CHAPTER 1:
The Drug Development Continuum, Preclinical to Market Access
Regulatory Affairs Professionals Society 11
trials are the pivotal safety and efficacy trials supporting the com-
mercial marketing authorization and labeling, defining the com-
mercial dose and actual conditions of use. Because Phase 3 trials
are more extensive and longer, the results are more likely to detect
long-term or rare side effects. Phase 3 trials often are referred to as
pivotal or registrational trials, and they form the substantial evidence
for approval of the drug. Data from trials conducted in Phase 1 and
2 are also submitted as supportive evidence for regulatory review.
Phase 4. After authorization, postauthorization trials usually are
carried out under the scope of postmarketing safety assessment or
surveillance, or as a result of a condition of authorization. Phase 4
trials also are conducted to gather more information on the drug’s
desired and undesired effects, to check performance in real life and
a larger user population, to identify long-term benefits and risks,
and to identify any rare side effects. The trials may involve specific
or varied patient populations (e.g., pregnant or nursing women)
generally excluded from clinical trials or confirm side effects associ-
ated with its long-term use in the approved patient population.
Where previous clinical trials were limited in thoroughly evaluating
factors that could influence the drug’s performance, Phase 4 trials
can be used to evaluate the factors more thoroughly. For example,
clinical trial participants may be instructed to follow a strict diet
and drug regimen. In contrast, Phase 4 trials are conducted on reg-
ular populations where various foods and other drugs may be taken.
Phase 4 trials also may be used to find new applications for
approved medicines (repurposing or reworking). Once identified,
clinical trials to support new indications with approved drugs enter
the drug development continuum at Phase 2 or Phase 3, depend-
ing on the indication and available supportive information.
Because Phase 3 trials are conducted in well-controlled trials
with a smaller population, previously unseen harmful effects can
be seen in postauthorization trials. Medicines have been removed
from the market based on new safety data not reported at the time
of the original authorization and in the supportive Phase 3 trials.
For example, the pain reliever rofecoxib (Vioxx) showed an in-
creased relative risk for serious cardiovascular events, including
heart attack and stroke, during long-term treatment (18 months)
for a new indication during a Phase 3 trial. Merck and Co. subse-
quently announced a voluntary, worldwide withdrawal of Vioxx
from the market.25
The results of Phase 3 confirmatory trials are key to moving
to Step 4, agency review and marketing authorization. Clinical re-
search and the clinical trial phases of the development continuum,
including conduct and objectives, are discussed in more detail in
Section 4.
Step 4: Agency Review and Marketing
Authorization
If all the data and evidence from discovery and development, pre-
clinical research, clinical research, and CMC (quality) development
demonstrate that the medicine is safe and effective for its intended
purpose, and the product developer has fully characterized the
medicine, including the quality, strength, purity, potency, and sta-
bility attributes, and the medicine can be reproducibly made, tested,
and supplied, the product development continuum moves to step 4,
agency review and marketing authorization.
In step 4, the sponsor compiles all the relevant information
demonstrating that the medicinal product is safe, effective, and of
appropriate quality and submits a marketing authorization applica-
tion (MAA, also called a regulatory dossier) to a regulatory agency
(e.g., US FDA, EMA, Brazilian Health Regulatory Agency
(ANVISA)) requesting authorization to market the product. The
MAA must include data and reports from preclinical research
through Phase 3 confirmatory clinical trials and CMC infor-
mation about the medicine following the rules and regulations of
that region. There are more than 150 regulatory agencies world-
wide regulating healthcare products in individual regions.26 Each
region has regulatory requirements to which the medicinal product
must conform to gain authorization. This means developers and
sponsors must understand each region’s requirements and create
multiple documents for submission to the different regulatory
agencies, adding to the complexity of product development.
Recognizing the diversity in technical requirements from
country to country and the challenges of making new medicines
available internationally, ICH in 1990 brought together the regu-
latory authorities from the US, EU, and Japan, along with phar-
maceutical industry representatives, to discuss scientific and
technical aspects of pharmaceuticals with the objective to develop
harmonized regulatory requirements and guidelines in these re-
gions. Since then, ICH has developed numerous guidelines on
safety, quality, and efficacy topics. The guidelines have been
adopted by an increasing number of regulatory agencies world-
wide. Now in its fourth decade, ICH is working to extend harmo-
nization beyond the founding regions.27
The Common Technical Document (CTD), finalized in
2003, fostered considerable harmonization in the technical re-
quirements for the authorization of medicinal products. The
agreement to organize all safety, efficacy, and quality information
in a common format to generate well-structured regulatory dossi-
ers negated the need to reformat the information submitted to the
different regulatory authorities. It is important to note that the
CTD does not address the content of information to regulatory
authorities. The CTD fundamentally changed the regulatory re-
view process and practices. The CTD is the mandatory submission
format for MAAs in major markets, including Canada, Japan, EU,
US, and Australia. Other regions, including the Middle East and
North Africa (MENA), are implementing CTD, including the
successful implementation of the electronic CTD (eCTD) specifi-
cation. For example, since 2015, Saudi Arabia, Jordan, and Qatar
have implemented the eCTD format.28 At the time of writing, a
major update to version 4.0 is planned to be rolled out in Septem-
ber 2025 with the FDA as first adopting agency, enabling major
feature updates (e.g., bidirectional communication, document re-
use, and a more granular data structure).29
The Drug Development Continuum, Preclinical to Market Access
Regulatory Affairs Professionals Society 11
trials are the pivotal safety and efficacy trials supporting the com-
mercial marketing authorization and labeling, defining the com-
mercial dose and actual conditions of use. Because Phase 3 trials
are more extensive and longer, the results are more likely to detect
long-term or rare side effects. Phase 3 trials often are referred to as
pivotal or registrational trials, and they form the substantial evidence
for approval of the drug. Data from trials conducted in Phase 1 and
2 are also submitted as supportive evidence for regulatory review.
