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Pharmacovigilance:
A Practical Approach
THAO DOAN, MD
Senior Medical Director
Safety Science
Pharmacovigilance and Patient Safety
AbbVie
North Chicago, Illinois, United States
CHERYL RENZ, MS, MD

Safety Science
AbbVie
MONDIRA BHATTACHARYA, MD
Former Senior Medical Director
Safety Science
AbbVie
FABIO LIEVANO, MD
Vice President
Safety Science
AbbVie
LINDA SCARAZZINI, MD
Vice President
AbbVie
]
3251 Riverport Lane
St. Louis, Missouri 63043
PHARMACOVIGILANCE: A PRACTICAL APPROACH ISBN: 978-0-323-58116-5
Copyright Ó 2019 Elsevier, Inc. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or
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This book and the individual contributions contained in it are protected under copyright by the Publisher
(other than as may be noted herein).
Notices
Practitioners and researchers must always rely on their own experience and knowledge in evaluating
and using any information, methods, compounds or experiments described herein. Because of rapid
advances in the medical sciences, in particular, independent verifi cation of diagnoses and drug
dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier,
authors, editors or contributors for any injury and/or damage to persons or property as a matter of
products liability, negligence or otherwise, or from any use or operation of any methods, products,
instructions, or ideas contained in the material herein.
Content Strategist: Kayla Wolfe

Content Development Manager: Christine McElvenny
Content Development Specialist: Jennifer Horigan
Publishing Services Manager: Shereen Jameel
Project Manager: Nadhiya Sekar
Designer: Gopalakrishnan Venkatraman
Printed in United States of America
Last digit is the print number: 9 8 7 6 5 4 3 2 1

List of Contributors
Jabeen Ahmad, BSc (Hons) James Duhig, PhD

Regional Director Director
Affiliate Vigilance Excellence Safety Science
Pharmacovigilance and Patient Safety Pharmacovigilance and Patient Safety
AbbVie AbbVie
Maidenhead, United Kingdom North Chicago, IL, United States
Hans Peter Bacher, MD, PhD Vicki Edwards, BPharm (Hons)

Mature Products Vice President
Global Medical Affairs Pharmacovigilance Excellence
AbbVie Pharmacovigilance and Patient Safety
North Chicago, IL, United States AbbVie
Maidenhead, United Kingdom
Mondira Bhattacharya, MD
Former Senior Medical Director Jawed Fareed, PhD, DSc, FAHA
Safety Science Professor of Pathology and Pharmacology
Pharmacovigilance and Patient Safety Director of Hemostasis and Thrombosis
AbbVie Research Laboratories
North Chicago, IL, United States Division Director Cardiovascular Institute,
Vascular Biology
Deepa H. Chand, MD, MHSA Chair, Institutional Animal Care and
Associate Medical Director Usage Committee
Safety Science Loyola University Medical Center
Pharmacovigilance and Patient Safety Maywood, IL, United States
AbbVie Carl Fischer, PhD
North Chicago, IL, United States Senior Advisor
Center for Device and Radiological Health
Monali Desai, MD, MPH U.S. Food & Drug Administration
Senior Medical Director Silver Spring, MD, United States
AbbVie Cheryl Foit, BS
North Chicago, IL, United States Director
Project Management
Thao Doan, MD Pharmacovigilance and Patient Safety
Senior Medical Director AbbVie
Safety Science North Chicago, IL, United States
AbbVie
North Chicago, IL, United States
v
vi LIST OF CONTRIBUTORS
Suzanne Pauline Green, MD, MBChB, FFPM Karolyn Kracht, MS

Former Medical Director Associate Director
Safety Science Safety Science
AbbVie AbbVie
Barbara A. Hendrickson, MD Gweneth Levy, MD

Senior Medical Director Medical Director
Safety Science Safety Science
AbbVie AbbVie
North Chicago, IL, United States North Chicago, IL, United States
Robert Hogan, PhD Fabio Lievano, MD

President Vice President
Terminologix LLC Safety Science
Antigo, WI, United States Pharmacovigilance and Patient Safety
AbbVie
Syed S. Islam, MBBS, MPH, MSPH, Dr.PH North Chicago, IL, United States
Epidemiology Murray Malin, MD, MBA
Pharmacovigilance and Patient Safety Senior Medical Director
AbbVie Medical Quality Assurance
Calvin Johnson, BSc (Hons), MSc (PhV)
Director Anthony G. Oladipo, PharmD, MPH, BCPS
Affiliate Vigilance Excellence Senior Director
Pharmacovigilance and Patient Safety Safety Science
AbbVie Pharmacoviligance and Patient Safety
Maidenhead, United Kingdom AbbVie
Jeremy D. Jokinen, PhD, MS
Senior Director Denise M. Oleske, PhD
Safety Science Director
Pharmacovigilance and Patient Safety Epidemiology
Ryan Kilpatrick, PhD
Senior Director Meenal Patwardhan, MD, MHSA
Epidemiology Senior Medical Director
Pharmacovigilance and Patient Safety Safety Science
LIST OF CONTRIBUTORS vii
James M. Pauff, MD, PhD Charles Schubert, MD, MPH

Associate Medical Director Senior Medical Director
Oncology Clinical Development Safety Science
Ariel Ramirez Porcalla, MD, MPH
Medical Director Sundeep Sethi, MD, MBA
Safety Science Vice President
Pharmacovigilance and Patient Safety Pharmacovigilance Operations
Radhika M. Rao, MD, MPH
Medical Director Arsalan Shabbir, MD, PhD
Pharmacovigilance Operations Former Associate Medical Director
Pharmacovigilance and Patient Safety Global Medical Affairs
AbbVie AbbVie
Nicholas Rees, MBBS, BSc Melissa M. Truffa, BSPharm

Medical Director Director
Pharmacovigilance Excellence Safety Science
AbbVie Abbvie
Cheryl Renz, MS, MD Jerzy Edward Tyczynski, PhD

Senior Medical Director Senior Director
Safety Science Epidemiology
AbbVie AbbVie
Adrienne M. Rothstein, PharmD Marietta Vazquez, MD, FAAP

Associate Director Associate Professor Pediatrics
Safety Science Infectious Diseases
Pharmacovigilance and Patient Safety Pediatrics
AbbVie Yale University School of Medicine
North Chicago, IL, United States New Haven, CT, United States
Linda Scarazzini, MD Verghese Mathew, MD, FACC, FSCAI

Vice President Chair in Cardiology
Pharmacovigilance and Patient Safety Director, Division of Cardiology
AbbVie Professor of Medicine
North Chicago, IL, United States Loyola University Medical Center
Maywood, IL, United States
Acknowledgments
We would like to thank our families, friends, and We wish to thank Dawn Dvorak, Shannon Gacke,
colleagues for their insights, support, and encourage- Jennifer Koeller, Mary Locicero, Rosalind Munoz, Pam
ment in this endeavor to make an impact on the future Spezialetti, and Adrienne Towles for their assistance.
of medical safety and pharmacovigilance. The authors acknowledge and thank their patients
We appreciate the following reviewers for their whose lived experiences have contributed to the science
thoughtful comments: Ronda Goldfein, Sherrie Gallas, of pharmacovigilance.
Katherine Hiegel, Paul J. Lee, Jianzhong Liu, Jennifer Finally, we appreciate the support from Elsevier,
Manski, Gregory Pawell, Pam Puttfarcken, Jorge Ng with special thanks to Kayla Wolfe, Nadhiya Sekar,
Zheng, Sudhir Penugonda, Diane Schommer, and and Jennifer Horrigan.
Susanna Sit.
We also acknowledge the help of Christopher Sinclair
and David Sternala with the artwork in several chapters.
ix
Introduction
After 20 years of protecting patients through pharma- Topics include

covigilance, Dr. Linda Scarazzini and Dr. Fabio Lievano l The Regulatory Environment
are acutely aware of the need for concise and accessible l Safety Data and Real-World Evidence
resources on drug safety. l Special Topics and Special Populations
Pharmacovigilance plays a lifesaving role in the
l The Next Frontier: the Future of Safety Science
practice of medicine, yet there is no definitive source-
book on the topic. Current textbooks are dense in Besides having timely information with graphics
black-and-white text, lack graphics, and are updated and pragmatic applications, the text is engaging and
infrequently. easy to read.
With Pharmacovigilance: A Practical Approach, Dr. Pharmacovigilance: A Practical Approach is an essen-
Linda Scarazzini and Dr. Fabio Lievano provide tial resource for clinical researchers and healthcare
comprehensive, easy-to-read, and up-to-date informa- students and professionals. This book can form the
tion on the principles and practice of pharmacovigi- basis for undergraduate, graduate, and professional
lance. This book focuses on the evolving regulatory level courses.
landscape, case studies, and current and future use of
digital technologies.
xi
SECTION I THE REGULATORY ENVIRONMENT
CHAPTER 1
Does Regulation Drive Science or

Does Science Drive Regulation?
JABEEN AHMAD, BSC (HONS) • CALVIN JOHNSON, BSC (HONS), MSC (PHV) •
VICKI EDWARDS, BPHARM (HONS) • NICHOLAS REES, MBBS, BSC
INTRODUCTION were given to patients and resulted in several deaths.

