CHAPTER 1:
The Drug Development Continuum, Preclinical to Market Access
Regulatory Affairs Professionals Society 13
for the seamless and automatic electronic submission of the CTD
to the regulatory agency. The eCTD provides a harmonized tech-
nical solution to implementing the CTD electronically. Submis-
sion of the regulatory dossier is through a method “gateway” of
securely providing regulatory dossiers for review (e.g., the EU
eSubmissions Gateway, the US Electronic Submission Gateway
[ESG], and Health Canada’s Common Electronic Submission
Gateway [CESG]).
After acknowledgment of receipt and validation by the regula-
tory agency that the regulatory dossier is complete for formal review,
the dossier is accepted, and a holistic, rigorous review begins. An
agency review team that may include scientists, chemists, biologists,
pharmacologists, toxicologists, statisticians, and physicians, among
other experts, begins to review the evidence generated by the appli-
cation holder that demonstrates the quality, safety, and effectiveness
of the medicine’s intended use and following proposed labeling. In
addition to making key decisions regarding the medicine’s safety and
effectiveness profile when used as intended, the CMC used to en-
sure and maintain product quality are assessed to demonstrate that
the processes are adequate to preserve the identity, purity, strength,
potency, and microbial control throughout product use and expiry.
Key to authorization is also demonstrating a favorable benefit-risk
profile. Prior to final authorization of new molecular entities, the
regulatory agency may require an inspection of the manufacturing
facility to verify the quality information and to ensure the facility is
compliant with cGMPs and is capable of manufacturing and supply-
ing a safe medicine.
Although global regulatory authorities share the same goal –
protecting public health by regulating medicinal products – the
processes and timelines for reviewing MAAs vary. The US and
EU are considered to have the most advanced and defined regula-
tory systems in the world. In the US, review fees and times are de-
fined and driven by the Prescription Drug and User Fee Act
(PDUFA) for new molecular entities, the Biosimilar User Fee
Amendments (BSUFA) for biosimilars, and the Generic Drug
User Fee Amendments (GDUFA) for generics.38 NDAs and
BLAs under standard FDA review have an action date of 10
months those under priority review have an action date of 6
months. The action date may be a decision to approve the drug,
not approve it, or issuance of a complete response letter when
more information and adequate review time are needed.
In the EU, EMA has four registration pathways to MA, de-
pending on the type of product and the number of countries tar-
geted: centralized, decentralized, national, and mutual recognition
procedures.39 Evaluation of the MAA under the centralized proce-
dure when used for authorization in the EU (27 member states)
can typically take up to 210 days, not including pauses in the re-
view cycle (clock stops) when applicants are asked to provide addi-
tional information from the Committee for Medicinal Products
for Human Use (CHMP). CHMP is EMA’s scientific committee
responsible for human medicines and prepares scientific opinions
on whether the medicine may be authorized after a thorough eval-
uation of the MAA. Ultimately, the scientific opinion issued by
CHMP is sent to the EMA.40 The EMA then sends the opinion
to the European Commission (EC), which makes a decision to is-
sue the MA if approved. Other regulatory agencies are improving
and enhancing their regulatory systems, and the process of harmo-
nization continues.
One significant enhancement to the regulatory review process
is the result of regulatory agencies recognizing that patients with
serious or rare conditions can derive clinical benefit by gaining ac-
cess to potential therapies more quickly than standard review
times. Accordingly, regulatory authorities across the globe have
developed expedited development and nonstandard review and au-
thorization pathways to facilitate the development of new medi-
cines (e.g., futibatinib, pembrolizumab) for such conditions. An
applicant may pursue more than one of the expedited pathways in
parallel. These pathways also encourage early and continued inter-
actions between the medicinal product developer and the regula-
tory agencies.
In the US, the FDA has developed four programs to facilitate
and expedite the development and review of new drugs to address
an unmet medical need in the treatment of a serious or life-threat-
ening condition. The four programs are fast-track designation,
breakthrough therapy designation, accelerated authorization, and
priority review designation.41
Similarly, EMA instituted PRIME (PRIority MEdicines) to
support the development of medicines that target an unmet medi-
cal need. Through PRIME, the agency offers early and proactive
support to medicine developers to optimize the generation of ro-
bust data about a medicine’s benefits and risks and to enable accel-
erated assessment of medicines applications.42
PMDA Japan developed the SAKIGAKE Designation System
to promote research and development and early clinical research/
trials in Japan aimed at early practical application for innovative
medical products with significant prospective efficacy. The
SAKIGAKE strategy includes priority consultations, prior assess-
ments, and priority reviews, as well as the Scheme for Rapid Au-
thorization of Unapproved Drugs.43 More detail is provided in
Chapter 26.
Receiving marketing authorization from any global regulatory
authority is a significant milestone in a medicine developer’s prod-
uct development continuum to provide therapeutics to treat large
population segments affected by a given disease and develop phar-
maceutical innovations targeting unmet medical needs (e.g., rare
diseases) for patients around the world. This step leads to Step 5
in the product development continuum, Market Access, making
the medicinal product available to the right patient at the right
time and at the right price.
