**Meet the editor**

Arli Aditya Parikesit is the Head of Bioinformatics Department of School of Life Sciences, Indonesia International Institute for Life Sciences. He finished his bachelor and master from Department of Chemistry, Faculty of Mathematics and Sciences, University of Indonesia, and his Ph.D. from Faculty of Mathematics and Informatics, University of Leipzig, Germany with the support of

DAAD fellowship of the German government. He has written more than 30 scientific publications on bioinformatics and has expertise in structural bioinformatics, and genome annotation methods.

Contents

**Preface VII**

Arli Aditya Parikesit

**Drug Lead 29** Seema Kohli

**Drug Design 45**

**through to Marketing 9**

**Section 1 General Information and Quality Control in Drug Design 1**

Chapter 1 **Introductory Chapter: The Contribution of Bioinformatics as**

Chapter 2 **Frameworks for Evaluating Qualitative and Quantitative**

**Section 2 Specific Molecular Mechanism and Lead Compounds for**

Chapter 4 **Molecular Classification of Antitubulin Agents with Indole Ring**

Chapter 5 **Multifunctional Polymeric Enveloped Nanocarriers: Targeting**

Chapter 6 **Multifunctional Nanoparticles for Successful Targeted Drug Delivery across the Blood-Brain Barrier 91** Débora Braga Vieira and Lionel Fernel Gamarra

Maria Hassan Kiani, Masoom Yasinzai and Gul Shahnaz

**Information on Adverse Drug Events throughout Development**

**Blueprint Lead for Drug Design 3**

Kaori Nomura and Brian David Edwards

Chapter 3 **Integrated Approach to Nature as Source of New**

**Binding at Colchicine-Binding Site 47** Francisco Torrens and Gloria Castellano

**Extracellular and Intracellular Barriers 69**

## Contents

**Preface XI**


Preface

The studies o drug design have improved significantly over this decade, starting with the implementation of nimotuzumab as a chemotherapy agent for glioma and squamous cell carcinomas. In this respect, nimotuzumab was design by taking into consideration the ad‐ vances in molecular biology, especially in proteomics study, with blocking the Epidermal Growth Factor Receptor (EGFR). Some approaches, whether it is computationally-based, or wet experimentally-based, has made the improvement of nimotuzumab into a much safer chemotherapy agent. In this end, science has seen some interesting progress that possibly could follow the successful example of nimotuzumab. The multidisciplinary nature of drug design has opened many new possibilities in combating pathogens or other cause for diseas‐ es. Although the role of medical, pharmacy, and nursery studies still be a focal point for drug design, the rising roles of the multidisciplinary sciences are taking place as well.

The approaches in drug design are mainly comprised of these three multidisciplinary scien‐ ces. First, Bioinformatics has successfully gather biological data in form of biomolecular se‐ quences, in order to construct knowledge on drug and vaccine design. It is of considerable importance for drug designers to comprehend the utilization of bioinformatics tools for re‐ solving their research questions. Second, Nanotechnology has made possible the design and delivery of the nano-based drug. Third, Pharmaceutical Chemistry made it possible to inves‐ tigate the adsorption, distribution, metabolism, and toxicology of the drug candidates in a fine-grained resolution. Although other approaches could be in place, the three of them are noted for providing a significant contribution to drug design. It is noticeable that many re‐ search groups have consisted of multidisciplinary team members with at least professionals in those three approaches. As drug design is becoming needier in experts in those ap‐ proaches, study programs in bioinformatics, nanotechnology, and pharmaceutical chemistry are enacted to educate and trains experts in those particular fields. Those programs are enacted as early as Bachelor level because the multidisciplinary approaches should be em‐ phasized as early as possible. The program managers of those study programs could be from diverse backgrounds, whether they are medical doctors, biologist, chemist, physicist, informaticians, engineers or others, but they should act as the scientist that love to work in a multidisciplinary environment and willing to defend the interest of many different scientific approaches accordingly. In this end, the graduates of those study programs are working to‐ gether in a very diverse background team for constructing novel design of modern drugs. This book is indeed showing that such initiatives are in place at academia and industry. In this end, it could be stated that the goal of this book is to give the clear picture of how those

Hopefully, this book will be a significant contribution to the resolution of the world's health problems in relation to the complexity of drug design. This contribution will be useful to

different approaches worked in solving problems in drug design.

