“Data Safety Monitoring Boards and Safety in High Risk Trials in Youths,”
Halifax, Nova Scotia, Canada; June 6, 2007
Dalhousie University, Department of Psychiatry, Clinical Conference
*Safety in high risk randomized controlled trials (RCTs) in young persons
*Data Safety Monitoring Boards (DSMBs)
*Defining the concept of “high risk”
*Capturing Adverse Events
*Recommendations for improvement of safety in pediatric psychiatry trials
*Case Study: Evaluating safety in a clinical trial
Patient safety has always been the industry’s focus during clinical trials. However, a recent spate of well-publicized patient safety issues have increased public scrutiny and the biotechnology, pharmaceutical and CRO industries' desire to improve study quality, resulting in larger, longer, more expensive trials. In this Q&A, James T. Gourzis, M.D., Ph.D., discusses issues affecting patient safety, including factors that have launched safety to the forefront; what to look for in evaluating CRO excellence; unique oncology considerations and the ramifications of the rare toxicity; optimizing the Data Monitoring Committee; budget decisions that affect patient safety and the evolution/future of FDA requirements.
Patient safety has always been the industry’s focus during clinical trials. However, a recent spate of well-publicized patient safety issues have increased public scrutiny and the biotechnology, pharmaceutical and CRO industries' desire to improve study quality, resulting in larger, longer, more expensive trials. In this Q&A, James T. Gourzis, M.D., Ph.D., discusses issues affecting patient safety, including factors that have launched safety to the forefront; what to look for in evaluating CRO excellence; unique oncology considerations and the ramifications of the rare toxicity; optimizing the Data Monitoring Committee; budget decisions that affect patient safety and the evolution/future of FDA requirements.
The Breast International Group (BIG) is the largest international network of academic breast cancer research groups. Facilitating international clinical trials is BIG's core expertise and for that reason, we have developed a slideshare presentation to explain the basics of clinical trials.
An introduction for those who may be interested in a career in clinical research, but need to understand the industry and their potential for a role in it.
Provides an overview of the later stages of drug development, explaining the phases of drug studies and explores in brief the key roles for those participating.
“Antidepressants and Suicidality in Youth,” Halifax, Nova Scotia, Canada; May 15, 2006, IWK Research Celebration, IWK Health Centre
*Discuss suicide risk associated with antidepressants in youth
*Discuss FDA post-hoc analysis of SSRI (Selective Serotonin Reuptake Inhibitor) youth studies
*Future Research Directions
The Breast International Group (BIG) is the largest international network of academic breast cancer research groups. Facilitating international clinical trials is BIG's core expertise and for that reason, we have developed a slideshare presentation to explain the basics of clinical trials.
An introduction for those who may be interested in a career in clinical research, but need to understand the industry and their potential for a role in it.
Provides an overview of the later stages of drug development, explaining the phases of drug studies and explores in brief the key roles for those participating.
“Antidepressants and Suicidality in Youth,” Halifax, Nova Scotia, Canada; May 15, 2006, IWK Research Celebration, IWK Health Centre
*Discuss suicide risk associated with antidepressants in youth
*Discuss FDA post-hoc analysis of SSRI (Selective Serotonin Reuptake Inhibitor) youth studies
*Future Research Directions
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.for more details please visit
www.indiandentalacademy.com
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.for more details please visit
www.indiandentalacademy.com
Join Dr. Dan Sullivan for a fascinating look into the world of clinical research. In this video, you’ll learn the magnitude and complexities of the national and international clinical research community, the drivers of adverse outcomes related to clinical research and the types of resulting litigation, and suggestions for improving patient and practitioner safety in the clinical research process.
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.
Pharmacovigilance Workshop
The workshop is designed to introduce pharmacovigilance to graduate students and working professionals interested in drug safety as a career field. After a brief introduction of publicly available data sources, each team received a case study that detailed a specific safety concern that resulted in a significant safety update of product labeling or product withdrawal.
Medicines may be withdrawn from markets because of risks to patients or business reasons. Change of benefit: risk profile is usually prompted by adverse effects that were either not previously detected, are more frequent, or more severe than anticipated based on the results of Phase III clinical trials. Market withdrawals are triggered by adverse events that were only made apparent from postmarketing surveillance data collected from population-wide use over more extended periods of time. The sources of information the regulatory agencies use when deciding on market withdrawal include meta-analyses and pooled analyses of data from clinical trials, clinical trials, spontaneous case reports, laboratory studies, observational studies, animal studies, and reviews of existing safety data.
In the U.S., individual case safety reports are collected in the FDA Adverse Event Reporting System (FAERS). In Europe, medication side effects are sent to national regulatory authorities and in the EU pharmacovigilance database EudraVigilance. The participants learned where to find clinical trials, market authorizations, and product labeling.
After the introductory presentation, each team received a case study that detailed a specific safety issue that resulted in a significant safety update of product labeling or product withdrawal. Each case study received product labeling and several scientific publications that discussed the safety concern in depth. Each team prepared a presentation with detailed overview of their assigned case study.
Are you interested in drug safety?
Try this for yourself!
Case studies:
Mylotarg (Gemtuzumab ozogamicin): no benefit, risk of death
Roaccutane (isotretinoin): teratogenic effect
Lariam (mefloquine): neuropsychiatric side effects
Zyprexa (olanzapine): stroke in patients with dementia
Avandia (rosiglitazone): myocardial infarction, death due to cardiovascular causes
Seroxat (paroxetine): suicidality
Xyrem (sodium oxybate): diversion, abuse
Coumadin (warfarin): bleeding
https://www.aretezoe.com/pharmacovigilance-workshop
Similar to Data Safety Monitoring Boards in Pediatric Clinical Trials (20)
"Psychosis in Youth"
Portland, Maine; March 30, 2004
Psychiatry Grand Rounds at Maine Medical Center
*Learn clinical assessment of psychosis in youth
*Learn neurobiology of psychosis
*Learn course and prognosis of psychosis
*Learn treatment of psychosis in youth
“Metyrosine and Psychosis”
Manila, Philippines; February 24, 2014
Presentation to the Department of Psychiatry and Research Department, University of the Philippines (Manila) College of Medicine, Philippine General Hospital.
