The Stages of Drug Discovery and Development Process

Abstract

Drug discovery is a process which aims at identifying a compound therapeutically useful in curing and treating disease. This process involves the identification of candidates, synthesis, characterization, validation, optimization, screening and assays for therapeutic efficacy. Once a compound has shown its significance in these investigations, it will initiate the process of drug development earlier to clinical trials. New drug development process must continue through several stages in order to make a medicine that is safe, effective, and has approved all regulatory requirements. One overall theme of our article is that the process is sufficiently long, complex, and expensive so that many biological targets must be considered for every new medicine ultimately approved for clinical use and new research tools may be needed to investigate each new target. From initial discovery to a marketable medicine is a long, challenging task. It takes about 12 - 15 years from discovery to the approved medicine and requires an investment of about US $1 billion. On an average, a million molecules screened but only a single is explored in late stage clinical trials and is finally made obtainable for patients. This article provides a brief outline of the processes of new drug discovery and development.

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Deore et al Asian Journal of Pharmaceutical Research and Development. 2019; 7(6): 62-67
ISSN: 2320-4850 [62] CODEN (USA): AJPRHS
Available online on 15.12.2019 at http://ajprd.com
Asian Journal of Pharmaceutical Research and Development
Open Access to Pharmaceutical and Medical Research
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Open Access Review Article
The Stages of Drug Discovery and Development Process
Amol B. Deore*, Jayprabha R. Dhumane, Hrushikesh V Wagh, Rushikesh B. Sonawane
MVP’s Institute of Pharmaceutical Sciences, Adgaon, Nashik-422003 (India)
A B S T R A C T
Drug discovery is a process which aims at identifying a compound therapeutically useful in curing and treating disease. This
process involves the identification of candidates, synthesis, characterization, validation, optimization, screening and assays for
therapeutic efficacy. Once a compound has shown its significance in these investigations, it will initiate the process of drug
development earlier to clinical trials. New drug development process must continue through several stages in order to make a
medicine that is safe, effective, and has approved all regulatory requirements. One overall theme of our article is that the process
is sufficiently long, complex, and expensive so that many biological targets must be considered for every new medicine ultimately
approved for clinical use and new research tools may be needed to investigate each new target. From initial discovery to a
marketable medicine is a long, challenging task. It takes about 12 - 15 years from discovery to the approved medicine and
requires an investment of about US $1 billion. On an average, a million molecules screened but only a single is explored in late
stage clinical trials and is finally made obtainable for patients. This article provides a brief outline of the processes of new drug
discovery and development.
Key words: Lead optimization, clinical trials, target validation, identification, new drug.
A R T I C L E I N F O : Received 18 Sep. 2019; Review Completed 25 Nov. 2019; Accepted 14 Dec. 2019; Available online 15 Dec. 2019
Cite this article as:
Deore, AB, Dhumane JR, Wagh HV, Sonawane RB, The Stages of Drug Discovery and Development Process. Asian Journal of
Pharmaceutical Research and Development. 2019; 7(6):62-67, DOI: http://dx.doi.org/10.22270/ajprd.v7i6.616
*Address for Correspondence:
Amol B. Deore, MVP’s Institute of Pharmaceutical Sciences, Adgaon, Nashik-India
INTRODUCTION
rug discovery is a multifaceted process, which
involves identification of a drug chemical
therapeutically useful in treating and management of
a disease condition. Typically, researchers find out new
drugs through new visions into a disease process that permit
investigator to design a medicine to stopover or contrary the
effects of the disease.[1] The process of drug discovery
includes the identification of drug candidates, synthesis,
characterization, screening, and assays for therapeutic
efficacy. When a molecule avails its satisfactory results in
these investigations, it will commence the process of drug
development subsequent to clinical trials. Drug discovery
and development is an expensive process due to the high
budgets of R&D and clinical trials. It takes almost 12-15
years to develop a single new drug molecule from the time it
is discovered when it is available in market for treating
patients.[2] The average cost for research and development
for each efficacious drug is likely to be $900 million to $2
billion. This figure includes the cost of the thousands of
failures: For every 5,000-10,000 compounds that enter the
investigation and development pipeline, ultimately only one
attains approval. These statistics challenge imagination, but a
brief understanding of the R&D process can explain why so
many compounds don‘t make it and why it takes such a
large, lengthy effort to get one medicine to patients.[3] The
Success requires immense resources the best scientific and