## Preface

The studies o drug design have improved significantly over this decade, starting with the implementation of nimotuzumab as a chemotherapy agent for glioma and squamous cell carcinomas. In this respect, nimotuzumab was design by taking into consideration the ad‐ vances in molecular biology, especially in proteomics study, with blocking the Epidermal Growth Factor Receptor (EGFR). Some approaches, whether it is computationally-based, or wet experimentally-based, has made the improvement of nimotuzumab into a much safer chemotherapy agent. In this end, science has seen some interesting progress that possibly could follow the successful example of nimotuzumab. The multidisciplinary nature of drug design has opened many new possibilities in combating pathogens or other cause for diseas‐ es. Although the role of medical, pharmacy, and nursery studies still be a focal point for drug design, the rising roles of the multidisciplinary sciences are taking place as well.

The approaches in drug design are mainly comprised of these three multidisciplinary scien‐ ces. First, Bioinformatics has successfully gather biological data in form of biomolecular se‐ quences, in order to construct knowledge on drug and vaccine design. It is of considerable importance for drug designers to comprehend the utilization of bioinformatics tools for re‐ solving their research questions. Second, Nanotechnology has made possible the design and delivery of the nano-based drug. Third, Pharmaceutical Chemistry made it possible to inves‐ tigate the adsorption, distribution, metabolism, and toxicology of the drug candidates in a fine-grained resolution. Although other approaches could be in place, the three of them are noted for providing a significant contribution to drug design. It is noticeable that many re‐ search groups have consisted of multidisciplinary team members with at least professionals in those three approaches. As drug design is becoming needier in experts in those ap‐ proaches, study programs in bioinformatics, nanotechnology, and pharmaceutical chemistry are enacted to educate and trains experts in those particular fields. Those programs are enacted as early as Bachelor level because the multidisciplinary approaches should be em‐ phasized as early as possible. The program managers of those study programs could be from diverse backgrounds, whether they are medical doctors, biologist, chemist, physicist, informaticians, engineers or others, but they should act as the scientist that love to work in a multidisciplinary environment and willing to defend the interest of many different scientific approaches accordingly. In this end, the graduates of those study programs are working to‐ gether in a very diverse background team for constructing novel design of modern drugs. This book is indeed showing that such initiatives are in place at academia and industry. In this end, it could be stated that the goal of this book is to give the clear picture of how those different approaches worked in solving problems in drug design.

Hopefully, this book will be a significant contribution to the resolution of the world's health problems in relation to the complexity of drug design. This contribution will be useful to students, researcher, industrialist, and even the business development of drug companies, in order to anticipate the future menace of human health. It could be seen that after the eluci‐ dation of modern molecular-based medication, the human health problems are still there. The cure for cancer is still yet on the way, while some diseases such as Tuberculosis are reemerged as antibiotic-resistant strain. Multidisciplinary approaches could be promising in resolving those issues because they observed scientific phenomenon based upon a very di‐ verse perspective that could enrich each other into much more holistic problem-solving pieces of advice.

Thus, in order to facilitate easy reading, this book is divided into two sections. The first section will discuss General Information and Quality Control in Drug Design. This particu‐ lar section will primarily emphasize on the general features of modern drug design and how to ensure its fine-grained quality control for consistent production outlook. It comprises of three chapters. The Chapter 1, introductory chapter will be useful for explaining the current trend in drug design.will discuss. The Chapter 2 will discuss Framework of Evaluating Qualitative and Quantitative Information on Drug Safety. Lastly, the chapter 3 will discuss Integrated Approach to Nature as Source of New Drug Lead.

While the second section will discuss Specific Molecular Mechanism and Lead Compounds for Drug Design. This particular section will primarily emphasize on the biomolecular and biochemical mechanism of drugs in a cell or in the laboratory. It comprises of four chapters. The Chapter 4 will discuss Molecular Classification of anti-tubulin Agents with Indole Ring Binding at Colchicine Binding site. The Chapter 5 will discuss Multifunctional Polymeric Enveloped Nanocarriers: Targeting Extracellular and Intracellular Barriers. The Chapter 6 will discuss Multifunctional Nanoparticles for Successful Targeted Drug Delivery and Diag‐ nostics Across Blood-Brain Barrier. gnostics Across Blood-Brain Barrier.

