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Editors
Timothy A. Yap, Jordi Rodon and David S. Hong

Phase I Oncology Drug Development

1st ed. 2020
Editors
Timothy A. Yap
University of Texas MD Anderson Cancer Center, Houston, TX, USA

Jordi Rodon
University of Texas MD Anderson Cancer Center, Houston, TX, USA

David S. Hong
University of Texas MD Anderson Cancer Center, Houston, TX, USA

ISBN 978-3-030-47681-6 e-ISBN 978-3-030-47682-3

https://doi.org/10.1007/978-3-030-47682-3

© Springer Nature Switzerland AG 2020

This work is subject to copyright. All rights are reserved by the

Publisher, whether the whole or part of the material is concerned,
specifically the rights of translation, reprinting, reuse of illustrations,
recitation, broadcasting, reproduction on microfilms or in any other
physical way, and transmission or information storage and retrieval,
electronic adaptation, computer software, or by similar or dissimilar
methodology now known or hereafter developed.

The use of general descriptive names, registered names, trademarks,

service marks, etc. in this publication does not imply, even in the
absence of a specific statement, that such names are exempt from the
relevant protective laws and regulations and therefore free for general
use.

The publisher, the authors and the editors are safe to assume that the
advice and information in this book are believed to be true and accurate
at the date of publication. Neither the publisher nor the authors or the
editors give a warranty, express or implied, with respect to the material
contained herein or for any errors or omissions that may have been
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claims in published maps and institutional affiliations.

This Springer imprint is published by the registered company Springer

Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham,
Switzerland
Foreword
The Times—They Are A-Changin’
—Bob Dylan
Nobel Laureate for Literature 2016

It is certainly no longer “the bad old days” in the field of oncology

phase I clinical trials.
The days of treating patients with advanced refractory cancer when
all prior treatments have failed them with just the next phase I agent
coming off the drug development assembly line are thankfully over.
Potential new therapeutic entities are becoming available for phase I
clinical trials at a rapid clip. Whether we are referring a patient for a
possible phase I trial or consenting a patient for a phase I study, we
must make sure we are offering our patients the best possible chance
they will actually benefit from that new agent.
In the “bad old days,” only about 1 in every 15 or so new agents
tried actually had evidence of helping someone in a phase I trial. Today,
it is thankfully at least 1 in every 3 new agents (that will provide
clinical benefit for a patient). In fact, with better science, better patient
selection, etc., if no participant in a phase I trial derives benefit from the
new agent, one quickly wonders whether there is any future at all for
that drug. Therefore, now, more than ever, it is critical that physicians
trying to do their very best for their oncology patient be familiar with
the very latest information on strategies for the most efficient ways to
develop a new anticancer agent. Presently, it can make a real difference
for patients, e.g., they have a greater chance of achieving clinical benefit
in the phase I trial. Done properly, a patient’s participation in a phase I
clinical trial has a much higher likelihood of helping them (30% today
versus 3% in the past). Therefore, in this day and age, to do the best for
our patients with advanced cancer, our patients should be offered
participation in a phase I clinical trial.
In this volume Phase I Oncology Drug Development, three of our
most outstanding physician investigators (Timothy Yap, David Hong,
and Jordi Rodon) have done all of us a service by assembling a most
important perspective on what we all should know about present-day
phase I clinical trials.
The authors in this volume cover perspectives from multiple
distinguished multinational experts. They, first of all, remind us not to
forget the basics like good pharmacokinetic/pharmacodynamic
principles and how a great biomarker wins the day for giving our
patients the best chance for clinical benefit. They also give the best
chance for FDA approval.
Other very helpful topics covered in this volume include:
(a) Differences in interactions required with different regulatory
agencies (for the USA and for the European Union)

(b) What pharmacokinetic and pharmacodynamic data should look

like in various preclinical models before proceeding to a phase I
clinical trial

(c) Strategies for the selection of patients most likely to benefit from
a phase I agent

(d) Dose–response relationships for new molecularly targeted

immuno-oncology agents or epigenetic modifying agents

(e) Tips on how state-of-the-art preclinical studies (e.g.,

CRISPR/Cas9, organoids) can be used for target discoveries and
for the validation of that target as a driver. These techniques can
“de-risk” a compound and give our patients the best chance for
clinical benefit

(f) How to set up an outstanding phase I unit so patients do not have

to travel far away from home

(g) Novel trial designs: for studying dose escalation (including

Bayesian optimal interval (BOIN) design) and selecting the
proper dose to take forward into expansion cohorts

(h) The critical area of attribution and management of toxicities

(i) Important consideration for situations that might alter
pharmacokinetics. This includes designs with consideration for
food effects, drug–drug interactions, and organ impairment

(j) Beautifully detailed description of the development of

biomarkers, including imaging and regulatory requirements

(k) Discussion of various new endpoints for detecting early signs of

efficacy in the phase I trial

(l) Special consideration for the development of novel technologies

(e.g., antibody–drug conjugate, novel formulations)

(m) A unique discussion of phase I combinatorial drug development

strategies

(n) How molecular profiling of patients in a phase I setting can

inform unexpected results of finding an actionable target, which
is incredibly helpful for their care, and which may have
implications for their relatives (e.g., germline mutations)

(o) Special strategies for phase I trials for immunotherapeutics,

including unique patient selection and agent-specific designs
(e.g., with STING agonists, Toll-like receptor agonists), as well as
combination strategies for such agents

(p) Novel phase I trial designs involving multiple types of radiation

(q) Special consideration for phase I trials for patients with

hematologic malignancies

Throughout the volume, there are multiple successful and

unsuccessful examples of therapeutic development. These are very
helpful examples. There are also some incredibly helpful tables and
diagrams to emphasize important points.
In summary, this is a must-read volume for all those who want to
provide the very best possibilities for their patients with advanced
cancer. The editors and authors have given us their very best. Yes, the
times in phase I trials, they are a-changin’.
Daniel Von Hoff
Contents
1 The Development of a Drug:​A Pharmaceutical Drug
Development Perspective
Michael Lahn
2 Paradigms in Cancer Drug Development:​A Universe with Many
Galaxies
Cinta Hierro and Jordi Rodon
3 Preclinical Studies to Enable First in Human Clinical Trials
Rajesh Chopra and Florence I. Raynaud
4 Practicalities of Setting Up a Phase I Clinical Trial Unit Within an
Academic Center
David S. Hong, Kathrina L. Marcelo-Lewis and Patricia LoRusso
5 Novel Trial Designs for Early Phase Clinical Trials
Chia-Chi Lin
6 Examining Performance of Phase I Designs:​3+3 Versus Bayesian
Optimal Interval (BOIN)
Kenneth R. Hess and Bryan M. Fellman
7 Considerations for the Attribution and Management of Toxicities
in Phase I Clinical Trials
Pedro C. Barata and David S. Hong
8 Strategies for Incorporating Pharmacokinetic Studies into
Oncology Phase I Trials
Lingzhi Wang, Wan Qin Chong, Pei Shi Ong and Boon Cher Goh
9 Development of Pharmacodynamic Biomarkers for Phase I Trials
María Vieito, Itziar Gardeazabal, Ignacio Matos and Elena Garralda
10 Efficacy Considerations in Phase I Trials
Kanan Alshammari, Kirsty Taylor and Lillian L. Siu
11 Considerations for the Development of Novel Chemotherapies
and Antibody Drug Conjugates in Phase I Trials
Vivek Subbiah and Roman Groisberg
12 Development of Molecularly Targeted Agents in Early Phase
Clinical Trials
Pedro C. Barata and Timothy A. Yap
13 Incorporating Precision Medicine into Phase I Clinical Trials
Funda Meric-Bernstam
14 Incorporating Circulating Biomarkers into Clinical Trials
Filip Janku
15 Development of Immunotherapeuti​c Strategies for Early Phase
Clinical Trials
Patricia Martin-Romano, Roman Chabanon, Adrien Procureur,
Sandrine Aspeslagh and Sophie Postel-Vinay
16 Radiotherapy Considerations and Strategic Approaches in
Phase I Trials
Lauren E. Colbert, Ying Yuan, Jaap D. Zindler, Clifton D. Fuller and
Charles R. Thomas
17 The Paradigm of Early Phase Studies in Hematological
Malignancies
Vishwanath Sathyanarayanan and Swaminathan P. Iyer
18 Pharmacokinetic Considerations for Organ Dysfunction Clinical
Trials in Early Drug Development
Analia Azaro, Mehmet Esat Demirhan, Joann Lim and Jordi Rodon
Index
© Springer Nature Switzerland AG 2020
T. A. Yap et al. (eds.), Phase I Oncology Drug Development
https://doi.org/10.1007/978-3-030-47682-3_1

