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TRIAL TO TRUST: A HISTORICAL
PERSPECTIVE ON DRUG SAFETY
Sonal Singh MD MPH FACP
Associate Professor
Department of Family Medicine and Community Health
Division of Health Systems Science, Department of Medicine
Department of Population and Quantitative Health Sciences
Patna Medical College Centenary Celebration February 24 2025, Patna, India

2
The Only Absolutely Safe Drug is
The One You Have Never Taken
• Patna Medical College Centenary Celebration, February 24 2025, Patna, India

Trial to Trust- A historical perspective on drug safety

Victor Ambros
receives the Nobel
Prize in Physiology
and Medicine (2024)
for the discovery of
mRNA and its role in
post-transcription
gene regulation

5
Moore TJ, Furberg CD, Glenmullen J, Maltsberger JT, Singh S. PLoS One. 2011;6(11):e27016
Singh et al. JAMA Intern Med. 2024; 184 (12)1426-1433
Singh et al. JAMA Intern Med 2013; 173 (7): 534-539
Singh et al. JAMA 2007; 298 (10): 1189-95
Singh et al. JAMA 2008; 300 (12): 1439-50
Singh et al. CMAJ 2011 (12); 183: 1359-66
Patna Medical College Centenary Celebration, February 24 2025, Patna, India
Objectives
Illustrate how complementary study designs can inform our
understanding of drug safety
Lessons I have learned along the way

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Lessons from a Career in Medicine
1. Long, winding path as there is no one
mountain to climb
2. Our educational background traps us. We
know certain fields of science but not others,
limiting what we can do. Every day, learn
something new.
3. Be open to the new as opportunities arise
from the most unexpected of places
4. You need mentors, friends, and family to get
you through hard times.

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The gangetic river dolphin is functionally blind so hunting has to rely on geolocation-
So much of clinical investigation is going up a blind alley
Where it all Started

Stumbling through Opportunities
Residency Internal Medicine (2002- 05) : Unity Health System, Rochester,
NY
Instructor/Assistant Professor (2005-09) Wake Forest University School of
Medicine, North Carolina
Assistant Professor (2009-16) Johns Hopkins University School of Medicine
and Bloomberg School of Public Health
Associate Director, Center for Drug Safety and Effectiveness

Patna Medical College Centenary Celebration, February 24 2025, Patna, India
Key Historical Events
105 patients died from use of Diethylene glycol used as the diluent in the
formulation o Elixir Sulfanilamide
U.S. Congress passed the 1938 Federal Food, Drug and Cosmetic Act,
requiring proof of safety before the release of a new drug.
Kelsey, a reviewer at the FDA found problems with the thalidomide
application and asked the company about the drug's effects in pregnancy
Thalidomide was teratogenic but was not approved in the USA, whereas
several children born with phocomelia in Europe.

Challenge of Studying Drug Safety
Pre-approval clinical trials are statistically underpowered to detect
rare adverse events because they are only conducted with few
hundred to thousand patients.
Progressive reduction in uncertainty after approval with
post-approval studies including systematic review and
meta-analysis, observational studies and spontaneous case
reports

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Systematic Review and Meta-Analysis
Singh et al. JAMA 2007; 298 (10): 1189-95
Singh et al. CMAJ 2011 (12); 183: 1359-66
Singh et al. JAMA 2008; 300 (12): 1439-50

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Long-term Risk of Cardiovascular Events with Rosiglitazone :
A Meta-analysis
Singh et al. JAMA 2007; 298 (10): 1189-1195

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Long-term Risk of Cardiovascular Events with
Rosiglitazone : A Meta-analysis
Singh et al. JAMA 2007; 298 (10): 1189-1195

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Inhaled Anticholinergics and Risk of Major Adverse Cardiovascular Events in Patients with Chronic
Obstructive Pulmonary Disease: A Systematic Review and Meta-analysis
Singh et al. JAMA 2008; 300 (12): 1439-1450

Date of download: 2/1/2025
Copyright © 2009 American Medical
Association. All rights reserved.
Inhaled Anticholinergics and Risk of Major Adverse Cardiovascular Events in Patients With Chronic Obstructive
Pulmonary Disease: A Systematic Review and Meta-analysis
JAMA. 2009;301(12):1227-1230. doi:10.1001/jama.2009.290
Cardiovascular outcomes composite indicates cardiovascular death, myocardial infarction, and stroke. Size of the data markers
indicates weight of the study. CI indicates conﬁdence interval.
Figure Legend:

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Risk of Serious adverse cardiovascular events associated with
varenicline: systematic review and meta-analysis
Singh et al. CMAJ 2011 (12); 183: 1359-66

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Risk of Serious adverse cardiovascular events associated with
varenicline: systematic review and meta-analysis
Singh et al. CMAJ 2011; 183: 1359-66