Based on those particular studies as aforementioned before, the future of drug design will be, fortunately, moving towards a much more multidisciplinary nature. Moreover, the cur‐ rent state of higher education and industry is on a very good moment in order to align themselves with this current development in drug design.

> **Arli Aditya Parikesit** Head of Bioinformatics Department School of Life Sciences Indonesia International Institute for Life Sciences Indonesia

**Section 1**

**General Information and Quality Control in**

**Drug Design**

**General Information and Quality Control in Drug Design**

students, researcher, industrialist, and even the business development of drug companies, in order to anticipate the future menace of human health. It could be seen that after the eluci‐ dation of modern molecular-based medication, the human health problems are still there. The cure for cancer is still yet on the way, while some diseases such as Tuberculosis are reemerged as antibiotic-resistant strain. Multidisciplinary approaches could be promising in resolving those issues because they observed scientific phenomenon based upon a very di‐ verse perspective that could enrich each other into much more holistic problem-solving

Thus, in order to facilitate easy reading, this book is divided into two sections. The first section will discuss General Information and Quality Control in Drug Design. This particu‐ lar section will primarily emphasize on the general features of modern drug design and how to ensure its fine-grained quality control for consistent production outlook. It comprises of three chapters. The Chapter 1, introductory chapter will be useful for explaining the current trend in drug design.will discuss. The Chapter 2 will discuss Framework of Evaluating Qualitative and Quantitative Information on Drug Safety. Lastly, the chapter 3 will discuss

While the second section will discuss Specific Molecular Mechanism and Lead Compounds for Drug Design. This particular section will primarily emphasize on the biomolecular and biochemical mechanism of drugs in a cell or in the laboratory. It comprises of four chapters. The Chapter 4 will discuss Molecular Classification of anti-tubulin Agents with Indole Ring Binding at Colchicine Binding site. The Chapter 5 will discuss Multifunctional Polymeric Enveloped Nanocarriers: Targeting Extracellular and Intracellular Barriers. The Chapter 6 will discuss Multifunctional Nanoparticles for Successful Targeted Drug Delivery and Diag‐

Based on those particular studies as aforementioned before, the future of drug design will be, fortunately, moving towards a much more multidisciplinary nature. Moreover, the cur‐ rent state of higher education and industry is on a very good moment in order to align

**Arli Aditya Parikesit**

School of Life Sciences

Indonesia

Head of Bioinformatics Department

Indonesia International Institute for Life Sciences

Integrated Approach to Nature as Source of New Drug Lead.

themselves with this current development in drug design.

nostics Across Blood-Brain Barrier. gnostics Across Blood-Brain Barrier.

pieces of advice.

VIII Preface

**Chapter 1**

**Provisional chapter**

**Introductory Chapter: The Contribution of**

**Introductory Chapter: The Contribution of** 

Additional information is available at the end of the chapter

Arli Aditya ParikesitAdditional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.79664

**1. Bioinformatics and drug design**

**2. Rational design of drugs**

Arli Aditya Parikesit

**Bioinformatics as Blueprint Lead for Drug Design**

**Bioinformatics as Blueprint Lead for Drug Design**

DOI: 10.5772/intechopen.79664

Drugs are the most utilized pharmacobiochemicals for sustaining human's health. Previously, the drug was designed unintentionally and mostly with trial and error. The well-known example is the discovery of antibiotics by Alexander Fleming which was found unintentionally [1]. However, as pharmaceutical technology is gaining momentum with the advance of molecular biology, the genome technology was applied as well to assist the development of the novel drugs. It has given a way for the development of the new kind of science, bioinformatics, which is a multidisciplinary study to integrate molecular biology and information technology [2]. There are some methods in bioinformatics that provided assistance to drug design. They are, namely, sequence alignment for determining the conservation of genome and proteome; homology modeling for determining the protein model; molecular docking method to enable high-performance screening of large amounts of lead compound [3]; molecular dynamics to set the standard to comprehend the trajectory of lead compound, as well as its interaction [4]; and ADME-TOX method to enable fine-grained detection of pharmacological and toxicological properties of lead compounds [5]. Those methods are eventually used as blueprint lead for molecular cloning or genetic engineering experiment to generate high throughput molecular

profiling of the drug leads, as a means of rational drug design approach [6].