1. The Development of a Drug: A

Pharmaceutical Drug Development
Perspective
Michael Lahn1
(1) iOnctura SA, Geneva, Switzerland

Michael Lahn
Email: m.lahn@ionctura.com

Abstract
Clinical investigation of New Molecular Entities (NME) in oncology is
changing. Drivers of this transformation are advances in
pharmacological platforms, such as antibody technology, changes in the
regulatory framework to accelerate approval of new treatments, and
rapid scientific discovery. As a result of this transformation the
established drug development process is being modified and continues
to adapt. Today significant resources are being moved towards early
clinical development and NME have to show early promise of
therapeutic activity. The ideal NME targets specific pathways, for which
diagnostic tools can be developed to select or enrich patients for the
treatment with NME. This chapter reviews the critical steps enabling
the early phase clinical development from the perspective of a
pharmaceutical drug developer. The required steps include non-clinical
pharmacokinetic (PK) studies, pharmacokinetic/pharmacodynamic
(PK/PD) models, pharmacology and toxicology studies, and biomarker
development plans.
Keywords Drug development – First in human dose studies –
Immuno-oncology – Kinase inhibitors – Targeted agents – Regulatory
approval – Antibody – Biomarkers

Key Points
1. Drug Development in Oncology is undergoing adaptation in
response to new scientific discoveries.

2. Resources are invested earlier in clinical development to reduce

attrition for new molecular entities (NME).

3. Success for identifying NME early appears to depend on the

selection of specific targets that can be readily assessed in patients

4. Regulatory framework is evolving to respond to the changes in the

clinical investigation of NME.

5. Pharmaceutical drug development continues to search for the right

model that will allocate the relevant resources in the overall drug
development in a timely manner.

1.1 Introduction
Today the drug development process for oncology NME is undergoing a
significant change. Drivers for this change include the evolving science,
operational complexities for trials and the need to develop NME in a
financially sustainable manner. Given the number of NME in clinical
development, in particular for immune-oncology NME [1], it is
important to share the perspective of the industry with academic
partners to successfully manage this change [2]. While the
pharmaceutical industry and academic research are struggling to find
efficient and sustainable ways to develop NME [3], the development
costs of NME are staggering given the low output [4]. In 2003, the cost
of launching a NME was estimated to be over 1 billion US dollars with
an expected approval rate of about 7% [5]. Researchers look for
reasons to explain the low output of this clinical research. For example,
the European Science Foundation commissioned a review on drug
development during the twentieth century to uncover the drivers of
successful drug development, but this review was not able to pinpoint a
single factor that predicted successful drug development [6]. Reviews
of recently approved NME found that biomarker-driven programs have
a higher success rate of about 13% compared to 7% when no
biomarkers are included [7]. Other researchers suggested that the
organizational structures of today’s pharmaceutical companies delay
innovation. In fact, small biotech companies developed over 60% of
recently approved NME [8–11]. Today pharmaceutical companies have
to answer to diverse shareholder interests and are subject to increasing
scrutiny from analysts or day traders, some of which have little or no
knowledge of the complexity of drug development [12]. By contrast,
small biotech companies may collaborate with large pharmaceutical
companies at the risk of failing if they do not produce innovation
attractive to larger pharmaceutical firms. Academic partners should be
prepared for the eventuality that a small pharmaceutical company may
be acquired by a larger pharmaceutical firm during the course of a
clinical development. Hence, a standardized process in clinical
development is needed and should be encouraged to allow the
necessary flexibility to transfer data from one sponsor to another
without interrupting the clinical trial.
Given this background, the following chapter will focus on the
biomedical approaches that have shown useful in reducing attrition in
drug development such as (a) leverage pre-existing information
including bioinformatics approaches; (b) integrating non-clinical
information to predict clinical properties of NME and (c) optimize the
operational costs to gain timely information in early trials [13, 14]. This
chapter will discuss the critical components leading to the early phase
studies of NME and how these should be integrated to justify the early
investment in clinical development.

1.2 Non-clinical Pharmacokinetic Studies

The role of non-clinical pharmacokinetic (PK) studies is particularly
critical for oral NME, which make up a third of all NME in clinical
development. Provided an appropriately selective oral NME has been
identified, the next step is to assess its properties of absorption,
distribution, metabolism and excretion (ADME). Such ADME studies
can be helpful in predicting the behavior of an NME in humans [15, 16].
The PK profile in animals is often first used to optimize subsequent
formulation for oral or intravenous NME. Once the desired profile is
achieved, the NME is ready to be explored in non-clinical pharmacology
and toxicology studies. The extent of early ADME work depends not
only on scientific but also on strategic merits. Consequently, the
development team needs to weigh early investments for comprehensive
ADME work with the possibility that a NME may not progress beyond
initial non-clinical toxicology studies. Thus, the costs for an early
comprehensive ADME work may be misplaced. Before embarking on
costly non-clinical ADME and toxicology studies it is important that the
development team determines the general strategy of a NME. For
example, early and comprehensive investment may be warranted if the
development team is convinced that the NME will have a unique profile
differentiating itself from other NME. Notwithstanding these strategic
considerations, without the desired PK properties, subsequent research
in non-clinical pharmacology and toxicology studies risk repetitive
work and delays, both of which can significantly impact the future
development of a NME.

1.3 Non-clinical Pharmacology Models

Non-clinical pharmacology models are often desirable to justify the
clinical evaluation of a NME. However, standard non-clinical cell line
derived xenograft (CDX) models have limited value to predict activity in
humans [17]. The use of patient-derived xenografts (PDX) promises to
improve the prediction of antitumor activity in humans than CDX,
mainly because PDX retain the original histopathological phenotype
and consequently reflect the diversity of tumors [18]. Today the use of
PDX has become an integral part of functional assessment of NME [19].
If the NME is targeting immune-related targets, then models with
immune-competent animals are preferred. Such immune-competent
animal models assess not only the involvement of the immune system,
but also the complexities of the tumor microenvironment [20]. While
these three model systems provide information that the NME targets a
physiologically important mechanism, they are not as predictive for
future activity in patients as desired by drug developers. One reason
why immune-competent rodent models do not predict behavior in
humans may be attributed to the differences of the species-specific
immune system. For example, mice have different immune systems
from humans in both innate and adaptive immunity, such as leukocyte
subsets, Toll receptors, NK cells, T and B cells [21, 22]. Therefore, it is
important to appropriately interpret results from animal studies and
ensure that these models are not used as predictors for antitumor
activity in patients. Because of these limitations, there is an increasing
interest in human organoids [23]. These in vitro 3D cultures can be
grown from embryonic and adult stem cells and display self-organizing
capacities, phenocopying essential aspects of the organs they are
derived from. Genetic modification of organoids allows disease
modeling in a setting that approaches the physiological environment.
Organoids can also be grown from patient-derived healthy and tumor
tissues, potentially enabling patient-specific drug testing and the
development of individualized treatment regimens.
For purposes of drug development non-clinical pharmacology
models are particularly useful if they are used to estimate drug levels
and exposure. Analyzed appropriately, PK studies in animals have
shown to be predictive for PK profiles in humans [16]. Non-clinical
pharmacology models provide important pharmacodynamic
information, which can be correlated with exposure information of a
NME (Fig. 1.1) [24]. Such pharmacokinetic/pharmacodynamic (PK/PD)
models are helpful to estimate clinical dose and dose schedules in
patients [25]. Today, this concept originally developed for
chemotherapies is being used for many NME, including monoclonal
antibodies [26]. Pharmaceutical companies use information derived
from PK/PD models to design: (a) non-clinical toxicology studies in
animals, (b) determine of drug requirements for Chemistry,
Manufacturing and Controls (CM&C); (c) time points for blood
sampling to assess pharmacokinetics and measurements of ADME in
humans. In conjunction with animal ADME/toxicology studies, PK/PD
models are also helpful to estimate the safe starting dose in an early
phase study and thus have become valuable in assessing the
benefit/risk for a NME (Fig. 1.2). This is particularly important if the
NME is considered to have potentially non-reversible toxicities and thus
the drug exposure must be below an anticipated toxicity level. One such
example was successfully developed for a small molecule inhibitor
targeting the Transforming Growth Factor beta Receptor Type I (TGF-
βRI), where the PK/PD model predicted cardiovascular toxicity if an
exposure threshold were to be exceeded [27]. Using the PK/PD model a
safe therapeutic window was predicted and later confirmed in clinical
trials [28, 29].