*Clinical utility of metyrosine
*Discuss case report of metyrosine in psychosis associated with VCFS
*Discuss proposed clinical study of metyrosine for acute treatment resistant psychosis
Lamotrigine for Treatment Refractory Mood Disorders in Adolescents: A Case Se...Carlo Carandang
“Lamotrigine for Treatment Refractory Mood Disorders in Adolescents: A Case Series,”
Halifax, Nova Scotia, Canada; September 14, 2005
Psychiatry Clinical Case Conference at IWK Health Centre
*Learn about prevalence and treatment interventions for refractory depression in adolescents
*Summarize the intervention studies in refractory mood disorders in adolescents
*Dissect the 9 cases of lamotrigine for treatment refractory mood disorders in adolescents
*Learn pharmacokinetics and pharmacodynamics of lamotrigine
*Learn safe titration schedule to minimize rash
“Anxiety Disorders,”
Scarborough, Maine; May 7, 2003
Community presentation, Scarborough Campus of Maine Medical Center.
*Anxiety disorders and how to cope
Metyrosine in Adolescent Psychosis Associated with 22q11.2 Deletion SyndromeCarlo Carandang
"Metyrosine in Adolescent Psychosis Associated with 22q11.2 Deletion Syndrome,"
Halifax, Nova Scotia, Canada; June 7, 2006
Dalhousie University, Department of Psychiatry, Clinical Conference
*Learn clinical features of velocardiofacial syndrome (VCFS)
*Learn association of psychosis with VCFS
*Learn genetic and biochemical abnormalities leading to psychosis in VCFS
*Discuss case report of metyrosine in psychosis associated with VCFS
*What can we learn from the association between VCFS and schizophrenia to design candidate gene studies for polygenic syndromes?
Velocardiofacial Syndrome Associated with Adolescent PsychosisCarlo Carandang
"Velocardiofacial Syndrome Associated with Adolescent Psychosis,"
Halifax, Nova Scotia, Canada; October 4, 2006
Psychiatry Clinical Case Conference at IWK Health Centre
*Learn clinical features of velocardiofacial syndrome (VCFS)
*Learn association of VCFS with psychosis and other psychiatric disorders
*Learn genetic and biochemical abnormalities leading to psychosis in VCFS
*Discuss case report of metyrosine in psychosis associated with VCFS
*Discuss case reports of VCFS in childhood-onset schizophrenia
Clinical Assessment of Children and Adolescents with DepressionCarlo Carandang
“Clinical Assessment of Children and Adolescents with Depression,”
Halifax, Nova Scotia, Canada; October 1, 2008
Pediatric Grand Rounds, IWK Health Centre
*Although the core symptoms of depression are similar across the life span, developmental differences exist and should be taken into account in the assessment
*With increasing age, there generally is an increase in melancholic symptoms, delusions, substance abuse, and suicidal ideation/attempts.
*In contrast, younger children tend to have more somatic sxs, separation anxiety, behavior problems, temper tantrums, and hallucinations
*Direct interviews with children and adolescents are critical because parents and teachers may not be aware of the youth’s depressive symptoms
*Discrepant information between parents and their children should be solve in a cordial and non judgmental way
*Assessment of suicidal and homicidal ideation and behaviors is mandatory
*The interview process and screening questions utilized by research interviews such as the Schedule for Affective Disorders and Schizophrenia for School Age Children, Present and Lifetime Version (KSADS-PL) can be useful
*Detection and diagnosis can be enhanced by available parent and child self-report measures
“Teen Depression and Suicide,”
South Portland, Maine; April 26, 2005
Suicide Conference, Maine Suicide Prevention Program.
*Learn clinical presentation of adolescent depression
*Learn course and prognosis of pediatric depression
*Learn treatment of pediatric depression
*Discuss controversy of antidepressant medications in youth and suicidality
“Bipolar Disorder in Youth: Does it Exist?” Halifax, Nova Scotia, Canada; March 22, 2006, Community presentation at IWK Health Centre
*Learn clinical presentation of pediatric bipolar disorder
*Differentiate pediatric bipolar disorder from other psychiatric disorders
*Learn genetics of bipolar disorder
*Learn treatment of pediatric bipolar disorder
“The Neurobiology of Adolescent Development,” Austin, Texas; May 6, 2008. Psychiatry resident didactics, Austin Medical Education Programs (AMEP) Psychiatry program, Seton Hospital. Learn about adolescent development. Correlate adolescent development with brain changes. Learn about the two distinct processes of behavioral maturation (adolescence) and gonadal maturation (puberty), and how both interact, with resulting mature, reproductively active adult
Canadian Psychiatry: The Case for Universal Health Care and How Psychiatry Be...Carlo Carandang
Presentation on universal healthcare in Canada and how psychiatry benefits. Portland, Maine, October 20, 2009, Psychiatry Grand Rounds at Maine Medical Center
This presentation was given to students and staff of the University of the Philippines (Manila) College of Medicine, May 30, 2015. Computer anxiety is an intense fear of using computers. Computers are avoided at all cost, and exposure to computers induces a panic attack. This presentation goes into detail about what it is, how it evolves, and how to treat it.
In this presentation, we approach a two-class classification problem. We try to find a plane that separates the class in the feature space, also called a hyperplane. If we can't find a hyperplane, then we can be creative in two ways: 1) We soften what we mean by separate, and 2) We enrich and enlarge the featured space so that separation is possible.
AI and Big Data in Psychiatry: An Introduction and OverviewCarlo Carandang
Dr. Carlo Carandang, a psychiatrist and data scientist, talks about how Big Data can be implemented into clinical psychiatric practice to improve patient care and reduce costs. Dr. Carandang introduces Big Data topics, Big Data systems, machine learning algorithms, and AI psychiatry applications. Dr. Carandang presented this talk at the 2019 Presidential Symposium in Washington, DC, sponsored by the Washington Psychiatric Society.
Air Pollution in Nova Scotia: Analysis and PredictionsCarlo Carandang
"Air Pollution in Nova Scotia: Analysis and Predictions"
Halifax, Nova Scotia, Canada; May 22, 2018
Presentation to the Department of Environment, Government of Nova Scotia.
Analysis of air fine particulate matter (PM 2.5) open datasets in Nova Scotia, showing both business intelligence and predictive analytics.