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

The implementations of rational drug design made it possible to customize drugs at the molecular and structural level. The possibilities are enormous as the molecular design is only limited by the extent of the available computational power. The availability of commercial

#### **Introductory Chapter: The Contribution of Bioinformatics as Blueprint Lead for Drug Design Introductory Chapter: The Contribution of Bioinformatics as Blueprint Lead for Drug Design**

DOI: 10.5772/intechopen.79664

#### Arli Aditya Parikesit Arli Aditya Parikesit

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.79664

#### **1. Bioinformatics and drug design**

Drugs are the most utilized pharmacobiochemicals for sustaining human's health. Previously, the drug was designed unintentionally and mostly with trial and error. The well-known example is the discovery of antibiotics by Alexander Fleming which was found unintentionally [1]. However, as pharmaceutical technology is gaining momentum with the advance of molecular biology, the genome technology was applied as well to assist the development of the novel drugs. It has given a way for the development of the new kind of science, bioinformatics, which is a multidisciplinary study to integrate molecular biology and information technology [2]. There are some methods in bioinformatics that provided assistance to drug design. They are, namely, sequence alignment for determining the conservation of genome and proteome; homology modeling for determining the protein model; molecular docking method to enable high-performance screening of large amounts of lead compound [3]; molecular dynamics to set the standard to comprehend the trajectory of lead compound, as well as its interaction [4]; and ADME-TOX method to enable fine-grained detection of pharmacological and toxicological properties of lead compounds [5]. Those methods are eventually used as blueprint lead for molecular cloning or genetic engineering experiment to generate high throughput molecular profiling of the drug leads, as a means of rational drug design approach [6].

#### **2. Rational design of drugs**

The implementations of rational drug design made it possible to customize drugs at the molecular and structural level. The possibilities are enormous as the molecular design is only limited by the extent of the available computational power. The availability of commercial

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

cyclic peptide database has made possible to design drugs in various molecular configurations of peptide sequences [7, 8]. However, the classical approach of the isolation of natural product-based is still in use due to the availability of its respective database [9]. Moreover, due to the influence of natural product chemistry, the design of semisynthetic or syntheticbased compounds is still on demands [10]. Researchers also look for a smarter pathway to deliver drug such as utilizing E-cadherin-based drug design [11].

**Author details**

Arli Aditya Parikesit

**References**

Institute for Life Sciences, Indonesia

[Accessed: Nov 12, 2013]

10.1038/35042090

med/12198485

1848

Address all correspondence to: johnkecops@gmail.com

Head of Bioinformatics Department, School of Life Sciences, Indonesia International

[1] Kingston W. Antibiotics, invention and innovation. Research Policy. 2000;**29**:679-710. Available from: http://www.sciencedirect.com/science/article/pii/S0048733399000451

Introductory Chapter: The Contribution of Bioinformatics as Blueprint Lead for Drug Design

http://dx.doi.org/10.5772/intechopen.79664

5

[2] Hagen JB. The origins of bioinformatics. Nature Reviews. Genetics. 2000;**1**:231-236. DOI:

[3] Shoichet BK, McGovern SL, Wei B, Irwin JJ. Lead discovery using molecular docking. Current Opinion in Chemical Biology. 2002;**6**:439-446. DOI: 10.1016/S1367-5931(02)00339-3

[4] Karplus M, McCammon JA. Molecular dynamics simulations of biomolecules. Nature Structural Biology. 2002;**35**:646-652. Available from: http://www.ncbi.nlm.nih.gov/pub-

[5] van de Waterbeemd H, Gifford E. ADMET in silico modelling: Towards prediction paradise?, Nature Reviews. Drug Discovery. 2003;**2**:192-204. DOI: 10.1038/nrd1032

[6] Lionta E, Spyrou G, Vassilatis DK, Cournia Z. Structure-based virtual screening for drug discovery: Principles, applications and recent advances. Current Topics in Medicinal

[7] Tambunan USF, Alkaff AH, Nasution MAF, Parikesit AA, Kerami D. Screening of commercial cyclic peptide conjugated to HIV-1 Tat peptide as inhibitor of N-terminal heptad repeat glycoprotein-2 ectodomain Ebola virus through in silico analysis. Journal of Molecular Graphics & Modelling. 2017;**74**:366-378. DOI: 10.1016/j.jmgm.2017.04.001 [8] Parikesit AA, Kinanty USFT. Screening of commercial cyclic peptides as inhibitor envelope protein dengue virus (DENV) through molecular docking and molecular dynamics. Pakistan Journal of Biological Sciences. 2013;**16**:1836-1848. DOI: 10.3923/pjbs.2013.1836.