Fig. 1.1 Relating pharmacokinetics (PK) and pharmacodynamics (PD) to establish a

PK/PD model for estimating antitumor responses in humans. NME is administered to
animals (generally rodent species) to deliver a dose estimated to produce a response
(for example antitumor response in a xenograft model). The PK is characterized and
related to the effect site. The degree of biosignal at the effect site and its transduction
to the expected responses represents the PD effect, which ideally should be measured
at multiple time points. The PK/PD model should include a dose range study to
understand the degree of response in relationship to drug concentration. (Reference:
Derendof H, Meibolm B. Modeling of PK/PD relationships: Concepts and
Perspectives. Pharmaceutical Research, Vol 16 (2), 1999)
Fig. 1.2 Non-clinical studies to estimate the benefit/risk prior to First-in-human
(FiH) dose study. Initial pharmacokinetic (PK) studies are conducted to understand
the ADME properties (absorption, distribution, metabolism and excretion, ADME) of
a New Molecular Entity (NME) to inform non-clinical toxicology study design,
detailed PK/ADME studies, pharmacodynamics (PD) and antitumor efficacy studies,
development of a PK/PD predictive model. Using the combined information from
non-clinical toxicology studies (risk assessment) and PK/PD model (benefit
assessment), a safe starting dose can be determined for the First-in-human (FiH)
dose study

1.4 Non-clinical Toxicology Studies

Non-clinical toxicology studies for oncology NMEs are conducted based
on the ICH S9 guidance [30]. The most relevant species, generally a
rodent and non-rodent species, are selected to estimate the potential
risk of a NME and to determine the no-observed adverse effect level
(NOAEL). The debate continues in finding alternatives to current
animal-based toxicology studies, but to date even “big data” approaches
have not been able to supplant the standard animal toxicology studies
[31]. In reviewing data from various therapeutic areas and the
subsequently observed adverse events in patients, the concordance
between animal and human toxicity was examined [32]. Data from 12
pharmaceutical companies and 150 compounds were reviewed and the
true positive concordance rate was 71% when a NME was assessed in
both rodent and non-rodent species. This observation was confirmed in
a recent study, in particular the prediction of cardiovascular arrhythmia
and risk of QTc prolongation [33].

1.5 Therapeutic Vaccines

The clinical development of therapeutic vaccines and NME targeting
immune cells, such as oncolytic virus, requires a different approach of
drug development [34, 35]. The vaccine development assumes that the
host will mount an immune responses and thus will not have an
immediate antitumor effect. Consequently, vaccine drug development
requires the participation of patients that are able to undergo long
treatment times to assess the anticipated antitumor effect. Because of
this mechanism of action, there has been an ongoing debate which type
of patients should be selected for a First-in-human (FiH) dose study.
Patients with a high tumor burden and refractory to prior treatments
are likely to be immune suppressed. Such patients are generally
considered for FiH dose studies, because their benefit/risk assessment
is favorable for such a FiH dose study, but they are less likely to respond
to vaccines. On the other hand, patients with low tumor and antigen
burden are considered to be more likely to respond to vaccines, but
they are at a higher potential risk to develop an autoimmune response
if the vaccine is potent. This last group has also a different benefit/risk
profile and the risks must be carefully weighed. Furthermore, the
classical dose-response paradigm generally observed with small
molecules or antibodies cannot be expected with vaccines. Monitoring
immune responses is therefore not only a measure of efficacy, but also
an assessment of safety. Currently, there is no agreement on the extent
and type of immune monitoring needed in such a FiH dose study [36].
The recommendation ranges from measuring lymphocytes subsets,
measurements of functional responses of the immune cells (such as
function of humoral and cellular immunity) as well as degree of antigen
processing, presentation and responses.

1.6 Translational Research Plan: The Importance

of Patient Selection
Previous successful developments of NME imply that patient selection
is a key component in reducing attrition in oncology drug development
[7]. With the development of the non-clinical pharmacology models, it
is useful to start incorporating pharmacodynamics measures that can
be serially examined in patients. A recent example is related to
inhibitors of the Fibroblast Growth Factor Receptor (FGFR) pathway
[37]. Hyperphosphatemia and increase of Fibroblast Growth Factor 23
(FGF23) levels are PD markers after administration of FGF receptor
(FGFR) inhibitors. Both markers are associated with activity in non-
clinical models and are used in the clinic for safety monitoring and
response measurements [38]. Another example is the use of Epidermal
Growth Factor Receptor (EGFR) inhibitors in targeting EGFR mutations
in NSCLC [39]. As with the FGFR inhibitors, targeting specific driver
mutations of the EGFR pathway are associated with clinical activity and
durable responses. The EGFR inhibitor osimertinib was specifically
developed to target the mutation T790M in NSCLC. During the FiH dose
study, patients were asked to submit to biopsy in order to provide
tumor tissue to measure the T790M mutation [40]. Using this approach
and observing durable responses surpassing 9 months, especially in
patients with T790M mutation, osimertinib was approved in about 4
years from the start of the FiH dose study. These two examples show
how patient selection can reduce attrition in clinical development.
Admittedly, biomarker-based patient selection will not be possible for
many NME and such biomarkers will have to be developed during the
clinical development. In such situations drug developers may benefit
from interrogating large tumor banks or cell lines [41].

1.7 Planning for the First-in-Human (FiH) Dose

Study
As exemplified by the drug development of osimertinib, FiH dose
studies are no longer just safety and PK studies, but include design
elements which may accelerate the drug development [40]. This is
especially true if the drug target is clearly defined and the NME proves
to predictably engage the target throughout all stages of non-clinical
and clinical development. Thus, the FiH dose study should be designed
with sufficient decision points, each of them associated with investment
triggers so that clinical development of NME can either be accelerated
or expand the clinical investigation with increased translational
research. Also, clinical developers must define stopping rules (for
example if the PK profile is unpredictable and associated toxicity profile
cannot be monitored and/or is not reversible). A project may also be
stopped if the NME shows insufficient innovation along with
unpredictable PK profiles as demonstrated by a multi-kinase inhibitor
program [42]. For pharmaceutical companies this “early kill” allows
them to focus on the most promising drugs in their pipeline.
Today most companies wish to stage the clinical development in
such a way that if data in the early phase program are encouraging, the
NME can be moved quickly towards registration. However, this general
concept comes at an investment cost that often is difficult to justify. A
company may decide to invest early in the development of an NME if
the company is convinced the NME holds a high treatment potential.
In addition to making such early strategic decisions, companies
need to select the appropriate centers to conduct clinical trials. Based
on a research conducted by Batelle Technology Partnership Practice in
2015, oncology trials are the costliest trials among all therapeutic areas
at US$60,000 per patient [43]. The reasons for this high cost are
complexity of oncology trials (including the cost for recruiting
patients), administrative staff costs for managing the trial and case
report forms, complex medical procedures (e.g., biopsies and imaging),
and site monitoring costs [44]. Once opened, nearly half of the selected
centers either do not enroll patients or enroll less than the projected
number. It is therefore understandable that drug developers are careful
not only in their design but also in the operational aspects of an early
phase trial.
Reducing attrition requires the following prerequisites: (a)
anticipated biologically efficacious dose and dose schedule based on
PK/PD models; (b) safe starting dose based on non-clinical toxicology
studies; (c) biomarker plan to identify or enrich for patients to respond;
(d) reduce operational uncertainties by selecting and collaborating
with trial centers; (e) well trained staff across all parts of the study.
Assuming these prerequisites are met, FiH dose studies consist of two
parts: the first part employs a standard dose escalation design and the
second part comprises of expansion cohorts (Fig. 1.3). In the first part,
the main objective is to confirm the predicted toxicity, PK and, ideally,
the PD profile of the NME. Provided a moderate or low variability of the
PK profile the first 3–6 patients may confirm the prediction of the
biological active dose. If the biological active dose is identified
subsequent steps may be triggered, including allowing CM&C to start
additional drug campaigns to support future expansion cohorts or
Phase 2/3 studies (Fig. 1.4). If antitumor activity is observed during the
dose escalation and the antitumor activity is associated with durable
responses, the developer of the NME will seek accelerated approval, as
exemplified by the development of osimertinib: dose extension and
expansion cohorts were started to gain deeper knowledge of the
benefit/risk profile and help with the initial development of a
companion diagnostic for the EGFR mutation T790M [40]. Based on
these cohorts and the initiation of additional studies, approval and
marketing authorization was sought. The timeline from FiH dose study
was under 4 years compared to the typical development of
approximately 7 years. Also the PD1 inhibitor pembrolizumab used a
complex FiH dose study (Keynote 001), where receptor occupancy on
circulating T cells and functional assays for T cell activation were used
to define the biological effective dose (BED) [45]. It is noteworthy, that
Keynote 001 used an adaptive design and thus facilitated an accelerated
approval, including the development of a companion diagnostic for
PDL1 expression in tumor tissue [46]. When the expansion cohorts of
Keynote 001 were initiated, pembrolizumab was evaluated in a wide
range of tumors from patients who had at least 1% of PDL1 expression
according to histological analysis of tumor biopsies [47]. This Phase 1b
study (Keynote 028) laid the foundation for subsequent Phase 2/3
studies. These examples of osimertinib and pembrolizumab illustrate
how a flexible design of early phase studies can accelerate the approval
of NME in a cost efficient manner.
Fig. 1.3 Example of First-in-human (FiH) dose study consisting of a Part A (dose
escalation) and a Part B (dose expansion). The safe starting dose is generally based on
the non-clinical toxicology studies (often referred to as GLP toxicology studies), but
more recently may also include a pharmacokinetic/pharmacodynamic (PK/PD)
model. The dose escalation should establish the biologically effective dose (BED) and
explore the full dose range of the drug up to the maximum tolerated dose (MTD). The
Part B (dose expansion) is generally specific solid tumor types to gain signals of
antitumor activity at either the BED (the preferable concept) or the MTD (the
traditional concept for chemotherapies). In this part, a particular emphasis on
pharmacodyanmic readouts is placed if this has not been integrated in the dose
escalation
Fig. 1.4 Simplified development path with corresponding standard go/no-go
decisions. After determining the benefit/risk using non-clinical GLP toxicology
studies and pharmacokinetic/pharmacodynamic (PK/PD) modeling (Decision 1), the
Phase 1 study (or First-in-human dose study) is initiated. During the dose escalation
in the Phase 1 study the drug must show acceptable variation in PK profile (Decision
1b). Once the drug has shown an acceptable safety profile, acceptable dose schedule
at the biologically active dose, confirmed the PK/PD relationship and shown signals
of single agent activity (Decisions 2 and 3), the agent may proceed to Phase 2 or 3,
where proof-of-concept (POC) or even significant antitumor activity must be
demonstrated (Decisions 4 and 5). This is the basis for the initiation of the last
milestone with significant investment for a global launch strategy (Product Decision,
PD)
Lastly, many studies will combine the NME with another drug to
determine whether the combination is superior to historic antitumor
responses observed with the combination partner. The risk of moving
NME quickly to combination studies is the lack of comparison and thus
responses may be over-interpreted. A renewed debate on the value of
randomized Phase 2 or Phase 1b studies is needed given the increase in
single-arm combination studies in expansion cohorts of FiH dose
studies [48].