Workplace Disability from Stress, Anxiety, and Depression: Solutions and Prev...Carlo Carandang
Mental health problems are the leading cause of disability in companies. This presentation focuses on disability from mental health problems, and looks at solutions and preventative measures to eradicate it.
Analysis of Air Pollution in Nova Scotia PresentationCarlo Carandang
This presentation is an analysis of air pollution in Nova Scotia. We detail how we obtain the dataset, how we clean it, how we process and analyze it, and then we visualize the results of the analysis.
Paxil Study 329 Retracted: A Critical Statistical AnalysisCarlo Carandang
I give a lecture regarding the statistical methodology employed in the 2001 Paxil (paroxetine) Study 329: Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial. Keller MB, Ryan ND, Strober M, Klein RG, Kutcher SP, Birmaher B, Hagino OR, Koplewicz H, Carlson GA, Clarke GN, Emslie GJ, Feinberg D, Geller B, Kusumakar V, Papatheodorou G, Sack WH, Sweeney M, Wagner KD, Weller EB, Winters NC, Oakes R, McCafferty JP. J Am Acad Child Adolesc Psychiatry. 2001 Jul;40(7):762-72.
How The Neurotransmitter GABA Works For AnxietyCarlo Carandang
This video explains how the neurotransmitter GABA works in the brain to decrease anxiety. Oral GABA does not cross the blood-brain barrier, and therefore is not effective for anxiety. This video is focused on the neurotransmitter GABA, not oral GABA.
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.
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
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- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
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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.
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.
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.
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
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.
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
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.
Couples presenting to the infertility clinic- Do they really have infertility...
Data Safety Monitoring Boards in Pediatric Clinical Trials
1. Data Safety Monitoring BoardsData Safety Monitoring Boards
and Safety in High Riskand Safety in High Risk
Therapeutic Trials in YouthsTherapeutic Trials in Youths
Carlo Carandang, MD, ABPN (Dip.)Carlo Carandang, MD, ABPN (Dip.)
Division of Child & Adolescent PsychiatryDivision of Child & Adolescent Psychiatry
Department of PsychiatryDepartment of Psychiatry
Dalhousie UniversityDalhousie University
IWK Mental Health and Addictions ProgramIWK Mental Health and Addictions Program
2. DisclosureDisclosure
Pharmaceutical Industry Conflicts: none over pastPharmaceutical Industry Conflicts: none over past
12 months12 months
Member, Dalhousie University Health SciencesMember, Dalhousie University Health Sciences
Research Ethics BoardResearch Ethics Board
Member, 2006 NIMH Antidepressants andMember, 2006 NIMH Antidepressants and
Suicidality Review CommitteeSuicidality Review Committee
Ad Hoc Reviewer, Pediatric PsychopharmacologicAd Hoc Reviewer, Pediatric Psychopharmacologic
Trials, JAACAPTrials, JAACAP
PI, lamotrigine study (2003-2005) with DSMBPI, lamotrigine study (2003-2005) with DSMB
oversightoversight
3. ObjectivesObjectives
Safety in high risk randomized controlled trialsSafety in high risk randomized controlled trials
(RCTs) in young persons(RCTs) in young persons
Data Safety Monitoring Boards (DSMBs)Data Safety Monitoring Boards (DSMBs)
Defining the concept of “high risk”Defining the concept of “high risk”
Capturing Adverse EventsCapturing Adverse Events
Recommendations for improvement of safety inRecommendations for improvement of safety in
pediatric psychiatry trialspediatric psychiatry trials
Case Study: Evaluating safety in a clinical trialCase Study: Evaluating safety in a clinical trial
4. Safety in High Risk RCTs: Suicidality inSafety in High Risk RCTs: Suicidality in
Pediatric Antidepressant TrialsPediatric Antidepressant Trials
Increase risk of suicidality onIncrease risk of suicidality on
antidepressant vs. placebo group (4% vsantidepressant vs. placebo group (4% vs
2%)2%)
– FDA metanalysis (Hammad et al., 2006)FDA metanalysis (Hammad et al., 2006)
Investigators of Pediatric SSRI trials:Investigators of Pediatric SSRI trials:
– ““The trials were not designed to assessThe trials were not designed to assess
suicidality.”suicidality.”
What they really meant:What they really meant:
– ““The trials were not designed to assess safetyThe trials were not designed to assess safety
and adverse events.”and adverse events.”
5. Safety in High Risk RCTs: Suicidality inSafety in High Risk RCTs: Suicidality in
Pediatric Antidepressant TrialsPediatric Antidepressant Trials
Controversy of antidepressant treatment-Controversy of antidepressant treatment-
emergent suicidality has raised criticalemergent suicidality has raised critical
issues with regards to safety of youngissues with regards to safety of young
persons in high risk RCTspersons in high risk RCTs
Also uncovered serious issues with regardsAlso uncovered serious issues with regards
to how adverse events are captured andto how adverse events are captured and
addressed in RCTsaddressed in RCTs
6. Safety in High Risk RCTs: Suicidality inSafety in High Risk RCTs: Suicidality in
Pediatric Antidepressant TrialsPediatric Antidepressant Trials
Retrospective analysis and armchairRetrospective analysis and armchair
criticisms have inherent flaws, but the PIscriticisms have inherent flaws, but the PIs
and sponsors should have anticipatedand sponsors should have anticipated
suicidality in light of:suicidality in light of:
– Increased impulsivity of adolescentsIncreased impulsivity of adolescents
– Depression as a risk factor for suicidalityDepression as a risk factor for suicidality
– Available RCTs did not reveal robust effect,Available RCTs did not reveal robust effect,
and therefore should have erred on the side ofand therefore should have erred on the side of
expecting no therapeutic effectexpecting no therapeutic effect
7. Safety Concerns: Emslie 2007Safety Concerns: Emslie 2007
Venlafaxine ER trial in Pediatric MDDVenlafaxine ER trial in Pediatric MDD
When reviewing the Emslie manuscript forWhen reviewing the Emslie manuscript for
publication, serious concerns arose overpublication, serious concerns arose over