Step 5: Market Access
The ultimate goal and focus of the medicinal product development
continuum is gaining authorization and commercialization so that
patients have access to a new, alternative treatment or one to meet
an unmet medical need. For global pharmaceutical and biotechnol-
ogy companies, this is market access, generally described as getting
the right treatment to the right patient at the right time for the right
The Drug Development Continuum, Preclinical to Market Access
Regulatory Affairs Professionals Society 13
for the seamless and automatic electronic submission of the CTD
to the regulatory agency. The eCTD provides a harmonized tech-
nical solution to implementing the CTD electronically. Submis-
sion of the regulatory dossier is through a method “gateway” of
securely providing regulatory dossiers for review (e.g., the EU
eSubmissions Gateway, the US Electronic Submission Gateway
[ESG], and Health Canada’s Common Electronic Submission
Gateway [CESG]).
After acknowledgment of receipt and validation by the regula-
tory agency that the regulatory dossier is complete for formal review,
the dossier is accepted, and a holistic, rigorous review begins. An
agency review team that may include scientists, chemists, biologists,
pharmacologists, toxicologists, statisticians, and physicians, among
other experts, begins to review the evidence generated by the appli-
cation holder that demonstrates the quality, safety, and effectiveness
of the medicine’s intended use and following proposed labeling. In
addition to making key decisions regarding the medicine’s safety and
effectiveness profile when used as intended, the CMC used to en-
sure and maintain product quality are assessed to demonstrate that
the processes are adequate to preserve the identity, purity, strength,
potency, and microbial control throughout product use and expiry.
Key to authorization is also demonstrating a favorable benefit-risk
profile. Prior to final authorization of new molecular entities, the
regulatory agency may require an inspection of the manufacturing
facility to verify the quality information and to ensure the facility is
compliant with cGMPs and is capable of manufacturing and supply-
ing a safe medicine.
Although global regulatory authorities share the same goal –
protecting public health by regulating medicinal products – the
processes and timelines for reviewing MAAs vary. The US and
EU are considered to have the most advanced and defined regula-
tory systems in the world. In the US, review fees and times are de-
fined and driven by the Prescription Drug and User Fee Act
(PDUFA) for new molecular entities, the Biosimilar User Fee
Amendments (BSUFA) for biosimilars, and the Generic Drug
User Fee Amendments (GDUFA) for generics.38 NDAs and
BLAs under standard FDA review have an action date of 10
months those under priority review have an action date of 6
months. The action date may be a decision to approve the drug,
not approve it, or issuance of a complete response letter when
more information and adequate review time are needed.
In the EU, EMA has four registration pathways to MA, de-
pending on the type of product and the number of countries tar-
geted: centralized, decentralized, national, and mutual recognition
procedures.39 Evaluation of the MAA under the centralized proce-
dure when used for authorization in the EU (27 member states)
can typically take up to 210 days, not including pauses in the re-
view cycle (clock stops) when applicants are asked to provide addi-
tional information from the Committee for Medicinal Products
for Human Use (CHMP). CHMP is EMA’s scientific committee
responsible for human medicines and prepares scientific opinions
on whether the medicine may be authorized after a thorough eval-
uation of the MAA. Ultimately, the scientific opinion issued by
CHMP is sent to the EMA.40 The EMA then sends the opinion
to the European Commission (EC), which makes a decision to is-
sue the MA if approved. Other regulatory agencies are improving
and enhancing their regulatory systems, and the process of harmo-
nization continues.
One significant enhancement to the regulatory review process
is the result of regulatory agencies recognizing that patients with
serious or rare conditions can derive clinical benefit by gaining ac-
cess to potential therapies more quickly than standard review
times. Accordingly, regulatory authorities across the globe have
developed expedited development and nonstandard review and au-
thorization pathways to facilitate the development of new medi-
cines (e.g., futibatinib, pembrolizumab) for such conditions. An
applicant may pursue more than one of the expedited pathways in
parallel. These pathways also encourage early and continued inter-
actions between the medicinal product developer and the regula-
tory agencies.
In the US, the FDA has developed four programs to facilitate
and expedite the development and review of new drugs to address
an unmet medical need in the treatment of a serious or life-threat-
ening condition. The four programs are fast-track designation,
breakthrough therapy designation, accelerated authorization, and
priority review designation.41
Similarly, EMA instituted PRIME (PRIority MEdicines) to
support the development of medicines that target an unmet medi-
cal need. Through PRIME, the agency offers early and proactive
support to medicine developers to optimize the generation of ro-
bust data about a medicine’s benefits and risks and to enable accel-
erated assessment of medicines applications.42
PMDA Japan developed the SAKIGAKE Designation System
to promote research and development and early clinical research/
trials in Japan aimed at early practical application for innovative
medical products with significant prospective efficacy. The
SAKIGAKE strategy includes priority consultations, prior assess-
ments, and priority reviews, as well as the Scheme for Rapid Au-
thorization of Unapproved Drugs.43 More detail is provided in
Chapter 26.
Receiving marketing authorization from any global regulatory
authority is a significant milestone in a medicine developer’s prod-
uct development continuum to provide therapeutics to treat large
population segments affected by a given disease and develop phar-
maceutical innovations targeting unmet medical needs (e.g., rare
diseases) for patients around the world. This step leads to Step 5
in the product development continuum, Market Access, making
the medicinal product available to the right patient at the right
time and at the right price.
Step 5: Market Access
The ultimate goal and focus of the medicinal product development
continuum is gaining authorization and commercialization so that
patients have access to a new, alternative treatment or one to meet
an unmet medical need. For global pharmaceutical and biotechnol-
ogy companies, this is market access, generally described as getting
the right treatment to the right patient at the right time for the right