1.8 Additional Clinical Studies to Facilitate

Accelerate Approval
Approval of an NME requires additional supportive studies, which are
often not widely published or rarely acknowledged by the wider
academic community. These studies are often part of discussions
between the drug developer and regulatory agencies. For example,
stability studies are critical and without which an approval can be
delayed. Because of the time requirements for such stability studies, it
is important to initiate stability studies as early as possible. Hence,
stability studies are often initiated before the FiH dose study, which in
turn requires a strategic decision by the pharmaceutical developer.
In addition to the CM&C-based studies for stability, there is
generally a need to conduct clinical pharmacology studies. These
additional studies can either be incorporated in ongoing studies or
require stand-alone studies in either patients or healthy volunteers. For
example, drug-drug-interaction (DDI), food studies,
electrophysiological studies (QTc), renal or hepatic insufficiency studies
are often needed. Electrophysiological studies in patients (in order to
measure QTc prolongation) are often conducted to assess the risk in the
intended indication. In such studies or cohort of patients EKGs should
be conducted along with PK sampling in approximation to the E14
guidance [29, 49]. In such PK-matched EKG studies it is possible to
associate the QTc prolongation with exposure, which in turn helps to
differentiate the QTc risk of the NME from co-medication generally
known to cause QTc changes (such as antibiotics). In order to isolate a
possible QTc prolongation risk, the drug developer may need to also
conduct a special QTc study in healthy volunteers. Furthermore, if there
is a change in formulation the earlier formulation should be compared
to the latest in a bio-equivalence or relative bioavailability study,
especially if the most recent formulation is intended for final use in
patients. Such studies can also be conducted in particular cohorts with
cancer patients [50]. Most of these clinical pharmacology studies are
started when the final or pre-final formulation is developed. Otherwise
the clinical drug developer risks to repeat such pharmacology studies
because they are meant to support the final drug product. Finally,
pediatric indication studies should be started as early as possible.
Ideally these studies can be started when the recommended Phase 2
dose is established at the time of or immediately after the FiH dose
study in adults. In summary, it is important to prepare all the
pharmacology or special indication studies as soon as possible in the
development cycle of an NME.

1.9 Regulatory Implications

In the past years drug developers have attempted to optimize drug
development and to reduce attrition in oncology. Biomarker-driven
clinical development have shortened time to registration and in some
instances also reduced the need for large numbers of patients within
trials [51, 52]. If this approach of biomarker-based drug development is
broadened, the medical and pharmaceutical community will need to
intensify research on pharmacodynamics markers that are combined
with NME. Recent advances in measuring circulating tumor DNA
(ctDNA) and re-evaluating standard laboratory tests may facilitate the
development of such pharmacodynamic markers.
While medical science progresses, the regulatory framework
between European Medicines Agency (EMA) and United States (US)
Food Drug Administration (FDA) remains different despite strives to
standardize the regulations (Table 1.1). Approval processes for diseases
with unmet medical seem to become similar between the two health
regulatory organizations [53]. For example, the European Union (EU)
recently introduced the “Prime” designation, which provides a more
rapid approval in the EU and is perhaps similar to the “accelerated
approval” regulated by the US FDA [54]. In a recent review by the EMA,
the Prime designation has been requested and granted mainly for
oncology and hematology NME [54]. Another area of recent
convergence is the use of patient-reported outcomes in clinical trials,
which was historically important to many EU member states and where
FDA has recently shown an increased interest. Independent of these
approval processes, the EU and US allow approvals for NME targeting
rare diseases under the orphan drug designation. One area where EU
and US differ is related to the biomarker-based development, which
may have an impact on the timely approval of a NME. The US FDA
regulation requires a companion diagnostic if treatment decisions are
based on the results of a diagnostic test. The EU has focused more on
ensuring that the diagnostic test is reliable and thus can be used in the
general laboratory setting. One example for this different approach is
the use of the PDL1 immunohistochemistry assay to detect PDL1 in
tumor tissue: companion diagnostics were developed for each
PD1/PDL1 inhibitor to measure the expression of the same target (that
is PDL1) without determining whether the tests could be interchanged.
Only subsequent comparative studies were able to clarify this
uncertainty [55]. The EU has been concerned with strengthen the
comparability of the testing across its member states and regions.
Hence, the EU has streamlined the use for companion diagnostic to
support such comparability of tests in the general diagnostic setting
[56].
Table 1.1 Important interactions with health authorities of the European Union
(EU), the European Medicines Agency (EMA) and the United States of America (USA)
Food and Drug Administration (FDA) and differences in approval
 EMA FDA
Important interactions with health authorities
Pre-investigational new drug No Yes
Scientific advice Yes No
Clinical Trial Application (CTA) Yes No
End-of Phase-1 (EOP1) and End-of-Phase 2 (EOP2) meeting No Yes
Scientific advice Yes No
Need of companion diagnostic No Yes
Special Protocol Assessment (SPA) No Yes
Scientific Advisory Group (SGA) Yes No
Advisory Committee Yes Yes
New Drug Application (NDA) or Biological License Agreement (BLA) No Yes
Marketing Authorization (MAA) Yes No
Type of approvals
Standard approval Yes Yes
Orphan drug designation and approval Yes Yes
Expedited approval programs Yes Yes
Priority review No Yes
Accelerated Assessment Yes No
Accelerated approval (need to demonstrate evidence of clinical No Yes
benefit and in need to be converted to standard approval with
appropriate Phase 3 trials)
Conditional approval (need to demonstrate evidence of clinical Yes No
benefit and requires renewal until full approval)
Prime designation Yes No
Breakthrough (BT) designation No Yes
Fast track (FT) designation No Yes
Rollover new drug application No Yes
Exceptional circumstances Yes No
 EMA FDA
Companion diagnostic (requirement of prior in vitro diagnostics No Yes
approval for NDA)

Key Expert Opinion Points

1. Leveraging non-clinical information as early as possible will allow
for the selection of better NME. One such example is the use of
pharmacokinetic/pharmacodynamics modeling.