safety of trial subjects in this studysafety of trial subjects in this study
– (Emslie et al., 2007)(Emslie et al., 2007)
Commentary on this concern:Commentary on this concern:
– Formation of a Data and Safety MonitoringFormation of a Data and Safety Monitoring
Board may have addressed safety concerns in aBoard may have addressed safety concerns in a
methodical, prospective fashionmethodical, prospective fashion
» (Carandang et al., 2007)(Carandang et al., 2007)
8. Safety Concerns: Emslie 2007 VenlafaxineSafety Concerns: Emslie 2007 Venlafaxine
ER trial in Pediatric DepressionER trial in Pediatric Depression
Clear signal of risk, and no efficacy advantage ofClear signal of risk, and no efficacy advantage of
venlafaxine over placebovenlafaxine over placebo
No third party oversight of adverse events in realNo third party oversight of adverse events in real
timetime
– REB only has oversight at study inception and onceREB only has oversight at study inception and once
yearly basisyearly basis
Spontaneous reporting by subjects of adverseSpontaneous reporting by subjects of adverse
eventsevents
No interim safety analysis to determine if risk ofNo interim safety analysis to determine if risk of
harm greater on drug vs. placeboharm greater on drug vs. placebo
9. Data and Safety MonitoringData and Safety Monitoring
BoardsBoards
The use of DSMBs is one method to assureThe use of DSMBs is one method to assure
subject safety in “high risk” therapeutic trialssubject safety in “high risk” therapeutic trials
A DSMB is an autonomous structure, independentA DSMB is an autonomous structure, independent
of study sponsors and investigatorsof study sponsors and investigators
Composed of a multidisciplinary group ofComposed of a multidisciplinary group of
individuals who have expertise in the study areaindividuals who have expertise in the study area
and clinical trial methodologyand clinical trial methodology
Also known as Data Monitoring CommitteeAlso known as Data Monitoring Committee
(DMC)(DMC)
10. DSMBDSMB
Commonly composed of biostatisticians,Commonly composed of biostatisticians,
scientists, bioethicists, and clinicians who arescientists, bioethicists, and clinicians who are
knowledgeable about the question being studiedknowledgeable about the question being studied
Principal role: ensure safety of study patients byPrincipal role: ensure safety of study patients by
analyzing adverse events and performing interimanalyzing adverse events and performing interim
analyses of the outcome dataanalyses of the outcome data
Authority to terminate a trial based on evidence ofAuthority to terminate a trial based on evidence of
harm or on evidence of efficacy; “stopping rules”harm or on evidence of efficacy; “stopping rules”
11. DSMBs and Youth AntidepressantDSMBs and Youth Antidepressant
TrialsTrials
Of the 14 published SSRI controlled trials:Of the 14 published SSRI controlled trials:
– Only 1 study reported the use of a DSMB andOnly 1 study reported the use of a DSMB and
an interim safety analysisan interim safety analysis
» TADS study (March et al. 2004)TADS study (March et al. 2004)
– Only 3 reported the prospective use of anOnly 3 reported the prospective use of an
Adverse Event ChecklistAdverse Event Checklist
– Most trials relied on spontaneous reporting ofMost trials relied on spontaneous reporting of
adverse eventsadverse events
13. DSMBs and RandomizedDSMBs and Randomized
Controlled Trials (RCTs)Controlled Trials (RCTs)
Most RCTs (psychiatric and non-Most RCTs (psychiatric and non-
psychiatric) to date have not utilizedpsychiatric) to date have not utilized
DSMBs to monitor safetyDSMBs to monitor safety
– About a quarter of RCTs utilized DSMBsAbout a quarter of RCTs utilized DSMBs
(Sydes et al. 2004)(Sydes et al. 2004)
DSMBs are currently being recommendedDSMBs are currently being recommended
as standards in National Institutes of Healthas standards in National Institutes of Health
(USA) and Medical Research Council (UK)(USA) and Medical Research Council (UK)
sponsored trialssponsored trials
14. Defining “High Risk” in TherapeuticDefining “High Risk” in Therapeutic
Trials as proposed by Dr. KutcherTrials as proposed by Dr. Kutcher
Features of the illness (SI)Features of the illness (SI)
Features of the intervention (activation)Features of the intervention (activation)
Features of the research environmentFeatures of the research environment
(nonacademic study sites with(nonacademic study sites with
inexperienced investigators)inexperienced investigators)
Novel cohorts (youth)Novel cohorts (youth)
Novel interventions (no data for particularNovel interventions (no data for particular
condition in particular population)condition in particular population)
15. Study Risk Assessment: University of IllinoisStudy Risk Assessment: University of Illinois
at Chicago General Clinical Research Centerat Chicago General Clinical Research Center
I. Experimental TreatmentI. Experimental Treatment
– Low Risk:Low Risk:
» No experimental treatment (1 point)No experimental treatment (1 point)
– Mod Risk:Mod Risk:
» Treatment effects documented from studies withTreatment effects documented from studies with
similar and/or different populations and/or settings.similar and/or different populations and/or settings.
No serious adverse events expected. Specific plansNo serious adverse events expected. Specific plans
to monitor AE’s detailed in DSMP (2 points)to monitor AE’s detailed in DSMP (2 points)
– High Risk:High Risk:
» Experimental treatment regulated by FDA (4 points)Experimental treatment regulated by FDA (4 points)
16. Study Risk Assessment: University of IllinoisStudy Risk Assessment: University of Illinois
at Chicago General Clinical Research Centerat Chicago General Clinical Research Center
II. Procedures, Measurements, and DataII. Procedures, Measurements, and Data
Collection MethodsCollection Methods
– Low Risk:Low Risk:
» Minimally invasive with low degree of emotional and/orMinimally invasive with low degree of emotional and/or
physical discomfort. Probability of adverse events is low.physical discomfort. Probability of adverse events is low.
Severity (magnitude) of adverse events is low (1 point)Severity (magnitude) of adverse events is low (1 point)
– Moderate Risk:Moderate Risk:
» Moderate degree of emotional and/or physicalModerate degree of emotional and/or physical
discomfort. Probability of adverse events is low.discomfort. Probability of adverse events is low.