[9] Tambunan USF, Parikesit A, Nasution MAF, Hapsari A, Kerami D. Exposing the molecular screening method of Indonesian natural products derivate as drug candidates for cervical cancer (summer 2017). Iranian Journal of Pharmaceutical Research.

[10] Tambunan USF, Parikesit AA, Ghifari AS, Satriyanto CP. In silico identification of 2-oxo-1,3-thiazolidine derivatives as novel inhibitors candidate of class II histone deacetylase

2017;**16**:1113-1127. Available form: http://ijpr.sbmu.ac.ir/article\_2088.html

Chemistry. 2014;**14**:1923-1938. DOI: 10.2174/1568026614666140929124445

Although the rational drug design approach has provided groundbreaking innovations such as the development of antiretroviral/HIV drugs and smart anticancer chemotherapy agent such as nimotuzumab, it does not mean that the progression of life-threatening diseases has been halted [12, 13]. The complexity of disease's molecular mechanism has long baffled the biomedical researchers. The threat of multidrug antibiotic resistance bugs, pandemic viral infections (Ebola, avian influenza, MERS-CO, etc.), and civilization disease such as aging is pushing the researchers to develop much more advanced drug designs. In this end, the intelligence modifications of existing bioinformatics methods are devised to propose the novel way of developing drugs. The fragment-based docking method was utilized in order to construct drugs based upon the molecular fragment database [14]. Moreover, the reverse docking method was devised to optimize the lead compounds based on the proteomics library [15–17]. Finally, the development of transcriptomics approach enables researchers to develop the new breed of drugs, such as silencing(si)RNA-based lead compounds [18]. In this end, the smart design enables novel wet laboratory experimental methods such as the blood-brain barrier drug design method [19] and high throughput screening [20]. Thus, the molecular elucidation of the drug could be elucidated in a fine-grained manner using the NMR and crystallography instruments that are already commonly utilized in the field of protein crystallography [21]. Based on the advanced crystallography techniques, more proteins structure is already elucidated. This could be a great help in providing fine-grained receptor structures for rational drug design. Moreover, although crystallizing RNA molecules are tougher than protein, more RNA structures are already elucidated and deposited in the online database [22].

#### **3. Outlook**

As bioinformatics and protein crystallography are getting their momentum to contribute greatly in the study of rational drug design, it is found that the molecular mechanism of diseases is possible should be revealed based upon post genomics and proteomics approaches especially transcriptomics and epigenetics-based ones. The interplay of transcriptomics and epigenetics in the molecular mechanism of disease should be considered as primary information in the biomedical research [23]. Moreover, due to the influx of transcriptomics data, RNA structure elucidation is getting a momentum to be considered as a blueprint in drug design [24]. In this end, due to the specificity of the human genetic fingerprint, personalized medicine was developed where each patient got different medication depending on their genomics fingerprint [25–27]. The role of big data and artificial intelligence methods will be crucial in screening the influx of omics data in order to generate useful information to be revealed as the blueprint of drug design.

### **Author details**

cyclic peptide database has made possible to design drugs in various molecular configurations of peptide sequences [7, 8]. However, the classical approach of the isolation of natural product-based is still in use due to the availability of its respective database [9]. Moreover, due to the influence of natural product chemistry, the design of semisynthetic or syntheticbased compounds is still on demands [10]. Researchers also look for a smarter pathway to