2. Ability to select patients for the right NME appears to reduce

attrition and accelerate the approval of NME.

3. The focus on identifying the Biologically Effective Dose/Dose range

in early clinical trials will likely accelerate the approval of a NME. It
likely will lead to hybrid protocols, where two phases of classical
drug development are merged into one (for example, a Phase I
study may merge into an accelerated registration study without a
Phase II).

4. Standardization of the clinical development process must include

close collaboration between regulatory, commercial and academic
contributors.

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Another Random Scribd Document
with Unrelated Content
be considered as the fountain of justice and honour, and do not
possess the abilities and magnanimity of a common man, in what a
wretched light must he be viewed by the eyes of discernment and
common sense?—And, if the framers of a constitution create a power
that must continually act at variance with itself, they not only
undermine the pillars of their own fabric, but they insert the scion of
a disease the most destructive to truth and morals.
After complying with this compulsatory request, Louis, who,
finding that he was left without any share of power, seems to have
thought very little of his suspensive veto, determined to play a part
that would give an air of sincerity to his present conduct, whilst his
object was secretly to favour the efforts of the counter-revolutionists;
and if possible effect his own escape.—But, in the mean time, he
endeavoured to make such use of it as might prevent the total
derangement of the old system, without unveiling his secret views,
and intentions. It is difficult to determine which was the most
reprehensible, the folly of the assembly, or the duplicity of the king.
If Louis were without character, and controlled by a court without
virtue, it amounted to a demonstration, that every insidious mean
would be employed by the courtiers to reinstate the old government;
and recover, if possible, their former splendour and voluptuous ease.
For, though they were dispersed, it was notorious to all France, nay,
to all Europe, that a constant correspondence was kept up between
the different parties, and their projects concerted by one of the most
intriguing of disappointed men[30]. It was obvious, therefore, to
Mirabeau, that the king ought to be gained over to the side of the
people; and made to consider himself as their benefactor, in order to
detach him from the cabal. But in this respect he was unfortunately
over-ruled. This mixture of magnanimity, and timidity, of wisdom
and headstrong folly, displayed by the assembly, appears, at the first
view, to involve such a contradiction, that every person unacquainted
with the french character would be ready to call in question the truth
of those undeniable facts, which crowd on the heels of each other
during the progress of the great events, that formed the revolution. A
superficial glance over the circumstances, will not enable us to
account for an inconsistency, which borders on improbability.—We
must, on the contrary, ever keep in our thoughts, that, whilst they
were directed in their political plans, by a wild, half comprehended
theory, their sentiments were still governed by the old chivalrous
sense of honour, which diffusing a degree of romantic heroism into
all their actions, a false magnanimity would not permit them to
question the veracity of a man, on whom they believed they were
conferring favours; and for whom they certainly made great
allowance, if they did not forgive him for countenancing plots, which
tended to undermine their favourite system.
It is, perhaps, the characteristic of vanity, to become enamoured
with ideas, in proportion as they were remote from it’s conception,
until brought to the mind by causes so natural, as to induce it to
believe, that they are the happy and spontaneous flow of it’s own
prolific brain. Their splendour then eclipsing his judgment, the man
is hurried on by enthusiasm and self-sufficiency, like a ship at sea,
without ballast or helm, by every breath of wind: and, to carry the
comparison still further, should a tempest chance to rise in the state,
he is swallowed up in the whirlpools of confusion, into the very midst
of which his conceit has plunged him; as the vessel, that was not
prepared to stem the violence of a hurricane, is buried in the raging
surge.
The occasions of remarking, that frenchmen are the vainest men
living, often occur, and here it must be insisted on; for no sooner had
they taken possession of certain philosophical truths, persuading
themselves, that the world was indebted to them for the discovery,
than they seem to have overlooked every other consideration, but
their adoption. Much evil has been the consequence; yet France is
certainly highly indebted to the national assembly for establishing
many constitutional principles of liberty, which must greatly
accelerate the improvement of the public mind, and ultimately
produce the perfect government, that they vainly endeavoured to
construct immediately with such fatal precipitation.
The consideration of several other articles of the constitution was
continually interrupted, and not more by the variety of business,
which came under the cognizance of the assembly, than by the want
of a proper arrangement of them. Much time was lost in disputing
about the choice of subjects of deliberation; and the order in which
they ought to proceed. The business of the day was perpetually
obliged to give place to episodical scenes; and men, who came
prepared to discuss one question, being obliged to turn to another,
lost in some measure the benefit of reflection, and the energy, so
different from the enthusiasm of the moment, with which a man
supports a well digested opinion.
Two or three slight debates had arisen on the subject of quartering
a thousand men, of the regular troops, at Versailles. The
commandant of the guards had requested permission of the
municipality; pointing out the necessity for the security of the town,
the national assembly, and the person of the king. The necessity did
not appear so obvious to the public, and, in fact, the demand seemed
calculated to provoke the tumults, against which they were so
officiously guarding. Mirabeau also observed, ‘that the executive
power had undoubtedly a right to augment the military force, in any
particular place, when private information, or urgent circumstances,
appeared to require it; and that the municipality had, likewise, a
right to demand the troops they judged necessary; yet he could not
help thinking it singular, that the ministers should have entrusted
the municipality with a secret, which they did not communicate to
the assembly,—who might be supposed at least as anxious to take
every precaution for the safety of the town and the king’s person.’ To
these pertinent remarks no attention was paid; and a letter from the
mayor of Paris, informing the assembly, that a great number of the
districts of the metropolis had remonstrated against the introduction
of regular troops into Versailles, to awe the national guards, was
equally neglected; whilst a letter to the president, in the name of the
king, informing him, that he had taken the different measures
necessary to prevent any disturbances in the place where the
national assembly were sitting, was thrown aside without any
comment.
The loan still failing, several individuals made magnificent
presents; sacrificing their jewels and plate, to relieve the wants of
their country. And the king sent his rich service to the mint, in spite
of the remonstrances of the assembly.—The disinterestedness of this
action, it is absurd to talk of benevolence, may fairly be doubted;
because, had he escaped, and the escape was then in contemplation,
it would have been confiscated; whilst the voluntary offer was a
popular step, which might serve for a little time to cover this design,
and turn the attention of the public from the subject of the
reinforcement of the guards to the patriotism of the king.
 These donations, which scarcely afforded a temporary supply,
rather amused than relieved the nation; though they suggested a new
plan to the minister. Necker, therefore, incapable of forming any
great design for the good of the nation, yet calculating on the general
enthusiasm, which pervaded all descriptions and ranks of people,
laid before the assembly the ruinous state of the finances, proposing
at the same time, as the only mode of remedying the evil, to require
of the citizens a contribution of one-fourth of their income. The
assembly was startled by this proposal, but Mirabeau, believing that
the people would now grant whatever their representatives required,
prevailed on the assembly, by a lively representation of the perilous
state of the kingdom, to adopt the only plan of salvation which had
yet been suggested—insisting, that this was the only expedient to
avoid an infamous national bankruptcy. ‘Two centuries of
depredations and pillage,’ he exclaimed, ‘have hollowed out an
immense gulph, in which the kingdom will soon be swallowed. It is
necessary to fill up this frightful abyss. Agreed!—Choose out the rich,
that the sacrifice may fall on the fewer citizens; but, determine
quickly! There are two thousand notables, who have sufficient
property to restore order to your finances, and peace and prosperity
to the kingdom. Strike; immolate without pity these victims!—
precipitate them into the abyss—it is going to close on them—ye draw
back, with horrour—ye men! pusillanimous and inconsistent!—and
see ye not in decreeing a bankruptcy, or, which is still more
contemptible, rendering it inevitable, ye are sullied by an act a
thousand times more criminal?’
But it is impossible to do justice to this burst of eloquence, in a
translation; besides, the most energetic appeals to the passions
always lose half their dignity, or, perhaps, appear to want the support
of reason, when they are coolly perused.—Nothing produces
conviction like passion—it seems the ray from heaven, that
enlightens as it warms.—Yet the effect once over, something like a
fear of having been betrayed into folly clings to the mind it has most
strongly influenced; and an obscure sense of shame lowers the spirits
that were wound up too high.
From the whole tenour of this speech it is clear, that Mirabeau was
in earnest; and that he had fired his imagination, by considering this
plan as an act of heroism, that would ennoble the revolution, and
reflect lasting honour on the national assembly. In this extemporary
flow of eloquence, probably the most simple and noble of modern
times, mixed none of the rhetoric which frequently entered into his
studied compositions; for his periods were often artfully formed;—
but it was the art of a man of genius. He proposed to the assembly to
address their constituents on this occasion; and he was accordingly
requested to prepare an address for their consideration.
His address to the nation is, indeed, a master-piece; yet, being
written to persuade, and not spoken to carry a point immediately,
and overwhelm opposition, there is more reasoning in it; and more
artful, though less forcible, appeals to the passions. And, though this
expedient appears to be the most wild that folly could have
blundered upon, the arguments ought to be preserved with which it
was glossed over.
To expect a man to give the fourth of what he lived on; and that in
the course of fifteen months, leaving it to him to make the estimate,
was expecting that from virtue, which could only have been produced
by enthusiasm. All the ancient acts of heroism, were excited by the
spur of present danger; and of this kind of virtue the french were
equally capable; yet, though the plan afforded them an opportunity
to give a splendid proof of their patriotism, it by no means answered;
because, it being the effect rather of temper than of principle,
selfishness had time to find a plausible pretext to elude it; and vanity
is seldom willing to hide it’s good works in the common measure.
As the removing the national assembly to Paris forms an epocha in
the history of the revolution, it seems proper to close this chapter
with Mirabeau’s address.
‘The deputies of the national assembly suspend a while their
labours to lay before their constituents the wants of the state, and to