Severity of adverse events is moderate to high (2 points)Severity of adverse events is moderate to high (2 points)
– High Risk:High Risk:
» Moderate to high degree of emotional and/or physicalModerate to high degree of emotional and/or physical
discomfort. Probability of adverse events is moderate todiscomfort. Probability of adverse events is moderate to
high. Severity of adverse events is high (4 points)high. Severity of adverse events is high (4 points)
17. Study Risk Assessment: University of IllinoisStudy Risk Assessment: University of Illinois
at Chicago General Clinical Research Centerat Chicago General Clinical Research Center
III. Decision-making CapabilityIII. Decision-making Capability
– Non-vulnerable:Non-vulnerable:
» Adult who 1) demonstrates decision-makingAdult who 1) demonstrates decision-making
capacitycapacity andand 2) demonstrates no perception of2) demonstrates no perception of
undue influence or coercion to participate (1undue influence or coercion to participate (1
point)point)
– Vulnerable:Vulnerable:
» Any minor. Adult who 1) demonstratesAny minor. Adult who 1) demonstrates
limitations in decision-making capacitylimitations in decision-making capacity and/orand/or
2) is prone to perception of undue influence or2) is prone to perception of undue influence or
coercion to participatecoercion to participate (2 points)(2 points)
18. Study Risk Assessment: University of IllinoisStudy Risk Assessment: University of Illinois
at Chicago General Clinical Research Centerat Chicago General Clinical Research Center
Overall Risk: tally pointsOverall Risk: tally points
– Low risk: 3 or 4 pointsLow risk: 3 or 4 points
– Moderate risk: 5 pointsModerate risk: 5 points
– Severe risk: 6 to 10 pointsSevere risk: 6 to 10 points
The monitor for low and moderate risk studiesThe monitor for low and moderate risk studies
may be the PImay be the PI
High (6 points) risk studies require a quarterlyHigh (6 points) risk studies require a quarterly
review of accumulated safety data and the monitorreview of accumulated safety data and the monitor
may be the PImay be the PI
High (7-10 points) risk, single site (UIC) studiesHigh (7-10 points) risk, single site (UIC) studies
must have an independent monitor (i.e. DSMB)must have an independent monitor (i.e. DSMB)
19. Measurement of Treatment-Measurement of Treatment-
Emergent Adverse EventsEmergent Adverse Events
Spontaneous ReportsSpontaneous Reports
General InquiryGeneral Inquiry
Specific InquirySpecific Inquiry
Specific following General InquirySpecific following General Inquiry
20. Tools to Capture Treatment-EmergentTools to Capture Treatment-Emergent
Adverse Events in Youth RCTsAdverse Events in Youth RCTs
No validated gold standard in youthNo validated gold standard in youth
psychopharmacologic trialspsychopharmacologic trials
Emslie: Side Effects Checklist, 30-itemEmslie: Side Effects Checklist, 30-item
– Based on the Subjective Treatment EmergentBased on the Subjective Treatment Emergent
Symptoms Scale from NIMHSymptoms Scale from NIMH
– Needs to include questions specific to psychiatry and toNeeds to include questions specific to psychiatry and to
youth population (suicidality, activation, catarsis, EPS,youth population (suicidality, activation, catarsis, EPS,
etc.)etc.)
March: ASAP, Emergency/Adjunct Services andMarch: ASAP, Emergency/Adjunct Services and
Attrition Prevention for Randomized ClinicalAttrition Prevention for Randomized Clinical
Trials in ChildrenTrials in Children
– Manual-based…too intensiveManual-based…too intensive
21. Recommendations for Improvement ofRecommendations for Improvement of
Safety in High Risk Clinical TrialsSafety in High Risk Clinical Trials
Establishment of Data and SafetyEstablishment of Data and Safety
Monitoring Plan (DSMP) for all trialsMonitoring Plan (DSMP) for all trials
A DSMP is a prospective strategy to assessA DSMP is a prospective strategy to assess
the progress of a research study on athe progress of a research study on a
periodic basis to ensure the safety ofperiodic basis to ensure the safety of
participants and the validity and integrity ofparticipants and the validity and integrity of
the datathe data
A DSMP for a high risk trial should almostA DSMP for a high risk trial should almost
always include a DSMBalways include a DSMB
22. Recommendations for Improvement ofRecommendations for Improvement of
Safety in High Risk Clinical TrialsSafety in High Risk Clinical Trials
DSMP and DSMB especially important forDSMP and DSMB especially important for
investigator-initiated, single-site trialsinvestigator-initiated, single-site trials
Multi-site trials usually have a DSMP, andMulti-site trials usually have a DSMP, and
usually have oversight from a DSMB, asusually have oversight from a DSMB, as
required by the sponsorrequired by the sponsor
– However, not all sponsors require a DSMBHowever, not all sponsors require a DSMB
(venlafaxine multi-site trial in pediatric(venlafaxine multi-site trial in pediatric
depression)depression)
23. Recommendations for Improvement ofRecommendations for Improvement of
Safety in High Risk Clinical TrialsSafety in High Risk Clinical Trials
In Summary, all human subjects research shouldIn Summary, all human subjects research should
have a Data and Safety Monitoring Plan (DSMP)have a Data and Safety Monitoring Plan (DSMP)
– Especially for investigator-initiated, single-site trialsEspecially for investigator-initiated, single-site trials
More risk entailing more oversight and increasingMore risk entailing more oversight and increasing
independence from study investigators, sponsorsindependence from study investigators, sponsors
– PI and REB monitoring for low risk trialsPI and REB monitoring for low risk trials
– DSMB monitoring for high risk trialsDSMB monitoring for high risk trials
– Interim analysis of data by those delegated by REB forInterim analysis of data by those delegated by REB for
moderate risk trials; may not need independent DSMBmoderate risk trials; may not need independent DSMB
All high risk youth trials should have a DSMBAll high risk youth trials should have a DSMB
24. Why a DSMB? Isn’t REB oversightWhy a DSMB? Isn’t REB oversight
enough?enough?