logical minds, highly sophisticated laboratory and
technology; and multifaceted project management. It also
takes persistence and good fortune.[4] Eventually, the process
of drug discovery brings hope, faith and relief to billions of
patients.[5]
D

Deore et al Asian Journal of Pharmaceutical Research and Development. 2019; 7(6): 62-67
ISSN: 2320-4850 [63] CODEN (USA): AJPRHS
Stages of drug discovery and development include:
 Target identification
 Target validation
 lead identification
 lead optimization
 Product characterization
 Formulation and development
 Preclinical research
 Investigational New Drug
 Clinical trials
 New Drug Application
 Approval
Figure 1: Stages of drug discovery and development process
Target Identification
The first step in the discovery of a drug is identification of
the biological origin of a disease, and the potential targets for
intervention. Target identification starts with isolating the
function of a possible therapeutic target (gene/nucleic
acid/protein) and its role in the disease. [6] Identification of
the target is followed by characterization of the molecular
mechanisms addressed by the target. An ideal target should
be efficacious, safe, meet clinical and commercial
requirements and be ‗druggable‘. The techniques used for
target identification may be based on principles of molecular
biology, biochemistry, genetics, biophysics, or other
disciplines.[7]
Approaches:
 Data mining using bioinformatics
— identifying, selecting and prioritizing potential
disease targets
 Genetic association
— genetic polymorphism and connection with the
disease
 Expression profile
— changes in mRNA/protein levels
 Pathway and phenotypic analysis
— In vitro cell-based mechanistic studies
 Functional screening
— knockdown, knockout or using target specific
tools[8]
Target Validation
Target validation is the process by which the expected
molecular target – for example gene, protein or nucleic acid
of a small molecule is certified. Target validation includes:
determining the structure activity relationship (SAR) of
analogs of the small molecule; generating a drug-resistant
mutant of the presumed target; knockdown or over
expression of the presumed target; and monitoring the known
signaling systems downstream of the presumed target.[9]
Target validation is the process of demonstrating the
functional role of the identified target in the disease
phenotype. Whilst the validation of a drug‘s efficacy and
toxicity in numerous disease-relevant cell models and animal
models is extremely valuable – the ultimate test is whether
the drug works in a clinical setting.[10]
Target validation can be broken down in to two key steps.
Reproducibility: Once a drug target is identified, whether it
be via a specific technique or from review of literature, the
first step is to repeat the experiment to confirm that it can be
successfully reproduced. The target validation technique
includes affinity chromatography, expression-cloning,
protein microarray, reverse transfected cell microarray,
biochemical suppression, siRNA, DNA microarray, system
biology and study of existing drugs.[11,12]
Introduce variation to the ligand (drug)-target-
environment
 Genetic manipulation of target genes (in vitro)
knocking down the gene (shRNA, siRNA, miRNA),
knocking out the gene (CRISPR), knocking in the genes
(viral transfection of mutant genes)
 Antibodies
interacting to the target with high affinity and blocking
further interactions
 Chemical genomics
chemical approaches against genome encoding protein[13]
Identification of Lead
A chemical lead is defined as a synthetically stable, feasible,
and drug like molecule active in primary and secondary
assays with acceptable specificity, affinity and selectivity for

Deore et al Asian Journal of Pharmaceutical Research and Development. 2019; 7(6): 62-67
ISSN: 2320-4850 [64] CODEN (USA): AJPRHS
the target receptor. This requires definition of the structure
activity relationship as well as determination of synthetic
feasibility and preliminary evidence of in vivo efficacy and
target engagement. Characteristics of a chemical lead are:
 SAR defined
 Drug ability (preliminary toxicity, hERG)
 Synthetic feasibility
 Select mechanistic assays
 In vitro assessment of drug resistance and efflux potential
 Evidence of in vivo efficacy of chemical class
 PK/Toxicity of chemical class known based on preliminary
toxicity or in silico studies
In order to decrease the number of compounds that fail in the
drug development process, a drug ability assessment is often
conducted. This assessment is important in transforming a
compound from a lead molecule into a drug. For a compound
to be considered druggable it should have the potential to
bind to a specific target; however, also important is the
compound‘s pharmacokinetic profile regarding absorption,
distribution, metabolism, and excretion. Other assays will
evaluate the potential toxicity of the compound in screens
such as the Ames test and cytotoxicity assay. [14]
Lead Optimization
Lead optimization is the process by which a drug candidate is
designed after an initial lead compound is identified. The
process involves iterative series of synthesis and
characterization of a potential drug to build up a
representation of in what way chemical structure and activity
are related in terms of interactions with its targets and its
metabolism.