call upon their patriotism to second the measures, which a country in
danger demands.
‘It were betraying you to dissemble. Two ways are open—the
nation may stride forward to the most glorious pre-eminence, or fall
head-long into a gulph of misfortune.
‘A great revolution, the very plan of which some months ago would
have appeared chimerical, has taken place amongst us. Accelerated
by unforeseen circumstances, the momentum has suddenly
overthrown our ancient institutions. Without allowing us time to
prop what must be preserved, or to replace what ought to be
destroyed, it has at once surrounded us with ruins.
‘Our efforts to support the government are fruitless, a fatal
numbness cramps all it’s powers. The public revenue is no more; and
credit cannot gain strength at a moment, when our fears equal our
hopes.—This spring of social power unbent, has weakened the whole
machine; men and things, resolution, courage, and even virtue itself,
have lost their tension. If your concurrence do not speedily restore
life and motion to the body-politic, the grandest revolutions,
perishing with the hopes it generated, will mingle again in the chaos,
whence noble exertions have drawn it; and they, who shall still
preserve an unconquerable love of liberty, will refuse to unworthy
citizens the disgraceful consolation of resuming their fetters.
‘Since your deputies have buried all their rivalry, all their
contending interests, in a just and necessary union, the national
assembly has laboured to establish equal laws for the common safety.
It has repaired great errours, and broken the links of countless
thraldoms, which degraded human nature: it has kindled the flame
of joy and hope in the bosoms of the people, the creditors of earth
and nature, whose dignity has been so long tarnished, whose hearts
have been so long discouraged: it has restored the long-obscured
equality of frenchmen, estabblished their common right to serve the
state, to enjoy it’s protection, to merit it’s rewards: in short,
conformably to your instructions, it is gradually erecting, on the
immutable basis of the imprescriptible rights of man, a constitution
mild as nature, lasting as justice, and the imperfections of which, the
consequence of the inexperience of it’s authors, will easily be
repaired. We have had to contend with the inveterate prejudices of
ages, whilst harassed by the thousand uncertainties which
accompany great changes. Our successors will have the beaten track
of experience before them; we have had only the compass of theory
to guide us through the pathless desert. They may labour peaceably;
though we have had to bear up against storms. They will know their
rights, and the limits of their power: we have had to recover the one,
and to fix the other. They will consolidate our work—they will
surpass us—What a recompense! Who shall dare, mean while, to
assign limits to the grandeur of France? Who is not elevated by
hope? Who does not felicitate himself on being a citizen of it’s
empire?
‘Such, however, is the crisis of the finances, that the state is
threatened with dissolution before this grand order of things can find
it’s centre. The cessation of the revenue has banished specie. A
thousand circumstances hasten it’s exportation. The sources of credit
are exhausted; and the wheels of government are almost at a stand. If
patriotism then step not forward to the succour of government, our
armies, our fleets, our subsistence, our arts, our trade, our
agriculture, our national debt, our country itself, will be hurried
towards that catastrophe, when she will receive laws only from
disorder and anarchy—Liberty would have glanced on our sight, only
to disappear for ever, only to leave behind the bitter consciousness,
that we did not merit the possession. And to our shame, in the eyes
of the universe, the evil could be attributed solely to ourselves. With
a soil so fertile, industry so productive, a commerce so flourishing,
and such means of prosperity—what is this embarrassment of our
finances? Our wants amount not to the expence of a summer’s
campaign—and our liberty, is it not worth more than those senseless
struggles, when even victory has proved ruinous?
‘The present difficulty overcome, far from burdening the people, it
will be easy to meliorate their condition. Reductions, which need not
annihilate luxury; reforms, which will reduce none to indigence; a
commutation of the oppressive taxes, an equal assessment of the
impost, together with the equilibrium which must be restored
between our revenue and our expenditure; an order that must be
rendered permanent by our vigilant superintendency.—These are the
scattered objects of your consolatory perspective.—They are not the
unsubstantial coinage of fancy; but real, palpable forms—hopes
capable of proof, things subordinate to calculation.
‘But our actual wants—the paralysis of our public strength, the
hundred and sixty extra millions necessary for this year, and the next
—What can be done? The prime minister has proposed as the great
lever of the effort, which is to decide the kingdom’s fate, a
contribution proportional to the income of each citizen.
‘Between the necessity of providing instantly for the exigencies of
the public, and the impossibility of investigating so speedily the plan
before us; fearing to enter into a labyrinth of calculations, and seeing
nothing contrary to our duty in the minister’s proposal, we have
obeyed the dictates of our consciences, presuming they would be
yours. The attachment of the nation to the author of the plan,
appeared to us a pledge of it’s success; and we confided in his long
experience, rather than trust to the guidance of our speculative
opinions.
‘To the conscience of every citizen is left the valuation of his
income: thus the effect of the measure depends on your own
patriotism. When the nation is bursting from the nothingness of
servitude to the creation of liberty—when policy is about to concur
with nature in unfolding the inconceivable grandeur of her future
destiny—shall vile passions oppose her greatness? interest stay her
flight? and the salvation of the state weigh less than a personal
contribution?
‘No; such madness is not in nature; the passions even do not listen
to such treacherous reckonings. If the revolution, which has given us
a country, cannot rouse some frenchmen out of the torpor of
indifference, at least the tranquillity of the kingdom, the only pledge
of their individual security, will influence them. No; it is not in the
whirl of universal overthrow, in the degradation of tutelary authority,
when a crowd of indigent citizens, shut out from the work-shops, will
be clamouring for impotent pity; when the soldiery disbanded will be
forming itself into hungry gangs of armed plunderers, when property
will be violated with impunity, and the very existence of individuals
menaced—terrour and grief waiting at the door of every family—it is
not amidst such complicated wretchedness, that these cruel and
selfish men will enjoy in peace the hoards which they denied their
country. The only distinction that awaits them, in the general wreck,
will be the universal opprobrium they deserve, or the useless
remorse that will corrode the inmost recesses of their hearts.
‘Ah! how many recent proofs have we of the public spiritedness,
which renders all success so easy! With what rapidity was formed the
national militia, those legions of citizens armed for the defence of the
country, the preservation of tranquillity, and the maintenance of the
laws! A generous emulation has beamed on all sides. Villages, towns,
provinces, have considered their privileges as odious distinctions,
and solicited the honour of depriving themselves of peculiar
advantages, to enrich their country. You know it: time was not
allowed to draw up the mutual concessions, dictated by a purely
patriotic sentiment, into decrees; so impatient was every class of
citizens to restore to the great family whatever endowed some of it’s
members to the prejudice of others.
‘Above all, since the embarrassment of our finances, the patriotic
contributions have increased. From the throne, the majesty of which
a beneficent prince exalts by his virtues, has emanated the most
striking example.—O thou, so justly the dearly beloved of thy people
—king—citizen—man of worth! it was thine to cast a glance over the
magnificence that surrounded thee, and to convert it into national
resources. The objects of luxury which thou hast sacrificed, have
added new lustre to thy dignity; and whilst the love of the french for
thy sacred person makes them murmur at the privation, their
sensibility applauds thy magnanimity; and their generosity will repay
thy beneficence by the return it covets, by an imitation of thy virtues,
by pursuing thy course in the career of public utility.
‘How much wealth, congealed by ostentation into useless heaps,
shall melt into flowing streams of prosperity! How much the prudent
economy of individuals might contribute to the restoration of the
kingdom! How many treasures, which the piety of our forefathers
accumulated on the altars of our temples, will forsake their obscure
cells without changing their sacred destination! “This I set apart, in
times of prosperity;” says religion; “it is fitting that I dispense it in
the day of adversity. It was not for myself—a borrowed lustre adds
nothing to my greatness—it was for you, and the state, that I levied
this honourable tribute on the virtues of your forefathers.”
‘Who can avoid being affected by such examples? What a moment
to display our resources, to invoke the aid of every corner of the
empire!—O prevent the shame, with which the violation of our
engagements, our most sacred engagements, would stain the birth of
freedom! Prevent those dreadful shocks, which, in overturning the
most solid institutions, and shattering the most established fortunes,
would leave France covered with the sad ruins of a shameful
hurricane. How mistaken are those, who at a certain distance from
the capital contemplate not the links, which connect public faith with
national prosperity, and with the social contract! They who
pronounce the infamous term bankruptcy, are they not rather a herd
of ferocious beasts, than a society of men just and free? Where is the
frenchman who will dare to look his fellow citizens in the face, when
his conscience shall upbraid him with having contributed to
empoison the existence of millions of his fellow creatures? Are we the
nation to whose honour it’s enemies bear witness, who are about to
sully the proud distinction by a BANKRUPTCY?—Shall we give them
cause to say, we have only recovered our liberty and strength to
commit, without shuddering, crimes which paled even the cheek of
despotism?
‘Would it be any excuse to protest, that this execrable mischief was
not premeditated? Ah! no: the cries of the victims, whom we shall
scatter over Europe, will drown our voice. Act then!—Be your
measures swift, strong, sure. Dispel the cloud, that lowers over our
heads, the gloom of which sheds terrour into the hearts of the
creditors of France.—If it burst, the devastation of our national
resources will be more tremendous than the terrible plague, which
has lately ravaged our provinces.
‘How will our courage in the exercise of the functions, you have
confided to us, be renewed! With what vigour shall we labour in
forming the constitution, when secured from interruption! We have
sworn to save our country—judge of our anguish, whilst it trembles
on the verge of destruction. A momentary sacrifice is sufficient; a
sacrifice offered to the public good, and not to the encroachments of
covetousness. And is this easy expiation of the faults and blunders of
a period, stigmatized by political servitude, above our strength?
Think of the price which has been paid for liberty by other nations,
who have shown themselves worthy of it:—for this, rivers of blood
have streamed—long years of woe, and horrid civil wars, have every
where preceded the glorious birth!—Of us nothing is required, but a
pecuniary sacrifice—and even this vulgar offering is not an
impoverishing gift:—it will return into our bosom, to enrich our
cities, our fields; augmenting our national glory and prosperity.’
 CHAPTER III.
REFLECTIONS ON THE NEW MODE OF RAISING SUPPLIES. NO JUST
SYSTEM OF TAXATION YET ESTABLISHED. PAPER MONEY.
NECESSITY OF GRADUAL REFORM.