The pharmaceutical industry is highly regulated to This led to the Biologics Control Act of 19021 that
protect both the patients taking medicines and the indus- required manufacturers to apply for a license to produce
try making them. No one wants to see a repeat of the and sell biological products. In addition clear product
serious drug-related disasters of the past that have shaped labeling was required and significant sanctions were
the current regulatory environment. However, we live in introduced if requirements were not metdtrue regula-
a fast-moving world of technology and innovative sci- tion was born!
ence where agility is key to ground-breaking new medi- In the 1930s, liquid sulfanilamide was introduced in
cines for patients. Regulations can take a long time to the US as an additional formulation to the established
develop and implement; changes are not easily made. capsules and tablet formulations available to treat strep-
They also have a reputation for being bureaucratic tococcal infections. The elixir was formulated using
and static while innovation races past. Regulators ideally diethylene glycol as a solvent. More than 100 adults
should balance the need for appropriate controls to and children died after taking the elixir. Investigations
ensure medicines have the best possible benefit-risk pro- showed diethylene glycol to be the cause of the deaths.
file while allowing innovation to drive the development This national disaster led to the Food, Drug and
of new medicines. Cosmetics Act of 19381 that required the food and
Historically, regulations related to pharmacovigilance drug administration (FDA) to monitor the safety of
(PV) were developed only in response to an event and new drugs. This act, although significantly modified, is
were fairly rudimentary in scope and application. Several still the basis of regulation in the US today.
key events, however, have triggered the evolution of PV Probably the most significant event that has shaped
regulations since the beginning of the 20th century. PV was the thalidomide disaster of the early 1960s.2
Over time, these regulations have become increasingly Thalidomide was a drug developed as a mild sedative
comprehensive and thoughtful. and marketed as being safe for adults and children. It
was also observed to be effective in alleviating morning
sickness and was used extensively by pregnant women
IMPORTANT EVENTS IN ”off label”, meaning the drug was not labeled to treat
PHARMACOVIGILANCE morning sickness. The drug was first marketed in
The most significant events in the history of PV regulation Germany in 1957 and was available in 43 countries,
are depicted in Fig. 1.1. At the end of the 19th century, although it was never approved by the FDA. The drug
large-scale production of vaccines for the prevention of was available over the counter. In 1961 the true horror
diphtheria and smallpox promised to save lives and of the effects of thalidomide began to unfold. Reports of
potentially eradicate these terrible diseases in the US. phocomelia; a very rare birth defect that results in short-
However, there were no government controls in place ened, deformed, or absent limbs, were received in
for biological products at the time. Consequently, safety distressingly large numbers. The drug was eventually
issues occurred; for example, vaccine products derived withdrawn in 1962 when it became clear that the birth
from the blood of a horse contaminated with tetanus defect was caused by thalidomide. It is estimated that
1
2 SECTION I The Regulatory Environment
FIG. 1.1 Important events in pharmacovigilance.
BOX 1.2
BOX 1.1 Thalidomide Use Today
The Trigger for Global PV Thalidomide is available today for the treatment of several
The thalidomide disaster triggered global regulations devastating medical conditions, such as leprosy and
requiring evaluation of both efficacy and safety of new multiple myeloma, due to risk minimization measures
medicines. being implemented.
24,000 affected babies were born worldwide, with a chapter 13). When thalidomide was reintroduced into
significantly large number of miscarriages and stillbirths the market, it came with one of the first comprehensive
in women also attributable to thalidomide. The Pregnancy Prevention Programs. The program provides
disaster resulted in significant changes globally to the educational information for both prescribers and pa-
regulation of medicines, requiring more rigorous clin- tients on the risks of using thalidomide and the impor-
ical trial testing and the need to demonstrate both the tance of avoiding pregnancy while receiving the drug.
efficacy and the safety of new medicines. Much of The supply of the drug is also carefully controlled.
what occurs today in PV is rooted in the lessons learned Dispensing pharmacies must register with the program
from thalidomide (Box 1.1). and understand the limited circumstances under which
Interestingly, the drug is still used today because it the drug can be dispensed. Female patients of child-
was found to be effective in a complication of leprosy bearing age must agree to use contraception and a nega-
and multiple myeloma.3 In addition to the lessons tive pregnancy test result must be provided before each
learned from the birth defects, the continued use of month’s supply of drug is issued. Pharmacies are
thalidomide has been made possible for diseases where required to maintain accurate records of treatment.
the benefit-risk balance is determined to be positive Although the program has been very successful, it has
(Box 1.2). This has provided the opportunity to develop not completely prevented further babies from being
strategies and methodologies for risk minimization (see born with the devastating birth defects.
CHAPTER 1 Does Regulation Drive Science or Does Science Drive Regulation? 3
Worldwide there was a unified desire to never let Two main organizations, supported by a number of
another thalidomide tragedy happen again. Countries non-profit industry trade organizations, are credited
began to set up national systems for the collection of with creating the foundation of modern PV: the Council
adverse drug reaction reports. In 1967 the World Health for International Organizations of Medical Sciences
Organization (WHO) received their mandate to start a (CIOMS) and the International Council for Harmonisa-
research project on the International Monitoring of tion (ICH).
Adverse Drug Reaction Reports; this work continues CIOMS was established in 1949. Based in
today.4 In 1968 the UK regulatory authority introduced Switzerland, the mission of CIOMS was to advance
the Medicines Act that governs the control of medicines public health through guidance on health research,
for human use and veterinary use, including the manu- including ethics, medicine development, and safety.
facture and supply of medicines. This act remains the Through its different expert advisory working groups,
foundation of UK legislation today. The importance CIOMS has set many of the global standards and
of PV took hold across the world but responses thinking around key PV topics. The CIOMS-1 form12
continued to be reactive. is one of the best known examples of CIOMS work
and it sets the international standard for exchange of
safety information between organizations, regulators,
IMPORTANT PHARMACOVIGILANCE and countries (Box 1.3).
ORGANIZATIONS ICH was formed by regulators in the United States,
The creation of the most influential PV organizations Europe, and Japan in the 1990s. By this time, some coun-
throughout the world is described in Fig. 1.2.5e11 tries had developed national PV regulation aimed at pro-
Some of these groups were developed as non-profit, tecting patient safety and public health. However, as each
non-governmental organizations whose aim was to set country’s regulations were developed in isolation, the re-
international harmonized PV principles and standards. sults were sometimes contradictory or duplicative. The
FIG. 1.2 Timeline of influential pharmacovigilance (PV) organizations.

frameworks. Significant progress has been made since

BOX 1.3
1990 to establish national PV systems, especially in
International Standards
low- to middle-income countries, by the WHO Interna-
The two main non-profit industry organizations that tional Drug Monitoring program16 and the Uppsala
continue to drive current global pharmacovigilance stan- Monitoring Centre. More than 150 countries have
dards are; The Council for International Organizations of now joined the WHO program, representing over 90%
Medical Sciences (CIOMS) and the International Council
of the world’s population.17
for Harmonisation (ICH).
Similar to the EMA model, regional PV frameworks
(in which more than one country adopts the same PV
mission of ICH is to achieve greater harmonization regulations) have begun developing throughout the
worldwide to ensure that safe, effective, and high- world. Although the intention of regional frameworks
quality medicines are developed and registered in the is to harmonize regulation across countries, this does
most resource-efficient manner. The ICH guidelines are not always happen. When countries transpose regional
recognized internationally as a neutral international regulation into their national laws, often additional re-
standard for the safety, quality, and efficacy of medicines quirements are added or requirements are removed. To
and they continue to be influential today (Box 1.3). date, none of the regional PV frameworks operate like
In Japan the Pharmaceuticals and Medical Devices the European Union, which has legal authority over
Agency (PMDA) was established in 2004. Its creation all the countries it operates in. Of note, however, a
consolidated existing bureaus for Adverse Drug Reac- multi-country regulatory agency is being planned for
tions. The PMDA is responsible for the review of new the continent of Africa; 54 countries!18
drug applications and postmarketing safety activities.
PDMA works closely with the Ministry of Health, THE WORLD OF REGULATORY SCIENCE
Labour and Welfare (MHLW) in Japan.13 In recent years, regulators have moved from a reactive to
A significant event for PV in Europe was the estab- a proactive approach to regulating medicines. In the
lishment of the European Medicines Agency (EMA) in past, legislation was put in place in response to an
2005.14 The mission of EMA is to foster scientific excel- event; typically, it was narrowly focused and inclined
lence in the evaluation and supervision of medicines for to be inflexible. New legislation therefore has tended
the benefit of public and animal health in the European not to take into account advances in science and medi-
Union. The EMA supervised medicines in 28 countries cine, innovative technologies, or changes in societal
of the European Union (known as the member states) behaviors and needs.
and in the countries (Norway, Liechtenstein, and Ice- Currently, EMA and FDA are aligned on
land) that are part of the European Economic Area the definition of regulatory science as the science of
(EEA) (Box 1.4).15 Together, the EMA, FDA, and developing new tools, standards, and approaches to
MHLW regulators have played a significant role in assess the safety, efficacy, quality, and performance of
shaping PV legislation today. medicinal products. Regulatory science informs
decision-making throughout the life cycle of a medicine
IMPORTANT REGULATORY AUTHORITIES and can encompass basic and applied medicinal science
AND REGIONS and social sciences.19,20 Today patients and the public
Most countries in the world now have a regulatory want more information about medicines and sooner;
authority whose aim is to protect public health. this is driving the need for regulatory transparency
Fig. 1.3 shows important global regulatory authorities and timely information sharing. Patients also want to
and countries which have regional multi-country PV participate in decision-making in the choice of their
treatments and to have a voice in the development of
new medicines.
BOX 1.4 Societal expectations have strongly influenced cur-
Aims of the EMA rent regulations. In 2010, the EMA updated the existing
directive on medicinal products for human use. This up-
To
date was implemented in 2012 by practical guidelines
1. facilitate development and access to medicines;
2. evaluate applications for marketing authorization; known as the Good Pharmacovigilance Practice Mod-
3. monitor the safety of medicines across their life cycle; ules or EU GVPs21 (Box 1.5). The aim of this legislation
4. provide information on human and veterinary was to reduce the number of adverse drug related reac-
machines to healthcare professionals and patients. tions in Europe through a wide range of measures. This
includes better data collection on medicines and their
FIG. 1.3 Important global regulatory authorities and regional frameworks.
heavily influenced by EU GVPs are the Arab GVPs and