In initial drug discovery, the resulting leads from hit-to-lead
high throughput screening tests undergo lead optimization, to
identify promising compounds. Potential leads are evaluated
for a range of properties, including selectivity and binding
mechanisms during lead optimization, as the final step in
early stage drug discovery. The purpose of lead optimization
is to maintain favorable properties in lead compounds, while
improving on deficiencies in lead structure. In order to
produce a pre-clinical drug candidate, the chemical structures
of lead compounds (small molecules or biologics) need to be
altered to improve target specificity and selectivity.
Pharmacodynamic and pharmacokinetic parameters and
toxicological properties are also evaluated. Labs must
acquire data on the toxicity, efficacy, stability and
bioavailability of leads, in order to accurately characterize
the compound and establish the route of optimization.[15]
Researchers in drug discovery need rapid methods to narrow
down the selection of drug candidates for this downstream
selectivity profiling and further investigation. High
throughput DMPK (drug metabolism and pharmacokinetics)
screens have become an essential part of lead optimization,
facilitating the understanding and prediction of in vivo
pharmacokinetics using in vitro tests. In order to make new
drugs with higher potency and safety profiles, chemical
modifications to the structure of candidate drugs are made
through optimization.
Automated screening systems are becoming an important
part of pharmaceutical and biopharmaceutical drug discovery
labs. Mass spectrometry is used for the detection and
quantitation of metabolites. MALDI imaging is a key
technique for evaluating drug candidates and their
metabolites in tissue structure rapidly and accurately.
Additionally, NMR Fragment-based Screening (FBS) in the
pharmaceutical industry has become a widely applied
method for the discovery and optimization of lead molecules
in targeted screening campaigns.[16]
Product Characterization
When any new drug molecule shows a promising therapeutic
activity, then the molecule is characterized by its size, shape,
strength, weakness, use, toxicity, and biological activity.
Early stages of pharmacological studies are helpful to
characterize the mechanism of action of the compound.
Formulation and Development
Pharmaceutical formulation is a stage of drug development
during which the physicochemical properties of active
pharmaceutical ingredients (APIs) are characterized to
produce a bioavailable, stable and optimal dosage form for a
specific administration route.
During preformulation studies the following parameters
are evaluated:
• Solubility in different media and solvents
• Dissolution of the active pharmaceutical ingredient (API)
• Accelerated Stability Services under various conditions
• Solid state properties (polymorphs, particle size, particle
shape etc.)
• Formulation services and capabilities
• Formulation development of new chemical entities (NCE)
• Optimization of existing formulations
• Process development for selected dosage forms
• Novel formulations for improved delivery of existing
dosage forms
• Controlled release and sustained release formulations
• Self-emulsifying drug delivery systems
• Colloidal drug delivery systems
• Sub-micron and nano-emulsions
Preclinical Testing
Pre-clinical research in drug development process involves
evaluation of drug‘s safety and efficacy in animal species
that conclude to prospective human outcome. The pre-
clinical trials also have to acquire approval by corresponding
regulatory authorities. The regulatory authorities must ensure
that trials are conducted in safe and ethical way and would
give approval for only those drugs which are confirm to be
safe and effective. ICH has established a basic guideline for
technical necessities of acceptable preclinical drug
development.[17]
The pre-clinical trials can be conducted in two ways: General
pharmacology and Toxicology. Pharmacology deals with the
pharmacokinetic and pharmacodynamic parameters of drug.
