CHAPTER 1:
The Drug Development Continuum, Preclinical to Market Access
Regulatory Affairs Professionals Society 9
It should be highlighted that the investigational product (test
article) used in Phase 1-enabling preclinical studies needs to be rep-
resentative of the investigational product used in Phase 1 clinical tri-
als to provide a pharmacokinetic and toxicokinetic profile repre-
sentative for the product to be used in the clinic. Thus, while the use
of quality material manufactured under Good Manufacturing Prac-
tice (GMP) is not required in the preclinical Phase 1–enabling trials,
a quality system should be in place for the manufacture and testing
of the investigational medicine to ensure adequate traceability and
records. The investigational product used in the preclinical studies is
typically referred to as non-GMP material or tox batches. The for-
mulation used at this stage should be as close as possible to the pro-
posed clinical formulation or at least demonstrate an exposure
scenario (i.e., level and duration of exposure, route of administra-
tion) comparable to the proposed clinical GMP material.
In addition, an analytical characterization capturing critical
properties of the investigational medicine must be performed. The
extent of the analytical characterization depends on the therapeutic
modality and is usually far more extensive for biological products
than small-molecule drugs. As with the discovery stage, analytical
methods do not need to be fully validated but they do need to be
fit-for-purpose or qualified, as described above, and align with GMP
principles. Any bioanalytical methods used in Phase 1–enabling pre-
clinical studies require full analytical validation.19
Once Phase 1–enabling preclinical studies are completed, the
program moves into clinical research.
Step 3: Clinical Research
Every treatment on the market takes years of research, including
clinical research. In its simplest terms, clinical research is the study
of human health and disease. Clinical research is an essential part
of the medicinal product development continuum and is the long-
est and most expensive step. Clinical research involves human par-
ticipants in some way, essentially translating preclinical research
into finding ways to help patients – finding the right drug at the
right dose for the right patient.
Clinical research conducted on human participants (i.e., pa-
tients, subjects, and volunteers) is called a clinical trial or clinical
study. These terms usually are interchangeable. The US National
Institutes of Health (NIH) in 2014 revised the definition of a clin-
ical trial to “a research study in which one or more human subjects
are prospectively assigned to one or more interventions (which
may include placebo or other control) to evaluate the effects of
those interventions on health-related biomedical or behavioral
outcomes.”20 Clinical trials in human subjects are conducted to in-
vestigate whether a new medicinal product is safe and effective to
treat, prevent, or diagnose a disease in a particular patient popula-
tion. Clinical trials may have different objectives depending on the
phase of development trials may investigate the clinical safety and
efficacy of a proposed treatment regimen and the pharmacody-
namic/pharmacokinetic characteristics of an investigational medi-
cine. Clinical trials ultimately establish the essential safety and
efficacy data for MA by global regulatory agencies.
Clinical trials investigating a new medicinal product are
called interventional trials because they are prospective and specifi-
cally tailored to evaluate a direct impact of a treatment or preven-
tive measure on disease. Each trial design has specific outcome
measures. In contrast, observational trial designs are often retro-
spective and are used to assess potential causation in exposure-out-
come relationships. In rare cases, observational studies may be
registration-enabling, because they may allow the building of an
external control group predicting the course of disease in a non-
treated patient population in lieu of exposing patients to placebo.21
Good clinical practice (GCP) is a scientific and ethical qual-
ity standard for the design, conduct, performance, auditing,
recordkeeping, analysis, and reporting of clinical trials involving
human subjects. GCP ensures that the integrity of a clinical trial
and the safety and well-being of trial subjects (participants) is pro-
tected. ICH adopted the Guideline for Good Clinical Practice E6
(Revision 3) on 6 January 2025.22 In addition, ICH issued several
clinical guidelines covering topics such as trials in specific patient
populations and indications and biostatistical evaluation to stand-
ardize clinical practice globally.
Apart from the ICH guidelines, national agencies have issued
numerous other guidelines and reflection papers defining minimum
quality standards and principles of clinical trial conduct.
Clinical Trial Overview
Clinical trials in human subjects are conducted in phases (see
Figure 1-4).23 Each phase is designed to answer a separate
research question and to collect specific information about a new
treatment, such as its delivery mechanism (e.g., pill, solution,
injection), administration regimen and schedule, safety profile,
and efficacy outcome(s). The clinical trial process is covered in
depth in Chapter 18.
The clinical research pathway is typically a linear progression,
but some clinical programs may include more than one phase, es-
pecially for rare diseases and significant unmet medical needs. In-
formation from each phase is used to inform the next phase and to
decide whether to continue clinical research, to return to a previ-
ous phase to gather additional information (e.g., PK or bioavaila-
bility), or to stop development of the investigational medicine.
Phase 0. A Phase 0 trial (Pre-Phase 1 or exploratory trial) is de-
signed to speed up the development of promising medicines by gen-
erating preliminary data in healthy human volunteers to see if the
agent performs as expected based on the preclinical research. A
Phase 0 trial is not required. The Phase 0 trial provides no safety or
efficacy data, because the dose is too low to produce a therapeutic
effect (microdosing studies). Phase 0 trials are very small, with fewer
than 15 participants, and the drug is administered for a short time.