The task certainly was very difficult, at this crisis, for a minister to
give satisfaction to the people, and yet supply the wants of the state;
for it was not very likely that the public, who had been exclaiming
against the incessant demands of the old government, would have
been pleased with new burdens, or patiently endured them. Still it is
always the height of folly in a financier, to attempt to supply the
exigencies of government by any but specific and certain means: for
such vague measures will ever produce a deficit, the consequences of
which are most pernicious to public credit and private comfort.
A man, who has a precise sum to live upon, generally takes into his
estimate of expences a certain part of his income as due to the
government, for the protection and social advantages it secures him.
This proportion of his income being commonly the same from period
to period, he lays it by for that particular purpose, and contentedly
enjoys the remainder. But, should a weak minister, or a capricious
government, call on him for an additional sum, because the taxes
have proved unproductive, either through the inability of some of the
members of the state, or that they were laid on articles of
consumption, and the consumption has not been equal to the
calculation; it not only deranges his schemes of domestic economy,
but may be the cause of the most serious inconvenience.
A man who has a limited income, and a large family, is not only
obliged to be very industrious to support them, but he is likewise
necessitated to make all his arrangements with the greatest
circumspection and exactness; because a trifling loss, by involving
him in debt, might lead to his ruin, including that of his family. The
rich man, indeed, seldom thinks of these most cruel misfortunes; for
a few pounds, more or less, are of no real importance to him. Yet the
poor man, nay even the man of moderate fortune, is liable to have his
whole scheme of life broken by a circumstance of this kind, and all
his future days embittered by a perpetual struggle with pecuniary
vexations.
Governments, which ought to protect, and not oppress mankind,
cannot be too regular in their demands; for the manner of levying
taxes is of the highest importance to political economy, and the
happiness of individuals. No government has yet established a just
system of taxation[31]: for in every country the expences of
government have fallen unequally on the citizens; and, perhaps, it is
not possible to render them perfectly equal, but by laying all the
taxes on land, the mother of every production.
In this posture of affairs, the enthusiasm of the french in the cause
of liberty might have been turned to the advantage of a new and
permanent system of finance. An able, bold minister, who possessed
the confidence of the nation, might have recommended with success
the taking of the national property under the direct management of
the assembly; and then endeavouring to raise a loan on that
property, he would have given respectability to the new government,
by immediately procuring the supplies indispensably necessary not
only to keep it, but to put it in motion.
In times of civil commotion, or during a general convulsion, men
who have money, and they are commonly most timid and cautious,
are very apt to take care of it, even at the expence of their interest;
and, therefore, it was to be presumed, that the monied men of France
would not have been very ready to subscribe to the different loans
proposed by the minister, unless the security had been obvious, or
the speculative advantages exorbitant. But if Necker, whom the
prudent usurer adored as his tutelar god, had said to the nation
‘there is a property worth 4,700,000,000 l. independent of the
property of the emigrants, take it into your immediate possession;
and, whilst the sales are going on, give it as a guarantee for the loan
you want. This just and dignified measure will not only relieve your
present necessities, but it will be sufficient to enable you to fulfil
great part of your former engagements.’ There would have been then
no need of the eloquence of Mirabeau; reason would have done the
business; and men, attending to their own interest, would have
promoted the public good, without having their heads turned giddy
by romantic flights of heroism.
 The immediate and incessant wants of a state must always be
supplied; prudence therefore, requires, that the directors of the
finances should rather provide by anticipation for it’s wants than
suffer a deficit. The government being once in arrears, additional
taxes become indispensable to bring forward the balance, or the
nation must have recourse to paper notes; an expedient, as
experience has shown, always to be dreaded, because by increasing
the debt it only extends the evil. And this increasing debt, like a ball
of snow, gathering as it rolls, soon attains a wonderful magnitude.
Every state, which has unavoidably accumulated it’s debt, ought,
provided those at the helm wish to preserve the government, and
extend the security and comforts of it’s citizens, to take every just
measure to render the interest secure, and to fund the principal; for
as it augments, like the petrifying mass, it stands in the way of all
improvement, spreading the chilling miseries of poverty around—till
the evil baffling all expedients, a mighty crash produces a new order
of things, overwhelming, with the ruins of the old, thousands of
innocent victims.
The precious metals have been considered as the best of all
possible signs of value, to facilitate the exchange of commodities, to
supply our reciprocal wants: and they will ever be necessary to our
comfort, whilst by the common consent of mankind they are the
standards of exchange. Gold and silver have a specific value, because
it is not easy to accumulate them beyond a certain quantity. Paper,
on the contrary, is a dangerous expedient, except under a well
established government: and even then the business ought to be
conducted with great moderation and sagacity.—Perhaps it would be
wise, that it’s extent should be consistent with the commerce of the
country, and the quantity of species actually in it—But it is the spirit
of commerce to stretch credit too far. The notes, also, which are
issued by a state before it’s government is well established, will
certainly be depreciated; and in proportion as they grow precarious,
the gold and silver, which was formerly in circulation will vanish, and
every article of trade, and all the comforts of life, will bear a higher
price.
These are considerations, which ought to have occurred to the
french minister, and have led him to take decided measures. The
interest of the national debt was 255,395,141 l. by a report for the
year 1792.—Necker, by his account dated the 1st of may, 1789, states
the income at 475,294,000 l., and the expences at 531,533,000 l.:
consequently there was a deficiency of 56,239,000 l.; and it was not
probable, it could not even be expected, that during the convulsions
of a revolution, the taxes would be regularly paid: the debt, then, and
the demands of the state, must increase.
The credit of every government greatly depends on the regulation
of it’s finances; and the most certain way to have given stability to
the new system, would have been by making such arrangements as
would have insured promptitude of payment. No minister ever had it
so much in his power to have taken measures glorious for France,
beneficial to Europe, happy for the people of the day, and
advantageous to posterity. No epocha, since the inflated system of
paper (the full blown bladders of public credit, which may be
destroyed by the prick of a pin) was invented, ever appeared so
favourable as that juncture in France, to have overturned it
completely: and by overlooking these circumstances, the nation has
probably lost most of the advantages, which her finances might have
gained by the revolution.
Such mistakes, whilst they involve in them a thousand difficulties,
prove the necessity of gradual reform; lest the light, suddenly
breaking-in on a benighted people, should overpower the
understanding it ought to direct. The line in which Necker had been
accustomed to move, by restraining what little energy his mind was
capable of exerting, precluded the possibility of his seeing the faint
lines marked on an expansive scale, which afforded the data for
calculations; and the nation, confiding to him the direction of a
business for which he had not sufficient talents, seems to have
contemplated in imagination a prospect, which has not yet been
realized; and whilst expectation hovered on it’s margin, the dazzling
scenery was obscured by clouds the most threatening and
tremendous.
These are evils that from the beginning of time have attended
precipitate and great changes. The improvements in philosophy and
morals have been extremely tardy. All sudden revolutions have been
as suddenly overturned, and things thrown back below their former
state. The improvements in the science of politics have been still
more slow in their advancement than those of philosophy and
morals; but the revolution in France has been progressive. It was a
revolution in the minds of men; and only demanded a new system of
government to be adapted to that change. This was not generally
perceived; and the politicians of the day ran wildly from one extreme
to the other, without recollecting, that even Moses sojourning forty
years in the wilderness could but conduct the jews to the borders of
the promised land, after the first generation had perished in their
prejudices; the most inveterate sins of men.
This is not a discouraging consideration. Our ancestors have
laboured for us; and we, in our turn, must labour for posterity. It is
by tracing the mistakes, and profiting from the discoveries of one
generation, that the next is able to take a more elevated stand. The
first inventor of any instrument has scarcely ever been able to bring
it to a tolerable degree of perfection; and the discoveries of every
man of genius, the optics of Newton excepted, have been improved, if
not extended, by their followers.—Can it then be expected, that the
science of politics and finance, the most important, and most
difficult of all human improvements; a science which involves the
passions, tempers, and manners of men and nations, estimates their
wants, maladies, comforts, happiness, and misery, and computes the
sum of good or evil flowing from social institutions; will not require
the same gradations, and advance by steps equally slow to that state
of perfection necessary to secure the sacred rights of every human
creature?
The vanity and weakness of men have continually tended to retard
this progress of things: still it is going forward; and though the fatal
presumption of the headstrong french, and the more destructive
ambition of their foreign enemies, have given it a check, we may
contemplate with complacent serenity the approximation of the
glorious era, when the appellations of fool and tyrant will be
synonymous.
 AN