It is essential to explore unwanted pharmacological effects in
suitable animal models and monitoring them in toxicological
studies. Pharmacokinetic studies are very important to make
known the safety and efficacy parameters in terms of

Deore et al Asian Journal of Pharmaceutical Research and Development. 2019; 7(6): 62-67
ISSN: 2320-4850 [65] CODEN (USA): AJPRHS
absorption, distribution, metabolism and excretion. These
studies give information on absorption rate for diverse routes
of administration, which helps in selection of dosage form,
distribution, rate of metabolism and elimination; which
governs the half-life of the drug. Half-life of the drug
clarifies the safety outline of the drug which is the obligatory
for a drug to get approved by regulatory agencies. The drug
distribution mechanism elucidates the therapeutic
effectiveness of the drug as it depends on the drugs
bioavailability and its affinity. Drug metabolism provides the
probability of through phases of biotransformation process
and formation of drug metabolites. It also helps in
understanding the reactions as well as enzymes involved in
biotransformation. [18]
Toxicological studies of the drug can be performed by in-
vitro and in-vivo test which evaluate the toxicological effects
of the drug. In-vitro studies can be performed to inspect the
direct effects on cell proliferation and phenotype. In-vivo
studies can be performed for qualitative and quantitative
determination of toxicological effects. As many drugs are
species specific, it is essential to select appropriate animal
species for toxicity study. In-vivo studies to evaluate
pharmacological and toxicological actions, including mode
of action, are often used to support the basis of the proposed
use of the product in clinical studies. [19]
The Investigational New Drug Process (IND)
Drug developers must file an Investigational New Drug
application to FDA before commencement clinical
research.[20] In the IND application, developers must include:
• Preclinical and toxicity study data
• Drug manufacturing information
• Clinical research protocols for studies to be conducted
• Previous clinical research data (if any)
• Information about the investigator/ developer[21]
Clinical Research
Clinical trials are conducted in people (volunteer)and
intended to answer specific questions about the safety and
efficacy of drugs, vaccines, other therapies, or new methods
of using current treatments. Clinical trials follow a specific
study protocol that is designed by the researcher or
investigator or manufacturer. As the developers design the
clinical study, they will consider what they want to complete
for each of the different Clinical Research Phases and starts
the Investigational New Drug Process (IND), a process they
must go through before clinical research begins. Before a
clinical trial begins, researchers review prior information
about the drug to develop research questions and
objectives.[22] Then, they decide:
• Selection criteria for participants
• Number of people take part of the study
• Duration of study
• Dose and route of administration of dosage form
• Assessment of parameters
• Data collection and analysis
Phase 0 clinical trial
Phase 0 implicates investigative, first-in-human (FIH)
trials that are conducted according to FDA guidelines. Phase
0 trials besides termed as human micro dose studies, they
have single sub-therapeutic doses given to 10 to 15
volunteers and give pharmacokinetic data or help with
imaging specific targets without exerting pharmacological
actions. Pharmaceutical industries perform Phase 0 studies to
pick which of their drug applicants has the preeminent
pharmacokinetic parameters in humans.[24]
Phase 1: Safety and dosage
Phase I trials are the first tests of a drug with a lesser number
of healthy human volunteers. In most cases, 20 to 80 healthy
volunteers with the disease/condition participate in Phase 1.
Patients are generally only used if the mechanism of action
of a drug indicates that it will not be tolerated in healthy
people. However, if a new drug is proposed for use in
diabetes patients, researchers conduct Phase 1 trials in
patients with that type of diabetes. Phase 1 studies are closely
monitored and collect information about Pharmacodynemics
in the human body. Researchers adjust dosage regimen based
on animal study data to find out what dose of a drug can
tolerate the body and what are its acute side effects. As a
Phase 1 trial continues, researchers find out research
mechanism of action, the side effects accompanying with
increase in dosage, and information about effectiveness. This
is imperative to the design of Phase 2 studies. Almost 70% of
drugs travel to the next phase.
