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The Stages of Drug Discovery and Development Process


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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
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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)
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:
*Address for Correspondence:
Amol B. Deore, MVP’s Institute of Pharmaceutical Sciences, Adgaon, Nashik-India
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
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
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
Data mining using bioinformatics
identifying, selecting and prioritizing potential
disease targets
Genetic association
genetic polymorphism and connection with the
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
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-
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)
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
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
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
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]
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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Drug development represents the most challenging phase to pharmaceutical industry, as it is extremely expensive and time consumable. But, under increasing demand to produce safe and innovative drugs faster and at a lower cost, the focus has switched to enhance the lead identification and the lead optimization at the early discovery phase by incorporating insilico recent technologies. Among recent technologies, Artificial Intelligence (AI) has been introduced as a powerful solution to the adressed issues, and it results to speed up significantly the development process. Where, machine-learning played a key role in producing fresh drug candidates. In this work, we walk through the fundamentals of machine learning algorithms, review and discuss their application and current issues in drug development.
... The process involves various steps like identifying the compound, its synthesis, characterization, screening, and assay for its therapeutic activity. On average, from a million molecules screened, only one potential molecule is explored in the later phase of the process for its therapeutic efficacy (Deore et al., 2019). To potentiate the process of drug discovery efficiently, various branches of science are contributing to the same, and one of them is the branch of toxicology. ...
Toxicodynamics (TD) is an essential toxicological counterpart of pharmacodynamics (PD) that confers responses to a compound when exposed to different organs/tissues in the body. The toxicokinetics (TK)-TD correlation indicates a close relationship between blood level of a compound and the level of response after frequent analysis of results obtained in relation to absorption, distribution, metabolism, and excretion process of the compound. In this chapter, we tried to cover different vital areas related to TD like TK-TD correlation, TD modeling, TD analysis and its risk assessment, and applications of TD in the management of poisoned patients. This chapter also summarizes some important topics on toxicity such as biomarkers of diseases, exosomes as mediators of chemical-induced toxicity, drug-induced nephrotoxicity, toxicities of topical ophthalmic anesthetics, the toxicity of pharmaceutical azo dyes, cryoprotectant toxicity, the toxicity of dental material, and methods to test their biosafety.
... This article offers a short description of how new medicines are found and produced. [5][6] A successful medication is estimated to cost between $900 million and $2 billion in research and development. The cost of the thousands of errors is included in this figure: Just one compound out of every 5,000-10,000 that join the investigation and production pipeline is approval. ...
ABSTRACT The establishment of a novel drug is still a costly, prolonged, difficult, and inefficient process with a high attrition rate of new therapeutic discovery. This approach can cost pharmaceutical companies an average $2.6 billion and 10–15 years of research and development. Drug design is the innovative process for the discovery of new medications, involves the design of new therapeutic entities that are complementary in shape and charge to the molecular target with which they interact and bind. A traditional approach is one of the oldest methods for finding new drugs of natural origin, involves the investigation of medicinal substances of plant, animal, or mineral origin in their crude or unprepared state. On the other hand, ultra-high-throughput drug screening and combinatorial chemistry-based development are being heavily employed to reduce the cost and the time of early drug discovery. The present review article will look deeper into the key concepts of drug discovery, drug development and clinical stages of the drug discovery. Our main objective of the review is to assist scientists whose research may be related to drug discovery and development to shape their research report in a way that relevantly places their findings into the drug discovery and development process, hence supporting effective and translation of preclinical research to humans. KEYWORDS: Drug discovery, Clinical researches, clinical trials, phases of clinical trials, Investigational drug, and Generic drug.
Deep learning has potential in the process of discovering drug, with enhanced method for analyzing image, structure of molecule and function prediction, along with preset synthesis based on the novel enzymatic structure along tailored features and its applications. Even with expanding quantity based on effective potential approaches, the statistical systems and Machine Learning algorithms that underpin them are sometimes difficult to grasp by the human mind. To meet the required recent paradigm for the automated structure of molecules, for the purpose of 'Explainable Artificial Intelligence' with deep learning approaches. In current era, there is a need for XAI with methods of deep learning to discourse the demand for a developed machine language of the molecular science. This review outlines the important concepts in XAI, possible approaches, and obstacles. It promotes to further development of XAI techniques.