HISTORICAL AND MORAL VIEW

OF THE

FRENCH REVOLUTION.
BOOK V.
 CHAPTER I.
ERROUR OF THE NATIONAL ASSEMBLY IN NEGLECTING TO
SECURE THE FREEDOM OF FRANCE. IT’S CONDUCT COMPARED
WITH THAT OF THE AMERICAN STATES. NECESSITY OF FORMING A
NEW CONSTITUTION AS SOON AS AN OLD GOVERNMENT IS
DESTROYED. THE DECLARING THE KING INVIOLABLE A WRONG
MEASURE. SECURITY OF THE FRENCH AGAINST A
COUNTERREVOLUTION. THE FLIGHT OF THE KING MEDITATED.

The conduct of the assembly in losing so much time—the most

precious time to secure the happiness of their country, and enable
the present generation to participate in the blessings they were
preparing for posterity, instead of having to encounter all the
miseries of anarchy, can never be sufficiently lamented. France had
already gained her freedom; the nation had already ascertained
certain, and the most important, political truths: it ought, therefore,
to have been the next consideration, how these were to be preserved,
and the liberty of the empire consolidated on a basis that time would
only render more firm.
Moderate men, or real patriots, would have been satisfied with
what had been gained, for the present, allowing the rest to follow
progressively. It was the most political and the most reasonable way
to secure the acquisition. In this situation France had to contend
with the prejudices of half Europe, at least, and to counteract the
influence of the insidious intriguers, who were opposing themselves
to her regeneration; to facilitate which the assembly ought to have
made it one of their main objects to render the king contented with
the change; and then the machinations of all the underminers of the
revolution, would not have loosened one fundamental stone, to
endanger the rising edifice.
 Such is the difference between men acting from a practical
knowledge, and men who are governed entirely by theory, or no
principle whatever. Most of the United States of America formed
their separate constitutions within a month, and none took more
than three, after the declaration of their independence by congress.
There certainly was a vast distinction between those States, then the
colonies of Great Britain, and France after the 14th of july; but both
countries were without a government. America with an enemy in the
heart of their empire, and France threatened with an attack. The
leading men of America, however, knew, that there was a necessity of
having some kind of government, and seem to have perceived the
ease, with which any subsequent alterations could be effected. The
members of the national assembly, on the contrary, found
themselves surrounded with ruins; and aiming at a state of
perfection for which the minds of the people were not sufficiently
mature; affecting likewise to be directed by a magnanimous
disinterestedness, they not only planted the germ of the most
dangerous and licentious spirit, but they continued to irritate the
desperate courtiers, who, having determined to oppose stratagem to
force, and not succeeding, rested all their future hopes on the king’s
escape.
The liberty of the press, which had been virtually established, at
this period, was a successful engine employed against the assembly.
And to a nation celebrated for epigrammatic fancy, and whose taste
had been so refined by art, that they had lost the zest of nature, the
simplicity of some of the members, their awkward figures, and rustic
gait, compared with the courtly mien, and easy assurance of the
chevaliers of Versailles, afforded an excellent subject. Some of these
satires were written with considerable wit, and such a happy turn of
caricature, that it is impossible not to laugh with the author, though
indirectly ridiculing the principles you hold sacred. The most
respectable decrees, the most important, and serious discussions,
were twisted into jests; which divided the people without doors into
two distinct parties; one, speaking of the assembly with sovereign
contempt, as a set of upstarts and babbling knaves; and the other,
setting up new thrones for their favourites, and viewing them with
blind admiration, as if they were a synod of demi-gods. The
contenancing of this abuse of freedom was ill-judged. The different
parties were already sufficiently heated; yet it would have been
impossible, perhaps, to have restrained the temper of the times, so
strong is the intoxication of a new folly, though it would have been
easy for the assembly to have passed a decree respecting libels. But
so ardent was become their passion for liberty, that they were unable
to discriminate between a licentious use of that important invention,
and it’s real utility. Treating then with an untimely disdain the many
abusive publications, which were sold within the very walls where
they were sitting, they were not aware of the effect which they
produced on the minds of mock heroes, who, having no principle but
honour, were ready to risk their lives to sooth distressed beauty, no
matter what produced it; or to alleviate the sufferings of a king,
though the consequence of his turpitude or tergiversation.
After the wreck of a government the plan of a new constitution
ought to be immediately formed, that is, as soon as circumstances
will possibly admit, and presented to the citizens for their
acceptance; or rather the people should depute men for that purpose,
and give them a limited time for framing one. A constitution is a
standard for the people to rally round. It is the pillar of a
government, the bond of all social unity and order. The investigation
of it’s principles makes it a fountain of light; from which issue the
rays of reason, that gradually bring forward the mental powers of the
whole community. And whenever the wheels of government, like the
wheels of any other machine, are found clogged, or do not move in a
regular manner, they equally require alteration and improvement:
and these improvements will be proportionably perfect as the people
become enlightened.
The authority of the national assembly had been acknowledged
nearly three months previous to this epocha, without their having
taken any decided steps to secure these important ends. Indeed it
does not appear to have been their first object. They seem not to have
known, or at least not to have been apprehensive, that, in proportion
to the length of time that the people are without an established
government, anarchists gain an ascendancy over their minds; and it
then becomes no easy task to form a constitution adapted to their
wayward tempers.
When a few fundamental principles are ascertained, and the state
has determined that they shall form the basis of it’s polity, it seems to
be no difficult matter to give motion to the new springs of
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