Unpractical for REB to analyze all dataUnpractical for REB to analyze all data
from all trials in a rigorous fashionfrom all trials in a rigorous fashion
– Manpower issuesManpower issues
– Not able to provide real-time oversightNot able to provide real-time oversight
REBs at most institutions are not reallyREBs at most institutions are not really
independent…answer to VP Researchindependent…answer to VP Research
REBs may not have the specific expertise toREBs may not have the specific expertise to
critically analyze safety issues involved in acritically analyze safety issues involved in a
given trialgiven trial
25. Advantage of DSMB rather than justAdvantage of DSMB rather than just
REB oversightREB oversight
DSMBs are independent of investigators,DSMBs are independent of investigators,
sponsors, and institutionssponsors, and institutions
– No conflicts of interest to make difficult decisions, suchNo conflicts of interest to make difficult decisions, such
as terminating a trialas terminating a trial
DSMBs provide oversight of trial in real timeDSMBs provide oversight of trial in real time
– DSMB chair convenes immediate meeting whenDSMB chair convenes immediate meeting when
serious adverse events occurserious adverse events occur
DSMB members are appointed by the REB and PIDSMB members are appointed by the REB and PI
according to specific expertise in the particularaccording to specific expertise in the particular
trialtrial
26. Disadvantages of DSMBsDisadvantages of DSMBs
Who pays the DSMB members’ time andWho pays the DSMB members’ time and
infrastructure support?infrastructure support?
– Unfair to expect investigators to pay all these costs, asUnfair to expect investigators to pay all these costs, as
it can be a substantial portion a grantit can be a substantial portion a grant
DSMB decisions can be contentiousDSMB decisions can be contentious
– Stopping a trial early due to safety concerns risksStopping a trial early due to safety concerns risks
losing valuable information that can potentially benefitlosing valuable information that can potentially benefit
othersothers
– Presupposes an optimal method to collect AE dataPresupposes an optimal method to collect AE data
– What are the thresholds for ending a study if validWhat are the thresholds for ending a study if valid
indicators are not present?indicators are not present?
27. Disadvantages of DSMBs: InterimDisadvantages of DSMBs: Interim
Analysis and Type I ErrorsAnalysis and Type I Errors
If the null hypothesis, HIf the null hypothesis, H00, of no difference between, of no difference between
groups is in fact true, and repeated tests of thatgroups is in fact true, and repeated tests of that
hypothesis are made at the same level ofhypothesis are made at the same level of
significance using accumulating data, at some timesignificance using accumulating data, at some time
the repeated test will be significant by chancethe repeated test will be significant by chance
alone and be larger than the significance selectedalone and be larger than the significance selected
(commonly P<0.05)(commonly P<0.05)
If repeated testing occurs indefinitely, the nullIf repeated testing occurs indefinitely, the null
hypothesis will eventually be rejected (incorrectly)hypothesis will eventually be rejected (incorrectly)
Type I error, rejecting the null hypothesisType I error, rejecting the null hypothesis
incorrectly, may result from multiple testingincorrectly, may result from multiple testing
28. Disadvantages of DSMBs: InterimDisadvantages of DSMBs: Interim
Analysis and Type I ErrorsAnalysis and Type I Errors
Solution to multiple testing problem:Solution to multiple testing problem:
– Limit the number of interim testingLimit the number of interim testing
– Stop trials only when there is overwhelmingStop trials only when there is overwhelming
evidence that one intervention is more effectiveevidence that one intervention is more effective
(or more harmful) than the other(or more harmful) than the other
» Set P<0.001 instead of P<0.05Set P<0.001 instead of P<0.05
– Stopping rules can be less stringent with respectStopping rules can be less stringent with respect
to evidence of harm than with respect toto evidence of harm than with respect to
evidence of efficacyevidence of efficacy
29. Case Study: Evaluating Safety inCase Study: Evaluating Safety in
a Clinical Triala Clinical Trial
Lamotrigine crossover trial, randomized,Lamotrigine crossover trial, randomized,
double-blinded, placebo controldouble-blinded, placebo control
Investigator-initiated, single-site trial,Investigator-initiated, single-site trial,
funded by GlaxoSmithKlinefunded by GlaxoSmithKline
Inclusion criteria: ages 13-18, has moderateInclusion criteria: ages 13-18, has moderate
to severe MDD (via KSADS)to severe MDD (via KSADS)
Power analysis: N=30Power analysis: N=30
– 81% power and 0.05 significance level81% power and 0.05 significance level
30. Group CBT/IPT with fluoxetine
8 weeks (Stage 1)
No Response: Augment fluoxetine with
either lamotrigine or placebo (Stage 2)
Fluoxetine with
lamotrigine: 8 weeks
Fluoxetine with placebo:
8 weeks
Response: continue fluoxetine and
psychotherapy
Taper lamotrigine, then
discontinue: 3 weeks
Taper placebo, then
discontinue: 3 weeks
Fluoxetine with placebo:
8 weeks
Fluoxetine with
lamotrigine: 8 weeks
No response: consider
alternative treatment
Response: continue
treatment for 6 months
(Stage 3)
Response: continue
treatment for 6 months
(Stage 3)
No response: consider
alternative treatment
Flowchart: LTG Study
31. Data Safety Monitoring Plan: LTGData Safety Monitoring Plan: LTG
Crossover StudyCrossover Study
Deemed moderate to high risk trial due to:Deemed moderate to high risk trial due to:
– Vulnerable population: adolescentsVulnerable population: adolescents
– Risk of serious rash with lamotrigineRisk of serious rash with lamotrigine
– Risk of suicide in youth with severe,Risk of suicide in youth with severe,
treatment-refractory depressiontreatment-refractory depression
The IRB mandated the formation of anThe IRB mandated the formation of an
independent DSMB, given the above risksindependent DSMB, given the above risks
factorsfactors
32. Data Safety Monitoring Plan: LTGData Safety Monitoring Plan: LTG
Crossover StudyCrossover Study
Adverse Event Grading SystemAdverse Event Grading System::
The following adverse event grading system will be used:The following adverse event grading system will be used:
MildMild: Experience of sign, symptom, or event, but easily: Experience of sign, symptom, or event, but easily
tolerated. The experience does not require treatment, andtolerated. The experience does not require treatment, and
does not interfere with daily activities.does not interfere with daily activities.
ModerateModerate: Discomfort enough to cause interference with: Discomfort enough to cause interference with
usual activity and may require treatment.usual activity and may require treatment.
SevereSevere: Incapacitating with inability to do usual activities: Incapacitating with inability to do usual activities
or significantly affects clinical status, and requiresor significantly affects clinical status, and requires
treatment. If hospitalization is required, it becomes atreatment. If hospitalization is required, it becomes a
serious adverse event.serious adverse event.
Life-threateningLife-threatening: Immediate risk of death.: Immediate risk of death.