BOX 1.5
the Eurasian GVPs. The Arab GVPs were developed by
EMA Good Vigilance Practice Modules
the Arab League organization22 and have been adopted
The EU good pharmacovigilance practices (GVPs) fully or partially by Egypt, Iraq, Jordan, Kuwait,
• Module I PV systems and their quality systems Oman, Tunisia, and Saudi Arabia. The Eurasian
• Module II PV system master file (PSMF) Economic Commission23 developed the Eurasian
• Module IIIPV inspections GVPs or EAEU GVPs (referred to in Fig. 1.3), which
• Module IV PV audits cover the Eurasian region of Russia, Belarus,
• Module V Risk management systems Kazakhstan, Armenia, and Kyrgyzstan.
• Module VI Management and reporting of adverse Fig. 1.4 shows a high-level comparison of the FDA
reactions to medicinal products
and EMA PV requirements. Although there are a few dif-
• Module VII Periodic safety update report (PSUR)
• Module VIII Postauthorization safety studies (PASS)
ferences, notably the requirement of a Qualified Person
• Module IX Signal management for Pharmacovigilance (QPPV)24 in every company
• Module X Additional monitoring marketing medicines in Europe and a PV System Master
• Module XV Safety communication File (PSMF),25 the overall general approach to drug
• Module XVI Risk minimization measures: Selection of safety is very similar.
tools and effectiveness indicators
EMA PHARMACOVIGILANCE RISK

ASSESSMENT COMMITTEE
safety, rapid assessment of safety issues, and empower- A significant component of the EU GVPs intended to
ment of patients. This regulatory change has had a sig- promote a more proactive safety approach and to
nificant impact on global PV requirements and strengthen transparency and communication was the
represents the current best practices. A number of coun- establishment of the Pharmacovigilance Risk Assess-
tries and regions have since developed regulation that ment Committee (PRAC).26 PRAC is responsible for
closely resembles the EU GVPs. Regional framework assessing and monitoring the safety of human
FIG. 1.4 Comparison between the US and EU pharmacovigilance regulations. (Sources: FDA & EMA
websites November 06, 2017.)
medicines and for reviewing and assessing all aspects of • Periodic Safety Update Reports;
risk management (Box 1.6). • Post authorization Safety Studies (PASS);
Specifically, the PRAC reviews: • Renewals of marketing authorizations.
• Product referrals for safety reasons;
Each PRAC member is chosen on the basis of the
• Safety signal assessment and prioritization;
strength of their expertise in PV and risk assessment
• Risk management plans, both pre- and post-
of medicines. Although the meetings themselves are
authorization;
authorities now want to receive the outcomes of assess-

BOX 1.6
ment at the same time as PRAC and want assurance that
Pharmacovigilance Risk Assessment Committee
any action taken with respect to European licenses will
The mandate of the EMA PRAC: be simultaneously taken with non-European licenses.
• All aspects of risk management of medicines including
detection, assessment, minimization, and communi-
cation of a medicine’s benefit and risk. NEW WAVE OF GLOBAL
• The design and approval of postauthorization safety PHARMACOVIGILANCE REGULATION
studies.
In the past, the most sophisticated and developed drug
• Input into the risk-based programme for routine PV
inspections. Recommendations on the need for in- safety regulation was isolated to the ICH regions: the
spections “for cause”, meaning unannounced PV in- United States, Europe, and Japan. In recent years, other
spections of companies triggered by specific safety regions have moved from no or rudimentary legislation
concerns. to adoption of robust and complex requirements.
The PRAC committee is composed of Although both commendable and understandable, if
• Six independent scientific experts the requirements are not harmonized with existing
• One health care professional global standards, this does put an increased burden
• One patient organization representative on industry. In response, the industry is monitoring
• One member and one alternate member nominated by the evolving legislation to promote international
each member state and the EEA countries Norway and harmonization. The recent wave of legislation in
Iceland. emerging markets is leading to a second wave of harmo-
nization efforts. However situations are very different in
resource-constrained countries, and decisions need to
not public, the agendas and minutes are publically be made by these regulatory authorities as to where is
available on the EMA website.26 Additionally, com- best to focus limited resource. Therefore the focus of
panies referred to as Marketing Authorisation Holders industry advocacy efforts should be to promote “right-
(MAHs) receive an advanced notification of products sized” PV systems that are harmonized where possible.
or new signals that will be discussed in each meeting. For example, aligning with complex PV frameworks,
PRAC may invite companies to participate in meet- such as the EMA GVPs, may not be the answer for coun-
ings by way of a Scientific Advisory Group meeting, tries with limited resources. Instead, regulators in
where experts on the topic under discussion are also emerging markets may decide to focus on the reporting,
invited or, in more formal circumstances, at an Oral collection and monitoring of local adverse reactions.
Hearing when there is a complex or controversial issue
under discussion.
Trade associations such as the European Federation THE EU QPPV
of Pharmaceutical Industries and Associations (EFPIA) Since 1995, European legislation has required the
view PRAC as a positive and effective part of the appointment of a Qualified Person for Pharmacovigi-
European medicine legislation. However, PRAC is not lance (QPPV). A QPPV (Box 1.7) is required for any
the ultimate decision-maker; rather, it makes recommen- MAH with a marketed product in any country within
dations to the Committee for Medicinal Products for Hu- the EEA.24 The QPPV must reside in a European country
man Use (CHMP) who then provides an opinion to the and act as the single point of contact for the EMA and
European Commission, which is the ultimate decision- any national competent authority on a 24 hour basis.
maker. On occasion, the CHMP will not agree with or The main duties of the QPPV are to maintain oversight
will reverse PRAC’s recommendation. The transparency of the global PV system including drug safety profiles
of PRAC activities have had unanticipated and in some re- and emerging safety concerns, to influence the perfor-
spects unintended consequences for the industry. The mance of the quality system for PV to improve compli-
publically available agendas and minutes are keenly ance, and to provide input into regulatory action such
read by regulatory authorities outside Europe. In conse- as updates of product information with healthcare pro-
quence, companies have seen an increase in questions fessionals and patients.25
from non-European authorities related to the issues un- Although the QPPV role is a European requirement,
der discussion. These questions may have a slightly the QPPV is required to have oversight of the global PV
different focus but are commonly seeking information system; therefore, the EU QPPV in a global company
related to the relevance of the issue to the population of should be authorized to have oversight of global PV
the requesting country. In addition, global regulatory matters. The QPPV assumes both individual and
suitably qualified candidate. Also, products are mar-

BOX 1.7
keted in countries where companies may not have a
Responsibilities of the EU QPPV
local office and therefore do not have any local staff resi-
• having an overview of product safety profiles and dent in the country to become the QPPV. This often re-
emerging safety concerns; sults in the company contracting a third party to meet
• having awareness of commitments related to safety or the local QPPV requirement. When a third party fulfils
the safe use of products; the role, it remains the responsibility of the company
• having awareness of risk minimization measures; to have oversight of the national QPPV.
• having sufficient authority over the content of risk In the case of third-party vendors fulfilling the QPPV
management plans; requirement, a good understanding of the role and the
• being involved in the review and sign off of protocols
importance of PV is required. The importance of
of post-authorization safety studies and awareness of
embedding the local QPPV role within the global orga-
their results;
• ensuring the quality, correctness, and completeness nization of a company has led to the development of
of PV data submitted; in-house national QPPV training by companies.
• ensuring a full and prompt response to requests for
additional information for the benefit-risk evaluation of
The Pharmacovigilance System Master File
a medicinal product;
• having input into regulatory action in response to The Pharmacovigilance System Master File (PSMF) is a
emerging safety concerns. mandatory requirement in Europe, as described in EU
GVP Module II.25 The PSMF is a dynamic document
which describes the global PV system of the MAH in a
prescribed format, with a focus on how the system
company responsibility for compliance with regulation; affects products authorized in Europe. It includes how
thus, the QPPV can be individually prosecuted for a all departments within a company interact with PV
company’s failings. and if any tasks have been delegated to third parties.
The PSMF is maintained and updated at frequent in-
tervals by MAHs. It contains contact details and the
THE RISE OF THE NATIONAL QPPV resume of the EU QPPV plus a summary of the PV
Some EU countries have a requirement for the appoint- organizational structure including the physical site(s)
ment of a national QPPV; an individual at the national where specific safety information is handled (such as
level who is responsible for PV in that country. For data entry of adverse events into the global database,
example, France, Germany, Italy, and Spain have this signal detection, and safety analysis). The PSMF
requirement. The national QPPV must reside in the spe- documents the sources of safety data, including clinical
cific country so that they are able to speak in the local trials and marketed drug data collection programs.
language and understand country-specific nuances. The purpose of the PSMF is to provide the EMA
Many non-European countries have begun to adopt and EU competent authorities with an overview of a
the requirement for a national QPPV. The requirements company’s PV system. It is used by EU regulators in a
to fulfil the national QPPV role varies from country to risk-based manner when selecting companies for PV
country. In some instances, the requirement is as inspection.
simple as providing the national regulatory agency Some non-European regulators still use the Detailed
with contact details for the responsible person. In Description of the PV System (DDPS) (referred to in su-
comparison, some countries require specific training perseded EU PV legislation), meaning that MAHs must
for the role. In Ghana, the QPPV must attend manda- maintain both document formats. To complicate
tory QPPV training provided by the Ghanaian regulato- matters, other countries have duplicated the EU
ry authority.27 For Arab countries who follow the Arab PSMF requirements and have added extra requirements.
Good Vigilance Practice Guidelines22, the training and For example, countries following the Arab GVPs accept
education of the QPPV is exactly the same as extensive the EU PSMF but also require an additional document
EU requirements. referred to as the Pharmacovigilance System Sub-File,
One of the challenges of the national QPPV concept which focuses on the national PV system. More recently,
is the requirement for the individual to reside in the the Eurasian Economic Union has requested a separate
local country. In emerging countries, there is a dearth Eurasian Union PSMF. This is clearly an area that lacks
of PV expertise and companies may struggle to find a harmonization.
Is Regulatory Guidance Just Guidance? from existing international requirements and promote
In addition to regulations stated in law, regulatory guid- alignment with neutral international standards (such
ance linked to PV activities can exist in different forms. as ICH or CIOMS) or influence the addition of new
This includes formal published guidance, question and requirements.
answer documents, letters to MAHs, written correspon- Regulators such as EMA and FDA hold regular public
dence between the MAH and the regulatory authority, meetings with all stakeholders who have an interest in
and verbal guidance given during conferences and sym- PV (for example, industry trade associations, academia,
posia. Additional detail provided in published guidance and patient associations) and are willing to meet with
enables clarity in interpretation of the legal obligations. the industry. Industries have been successful in driving
There is a hierarchy associated with guidance. For meaningful change through these interactions.
example, in Europe the EU GVP guidance28 is at the
top of this hierarchy, so any deviation from it should Enforcement of Pharmacovigilance
be carefully considered. When it comes to the assess- Regulations
ment of compliance with the EU guidance through reg- Similar to other industries, regulatory authorities who
ulatory inspections, a critical finding is defined as define PV regulations need to have an effective mecha-
nism in place to monitor and enforce compliance to
A deficiency in pharmacovigilance systems, practices or
the requirements (Box 1.8). There are slightly different
processes that adversely affects the rights, safety or well-being
approaches taken globally, but the key to achieve the
of patients or that poses a potential risk to public health or that
represents a serious violation of applicable legislation and greatest degree of compliance is linked to the effective-
guidelines.29 ness of the following strategies:
1. Setting the standards
This is in contrast to the more pragmatic approach of If requirements are sufficiently detailed and are clear
the formal FDA Guidance for Industry that states that and proportionate to the local environment and
that guidance contains nonbinding recommendations needs, there is a greater likelihood of compliance
and includes the following statement: being achieved for the majority of companies that
This guidance represents the current thinking of the Food and strive to comply.
Drug Administration (FDA or Agency) on this topic. It does 2. Performing inspections
not establish any rights for any person and is not binding on This is the main approach to assess compliance.
FDA or the public. You can use an alternative approach if Regulatory inspectors visit MAHs to assess the
it satisfies the requirements of the applicable statutes and systems, personnel, and procedures in place to
regulations. To discuss an alternative approach, contact the
determine the degree of compliance. Any de-
FDA office responsible for this guidance as listed on the title
ficiencies are graded into three categories: critical,
page.30
major and minor. A report is usually provided, to
Collaborative partnership among MAHs, regulatory which the company must respond and commit to
agencies, and patients will facilitate evolution of taking action to address any deficiency. Adequacy of
thoughtful and practical PV regulations, which is critical these actions can be assessed on re-inspection of the
for advancing benefit-risk monitoring of medicines and MAH at a future date. If the finding is significant some
their use in the real world.
How can Industry Influence Regulation?