Although the rational drug design approach has provided groundbreaking innovations such as the development of antiretroviral/HIV drugs and smart anticancer chemotherapy agent such as nimotuzumab, it does not mean that the progression of life-threatening diseases has been halted [12, 13]. The complexity of disease's molecular mechanism has long baffled the biomedical researchers. The threat of multidrug antibiotic resistance bugs, pandemic viral infections (Ebola, avian influenza, MERS-CO, etc.), and civilization disease such as aging is pushing the researchers to develop much more advanced drug designs. In this end, the intelligence modifications of existing bioinformatics methods are devised to propose the novel way of developing drugs. The fragment-based docking method was utilized in order to construct drugs based upon the molecular fragment database [14]. Moreover, the reverse docking method was devised to optimize the lead compounds based on the proteomics library [15–17]. Finally, the development of transcriptomics approach enables researchers to develop the new breed of drugs, such as silencing(si)RNA-based lead compounds [18]. In this end, the smart design enables novel wet laboratory experimental methods such as the blood-brain barrier drug design method [19] and high throughput screening [20]. Thus, the molecular elucidation of the drug could be elucidated in a fine-grained manner using the NMR and crystallography instruments that are already commonly utilized in the field of protein crystallography [21]. Based on the advanced crystallography techniques, more proteins structure is already elucidated. This could be a great help in providing fine-grained receptor structures for rational drug design. Moreover, although crystallizing RNA molecules are tougher than protein, more RNA structures are already elucidated and

As bioinformatics and protein crystallography are getting their momentum to contribute greatly in the study of rational drug design, it is found that the molecular mechanism of diseases is possible should be revealed based upon post genomics and proteomics approaches especially transcriptomics and epigenetics-based ones. The interplay of transcriptomics and epigenetics in the molecular mechanism of disease should be considered as primary information in the biomedical research [23]. Moreover, due to the influx of transcriptomics data, RNA structure elucidation is getting a momentum to be considered as a blueprint in drug design [24]. In this end, due to the specificity of the human genetic fingerprint, personalized medicine was developed where each patient got different medication depending on their genomics fingerprint [25–27]. The role of big data and artificial intelligence methods will be crucial in screening the influx of omics data in order to generate useful information to be revealed as

deliver drug such as utilizing E-cadherin-based drug design [11].

deposited in the online database [22].

the blueprint of drug design.

**3. Outlook**

4 Molecular Insight of Drug Design

Arli Aditya Parikesit

Address all correspondence to: johnkecops@gmail.com

Head of Bioinformatics Department, School of Life Sciences, Indonesia International Institute for Life Sciences, Indonesia

#### **References**


(HDAC) in cervical cancer treatment. Arabian Journal of Chemistry. 2015;**1**:1-6. DOI: 10.1016/j.arabjc.2015.07.010

[23] Fachrul M, Utomo DH, Parikesit AA. lncRNA-based study of epigenetic regulations in diabetic peripheral neuropathy. Silico Pharmacology. 2018;**6**:7. DOI: 10.1007/s40203-

Introductory Chapter: The Contribution of Bioinformatics as Blueprint Lead for Drug Design

http://dx.doi.org/10.5772/intechopen.79664

7

[24] Parikesit AA, Utomo DH, Karimah N. Determination of secondary and tertiary structures of cervical cancer lncRNA diagnostic and siRNA therapeutic biomarkers. Indian

[25] Youngblood MW, Erson-Omay EZ, Günel M. Personalized medicine through advanced genomics. In: Malig. Brain Tumors. Cham: Springer International Publishing; 2017.

[26] Pi C, Zhang M, Peng X, Zhang Y, Xu C, Zhou Q. Liquid biopsy in non-small cell lung cancer: A key role in the future of personalized medicine? Expert Review of Molecular

[27] Tsimberidou A-M. Initiative for molecular profiling and advanced cancer therapy and challenges in the implementation of precision medicine. Current Problems in Cancer.