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Abstract Hearing loss is a substantial health issue that affects approximately 18.5% of the world population. Currently there is no medical treatment that would cure cochlear malfunction. Once the hearing deteriorates only hearing rehabilitation with hearing aids and implantable hearing devices can be offered to the patients. To overcome this global health problem novel methods of treatment are being studied. Extracellular vesicles could have regenerative and therapeutical effect on the inner ear. Gene therapy is another new developing treatment. The delivery of therapeutic agents to the inner ear presents an obstacle and a lot of studies are investigating the best way to overcome it. Studies show that extracellular vesicles may serve as nanocarriers for the delivery of different agents that will act against preventing and treating hearing loss.
Although pharmacology and epidemiology seem to be quite distant disciplines, both depend on each other. On one hand, it is essential to know the epidemiological importance of diseases to develop novel relevant drugs. On the other hand, the drug development process involves using several epidemiological tools for its studies. The development of a novel compound needs several amounts of information from preclinical to clinical data to develop a clear hypothesis that involves the inhibition or activation of a particular signaling pathway that eventually will result in a therapeutic effect, changing the pathological state of the patient. In the present chapter, we will cover some of the most recent pharmacology advances used over recent years. For instance, the quantitative structure–activity relationship (QSAR) is used to build computational or mathematical models to find a statistically significant correlation between structure and biological activity or docking used to predict the interaction of two molecules (drug–target), generating a binding model. Likewise, among the most recent tools implemented for the acceleration of drug discovery, we found the so-called network pharmacology, which takes advantage of the vast amount of information generated by the advances in systems biology and polypharmacology or quantitative systems pharmacology (QSP), which has attracted interest over recent years in the pharmaceutical industry.
The Process of New Drug Discovery and Development, Second Edition presents a practical methodology and up-to-date scientific information for maximizing the ability of a multidisciplinary research team to discover and bring new drugs to the marketplace. This new addition updates the scientific advances in new drug discovery and development for areas such as combinatorial chemistry, screening technologies, metabonomics, biotechnology approaches and preclinical testing. It also greatly expands the focus on the business aspects of bringing new drugs to the market and offers coverage of essential topics for companies involved in drug development, such as the financial aspects of starting up a pharmaceutical enterprise, the regulatory process, liability and litigation, and patent law.
Phenotypic drug discovery (PDD) approaches do not rely on knowledge of the identity of a specific drug target or a hypothesis about its role in disease, in contrast to the target-based strategies that have been widely used in the pharmaceutical industry in the past three decades. However, in recent years, there has been a resurgence in interest in PDD approaches based on their potential to address the incompletely understood complexity of diseases and their promise of delivering first-in-class drugs, as well as major advances in the tools for cell-based phenotypic screening. Nevertheless, PDD approaches also have considerable challenges, such as hit validation and target deconvolution. This article focuses on the lessons learned by researchers engaged in PDD in the pharmaceutical industry and considers the impact of 'omics' knowledge in defining a cellular disease phenotype in the era of precision medicine, introducing the concept of a chain of translatability. We particularly aim to identify features and areas in which PDD can best deliver value to drug discovery portfolios and can contribute to the identification and the development of novel medicines, and to illustrate the challenges and uncertainties that are associated with PDD in order to help set realistic expectations with regard to its benefits and costs.