Even as recently as 10 years ago the pace of change in BOX 1.8
regulations was relatively slow. More recently, there Pharmacovigilance Enforcement
has been an unprecedented explosion of new global Pharmacovigilance regulation enforcement strategies:
PV legislation. 1. Setting standards: publishing clear and detailed PV
The pharmaceutical industry has undertaken efforts regulations proportionate to the country need.
to “speak with one voice” via trade associations (see 2. Performing inspections of marketing authorization
Fig. 1.1) such as the International Federation of Phar- holders.
3. Education and advisory tools: through conferences,
maceutical Manufacturers and Associations (IFPMA),
written guides, and engagement with trade
EFPIA (European Union), and the Pharmaceutical associations.
Research and Manufacturers of America (PhRMA, 4. Warning letters published in the public domain.
United States). When new legislation is issued as a draft 5. Enforcement actions: legal process such as product
for public consultation, the industry and trade associa- withdrawal and financial penalties.
tions can proactively identify any potential divergence
regulatory authorities require written evidence of assessment of medicines has become much more trans-
completion of the action. There is a harmonized parent and dynamic. Leading regulatory agencies are
approach to inspections in the EU that is coordinated hugely influential globally and information made pub-
by the EMA;31 however, there is no international lic from these agencies can lead to a global focus on
harmonization for PV inspections. A risk-based safety issues. However the breadth and complexity of
approach is commonly adopted to determine which PV frameworks in well-resourced countries, may not
companies are inspected and how frequently they are be the right approach for resource-limited regulators.
inspected. This may include gathering information A “right-size” PV approach is advised to newer regula-
from other parts of the regulatory agency that tors, with harmonization of PV legislation where
monitor quality and timeliness of safety information possible. Early identification of safety issues via more
submitted by a company. recent sources of safety information such as social me-
3. Educating and advising dia is a priority for regulators and the industry alike.
Regulatory authorities engage and educate stake- Regulators are working hard to keep up with new
holders through trade association meetings or con- technologies such as robotic automation and artificial
ferences to enhance understanding and practical intelligence, and with innovation in drug development
application of the requirements, which in turn and delivery. However, the rate of change is very fast.
increases the likelihood of compliance. Additional Therefore the answer to whether regulation drives sci-
methods include publishing guidance such as the ence or whether science drives regulation is that science
Medicines and Healthcare products Regulatory and technology appear to be driving regulation in our
Agency’s (MHRA) Good Pharmacovigilance Practice rapidly moving digital environment.
guide (the “Purple” guide) and publishing inspec-
tion metrics.32,33
4. Warnings REFERENCES
Warning letters and making information public 1. US Food and Drug Administration. http://wwwfda.gov.
where there is significant and/or persistent AboutFDA/WhatWedo/History; 2017.
noncompliance provides an opportunity for the 2. Thalidomide Society. www.thalidomidesociety.org; 2017.
recipient to rectify the noncompliance before formal 3. Greenstone G. Special feature: the revival of thalidomide:
legal action is taken. It also acts as either a deterrent from tragedy to therapy. BC Med J. 2011;53(5):203e233.
to others or a means of educating and adds further 4. World Health Organization. http://www.who.int/medic-
clarity to the authorities’ expectations. Two examples ines/areas/quality_safety/safety_efficacy/advdrugreactions/
en/; 2017.
of these letters are the used in the United Kingdom
5. World Health Organization. http://www.who.int/about/
and the FDA 483 warning letters.32,34
en/; 2017.
5. Enforcement action 6. Council for international Organizations of Medical
Regulators can take legal action for the most serious Sciences. https://cioms.ch/about/; 2017.
and persistent contravention of PV regulations. For 7. International Federation of Pharmaceutical Manufacturers
example, in the EU, financial penalties can be & Associations. https://www.ifpma.org/who-we-are/ifpma-
imposed for the infringement of PV obligations. This in-brief/; 2017.
can be up to 5% of the company’s European sales, in 8. European Federation of Pharmaceutical Industries and
the preceding business year, which is a significant Associations. https://www.efpia.eu/about-us/; 2017.
deterrent.35 9. Uppsala Monitoring Centre. https://www.who-umc.org/
global-pharmacovigilance/who-programme/; 2017.
10. The International Council for Harmonization of Technical
CONCLUSIONS Requirements for Pharmaceuticals for Human Use. http://
In recent years, regulators and This is resulting in newer www.ich.org/home.html; 2017.
regulations are more focused on proactive safety 11. The International Society of Pharmacovigilance. http://
measures. There is emphasis on earlier signal detection isoponline.org/; 2017.
12. CIOMS-1. Form: https://cioms.ch/wp-content/uploads/
capabilities and risk proportionate approaches to
2017/05/cioms-form1.pdf; 2017.
decision-making. This is resulting in earlier provision 13. The Pharmaceutical and Medical Devices Agency. https://
of relevant safety information to prescribers and www.pmda.go.jp/english/; 2017.
patients. Robust and comprehensive PV legislation is 14. European Medicines Agency. http://www.ema.europa.
in place in countries with mature PV systems, which eu/ema/index.jsp?curl¼pages/about_us/general/general_
include education and enforcement processes. Risk content_000091.jsp; 2017.
15. European Economic Area. http://www.europarl.europa. 27. Ghana Food and Drugs Authority Guidelines for Qualified
eu/atyourservice/en/displayFtu.html?ftuId¼FTU_6.5.3. Person for Pharmacovigilance. March 1, 2013. FDA/SMC/
html; 2017. SMD/GL-QPP/2013/03, Version 2.
16. Olsson S, Pal SN, Dodoo A. Pharmacovigilance in resource- 28. EMA GVP Modules; 2017. http://www.ema.europa.eu/
limited countries. Expert Rev Clin Pharmacol. 2015;8(4): ema/index.jsp?curl¼pages/regulation/document_listing/
449e460. document_listing_000345.jsp.
17. UMC. https://www.who-umc.org/vigibase/vigibase/; 2017. 29. EMA. Union Procedure on the Preparation, Conduct and
18. Website: African Medicines Regulatory Harmonisation Reporting on EU Pharmacovigilance Inspections. March 21,
(AMRH) NEPAD; 2017. www.nepad.org. 2014. EMA/INS/PhV/192230/2014.
19. EMA. European Medicines Agency Process for Engaging in 30. FDA Providing Postmarketing Periodic Safety Reports in
External Regulatory Sciences and Process Improvement Activ- the ICH E2C (R2) Format (Periodic Benefit Risk-Benefit
ities for Public and Animal Health. 2017. EMA/573402/ Evaluation Report) Guidance for Industry, CDER, CBER.
2017. November 2016.
20. FDA. Office of the Chief Scientist: Advancing Regulatory 31. EMA Coordination of Pharmacovigilance Inspections; 2017.
Science for Public Health. Oct. 2010. http://www.ema.europa.eu/ema/index.jsp?curl¼pages/reg-
21. EMA Good Vigilance Practices; 2017. http://www.ema. ulation/general/general_content_000160.jsp&mid¼WC0b
europa.eu/ema/index.jsp?curl¼pages/regulation/docu- 01ac058002708a.
ment_listing/document_listing_000345.jsp. 32. MHRA Good Pharmacovigilance Practice (GPvP); November
22. The League of Arab Common States; Guideline on Good 11, 2017. https://www.gov.uk/guidance/good-pharmaco
Pharmacovigilance Practices (GVP) for Arab Countries, Version vigilance-practice-gpvp#history.
2. December 2014. 33. MHRA Good Pharmacovigilance Practice Guide. 1st ed.
23. The Eurasian Economic Commission. Rules of Good London: Pharmaceutical Press; 2008.
Pharmacovigilance Practice (GV) of Eurasian Economic Union, 34. US FDA 4-1- Warning Letters. In: https://www.fda.gov/
Decision No. 87. November 3, 2016. ICECI/ComplianceManuals/RegulatoryProceduresManual/
24. EU Guideline on Good Pharmacovigilance Practices ucm176870.htm#SUB4-1-1; 2017.
Module I: Pharmacovigilance Systems and Their Quality 35. EU Commission Regulation (EC) Concerning Financial Pen-
Systems, June 25, 2012. EMA/541760/2011. alties for Infringement of Certain Obligations on Connection
25. EU Guideline on Good Pharmacovigilance Practices Module II: with Marketing Authorisations Granted under Regulation
Pharmacovigilance System Master File. March 28, 2017. (EC) No 726/2004 of the European Parliament and of the
EMA/816573/2011 Revision 2. Council, No 658/2007. June 14, 2017.
26. EMA Pharmacovigilance Risk Assessment Committee
(PRAC). http://www.ema.europa.eu/ema/index.jsp?curl¼
pages/about_us/general/general_content_000537.jsp; 2017.
SECTION II SAFETY DATA AND REAL WORLD EVIDENCE
CHAPTER 2
Signal Management and Methods of

