CHAPTER 1:
The Drug Development Continuum, Preclinical to Market Access
Regulatory Affairs Professionals Society 3
he medicinal product development process follows specific
steps, from discovery through clinical investigation and
ultimately to the market. The collective steps often are re-
ferred to as the product development continuum or de novo product
development. This chapter will identify the steps in the product
development continuum of new (novel) pharmaceuticals (chemi-
cally derived) and biopharmaceuticals (made from or containing
living organisms).
A Five-Step Process
All medicinal products manufactured with a new drug substance
(new molecular entity) move through five steps of the medicinal
product development continuum: discovery and development, pre-
clinical research, clinical research, agency review, and market ac-
cess, including postmarketing safety monitoring and reporting.1,2
New drug substances and new medicinal products are devel-
oped under patent protection. While the patent is in effect, the
application holder retains exclusive rights (market exclusivity) to
market the product. In addition, a health authority can grant an
additional period of market exclusivity upon approval of the me-
dicinal product in a specific country or region.3
The five steps in the development continuum are illustrated
in Figure 1-1. The steps described below may proceed sequen-
tially, and some steps will overlap. Often, the output of one step is
used to make decisions to proceed to the next step, move back to
the previous step to generate more information, or stop the devel-
opment of the medicinal product.
An integral part of the medicinal product development con-
tinuum is the chemistry, manufacturing, and controls (CMC) pro-
cess. This process ensures that the quality, consistency, and safety
of the medicinal product will be evaluated in participants (i.e., pa-
tients, subjects, volunteers) and ultimately approved for distribu-
tion and use. CMC development is also referred to as
pharmaceutical (biopharmaceutical) development. The tasks in-
clude formulation development, manufacturing development,
identifying product characteristics, defining critical quality attrib-
utes, product testing, and specifications that meet all global quality
and regulatory requirements, for example, current good manufac-
turing practices (cGMPs) and International Council for Harmoni-
sation of Technical Requirements for Pharmaceuticals for Human
Use (ICH) guidelines.
CMC development has its own continuum, timeline, re-
sources, and cost that run in parallel with the clinical activities in
the development continuum. CMC development begins in Step 1,
discovery and development, after a compound (drug or biologic
candidate) is identified. The CMC continuum is phase-appropri-
ate and becomes more complex and costly through the product de-
velopment continuum, because CMC activities continue through
every stage of development, commercial launch, and postauthori-
zation. The CMC tasks must be identified and included in the
planning of the medicinal product development continuum, or
they may become a risk to the program timeline or authorization.
The tasks in the CMC continuum may occur sequentially and of-
ten overlap. The key is that CMC parallels the product develop-
ment continuum to ensure the availability of an adequately
characterized product manufactured according to GMP require-
ments for each stage of development.
After a new medicinal product has gone through the drug
development continuum and the marketing authorization appli-
cation (MAA) has been submitted to and approved by a regulatory
agency, an opportunity becomes available for companies focused on
different approaches to traditional drug discovery and development
once the patent/exclusivity period expires. Such approaches include
generic medicines, biosimilars, and repurposing/repositioning of
existing drugs. Except for biosimilars, these approaches develop
the same active ingredient or previously approved active ingredient
to identify opportunities to expedite drug development using a
505(b)(2) or 505(j) regulatory pathway4 in the US and Article 8(3)
“Mixed Use” or Article 10 of Directive 2001/83/EC5 in the EU.
Generic medicines and therapeutic protein biosimilars are ex-
amples of product development approaches that do not follow the
traditional de novo product development continuum. When the in-
novator’s patent(s) or other periods of exclusivity expire, generic
medicines and biosimilar manufacturers can submit applications
505(b)(2) new drug application (NDA) and abbreviated new drug
application (505(j) pathway, ANDA) in the US, an abbreviated new
drug submission (ANDS) in Canada, an MAA in the EU, or a 351(k)
Biologics License Application (BLA) in the US to the respective
regulatory agency to seek authorization for their generic or biosimi-
lar version. A generic drug/medicine is identical – or bioequivalent –
to the brand name drug in dosage form, safety, strength, route of
administration, quality, performance characteristics, and intended
use.6,7 For example, gefitinib tablets were authorized originally for
T
The Drug Development Continuum,
Preclinical to Market Access
Darlene (Dar) Rosario, MBA, BS, RAC-US Pragnesh Donga, MPharm, MBA, RAC-Drugs
Kathrin Schalper, PhD, RAC-Devices, RAC-US, RAC-CAN, RAC-EU
CHAPTER 1
The Drug Development Continuum, Preclinical to Market Access
Regulatory Affairs Professionals Society 3
he medicinal product development process follows specific
steps, from discovery through clinical investigation and
ultimately to the market. The collective steps often are re-
ferred to as the product development continuum or de novo product
development. This chapter will identify the steps in the product
development continuum of new (novel) pharmaceuticals (chemi-
cally derived) and biopharmaceuticals (made from or containing
living organisms).