Journal of Biotechnology. 2018;**23**:1. DOI: 10.22146/ijbiotech.28508

Diagnostics. 2017;**17**:1089-1096. DOI: 10.1080/14737159.2017.1395701

2017;**41**:176-181. DOI: 10.1016/j.currproblcancer.2017.02.002

pp. 31-48. DOI: 10.1007/978-3-319-49864-5\_3

018-0042-8


[23] Fachrul M, Utomo DH, Parikesit AA. lncRNA-based study of epigenetic regulations in diabetic peripheral neuropathy. Silico Pharmacology. 2018;**6**:7. DOI: 10.1007/s40203- 018-0042-8

(HDAC) in cervical cancer treatment. Arabian Journal of Chemistry. 2015;**1**:1-6. DOI:

[11] Prasasty VD, Tambunan USF, Siahaan TJ. Homology modeling and molecular dynamics studies of EC1 domain of VE-cadherin to elucidate docking interaction with cadherinderived peptide. OnLine Journal of Biological Sciences. 2014;**14**:155. DOI: 10.3844/

[12] Lengauer T, Sing T. Bioinformatics-assisted anti-HIV therapy. Nature Reviews. Micro-

[13] Spicer J. Technology evaluation: Nimotuzumab, the Center of Molecular Immunology/ YM BioSciences/Oncoscience. Current Opinion in Molecular Therapeutics. 2005;**7**: 182-191. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15844627 [Accessed:

[14] Chen Y, Shoichet BK. Molecular docking and ligand specificity in fragment-based inhibitor discovery. Nature Chemical Biology. 2009;**5**:358-364. DOI: 10.1038/nchembio.155 [15] Lee A, Lee K, Kim D. Using reverse docking for target identification and its applications for drug discovery. Expert Opinion on Drug Discovery. 2016;**11**:707-715. DOI:

[16] Lee M, Kim D. Large-scale reverse docking profiles and their applications, BMC

[17] Kharkar PS, Warrier S, Gaud RS. Reverse docking: A powerful tool for drug repositioning and drug rescue. Future Medicinal Chemistry. 2014;**6**:333-342. DOI: 10.4155/fmc.13.207

[18] Tafer H, Ameres SL, Obernosterer G, Gebeshuber CA, Schroeder R, Martinez J, Hofacker IL. The impact of target site accessibility on the design of effective siRNAs. Nature

[19] Prasasty VD, Krause ME, Tambunan USF, Anbanandam A, Laurence JS, Siahaan TJ. 1H, 13C and 15N backbone assignment of the EC-1 domain of human E-cadherin.

[20] Blondelle SE, Lohner K. Optimization and high-throughput screening of antimicrobial peptides. Current Pharmaceutical Design. 2010;**16**:3204-3211. Available form: http://

[21] Ferreon JC, Volk DE, Luxon BA, Gorenstein DG, Hilser VJ. Solution structure, dynamics, and thermodynamics of the native state ensemble of the Sem-5 C-terminal SH3 domain.

[22] Coimbatore Narayanan B, Westbrook J, Ghosh S, Petrov AI, Sweeney B, Zirbel CL, Leontis NB, Berman HM. The nucleic acid database: New features and capabilities.

Biomolecular NMR Assignments. 2015;**9**:31-35. DOI: 10.1007/s12104-013-9539-6

www.ncbi.nlm.nih.gov/pubmed/20687884 [Accessed: Mar 8, 2013]

Nucleic Acids Research. 2014;**42**:D114-D122. DOI: 10.1093/nar/gkt980

Biochemistry. 2003;**42**:5582-5591. DOI: 10.1021/bi030005j

Bioinformatics. 2012;**13**(Suppl 1):S6. DOI: 10.1186/1471-2105-13-s17-s6

Biotechnology. 2008;**26**:578-583. DOI: 10.1038/nbt1404

10.1016/j.arabjc.2015.07.010

10.1080/17460441.2016.1190706

biology. 2006;**4**:790-797. DOI: 10.1038/nrmicro1477

ojbsci.2014.155.162

6 Molecular Insight of Drug Design

May 4, 2018]


**Chapter 2**

**Provisional chapter**

**Frameworks for Evaluating Qualitative and**

**Frameworks for Evaluating Qualitative and** 

Kaori Nomura and Brian David Edwards

Kaori Nomura and Brian David Edwards

http://dx.doi.org/10.5772/intechopen.76331

**Abstract**

**1. Introduction**

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

**Quantitative Information on Adverse Drug Events**

**Quantitative Information on Adverse Drug Events** 

Significant public health issues caused by adverse drug reactions in the post-marketing phase, such as birth defects by thalidomide, have been well described. Unfortunately, subjects in clinical trials cannot completely avoid severe harm during drug development. TGN1412 in 2006 and BIA 10-2474 in 2016 were withdrawn from development due to severe adverse reactions in first-into-man studies. Thus, monitoring drug safety is important throughout all phases of development. In twenty-first century, minimizing drug development cost and time is a challenge for pharmaceutical companies. When a drug is approved with a smaller size and fewer number of clinical trials, pharmacovigilance and benefit-risk evaluation after marketing need to be sufficiently performed. Underpinned by understanding of the traditional methods of evaluating adverse drug reactions, new developments in IT and computing might well help us to detect drug safety signals earlier, enabling prompt intervention for protecting the rights of subjects and public health.