Signal Detection
MELISSA M. TRUFFA, BS PHARM • ADRIENNE M. ROTHSTEIN, PHARMD •
CHERYL FOIT, BS • JEREMY D. JOKINEN, PHD, MS
INTRODUCTION patterns for recognized signals (e.g., risk factors, severity,

Understanding both the benefits and the risks of and outcome). PV utilizes data gathered from multiple
medicines is essential to prescribers and patients. This sources such as clinical trials, spontaneous individual
understanding is based on the idea of collecting data case reports, scientific literature, observational studies,
(adverse events), weighing the importance of the data, and electronic medical records. Examples of how
processing the information, and providing insight into adverse event data are gathered from different sources
the safety profile that can result in informed decisions are provided in the following. The MedWatch form to
by prescribers and patients about the treatment of their report to the US Food and Drug Administration (FDA)
diseases and medical conditions. These activities are the is shown in Fig. 2.1. There are also mobile applications
cornerstone of the science of pharmacovigilance (PV) (apps) for reporting adverse events directly to regulatory
and start with an adverse event report (Box 2.1). authorities (see Fig. 2.2).
An adverse event is any untoward medical occurrence Adverse events from clinical trials can be submitted
associated with the use of a drug in humans, whether directly to the sponsor of the clinical trial or to a
or not considered related. Not all adverse events are regulatory authority for a government-funded study.
necessarily risks, but determining which ones are risks Large safety databases of adverse events provide a rich
and which ones are not is critical to understand the safety source of data for PV activities for interested stakeholders
profiles of drugs, biologics, or vaccines. such as global regulatory authorities, pharmaceutical
The science and activities related to the detection, companies, and researchers. The FDA Adverse Events
assessment, understanding, and minimization of adverse Reporting System (FAERS) and the EudraVigilance
events or any other drug-related problems are referred to database are two such large safety databases. The FAERS
as PV. The key aspects of PV are the detection of new public dashboard allows users to visualize and search
safety signals and the further characterization of new safety data in the FAERS database. Fig. 2.3A shows
screenshots of the FAERS dashboard, with an example
of an overview for acetaminophen (see Fig. 2.3B).
BOX 2.1
The EudraVigilance database is the European
Pharmacovigilance
information system of adverse events for medicines
• Pharmacovigilance is the science of identifying, that are authorized or being studied in clinical trials
assessing, and minimizing the risk of adverse events in the European Economic Area. The EudraVigilance
within a population. system also has a public dashboard. Sample views of
• Clinical trials, case reports, studies, and medical re- this data are shown for ACTOS in Fig. 2.4A and 2.4B.
cords are data sources used in PV practices.
• Data is collected via submissions to regulatory au-
thorities, mobile applications, and from clinical trial SIGNALS (BOX 2.2)
submissions Detection of safety signals is a key aspect of PV but
• Public data is housed in FAERS (FDA) and EudraVigi- what is a signal? There are many definitions for a
lance (EU). signal. For the purposes of PV, there are two commonly
13
14 SECTION II Safety Data and Real World Evidence
FIG. 2.1 The US Food and Drug Administration MedWatch form. (Data from: https://www.fda.gov/
downloads/AboutFDA/ReportsManualsForms/Forms/UCM163919.pdf.)
Another random document with
no related content on Scribd:
"Madam, I crave pardon, but Mr. Whitney has just this to do with the
matter. It appears, from all I have heard, that Lucy herself does not care for
Mr. Rockwell as she should care for the man she marries. Also—I believe—
she does so care for Mr. Whitney."
"Let me ask, Mr. Whitney, what means you have at your disposal for this
young lady's support? How many slaves have you? How—
"I have no slaves at all, Mr. Rockwell, being a Christian!" retorted

Whitney, forgetting himself for an instant. Then, after an ominous little
pause, he remarked, in another tone: "I crave your pardon. I have one
hundred pounds a year from my parish, and something laid by. It is quite true
that I cannot give Mistress Lucy a home like this; but I will engage to keep
her always housed from God's weather, well shielded from cold, and with
enough to eat—if not of the finest, at least of such as should satisfy her,
provided it be served with the sauce of sweet content. Moreover—I will take
no dower with my wife."
At this last Claude opened his eyes widely, Rockwell looked put out, and
Madam Trevor glanced at the speaker with a new expression.
Vincent, turning from the Puritan with the barest smile at his earnestness,
addressed his rival: "And you, George Rockwell—what have you?"
Rockwell cleared his throat, and rose as if he were to speak from the
pulpit: "My income from St. Anne's is, I confess without mortification, no
greater than that which this gentleman—um—ah—has just said to be his
portion from the meeting-house. My fees and perquisites as Church of
England clergyman, however, make the sum far larger annually. I think also
that you, madam, and Mistress Lucy, will recognize the difference between
the—to speak gently—the somewhat humble abode of Mr. Whitney and the
rectory which I myself have the honor to occupy, and where I am
accustomed to entertain his excellency himself."
"Pardon me, sir, but could you indeed imagine that, after my marriage, I
should not instantly remove to an abode more suited than my present one to
a lady's convenience? Do you imagine—"
"You interrupt, sir. I make no observations on what your conduct will be.
I am only aware of what it is."
"It is, sir, so far as I am aware, irreproachable!"
"Come, come, gentlemen," interposed Vincent, in some displeasure, "we

wander from the subject. You—a—have not spoken of dower, Rockwell. Of
course, my sister, being of our family, would not lack suitable outfit and
settlement on entering a new estate. Still—"
"I was sure," interrupted Rockwell, hastily, for the point was delicate—"I
was sure that you would regard it as well—nay, might as a pride consider it
indispensable, Vincent, that—"
"Stop! Let me go away." Lucy had risen, quivering, to her feet, her mild
eyes blazing, her voice low and unnatural. "I will not be bargained for,
bought and sold, as slaves or horses are. Vincent, you have insulted me by
permitting such a scene. And you—" turning to Whitney and Rockwell
—"you are heartless and soulless. Love! What do you know of that?"
She turned, with Virginia at her side, and, not looking again at any one in
the room, swept away towards the west wing. As her daughter departed,
Madam Trevor rose undecidedly, then reseated herself, with a new and firm
intention of having more to say in the forthcoming battle than she had had
heretofore. Three of the men, Vincent and the rivals, were staring at each
other, Whitney and Trevor in mortification, Rockwell merely in surprise.
"Egad!" murmured Vincent, softly, "the little girl was right."
"I apologize to you, Mr. Trevor, and to Mistress Lucy, for my utterly
thoughtless and discourteous behavior," cried Whitney. "Indeed, I was
thoughtless and unfeeling. I most painfully acknowledge that your sister's
anger became the situation."
"Oh—the lady was piqued, sir, at your lack of worldly goods," observed
Rockwell, with a grin of ingenuous conceit.
Claude regarded the man with languid disgust. Vincent flushed angrily,
and Madam Trevor rose.
"We waste time, gentlemen," she said. "It is perfectly fitting that these
matters should form part of the discussion. For my part, Mr. Rockwell, I am
entirely with you. I wish my daughter to marry you, since I believe you
competent of caring for her as should be. As to the settlements, of course—"
"Pardon me, madam, but this is quite useless," interrupted Vincent,

coming forward, with the light of sudden resolve in his eyes. "You are aware
that once before this matter has been most unsatisfactorily decided in this
way. My sister has continually denied your statement that she was affianced
to Mr. Rockwell, and I have been led to believe that it was through her
attachment to Mr. Whitney, who some time since honorably professed to me
his love for her. As legal head of this house, then, I cannot feel it otherwise
than just to insist that my sister herself, and none other, shall choose between
these two; and I now say that it shall be entirely without consideration of
dower, settlement, or—perquisite. Further, I maintain that, if Lucy choose to
reject both of these gentlemen, of her own free will, she shall thereafter be
housed and protected under my roof till she find some one to her taste, or till
she die here unmarried."
"Well spoken, sir!" cried Whitney, bravely, while Madam Trevor stood
aghast, and Claude, intensely interested in the scene, deliberatively crossed
the room and sat down with his back to the wall.
"You mean to inform me that my authority is at naught in this