This is the fifth edition of a very successful textbook on clinical trials methodology, written by recognized leaders who have long and extensive experience in all areas of clinical trials. The three authors of the first four editions have been joined by two others who add great expertise. A chapter on regulatory issues has been included and the chapter on data monitoring has been split into two and expanded. Many contemporary clinical trial examples have been added. There is much new material on adverse events, adherence, issues in analysis, electronic data, data sharing and international trials.This book is intended for the clinical researcher who is interested in designing a clinical trial and developing a protocol. It is also of value to researchers and practitioners who must critically evaluate the literature of published clinical trials and assess the merits of each trial and the implications for the care and treatment of patients. The authors use numerous examples of published clinical trials to illustrate the fundamentals. The text is organized sequentially from defining the question to trial closeout. One chapter is devoted to each of the critical areas to aid the clinical trial researcher. These areas include pre-specifying the scientific questions to be tested and appropriate outcome measures, determining the organizational structure, estimating an adequate sample size, specifying the randomization procedure, implementing the intervention and visit schedules for participant evaluation, establishing an interim data and safety monitoring plan, detailing the final analysis plan and reporting the trial results according to the pre-specified objectives. Although a basic introductory statistics course is helpful in maximizing the benefit of this book, a researcher or practitioner with limited statistical background would still find most if not all the chapters understandable and helpful. While the technical material has been kept to a minimum, the statistician may still find the principles and fundamentals presented in this text useful. © Springer International Publishing Switzerland 2015. All rights reserved.
Secondary screening and lead optimization, where a large number of "hit" compounds are refined to a viable set of "lead" drug candidates, are considered to be bottlenecks to the drug discovery process and are targets for streamlining. Surface plasmon resonance (SPR) is a nonlabel technology that can generate kinetic data on biomolecular interactions. This allows researchers to quantitate the binding characteristics of lead compounds with their targets in terms of affinity, specificity, and association/dissociation rates in parallel. The latest generation of SPR biosensors integrate the hit-to-lead process and generate a greater depth of information, providing answers that cannot be addressed by traditional end-point assays. This allows users to make more informed choices on the selection of candidate molecules prior to preclinical development. A number of studies have used SPR biosensors; in secondary screening, lead optimization, quantitative structure-activity relationship analysis, and predictive adsorption, distribution, metabolism, excretion, and/or toxicity evaluations.
A Comprehensive Guide to Toxicology in Preclinical Drug Development is designed for toxicologists who need a thorough understanding of the drug development process. This multi-contributed reference will provide a detailed picture of the complex and highly interrelated activities of preclinical toxicology in both small molecules and biologics. Intended as a comprehensive resource for toxicologists in industry and regulatory settings, as well as directors working in contract resource organizations (CRO), this book will discuss discovery toxicology and the international guidelines for safety evaluation and present both traditional and nontraditional toxicology models. By incorporating the latest research in this area and featuring real-life examples and scenarios, this reference is a complete and practical guide to all aspects of preclinical drug testing. Chapters written by world-renowned contributors who are experts in their fields. Includes the latest research in preclinical drug testing and international guidelines. Covers preclinical toxicology in small molecules and biologics in one single source. Incorporates real-life case studies and examples and offers readers a practical resource that outlines day-to-day activities and experiences in preclinical toxicology.
Current approaches to drug target validation include antisense and gene knockout technologies. Although popular, their revelance is limited because they do not work directly at the protein, the target of most drugs. Chromophore-assisted laser inactivation (CALI) represents a major breakthrough that addresses an anmet need in pharmaceutical drug target discovery and validation.
Q.1 Regulations for the care and use of laboratory animals in various countriesQ.2 Techniques of blood collection in laboratory animalsQ.2.1 IntroductionBlood is collected from laboratory animals for various scientific purposes, for example, to study the effects of a test drug on various constituents, such as hormones, substrates, or blood cells. In the field of pharmacokinetics and drug metabolism, blood samples are necessary for analytical determination of the drug and its metabolites. Blood is also needed for some in vitro assays using blood cells or defined plasma protein fractions.The techniques for blood collection depend on specific factors which differ from one experiment to the other. There is a difference between terminal and non-terminal blood collection techniques. The conditions of blood collection at the end of an experiment which includes death of the animal (terminal experiment) are completely different (anesthesia, volume of blood) from those of single or repeated bloo ...
The current trend in the drug design is to develop new clinically effective agents through the molecular modification of a lead nucleus. A lead compound in drug discovery is a chemical compound that has pharmacological or biological activity. Lead optimization is the synthetic modification of a biologically active compound, to fulfill all stereoelectronic, physicochemical, pharmacokinetic and toxicologic required for clinical usefulness. The main objective of this review is to discuss the methods of lead discovery, lead optimization and its role in molecular modification of lead compound in analog design.