Meta-analysis of double-blind placebo-controlled randomized trials of the risk of
serious adverse cardiovascular events associated with the use of varenicline
Sonal Singh et al. CMAJ 2011;183:1359-1366
©2011 by Canadian Medical Association

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Observational Study
Case Control Study

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Glucagonlike Peptide 1–Based Therapies and Risk of
Hospitalization for Acute Pancreatitis in Type 2 Diabetes Mellitus
A Population-Based Matched Case-Control Study

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Glucagonlike Peptide 1–Based Therapies and Risk of Hospitalization for Acute Pancreatitis in
Type 2 Diabetes Mellitus A Population-Based Matched Case-Control Study
Objective Test whether GLP-1–based therapies ( e.g., exenatide and sitagliptin ) associated with an
increased risk of AP in a large database in the US from Feb 1, 2005, through Dec 31, 2008.
Participants: Adults with T2DM aged 18 to 64 years. 1629 hospitalized cases with AP and 1269
controls matched for age category, sex, enrollment pattern, and diabetes complications.
Main Outcome Measure Hospitalization for acute pancreatitis.
Results: After adjusting for available confounders and metformin use, current use of GLP-1
therapies within 30 d (adjusted OR, 2.24 [95% CI, 1.36-3.68]) and recent use past 30 days and <
than 2 years (2.01 [1.37-3.18]) were associated with significantly increased odds of AP relative to the
odds in nonusers.
Conclusions. Treatment with the GLP–1–based therapies sitagliptin and exenatide was associated
with increased odds of hospitalization for AP.

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Disproportionality Analysis of
Food and Drug Administration
Adverse Events
Moore TJ, Furberg CD, Glenmullen J, Maltsberger JT, Singh S.
Suicidal behavior and depression in smoking cessation
treatments. PLoS One. 2011;6(11):e27016

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Suicidal Behavior and Depression in Smoking Cessation Treatments
Moore TJ, Furberg CD, Glenmullen J, Maltsberger JT, Singh S.
Suicidal behavior and depression in smoking cessation treatments. PLoS One. 2011;6(11):e27016

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Moore TJ, Furberg CD, Glenmullen J, Maltsberger JT, Singh S. PLoS One. 2011;6(11):e27016
Background. Varenicline and bupropion—carry Boxed Warnings from the U.S. FDA about
SI/self-injurious behavior and depression.
Methods. From the FAERS database from 1998 through September 2010 we selected domestic,
serious reports for varenicline (n=9,575), bupropion for smoking cessation (n=1,751), and nicotine
replacement products (n=1,917).
A composite endpoint of suicidal/self-injurious behavior or depression was defined as a case with
Preferred Terms in Standardized MedDRA Query (SMQ).
The main outcome was the ratio of reported suicide/self-injury or depression cases for each drug
compared to all other serious events for that drug.

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Thomas J. Moore ,Curt D. Furberg,Joseph Glenmullen,John T. Maltsberger,Sonal Singh. PLoS One. 2011;6(11):e27016.
Compared to nicotine replacement, the disproportionality results (OR (95% CI)) were higher for
varenicline 8.4 (6.8–10.4), and bupropion 2.9 (2.3–3.7)

Disproportionality Analyses
Strengths : Important to detect rare outcomes
Limitations : Incomplete and Duplicate reporting
Limitations : Stimulated reporting
Limitations : Minimal data on confounders
Limitations : Unable to calculate incidence because no denominator

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Randomized Clinical Trial

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High Risk Medications in Persons Living with
Dementia A Randomized Clinical Trial

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High Risk Medications in Persons Living with Dementia A Randomized Clinical Trial

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Funding
National Institute of Health
Patient-Centered Outcome Institute
Agency for Health Care Research and Quality
World Bank
World Health Organization International Agency for
Research on Cancer

Mentors
Curt D Furberg, MD, PhD Professor Emeritus of Public Health Sciences at Wake Forest University,
Winston-Salem, North Carolina
Chris Beyrer, MD MPH Professor and Director of Duke Global Health Institute, Raleigh, Durham, NC
Jerry Gurwitz, MD John Meyers Professor in Primary Care Medicine, UMass Chan Medical School
Kathy Mazor, EdD, Professor, Health Systems Science dicine, UMass Chan Medical School
Professor Yoon Kong Loke, MBBS, MRCP Professor of Medicine and Pharmacology, East Anglia
University, Norwich, UK
Edward Mills, PhD, FRCP, Edward Mills, PhD, FRCP Professor Department of Health Research Methods,
Evidence & Impact McMaster University, Canada

Family

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Lessons from a Career in Medicine
1. Long, winding path as there is no one
mountain to climb
2. Our educational background traps us. We
know certain fields of science but not others,
limiting what we can do. Every day, learn
something new.
3. Be open to the new as opportunities arise
from the most unexpected of places
4. You need mentors, friends, and family to get
you through hard times.

�ݺ�ߣ

Trial to Trust- A historical perspective on drug safety

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Trial to Trust- A historical perspective on drug safety