household?" inquired Madam Trevor, hoarse with excitement and anger.
"I am thinking only of Lucy's happiness," returned her son, gently. "She
must be called to come back."
"I, certainly, shall not remain to witness this scene."
"Gentlemen, excuse me for one instant. I will summon my sister."
Vincent left the room; but, in spite of herself, his mother stayed. She was
too deeply interested to go; and, despite her traditions, Lucy's happiness was
really quite as dear to her as to her son. Claude, from behind the others,
philosophized a little in the silence. How differently had such a scene been
conducted in his country! There would have been no argument, no difficulty.
Above all, Lucy herself would have been the last person to be consulted.
Rockwell, for his means and position, would certainly have been chosen;
and, if it were a Court affair, Whitney might have become her general escort
afterwards. Claude sighed. This colonial boorishness produced far better
results. Ethics here were regarded with some degree of blind appreciation. In
his own country it was not so. A second sigh was in his heart when Lucy,
preceded by her brother, re-entered the room.
There was still perfect silence. Near the doorway the young girl paused.
She was pale and red-eyed, but steady of manner. The two clergymen, side
by side, faced her, with Vincent to the right, and his mother upon the left.
Claude, quite forgotten, still looked on from the opposite wall.
"Lucy, I have brought you back here that you yourself may make choice
between these men. Let me now, then, entreat you, most earnestly, to
consider, to decide not hastily, but as in heart and mind you deem wisest.
Love is not always all. Respect—firmness—wisdom—ability to protect—
these are as strong. I place confidence in you, Lucy; and, in return, I ask
sincerity from you. We will wait as long as you will. Choose."
During his words Lucy had looked earnestly at her brother. Now,
however, her eyes fell. A delicate smile broke over her face, and when
finally she looked up it was to encounter the eyes of John Whitney, who was
regarding her with a look of such mingled love, fear, and longing, that she
would not torture him by suspense. Gently she extended one hand, one arm
to him, while her lips smiled "Come," and her face grew beautiful with the
love-light in it.
He went, never heeding the rest, no longer aware, perhaps, that they were
by. And, as he clasped her in his strong, young, Puritan arms, Claude looked
courteously out o' window, but Madam Trevor, with a curious dryness in her
throat, turned suddenly away.
As to Rockwell, he left the house very quietly, with just what feeling in
his heart no one ever knew.
Then Vincent, all at once perceiving Claude, and remembering his pink
satin errand, took him quietly by the arm, and led him into the parlor,
Madam Trevor following them. The three sat down in the stiff little
apartment, the closed door shutting the two in the hall from their sight.
Claude's hour of patience was ended. His time had come now, and he was
astonished to find himself nervous.
"I must, sir, crave your indulgence for my seeming discourtesy in

keeping you waiting so long. However, as you have been a witness of the
affair which detained me, you may perhaps be lenient with my rudeness."
Claude made a proper rejoinder. He was but half conscious of what he

said, but most vigorously aware that Madam Trevor's eyes were travelling
rapidly over his costume.
"You have already announced, monsieur, the surprising nature of your

errand, and I presume that you now desire to discuss it with us."
Inwardly, Claude smiled at the words. They struck him as being very
absurd, though, according to prevailing English notions, they were
excellently chosen.
"I love your cousin, Mistress Deborah Travis, Mr. Trevor, and I am come
to you to request permission to—address her on the subject of marriage. I am
a stranger in your colony. I have no friends who know my family and estate.
I have brought with me such papers as I possess, such as can in any way
speak for the assurance of my birth, and them, and my word as a gentleman,
I must ask you to believe."
Vincent was silent for some moments, considering; while Claude drew
from one of his side pockets a little, flat parcel of papers, and sat nervously
fingering them. It was Madam Trevor, who, after she had once more
minutely examined him, from his bag-wig to his red-heeled shoes, voiced
Vincent's wish:
"Will you, sir, be so vastly obliging as to tell us, in your own manner,
your title, estate, lineage, and means of livelihood? I am sure, sir, that
common prudence and the ardent desire for the welfare of my ward will
seem to you adequate reason for such a request, and that you will have no
hesitation in being perfectly frank with us."
Whatever the reason, madam's manner was as suavely gracious during
this speech as Vincent could have wished, and he, therefore, did not add to it,
but, expressing his approval with a slight nod, was expectantly silent as
Claude began:
"My name, Madam Trevor, is Claude Vincent Armand Victor Anne de

Nesle, Comte de Mailly. I am of the younger branch of the family Mailly-
Nesle, my father having been the second son of Victor Armand Henri
Claude, who died in the year ninety of the last century. My estates, which are
in Languedoc, in the south of France, provide me with sufficient rental to
maintain me comfortably at Versailles, where I have resided for many years.
The elder branch of my family, which takes the title of Marquis de Mailly-
Nesle, is well known and of high position at Court. Seven months ago I fell
into disfavor because of my desire that a cousin of mine should—wed a
gentleman of whom—his Majesty did not approve. I was requested to leave
Versailles for the time, and so, determining to travel, I came first to the
colonies; and how I have lived here you know. I should be—free to return to
Court if—if Mistress Travis, should she accept me, would care to go thither.
To be frank, I am myself a little homesick for my country. I should like to go
home."
Claude stopped, having wandered too far in his explanation. He saw

Madam Trevor regarding him blankly, and he read suspicion in Vincent's
face.
"It is—pardon me, sir—an unusual story. Do they exile men in France
for having opinions concerning a cousin's marriage?"
"So it would appear, from my case," returned Claude, dryly.
"Again pardon me—but—have you a document of exile with you?"
Claude hesitated. The last sentence in that royal letter was the most
awkward possible thing for a man who wished, in all sincerity, to marry.
Long he studied young Trevor's face, and he saw the distrust therein growing
with every instant. At last, with an imperceptible shrug, and a sigh, he took
from his other pocket the small, worn paper with its red-brown seals that he
had read to Deborah.
"It is in French, monsieur. You doubtless read it?"
Vincent took the paper scornfully, and began its perusal with a facility
due to intercourse with Aimé St. Quentin. When he finished it, his mother
held out her hand for the letter, and, as she read, Vincent, looking squarely
into the other's eyes, said, slowly:
"You, monsieur, were the gentleman of whose marriage with your cousin
the King did not approve?"
Claude, returning the look eye for eye, bowed.
"And who is this cousin?"
"The Duchesse de Châteauroux."
"Good Heaven!"
Madam Trevor, her face suddenly all alight, was looking at the young
fellow in amazement—and something else. Could the other be admiration?
"Your cousin is—the—the—"
Claude nodded.
Silence.
It lasted for a long time. De Mailly felt his cause to be growing

desperate. He did not understand. Morals, which were stanch in so far as
Episcopal rectorship and five hundred a year were concerned, were
nevertheless to be differently regarded in the presence of a courtier Count
and cousinship to an almost queen, It was again Madam Trevor who finally
ejaculated, from her whirling chaos of thoughts and plans:
"Deborah shall be fetched at once. Vincent, you will arrange the

settlements."
Claude started with astonishment, and young Trevor rose:

"M. de Mailly, you may speak to Deborah. She has free choice—as did
Lucy. She is now—in the rose-garden, I think."
Claude sprang to his feet and moved forward a pace or two, looking
easily from one to the other of Deborah's guardians. He could not refrain
from taking snuff, nor, having finished, from remarking, slowly:
"I shall certainly, Madame and Monsieur Trevor, endeavor to show

myself worthy of the trust which you so readily place in me."
Thereupon, with two very polite bows, he left the parlor, alone. On
entering the hall he was greeted by the sound of pawing hoofs, a negro's
voice, and the steps of two men on the portico. The half-closed door was
flung wide open, and Benedict Calvert, with Fairfield at his heels, entered
the house. Claude stopped and turned to them.
"The devil!" said Sir Charles, his brows growing heavy.
"Monsieur, your eyes deceive you," responded de Mailly, pleasantly.
Calvert laughed.
"What's your business here?" demanded Fairfield in an ugly voice. He

had been in no pleasant humor on his ride, a fact explained by his red eyes,
pallid face, and slouching dress; and the unexpected presence of Claude was
not calculated to render him better-natured.
"My business here, Sir Charles, concerns myself. However, if you are
curious, I am about to offer myself to your cousin, Miss Travis."
Claude spoke with muscles tense, prepared to evade a sword thrust, for
he himself wore no rapier to-day. To his amazement, his words for a moment
produced no effect whatever on his quondam rival. Then, suddenly, while
Calvert gazed at his comrade, Fairfield burst into a laugh. It was not a
pleasant laugh, but it served its turn.
"What a household 'twill be! You and Deb, I and Virginia, Lou and her
Puritan parson—for whom Benedict's come to plead. A fine match-maker
y'are, Calvert. Why, monsieur, if 't'adn't been for him," pointing to the dark-
browed ex-commissioner, "I would ha' called you out. As 'tis now, I'll—
marry in a week, and be off for God's country, the Mall, St. Paul's, and
White's as soon as a vessel will sail; and be damned to the colonies!"
"Hush, Charlie! Get to your room," whispered Calvert, laying a quiet

hand on Fairfield's arm.
"I wish you good-afternoon, messieurs," added Claude, bowing.
Fairfield leered at him, with a glint of desperation in his eyes, and started
off to the west wing, with Benedict Calvert at his elbow, while Claude de
Mailly, musing gently, passed out into the golden mist of early twilight, on
his way to the rose-garden and Deborah.
CHAPTER XI
Distant Versailles
He walked, quite leisurely, over the turf beside the house, past the
western wing, towards the terraces that led into the garden. The sunset faced
him in a blinding, hazy radiance. At the top of the little flight of white steps
he paused. Silence, perfect, lonely, was all about, undisturbed by the bird-
notes from the woods, or the murmurous lapping of the river along its bank.
Once or twice he breathed, long and deeply, delighted with the pure
fragrance of the air. Then, without haste, he passed down into the garden.
What a chaotic mass of color it was! All the common garden flowers,
perennials and exotics, were at his feet; clove-pinks, sweet-williams,
marigolds, blue iris, candy-tuft, corn-flowers, purple-stock, cyanus,
carnations, poppies, balsam, fragrant herbs innumerable, the last sweet-
pease, pansies and dahlias—all in a disorderly tangle of glory. But beyond
these bourgeoisie of the flowers, in statelier rows, with only here and there a
blossom in their dark and lustrous foliage, was the noblesse, the court of the
flowers—the rose-garden. In the midst of this, upon a little rustic seat against
the northern wall, in a tumbled, forlorn heap, her face hidden in her arm, her
unkempt curls all loose upon her neck, lay Deborah—poor Deborah, whose
little colonial world had crumbled about her, and left her alone, wretched,
hopeless, in space. In the afternoon despair overcame her. Her work was
over, and she was at liberty to think unprofitable thoughts. So, after an hour
of tears here in the drowsy garden, the day finally brought what peace it had
to give, and she slept—was sleeping now, in the twilight, while Claude and
her new world came to her.
He had discovered her almost as soon as he entered the garden, more by