33. Data Safety Monitoring Plan: LTGData Safety Monitoring Plan: LTG
Crossover StudyCrossover Study
Serious Adverse Events (SAE’s)Serious Adverse Events (SAE’s)::
All serious adverse events, whether or not deemedAll serious adverse events, whether or not deemed
procedure-related or expected, must be reported by theprocedure-related or expected, must be reported by the
investigator to the IRB and DSMB within 24 hours (oneinvestigator to the IRB and DSMB within 24 hours (one
working day) by telephone.working day) by telephone.
A serious adverse event is any event that:A serious adverse event is any event that:
– Is fatal or life threateningIs fatal or life threatening
– Is significantly or permanently disablingIs significantly or permanently disabling
– Requires hospitalization, or prolongs hospitalizationRequires hospitalization, or prolongs hospitalization
– Is a congenital anomaly or birth defectIs a congenital anomaly or birth defect
In this trial, SAE may be Stevens Johnson Syndrome orIn this trial, SAE may be Stevens Johnson Syndrome or
suicidalitysuicidality
34. Data Safety Monitoring Plan: LTGData Safety Monitoring Plan: LTG
Crossover StudyCrossover Study
Interim Efficacy AnalysisInterim Efficacy Analysis::
An interim analysis for efficacy will be conducted after 15An interim analysis for efficacy will be conducted after 15
study subjects have completed the protocol (half of thestudy subjects have completed the protocol (half of the
projected sample size, n=30). At the time of interimprojected sample size, n=30). At the time of interim
efficacy analysis, a comprehensive statistical report will beefficacy analysis, a comprehensive statistical report will be
generated for all members of the DSMB to review. Agenerated for all members of the DSMB to review. A
compilation of the outcome data will be prepared by thecompilation of the outcome data will be prepared by the
study methodologist/CI, William Cook Ph.D. The DSMBstudy methodologist/CI, William Cook Ph.D. The DSMB
will analyze the data unblinded, and will compare efficacywill analyze the data unblinded, and will compare efficacy
of lamotrigine versus placebo. The purpose of this reviewof lamotrigine versus placebo. The purpose of this review
is to determine whether or not the study should beis to determine whether or not the study should be
terminated for reasons of efficacyterminated for reasons of efficacy
35. Data Safety Monitoring Plan: LTGData Safety Monitoring Plan: LTG
Crossover StudyCrossover Study
Stopping Rules Based on EfficacyStopping Rules Based on Efficacy::
The DSMB may recommend termination of theThe DSMB may recommend termination of the
study if there is a sufficiently robust effectstudy if there is a sufficiently robust effect
favoring lamotrigine over placebo, such thatfavoring lamotrigine over placebo, such that
subsequent subjects will experience thesubsequent subjects will experience the
categorical risk of being denied optimal andcategorical risk of being denied optimal and
efficacious (as demonstrated in the DSMBefficacious (as demonstrated in the DSMB
analysis) treatment. A significant effect at n of 15analysis) treatment. A significant effect at n of 15
would indicate an effect size so large that it wouldwould indicate an effect size so large that it would
subject the placebo group to excess risk.subject the placebo group to excess risk.
36. Data Safety Monitoring Plan: LTGData Safety Monitoring Plan: LTG
Crossover StudyCrossover Study
Interim Safety AnalysisInterim Safety Analysis::
Interim safety analysis will be conducted on a quarterlyInterim safety analysis will be conducted on a quarterly
basis. At the time of interim analysis, a comprehensivebasis. At the time of interim analysis, a comprehensive
safety report will be generated for all members of thesafety report will be generated for all members of the
DSMB to review. The safety report will be prepared byDSMB to review. The safety report will be prepared by
the study methodologist/CI, William Cook Ph.D., and willthe study methodologist/CI, William Cook Ph.D., and will
include a blinded summary of adverse event rates. Theinclude a blinded summary of adverse event rates. The
DSMB will have the option to assess safety data unblindedDSMB will have the option to assess safety data unblinded
to compare treatment group and placebo group. Theto compare treatment group and placebo group. The
purpose of this review is to determine whether or not thepurpose of this review is to determine whether or not the
study should be terminated for reasons of subject safety.study should be terminated for reasons of subject safety.
The quarterly interim analysis will only address safetyThe quarterly interim analysis will only address safety
concerns and not efficacy.concerns and not efficacy.
37. Data Safety Monitoring Plan: LTGData Safety Monitoring Plan: LTG
Crossover StudyCrossover Study
Stopping Rules Based on SafetyStopping Rules Based on Safety::
The DSMB may recommend early termination ofThe DSMB may recommend early termination of
the study for reasons of patient safety based on thethe study for reasons of patient safety based on the
interim review of this data.interim review of this data.
As an example of a stopping rule based on safety,As an example of a stopping rule based on safety,
a pattern of suicide attempts while on lamotriginea pattern of suicide attempts while on lamotrigine
or a pattern of serious rash occurrence withor a pattern of serious rash occurrence with
lamotrigine compared to placebo may prompt thelamotrigine compared to placebo may prompt the
DSMB to terminate the study.DSMB to terminate the study.
DSMB recommendations for early terminationDSMB recommendations for early termination
will be communicated directly to the PI, Carlowill be communicated directly to the PI, Carlo
Carandang M.D.Carandang M.D.
38. Data Safety Monitoring Plan: LTGData Safety Monitoring Plan: LTG
Crossover StudyCrossover Study
When considering termination, the DSMB shouldWhen considering termination, the DSMB should
consider the following selected reasons to proceed withconsider the following selected reasons to proceed with
this clinical trialthis clinical trial::
A different conclusion might result.A different conclusion might result.
Greater acceptance of the data will occur.Greater acceptance of the data will occur.
This clinical trial is unique and complex, and it may neverThis clinical trial is unique and complex, and it may never
be possible to repeat it.be possible to repeat it.
Almost no data exists for treatment-refractory depressionAlmost no data exists for treatment-refractory depression
in youth.in youth.
Effective treatments for depression in youth areEffective treatments for depression in youth are
desperately needed, as a common outcome for youth withdesperately needed, as a common outcome for youth with
untreated depression is suicide.untreated depression is suicide.
39. Data Safety Monitoring Plan: LTGData Safety Monitoring Plan: LTG
Crossover StudyCrossover Study
DSMB Communication with the PIDSMB Communication with the PI::
The DSMB will communicate with the PI andThe DSMB will communicate with the PI and
report the following:report the following:
– The nature of the review (including pertinent safetyThe nature of the review (including pertinent safety
data).data).