Figure 2: Phases of clinical trials

Deore et al Asian Journal of Pharmaceutical Research and Development. 2019; 7(6): 62-67
ISSN: 2320-4850 [66] CODEN (USA): AJPRHS
Phase 2: Efficacy and side effects
Phase II trials are conducted on larger groups of patients (few
hundreds) and are aimed to evaluate the efficacy of the drug
and to endure the Phase I safety assessments. These trials
aren‘tsufficient to confirm whether the drug will be
therapeutic. Phase 2 studies provide with additional safety
data to the researchers. Researchers use these data to refine
research questions, develop research methods, and design
new Phase 3 research protocols. Around 33% of drugs travel
to the next phase.
Most prominently, Phase II clinical studies aid to found
therapeutic doses for the large-scale Phase III studies.
Phase 3: Efficacy and adverse drug reactions monitoring
Researchers plan Phase 3 studies to prove whether a product
deals anaction benefit to a specific peopleor not. Sometimes
known as pivotal studies, these studies comprise 300 to 3,000
volunteers. Phase 3 studies deliver most of the safety data.
Theprevious study might not able to detect less common side
effects.Butphase 3 studies are conducted on large no. of
volunteers and longer in duration, the results are more
probable to detect long-term or uncommon side effects.
Around 25-30% of drugs travel to the next phase of clinical
research.
If a drug developer has data from its previous tests,
preclinical and clinical trials that a drug is safe and effective
for its intended use, then the industry can file an application
to market the medicine. The FDA review team
comprehensivelyinspects all submitted data on the drug and
makes a conclusion to approve or not to approve it.[25]
New Drug Application
A New Drug Application (NDA) expresses the full story of a
drug molecule. Its purpose is to verify that a drug is safe and
effective for its proposed use in the people studied. A drug
developer must include all about a drug starting from
preclinical data to Phase 3 trial datain the NDA. Developers
must include reports on all studies, data, and
analysis.[26]Beside with clinical trial outcomes, developers
must include:
• Proposed labeling
• Safety updates
• Drug abuse information
• Patent information
• Institutional review board compliance information
• Directions for use
FDA Review
Once FDA obtains a complete NDA then FDA team of
review may require about 6 to 10 months to take a
pronouncement on whether to approve the NDA. If Once
FDA obtains a incomplete NDA then FDA team of review
refuse the NDA.
If FDAgoverns that a drug has been revealed to be safe and
effective for its proposed use, it is then essential to work with
the developerforupgrade prescribing information. This is
denoted as ―labeling.‖ Labeling preciselydefines the basis for
approval and directionhow to use the drug. Although,
remaining issues required to be fixed before the drug to be
approved for marketing. In other cases, FDA have need of
additional studies. At this situation, the developer can choose
whether to continue further developmentor not. If a
developer distresses with an FDA decision, there are tools
for official appeal.[27]
Phase 4: Post-Market Drug Safety Monitoring
Phase 4 trials are conductedwhen the drug or devicehas been
approved by FDA.These trials are also recognized as post-
marketing surveillance involving pharmacovigilance and
continuing technical support after approval. There are
numerous observational strategies and assessmentpatterns
used in Phase 4trials to evaluate the efficacy, cost-
effectiveness, and safety of an involvement in real-world
settings. Phase IV studies may be required by regulatory
authorities (e.g. change in labelling, risk
management/minimization action plan) or may be undertaken
by the sponsoring company for competitive purposes or other
reasons. Therefore, the true illustration of a drug‘s safety
essentiallyrequires over the months and even years that mark
up a drug‘slifespan in the market. FDA reviews reports of
complications with prescription and OTC drugs, and can
decide to add precautions to the dosage or practice
information, as well as other events for more serious adverse
drug reactions. [28]
ACKNOWLEDGEMENT
We all express heartfelt gratitude to Dr. Nitin Hire, Principal
of MVP‘s Institute of Pharmaceutical Sciences, Adgaon for
their guidance and also for providing digital library.
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