A Five-Step Process
All medicinal products manufactured with a new drug substance
(new molecular entity) move through five steps of the medicinal
product development continuum: discovery and development, pre-
clinical research, clinical research, agency review, and market ac-
cess, including postmarketing safety monitoring and reporting.1,2
New drug substances and new medicinal products are devel-
oped under patent protection. While the patent is in effect, the
application holder retains exclusive rights (market exclusivity) to
market the product. In addition, a health authority can grant an
additional period of market exclusivity upon approval of the me-
dicinal product in a specific country or region.3
The five steps in the development continuum are illustrated
in Figure 1-1. The steps described below may proceed sequen-
tially, and some steps will overlap. Often, the output of one step is
used to make decisions to proceed to the next step, move back to
the previous step to generate more information, or stop the devel-
opment of the medicinal product.
An integral part of the medicinal product development con-
tinuum is the chemistry, manufacturing, and controls (CMC) pro-
cess. This process ensures that the quality, consistency, and safety
of the medicinal product will be evaluated in participants (i.e., pa-
tients, subjects, volunteers) and ultimately approved for distribu-
tion and use. CMC development is also referred to as
pharmaceutical (biopharmaceutical) development. The tasks in-
clude formulation development, manufacturing development,
identifying product characteristics, defining critical quality attrib-
utes, product testing, and specifications that meet all global quality
and regulatory requirements, for example, current good manufac-
turing practices (cGMPs) and International Council for Harmoni-
sation of Technical Requirements for Pharmaceuticals for Human
Use (ICH) guidelines.
CMC development has its own continuum, timeline, re-
sources, and cost that run in parallel with the clinical activities in
the development continuum. CMC development begins in Step 1,
discovery and development, after a compound (drug or biologic
candidate) is identified. The CMC continuum is phase-appropri-
ate and becomes more complex and costly through the product de-
velopment continuum, because CMC activities continue through
every stage of development, commercial launch, and postauthori-
zation. The CMC tasks must be identified and included in the
planning of the medicinal product development continuum, or
they may become a risk to the program timeline or authorization.
The tasks in the CMC continuum may occur sequentially and of-
ten overlap. The key is that CMC parallels the product develop-
ment continuum to ensure the availability of an adequately
characterized product manufactured according to GMP require-
ments for each stage of development.
After a new medicinal product has gone through the drug
development continuum and the marketing authorization appli-
cation (MAA) has been submitted to and approved by a regulatory
agency, an opportunity becomes available for companies focused on
different approaches to traditional drug discovery and development
once the patent/exclusivity period expires. Such approaches include
generic medicines, biosimilars, and repurposing/repositioning of
existing drugs. Except for biosimilars, these approaches develop
the same active ingredient or previously approved active ingredient
to identify opportunities to expedite drug development using a
505(b)(2) or 505(j) regulatory pathway4 in the US and Article 8(3)
“Mixed Use” or Article 10 of Directive 2001/83/EC5 in the EU.
Generic medicines and therapeutic protein biosimilars are ex-
amples of product development approaches that do not follow the
traditional de novo product development continuum. When the in-
novator’s patent(s) or other periods of exclusivity expire, generic
medicines and biosimilar manufacturers can submit applications
505(b)(2) new drug application (NDA) and abbreviated new drug
application (505(j) pathway, ANDA) in the US, an abbreviated new
drug submission (ANDS) in Canada, an MAA in the EU, or a 351(k)
Biologics License Application (BLA) in the US to the respective
regulatory agency to seek authorization for their generic or biosimi-
lar version. A generic drug/medicine is identical – or bioequivalent –
to the brand name drug in dosage form, safety, strength, route of
administration, quality, performance characteristics, and intended
use.6,7 For example, gefitinib tablets were authorized originally for
T
The Drug Development Continuum,
Preclinical to Market Access
Darlene (Dar) Rosario, MBA, BS, RAC-US Pragnesh Donga, MPharm, MBA, RAC-Drugs
Kathrin Schalper, PhD, RAC-Devices, RAC-US, RAC-CAN, RAC-EU
CHAPTER 1