instinct than observation. And he made no haste to go to her, not because he
was indifferent, but because he could not bear to mar the perfect progress of
the hour by haste. It was almost with regret that he left behind the lower half
of the garden and entered the turfy walk between the rose-bushes. From a
perpetual he plucked one full pink rose, infinitely beautiful in its solitude,
from where it glowed, half hidden, beneath the leaves. Gazing half at it and
half at her, he softly approached the rustic bench, till his knee touched her
gown.
"Deborah!" he whispered; and then again, a little louder, "Deborah!"
She stirred in her sleep, under the spell of a wandering dream.
"Deborah!"
In slow wonderment the tangled head lifted, the white face, with its tear-
stained cheeks, was raised, and the gray-blue eyes fell open sleepily. He did
not speak while she looked at him, the actual presence corresponding, with
startling accuracy, to her dream.
"I thought—you had gone away," she said, softly.
"I could not go while you were here," he answered, seating himself
beside her.
She sighed like a child. She seemed to-day many years younger than
usual, and Claude looked at her curiously, wondering at her manner.
"Deborah," he said, gravely, without offering to touch her, "I am going
back—home. Will you come with me? Will you trust me? Will you let me
make a new life, a new home, for you?"
She caught her breath, as a child, after a long crying-spell, sobs,

reminiscently. Then she sat silent while he waited.
"I can't be happy here after—last night," she said, at length.
"I will try to make you happy."
She made no answer, but perhaps he read her mind, for he grew troubled.
One thought held each of them. It was that of the fair and stately Duchess—
la Châteauroux, whom Claude had loved. And which picture was the fairer,
Claude's memory or Deborah's imagination, it were hard to tell.
After a moment or two the pause became more than uncomfortable. Both
sat in growing rigidity, looking straight before them, thinking, helplessly.
Then, all at once, Deborah, with fearful hesitation, turned her head and
looked into his face. And suddenly, when Claude's poor hope was all but
dead, one of her hands, cold and tremulous, crept into that passive one of his
that lay beside her on the seat. It was her answer. How the promise was
sealed—need not be told.
Twilight deepened over the shadow of the dead day. Behind the black,
lacy tree-tops of the forest a sunset flush pulsated in crimson and gold. From
the still garden the evening fragrance, intoxicating, heart-stilling, to which
neither the sunny morning odors nor the night's holy incense could be
compared, floated in warm, rich breaths about the figures of the man and
woman whose lives had come to join each other over wide seas and many
lands. The spell of the evening was over them both. Their eyes wandered.
Their thoughts were still. Hand in hand, two of God's pilgrims met here to
rest a little ere they moved on again, they sat, silent, nerveless, feeling,
perhaps, more of the universal love than that of individuals. No prophecy of
storms to come disturbed their hour. Only the garden and the timeless
twilight enfolded them. The bird-songs, one by one, melted away. The waves
whispered unutterable things. And so, out upon the pale sunset, hanging
tremulous as by a thread of heaven, came a fair silver jewel—the evening
star. Deborah's eyes beheld it, and were riveted upon its liquid beauty.
"Look," she breathed, gently; "they call it the emblem of hope."
"Hope—dearest? What need have we of hope?"
She made no answer, only her hand tightened within his, as the evening
wind blew softly from the west.
Book III
THE POST
CHAPTER I
From Metz
"Good-morning, Belle-Isle! Is it good-morning? What news from the

royal apartments?"
"None."
"None! Ah! Then madame—"
"Is still on guard; sees none but her own servants, and—"
"Richelieu, of course. Then it is unchanged."
"I fear not. There fly rumors—that his Majesty grows hourly worse. If
this continues, the army will be in revolt, the women will be mobbed, and—
Quesnay may be permitted to prolong the reign."
"Madame is playing a losing game. She is daring France. I am going to

seek Richelieu, if he is accessible. This suspense cannot continue."
"I return to Saxe and the council."
"Au revoir, then."

"Au revoir! I wish you fortune with du Plessis. You are one of the few
who can risk his anger."
The two marshals uncovered ceremoniously. Jules de Coigny passed into

the Château de Metz, and Belle-Isle continued on his way to the camp.
It was August in the same year of 1744, and the heart of France, her
army, her Court, her King, and—her Châteauroux, was at Metz, in Alsace, a
resting-place sought after Dettingen and the long summer campaign. And
here at Metz, whence all had thought to depart a week before for Nancy, on
the road to Strasbourg, Louis XV. fell ill. That had been upon the 8th day of
the month. Now, on the 14th, slow-gathering consternation was spreading
through city, Court, and camp, though, since the morning of his seizure, not
a single soul save Mme. de Châteauroux, her sister Mme. de Lauraguais,
their personal servants, and Louis Armand de Richelieu had seen the King.
Dim rumors that the illness was feigned at first circulated through the
château. Then, latterly, more vivid and more startling theories, originating
none knew where, but spreading with the conviction of truth, voiced the
insistence that Louis was ill, worse than any one knew, and that the favorite,
coercing Richelieu into her service, desperate with the fear of dismissal from
Court when his Majesty's condition came to be discovered, was at Louis'
side, keeping at bay the army, the Court, and the kingdom. Marie Leczinska
and her dauphin were still at Versailles, praying and fasting, along with the
Jesuit fathers and the wearied dames du palais, who, in the absence of la
Châteauroux, had not a single crumb of gossip with which to comfort their
souls till the return of the Court.
Marshal Coigny, much disturbed by his short conversation with Belle-

Isle, yet anxious for confirmation of his fears before taking any possible rash
steps, hurried into the morning-room of the château, temporary residence of
Majesty. The place was crowded with familiar faces, mostly men, for the
women who took part in the campaign had learned that their proper place in
it was background. Two or three, however, had been drawn hither from
curiosity. Among them was a certain pretty Mme. Lenormand d'Etioles, who,
to the displeasure of la Châteauroux, had, for the past year, figured often in
royal hunts, and, latterly, played a very conspicuous part in certain
thanksgiving services at Lille after the first siege. So far as it could be
surmised she had never been addressed by the King, but she was well
enough known at Court to obtain bows from most of the men and one or two
of the women. This morning she remained beside her husband at one side of
the room, watching the throng that eddied about the young Duc de Chartres,
who, as son of the pious d'Orléans, was at this time sole representative of the
blood in Metz, and, consequently, was vested with a power which made him
of the highest consequence. He alone, of all these nobles and courtiers, had
the right to proceed to extreme measures, and force an entrance to the royal
apartments when such were closed to the world. He might also, if he dared,
demand of Majesty's self, in the face of a created Duchess, his wife's friend,
whether such Duchess alone were Majesty's will and pleasure. But the man
who did this, though he were of King's blood, must have grave reason ere he
should so risk the royal anger.
As d'Orléans' son perceived, from the midst of the throng of courtiers,

the openly curious anxiety with which he was regarded on all sides, the
expression of care and responsibility in his youthful face deepened. Looking
about him uneasily, while he talked, he perceived that de Coigny had entered
the room and was coming towards him with rapid steps and preoccupied
manner.
"What news of his Majesty's condition?" asked the marshal, abruptly and
aloud, with a directness that startled the room.
The throng about Chartres pressed silently closer, and the salon waited
breathlessly for reply. The young Duke turned a shade paler, and did not
open his lips.
"His Majesty is worse," muttered de Coigny, half to himself.
"His Majesty is worse," responded a sudden voice from behind.
The entire company turned sharply around. De Richelieu, who had

entered from an inner door, stood before them, snuff-box in hand. His face
was nearly as pale as his wig. His eyes were heavy. He looked haggard and
anxious.
"Monseigneur de Chartres—if I might be granted the honor of a word

with you?"
"But too gladly, monsieur. Come."
Chartres hurried forward through the respectful but eager throng, seized
Richelieu's arm with a whispered sentence, and drew him out of the salon to
a room inaccessible to courtiers.
Behind they left a tumult of excitement. Above them, back of closed

doors, Marie Anne de Mailly-Nesle, together with her sister, leaned over the
bedside of the King of France, alone with a great fear, yet unspeakably
dreading company.
Ah, Marie! Marie Anne de Mailly—a dangerous, a desperate game hast

thou played for six days—six ages, rather—past! On the one hand Louis'
prayed-for recovery; on the other, banishment, perhaps worse, for you; what
for him—the Almighty knows. Here in this sultry August morning, in the
second story of the ancient Château de Metz, you stand at the bed of the
King; not thinking of much, it must be confessed, anxiety and sleeplessness
having taken the poignancy from thought. These last days have been very
wearing ones.
On the morning of Saturday, the 8th, that morning when headache had
driven the King from prospective gayeties to the solitude of his own
apartment, he summoned his Duchess to his side to bear him company. The
morning was tedious. He could not be amused. In the afternoon, together
with fever, came Richelieu, and graceful, caustic-tongued Elise de
Lauraguais. And upon that afternoon, when no one dreamed how ill Louis
already was, and madame and the Duke were alone with him, Richelieu the
daring, now owing half his prestige to the favorite whose sponsor he had
once been, and who, without her, would have found his Court life infinitely
difficult, had thought, foreseen, dreaded, decided, and easily drawn the
woman into his plan. The admission of any other to the rooms must mean,
eventually, the confession, absolution, and unction of his Majesty. Before the
performance of this last, Louis must repent of his irregular life, and as proof
of repentance madame must receive her congé—for such was only
customary at the great Court of France.
"And so, Anne," Richelieu said to her, in a low, menacing tone, "we keep
our places here, you and I. If the King recovers, our power is unlimited."
"If he is worse?"—she looked.
"It is destiny. When we play for lives, we must risk them."
So madame stayed. She thought of that momentous little conversation

