical trials
– Rare, severe, drug-related: detect via
• risk biomarkers (e.g., QT prolongation)
• epidemiologic studies (e.g., valvulopathy)
– Spontaneous events ↑ rate with drug: single
event usually not interpretable; detect via
• large enough controlled trial (e.g., Vioxx)