These trials are typically conducted to rank drug candidates to de-
cide which candidate has the best PK parameters to move forward
into further development. Recent progress extends Phase 0 benefits
beyond assessment of PK to include understanding of mechanism of
action and pharmacodynamics (PD) and enable more informed
The Drug Development Continuum, Preclinical to Market Access
Regulatory Affairs Professionals Society 9
It should be highlighted that the investigational product (test
article) used in Phase 1-enabling preclinical studies needs to be rep-
resentative of the investigational product used in Phase 1 clinical tri-
als to provide a pharmacokinetic and toxicokinetic profile repre-
sentative for the product to be used in the clinic. Thus, while the use
of quality material manufactured under Good Manufacturing Prac-
tice (GMP) is not required in the preclinical Phase 1–enabling trials,
a quality system should be in place for the manufacture and testing
of the investigational medicine to ensure adequate traceability and
records. The investigational product used in the preclinical studies is
typically referred to as non-GMP material or tox batches. The for-
mulation used at this stage should be as close as possible to the pro-
posed clinical formulation or at least demonstrate an exposure
scenario (i.e., level and duration of exposure, route of administra-
tion) comparable to the proposed clinical GMP material.
In addition, an analytical characterization capturing critical
properties of the investigational medicine must be performed. The
extent of the analytical characterization depends on the therapeutic
modality and is usually far more extensive for biological products
than small-molecule drugs. As with the discovery stage, analytical
methods do not need to be fully validated but they do need to be
fit-for-purpose or qualified, as described above, and align with GMP
principles. Any bioanalytical methods used in Phase 1–enabling pre-
clinical studies require full analytical validation.19
Once Phase 1–enabling preclinical studies are completed, the
program moves into clinical research.
Step 3: Clinical Research
Every treatment on the market takes years of research, including
clinical research. In its simplest terms, clinical research is the study
of human health and disease. Clinical research is an essential part
of the medicinal product development continuum and is the long-
est and most expensive step. Clinical research involves human par-
ticipants in some way, essentially translating preclinical research
into finding ways to help patients – finding the right drug at the
right dose for the right patient.
Clinical research conducted on human participants (i.e., pa-
tients, subjects, and volunteers) is called a clinical trial or clinical
study. These terms usually are interchangeable. The US National
Institutes of Health (NIH) in 2014 revised the definition of a clin-
ical trial to “a research study in which one or more human subjects
are prospectively assigned to one or more interventions (which
may include placebo or other control) to evaluate the effects of
those interventions on health-related biomedical or behavioral
outcomes.”20 Clinical trials in human subjects are conducted to in-
vestigate whether a new medicinal product is safe and effective to
treat, prevent, or diagnose a disease in a particular patient popula-
tion. Clinical trials may have different objectives depending on the
phase of development trials may investigate the clinical safety and
efficacy of a proposed treatment regimen and the pharmacody-
namic/pharmacokinetic characteristics of an investigational medi-
cine. Clinical trials ultimately establish the essential safety and
efficacy data for MA by global regulatory agencies.
Clinical trials investigating a new medicinal product are
called interventional trials because they are prospective and specifi-
cally tailored to evaluate a direct impact of a treatment or preven-
tive measure on disease. Each trial design has specific outcome
measures. In contrast, observational trial designs are often retro-
spective and are used to assess potential causation in exposure-out-
come relationships. In rare cases, observational studies may be
registration-enabling, because they may allow the building of an
external control group predicting the course of disease in a non-
treated patient population in lieu of exposing patients to placebo.21
Good clinical practice (GCP) is a scientific and ethical qual-
ity standard for the design, conduct, performance, auditing,
recordkeeping, analysis, and reporting of clinical trials involving
human subjects. GCP ensures that the integrity of a clinical trial
and the safety and well-being of trial subjects (participants) is pro-
tected. ICH adopted the Guideline for Good Clinical Practice E6
(Revision 3) on 6 January 2025.22 In addition, ICH issued several
clinical guidelines covering topics such as trials in specific patient
populations and indications and biostatistical evaluation to stand-
ardize clinical practice globally.
Apart from the ICH guidelines, national agencies have issued
numerous other guidelines and reflection papers defining minimum
quality standards and principles of clinical trial conduct.
Clinical Trial Overview
Clinical trials in human subjects are conducted in phases (see
Figure 1-4).23 Each phase is designed to answer a separate
research question and to collect specific information about a new
treatment, such as its delivery mechanism (e.g., pill, solution,
injection), administration regimen and schedule, safety profile,
and efficacy outcome(s). The clinical trial process is covered in
depth in Chapter 18.
The clinical research pathway is typically a linear progression,
but some clinical programs may include more than one phase, es-
pecially for rare diseases and significant unmet medical needs. In-
formation from each phase is used to inform the next phase and to
decide whether to continue clinical research, to return to a previ-
ous phase to gather additional information (e.g., PK or bioavaila-
bility), or to stop development of the investigational medicine.
Phase 0. A Phase 0 trial (Pre-Phase 1 or exploratory trial) is de-
signed to speed up the development of promising medicines by gen-
erating preliminary data in healthy human volunteers to see if the
agent performs as expected based on the preclinical research. A
Phase 0 trial is not required. The Phase 0 trial provides no safety or
efficacy data, because the dose is too low to produce a therapeutic
effect (microdosing studies). Phase 0 trials are very small, with fewer
than 15 participants, and the drug is administered for a short time.
These trials are typically conducted to rank drug candidates to de-
cide which candidate has the best PK parameters to move forward
into further development. Recent progress extends Phase 0 benefits
beyond assessment of PK to include understanding of mechanism of
action and pharmacodynamics (PD) and enable more informed