now, as she sat watching the sunlight play over the drawn bed-curtain. She
and her sister had removed from their rooms in the Abbaye St. Arnold beside
the château, where they had lodged at first, and taken possession of the royal
suite. Their own servants prepared the sick man's food, their own hands
smoothed the hot pillow. They had shut the clamorous Court away, letting
rumor fly as she would. During the first three days Louis, for the most of the
time, sat bravely up, in satin lounging-robe, cap, and slippers. None could
have striven more anxiously to distract and please him than the two favorites
and the sister. Notwithstanding, upon the fourth day, Wednesday—now the
day before yesterday—his body had mastered his will, and he did not rise.
Since then time had not moved; eternity seemed settling down upon the trio
of watchers. The King wanted no amusement now. He was perfectly content
to lie, half sleeping, through the whole day, smiling faintly when madame
brought his food, accepting a few mouthfuls with an effort, because they
came from her fingers; otherwise unmoved, unspeaking, unthinking.
Thursday was the same, ay, longer than ever; and as the three sat silent in the
dusk, beside the open window, they had not much cared to talk. Only
madame, with what composure she could gather, asked of Richelieu, who
had for a moment that day seen de Gêvres:
"What are the people saying, good uncle?"
And Richelieu, nervously smoothing his knee, looked at her with grim
significance. "We stake high," he said.
The Duchesse de Lauraguais gave a little cough.
Then silence fell again, while the lips of la Châteauroux closed more
firmly, and a rarely seen light came into her eyes. Richelieu's expression,
however, did not change. Was it possible that her courage in desperation was
greater than his? No. It was this. Richelieu was not yet desperate. There was,
for him, still one move that was not left to her. He would not necessarily be
banished from Court if it came to a point of extreme unction and madame.
But if the King of France were to expire here alone, with them, then Louis
Armand du Plessis might, indeed, tremble for what happiness life held for
him. He said nothing, however, yet. Twilight mingled with the dark. From
many windows glimmered forth the city lights, and madame finally
swallowed a cup of chocolate and sought her rest. Richelieu was left to
watch alone, in the darkness, by the King.
Louis XV. slept, now and then restless with fever, but for the most part
quietly. The Duke sat in his chair by the window, the sultry night air stealing
in to him, not asleep, but thinking of many things, of much history known to
him alone of Court, of camp, of street, and of the lives of real men. All men,
beneath their masks of manners, are very real! What a little game these
courtiers played! How lives were broken and intellects stunted for the sake
of being, for one little hour, associated with that single man born, willy-nilly,
to immortality in history! This very King, for whom he, Richelieu, was
living a life envied and unenviable, what was he but a disagreeable fellow,
handsome, rather sulky, either really or unaffectedly stupid, lazy, unutterably
weary of himself and his business, with more of a taste for turning and
cookery than for governing a kingdom or managing an army? After all, these
Bourbons might have made an excellent line of workmen, all but Louis
XIV., who would have been the ne'er-do-weel of them. Not one but had his
taste and real talent for an honest profession. And how were France to-day,
we wonder, had Louis XV. turned chef and Louis XVI. cultivated to its
utmost his no mean ability for locks and clocks? The night grew hotter as it
advanced, and rain was promised for the morrow.
At midnight, suddenly, the King woke, and demanded, in a voice much

changed, something to drink. Richelieu hastily brought wine and water, not
too cool. His Majesty drank thirstily, and lay back once more, but with eyes
open, till the Duke had put away the glass. Then, with unusual directness, he
said:
"Here, du Plessis, sit by the bed. I want to talk with you."
"Will you have light, Sire?"
"No. It disturbs my eyes. Listen to what I shall say. You are here? Yes.
Well, then, I am going to die."
"Sire! For God's sake—let me call some—"
"Chut! I want no one. It'll be a comfort to go in peace. I am going to die.

I have always feared the thought; but when one really arrives at the time—it
is not much. I am not afraid, du Plessis. I wish to express to you my
gratitude for having kept the Court and the doctors and the Orléans lot away
from me. They are bores. What I would say is this: When I am really gone,
there will, of course, be a scandal concerning my sickness and death, having
none but you and—her—to attend me. You'll get through it, du Plessis.
Parbleu! There is no nation that can withstand your manner. My dear
Dauphin—ought to love you. But Anne—Anne! Where will she go? What to
do for her? Richelieu, I love her. Yes, truly, as no woman before. Take her,
then, under your protection. I leave her to your care. Get her from here
safely. Send her for a little to her estates, or one of yours. Say that I
command her title to remain to her. But, my friend, do not let her marry.
Keep her from that. Par le ciel! If I dreamed that she would—d'Agenois, or
that de Mailly, or any other—promise, du Plessis!"
"Your will, always, Sire!"
"More wine, then. Diable! My head is on fire! More wine, and I sleep
again."
Richelieu refilled the glass, which his master drained to the last drop.
Then he sank back to the pillows, turned restlessly half a dozen times,
whistled a bar or two in the darkness, and so dozed again, while the Duke,
with a new and very heavy weight upon his heart, returned to the window.
The King had frightened him more than he dared confess to himself.
Certainly Louis' words had been unmistakably sincere. He believed that he
was going to die. The King's fear of danger to his favorite Duchess was well
founded, unquestionably. But the King's confidence in Richelieu's ability to
rise again in the world, Richelieu himself held in very decided doubt. If
matters were come to this pass, it were well to act. When a man's Damocles
has actually got to the single-hair state, that man, if there be any way in
which to move, does very well to get from under it, though he must leave a
companion behind, helpless, in his place. The King must live till morning,
must absolutely live till morning, and then—Richelieu would once more
prove himself a wise man. He must turn traitor to his personal trust with
madame and the King, too, for the sake of the safety of the King, and,
therefore, his own. If he regretted the inevitable consequences in the career
of la Châteauroux, he was philosopher enough to wave them aside without
difficulty. Something one must lose in such a place. It should be as little as
possible.
On Friday morning the King awoke to find his three attendants all beside
him, and what repast he might take—chocolate, a roll, a jelly—not too well
prescribed, waiting. From his manner one could not have told whether or not
he recalled that midnight conversation with du Plessis. Certainty he looked
ill enough this morning. His flushed face was haggard, his lips cracked, his
blue eyes dull, his brain feeble, but half working. Madame looked upon him
with a pang of grief and fear. While she smoothed out his bright yellow
locks, freed from their wig, and bathed his unpainted face and dry hands
with scented water, her sister holding the silver basin, Richelieu disappeared.
An hour later, when the room was again still, a fly or two buzzing at the
window, Mme. de Lauraguais purfling, Marie Anne beside the drowsy King,
the Duke had not yet returned. It was the longest absence that he had made
from the bedside, except for sleep. That he was not asleep now, madame
knew very well. His bed in the royal suite had been made. He had let himself
quite out of these rooms, and was gone—to whom? Whither? And Mme. de
Châteauroux, though she trusted Richelieu as she did herself, became, after a
little, nervous with anxiety for his return. Presently she moved over to Mme.
de Lauraguais, her puppet-shadow.
"Elise, du Plessis is absent still. I am disturbed. Why should he be so

long away? Do you think—do you think—"
"I think that he has gone to de Gêvres. He will bring us back some news
of the Court. It will be something to divert his Majesty this afternoon, and
something for us to listen to this morning. Heigh-ho!"
At this moment the King's hand slipped through the bed-curtains and
drew one of them aside till his face was visible. Smiling faintly at the
Duchess, he motioned her to him with a peculiar glance. "Du Plessis is out,
you say?"
Madame nodded.

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PHARMACOVIGILANCE: A PRACTICAL APPROACH ISBN: 978-0-323-58116-5

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Linda Scarazzini, MD Verghese Mathew, MD, FACC, FSCAI

After 20 years of protecting patients through pharma- Topics include

Does Regulation Drive Science or

INTRODUCTION were given to patients and resulted in several deaths.

FIG. 1.1 Important events in pharmacovigilance.

FIG. 1.2 Timeline of inﬂuential pharmacovigilance (PV) organizations.

frameworks. Signiﬁcant progress has been made since

FIG. 1.3 Important global regulatory authorities and regional frameworks.

heavily inﬂuenced by EU GVPs are the Arab GVPs and

EMA PHARMACOVIGILANCE RISK

authorities now want to receive the outcomes of assess-

suitably qualiﬁed candidate. Also, products are mar-

How can Industry Inﬂuence Regulation?

Signal Management and Methods of

INTRODUCTION patterns for recognized signals (e.g., risk factors, severity,

"I have no slaves at all, Mr. Rockwell, being a Christian!" retorted

"It is, sir, so far as I am aware, irreproachable!"

"Come, come, gentlemen," interposed Vincent, in some displeasure, "we

"Egad!" murmured Vincent, softly, "the little girl was right."

"Pardon me, madam, but this is quite useless," interrupted Vincent,

"You mean to inform me that my authority is at naught in this

"I, certainly, shall not remain to witness this scene."

"Gentlemen, excuse me for one instant. I will summon my sister."

"I must, sir, crave your indulgence for my seeming discourtesy in

Claude made a proper rejoinder. He was but half conscious of what he

"You have already announced, monsieur, the surprising nature of your

"My name, Madam Trevor, is Claude Vincent Armand Victor Anne de

Claude stopped, having wandered too far in his explanation. He saw

"So it would appear, from my case," returned Claude, dryly.

"Again pardon me—but—have you a document of exile with you?"

Claude, returning the look eye for eye, bowed.

"And who is this cousin?"

"The Duchesse de Châteauroux."

"Your cousin is—the—the—"

It lasted for a long time. De Mailly felt his cause to be growing

"Deborah shall be fetched at once. Vincent, you will arrange the

Claude started with astonishment, and young Trevor rose:

"I shall certainly, Madame and Monsieur Trevor, endeavor to show

"The devil!" said Sir Charles, his brows growing heavy.