– A brief description of any serious adverse events orA brief description of any serious adverse events or
concerns regarding systematic adverse events.concerns regarding systematic adverse events.
– Decisions of the DSMB regarding the study.Decisions of the DSMB regarding the study.
The PI will forward the DSMB communications toThe PI will forward the DSMB communications to
the IRB.the IRB.
40. Data Safety Monitoring Plan: LTGData Safety Monitoring Plan: LTG
Crossover StudyCrossover Study
DSMB MembersDSMB Members::
Chair: Francis L. Lucas, Ph.D.,Chair: Francis L. Lucas, Ph.D.,
biostatisticianbiostatistician
Members :Members :
– Paul Dyment, M.D., pediatricianPaul Dyment, M.D., pediatrician
– Jessica Oesterheld, M.D., child psychiatristJessica Oesterheld, M.D., child psychiatrist
– Alyce Schultz, Ph.D., research nurseAlyce Schultz, Ph.D., research nurse
41. Further Needs: Safety of Youths inFurther Needs: Safety of Youths in
High Risk Therapeutic TrialsHigh Risk Therapeutic Trials
Need standard guidelines to delineate riskNeed standard guidelines to delineate risk
levels in pediatric trialslevels in pediatric trials
Need optimal and validated method ofNeed optimal and validated method of
collecting adverse event data in childcollecting adverse event data in child
psychiatry trialspsychiatry trials
Standardizing (or at least requiring) DataStandardizing (or at least requiring) Data
and Safety Monitoring Plans acrossand Safety Monitoring Plans across
institutions, with special monitoring of childinstitutions, with special monitoring of child
and adolescent populations in research trialsand adolescent populations in research trials
42. Safety and Research Ethics inSafety and Research Ethics in
YouthsYouths
Research Ethics based on 3 principles asResearch Ethics based on 3 principles as
articulated in the Belmont Report (1978)articulated in the Belmont Report (1978)
– Respect for PersonsRespect for Persons
– BeneficienceBeneficience
– JusticeJustice
43. Safety and Research Ethics inSafety and Research Ethics in
Youths: Respect for PersonsYouths: Respect for Persons
Respect for PersonsRespect for Persons. Researchers have an. Researchers have an
obligation to treat individuals asobligation to treat individuals as
autonomous beings and to provide specialautonomous beings and to provide special
protection to those persons with diminishedprotection to those persons with diminished
autonomy.autonomy.
– Enrolling vulnerable children in high riskEnrolling vulnerable children in high risk
research studies without rigorous safetyresearch studies without rigorous safety
oversight is not in line with this principle.oversight is not in line with this principle.
44. Safety and Research Ethics inSafety and Research Ethics in
Youths: BeneficenceYouths: Beneficence
Beneficence.Beneficence. Researchers have a responsibility toResearchers have a responsibility to
maximize the benefits and minimize the potentialmaximize the benefits and minimize the potential
for harm or risk that the research poses to subjects.for harm or risk that the research poses to subjects.
– Allowing subjects to continue in a trial whereAllowing subjects to continue in a trial where
suicidality is twice that on drug versus placebo is not insuicidality is twice that on drug versus placebo is not in
line with this principle.line with this principle.
– Use of placebo in vulnerable youths where a standardUse of placebo in vulnerable youths where a standard
treatment exists is not in line with this principletreatment exists is not in line with this principle..
» Clinical EquipoiseClinical Equipoise
45. Safety and Research Ethics inSafety and Research Ethics in
Youths: JusticeYouths: Justice
Justice.Justice. This principle relates primarily to howThis principle relates primarily to how
subjects are selected for research, and to thesubjects are selected for research, and to the
responsibility of researchers to spread both theresponsibility of researchers to spread both the
benefits and burdens of the research equitably.benefits and burdens of the research equitably.
– Not performing research studies in youths due toNot performing research studies in youths due to
paternalistic concerns that children need protection ispaternalistic concerns that children need protection is
not in line with this principle, as the benefits ofnot in line with this principle, as the benefits of
research should not be reserved for adults only.research should not be reserved for adults only.
Adult data does not generalize to youths.Adult data does not generalize to youths.
46. Safety and Research Ethics inSafety and Research Ethics in
YouthsYouths
Take home point: Unethical to avoidTake home point: Unethical to avoid
research in youths due to paternalisticresearch in youths due to paternalistic
concerns to protect children, but alsoconcerns to protect children, but also
unethical to avoid rigorous safety oversightunethical to avoid rigorous safety oversight
in youths who enroll in high risk trialsin youths who enroll in high risk trials
Win-win: PI, sponsor, and REB can rely onWin-win: PI, sponsor, and REB can rely on
the DSMB to rigorously assess safety, andthe DSMB to rigorously assess safety, and
research subjects will feel saferresearch subjects will feel safer
47. Suggested ReadingSuggested Reading
Friedman L, Furberg C, DeMets D (1998),Friedman L, Furberg C, DeMets D (1998),
Fundamentals of Clinical Trials.Fundamentals of Clinical Trials. New York:New York:
Springer, Chapter 15 (Monitoring ResponseSpringer, Chapter 15 (Monitoring Response
Variables)Variables)
Slutsky A, Lavery J (2004), Data safety andSlutsky A, Lavery J (2004), Data safety and
monitoring boards.monitoring boards. NEJMNEJM 350:1143-1146.350:1143-1146.
Ellenberg SS, Fleming TR, DeMets DL(2002),Ellenberg SS, Fleming TR, DeMets DL(2002),
Data monitoring committees in clinical trials: aData monitoring committees in clinical trials: a
practical perspectivepractical perspective. Chichester, UK: Wiley. Chichester, UK: Wiley..
48. AcknowledgementsAcknowledgements
Darcy Santor PhD, University of OttawaDarcy Santor PhD, University of Ottawa
David Gardner PharmD, DalDavid Gardner PharmD, Dal
Normand Carrey MD, DalNormand Carrey MD, Dal
Stan Kutcher MD, DalStan Kutcher MD, Dal
Mina Dulcan MD, Past Editor JAACAPMina Dulcan MD, Past Editor JAACAP