Phase 4. After authorization, postauthorization trials usually are
carried out under the scope of postmarketing safety assessment or
surveillance, or as a result of a condition of authorization. Phase 4
trials also are conducted to gather more information on the drug’s
desired and undesired effects, to check performance in real life and
a larger user population, to identify long-term benefits and risks,
and to identify any rare side effects. The trials may involve specific
or varied patient populations (e.g., pregnant or nursing women)
generally excluded from clinical trials or confirm side effects associ-
ated with its long-term use in the approved patient population.
Where previous clinical trials were limited in thoroughly evaluating
factors that could influence the drug’s performance, Phase 4 trials
can be used to evaluate the factors more thoroughly. For example,
clinical trial participants may be instructed to follow a strict diet
and drug regimen. In contrast, Phase 4 trials are conducted on reg-
ular populations where various foods and other drugs may be taken.
Phase 4 trials also may be used to find new applications for
approved medicines (repurposing or reworking). Once identified,
clinical trials to support new indications with approved drugs enter
the drug development continuum at Phase 2 or Phase 3, depend-
ing on the indication and available supportive information.
Because Phase 3 trials are conducted in well-controlled trials
with a smaller population, previously unseen harmful effects can
be seen in postauthorization trials. Medicines have been removed
from the market based on new safety data not reported at the time
of the original authorization and in the supportive Phase 3 trials.
For example, the pain reliever rofecoxib (Vioxx) showed an in-
creased relative risk for serious cardiovascular events, including
heart attack and stroke, during long-term treatment (18 months)
for a new indication during a Phase 3 trial. Merck and Co. subse-
quently announced a voluntary, worldwide withdrawal of Vioxx
from the market.25
The results of Phase 3 confirmatory trials are key to moving
to Step 4, agency review and marketing authorization. Clinical re-
search and the clinical trial phases of the development continuum,
including conduct and objectives, are discussed in more detail in
Section 4.
Step 4: Agency Review and Marketing
Authorization
If all the data and evidence from discovery and development, pre-
clinical research, clinical research, and CMC (quality) development
demonstrate that the medicine is safe and effective for its intended
purpose, and the product developer has fully characterized the
medicine, including the quality, strength, purity, potency, and sta-
bility attributes, and the medicine can be reproducibly made, tested,
and supplied, the product development continuum moves to step 4,
agency review and marketing authorization.
In step 4, the sponsor compiles all the relevant information
demonstrating that the medicinal product is safe, effective, and of
appropriate quality and submits a marketing authorization applica-
tion (MAA, also called a regulatory dossier) to a regulatory agency
(e.g., US FDA, EMA, Brazilian Health Regulatory Agency
(ANVISA)) requesting authorization to market the product. The
MAA must include data and reports from preclinical research
through Phase 3 confirmatory clinical trials and CMC infor-
mation about the medicine following the rules and regulations of
that region. There are more than 150 regulatory agencies world-
wide regulating healthcare products in individual regions.26 Each
region has regulatory requirements to which the medicinal product
must conform to gain authorization. This means developers and
sponsors must understand each region’s requirements and create
multiple documents for submission to the different regulatory
agencies, adding to the complexity of product development.
Recognizing the diversity in technical requirements from
country to country and the challenges of making new medicines
available internationally, ICH in 1990 brought together the regu-
latory authorities from the US, EU, and Japan, along with phar-
maceutical industry representatives, to discuss scientific and
technical aspects of pharmaceuticals with the objective to develop
harmonized regulatory requirements and guidelines in these re-
gions. Since then, ICH has developed numerous guidelines on
safety, quality, and efficacy topics. The guidelines have been
adopted by an increasing number of regulatory agencies world-
wide. Now in its fourth decade, ICH is working to extend harmo-
nization beyond the founding regions.27
The Common Technical Document (CTD), finalized in
2003, fostered considerable harmonization in the technical re-
quirements for the authorization of medicinal products. The
agreement to organize all safety, efficacy, and quality information
in a common format to generate well-structured regulatory dossi-
ers negated the need to reformat the information submitted to the
different regulatory authorities. It is important to note that the
CTD does not address the content of information to regulatory
authorities. The CTD fundamentally changed the regulatory re-
view process and practices. The CTD is the mandatory submission
format for MAAs in major markets, including Canada, Japan, EU,
US, and Australia. Other regions, including the Middle East and
North Africa (MENA), are implementing CTD, including the
successful implementation of the electronic CTD (eCTD) specifi-
cation. For example, since 2015, Saudi Arabia, Jordan, and Qatar
have implemented the eCTD format.28 At the time of writing, a
major update to version 4.0 is planned to be rolled out in Septem-
ber 2025 with the FDA as first adopting agency, enabling major
feature updates (e.g., bidirectional communication, document re-
use, and a more granular data structure).29