**Keywords:** risk management, pharmacovigilance, DSUR, PSUR, ADR, causality

A new drug application dossier, accompanied with the Common Technical Document (CTD), needs to provide a risk management plan, and a marketing authorization holder needs to set up both the policy framework and a quality system for pharmacovigilance. This approach has become more important and valuable in regulating drugs, because the novelty, rarity, or technical specificity of drugs produces complexities to evaluating efficacy and safety.

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

DOI: 10.5772/intechopen.76331

**throughout Development through to Marketing**

**throughout Development through to Marketing**

#### **Frameworks for Evaluating Qualitative and Quantitative Information on Adverse Drug Events throughout Development through to Marketing Frameworks for Evaluating Qualitative and Quantitative Information on Adverse Drug Events throughout Development through to Marketing**

DOI: 10.5772/intechopen.76331

Kaori Nomura and Brian David Edwards Kaori Nomura and Brian David Edwards

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.76331

#### **Abstract**

Significant public health issues caused by adverse drug reactions in the post-marketing phase, such as birth defects by thalidomide, have been well described. Unfortunately, subjects in clinical trials cannot completely avoid severe harm during drug development. TGN1412 in 2006 and BIA 10-2474 in 2016 were withdrawn from development due to severe adverse reactions in first-into-man studies. Thus, monitoring drug safety is important throughout all phases of development. In twenty-first century, minimizing drug development cost and time is a challenge for pharmaceutical companies. When a drug is approved with a smaller size and fewer number of clinical trials, pharmacovigilance and benefit-risk evaluation after marketing need to be sufficiently performed. Underpinned by understanding of the traditional methods of evaluating adverse drug reactions, new developments in IT and computing might well help us to detect drug safety signals earlier, enabling prompt intervention for protecting the rights of subjects and public health.

**Keywords:** risk management, pharmacovigilance, DSUR, PSUR, ADR, causality

#### **1. Introduction**

A new drug application dossier, accompanied with the Common Technical Document (CTD), needs to provide a risk management plan, and a marketing authorization holder needs to set up both the policy framework and a quality system for pharmacovigilance. This approach has become more important and valuable in regulating drugs, because the novelty, rarity, or technical specificity of drugs produces complexities to evaluating efficacy and safety.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Furthermore, in this decade, the risk-based approach for application has been proposed to address and evaluate potential risks associated with the clinical use of medicines, with regard to quality, safety, and efficacy. While the risk-based approach is to be differentiated from the risk management system or the benefit-risk assessment for evaluating marketing authorization, the idea is very close to it. This chapter introduces pharmacovigilance in the clinical development phase, especially with the aim of stimulating discussion about identification of risks associated with the clinical use of drugs qualitatively and quantitatively.

Although many new drugs implement a lifecycle risk management, another tragedy in clinical trial happened with a dose-finding study for BIA 10-2474, an experimental fatty acid amide hydrolase inhibitor for the treatment of anxiety disorder, Parkinson's disease, etc. An acute and rapid progressive neurologic syndrome developed on the fifth day of BIA 10-2474 administration (50 mg). The underlying mechanism of adverse drug reaction is still unknown regarding BIA 10-274, but it is supposed to be associated with drug accumulation as no clinical severe adverse events had been observed in single dose (0.25–100 mg) and 10-day admin-

Frameworks for Evaluating Qualitative and Quantitative Information on Adverse Drug Events…

http://dx.doi.org/10.5772/intechopen.76331

11

The stories addressed above are extreme examples. However, a number of drug development programmes have been abandoned because of safety concerns or lack of efficacy. As mentioned in ICH Good Clinical Practice (GCP) [4], "A trial should be initiated and continued only if the anticipated benefit justifies the risks." Thus, sponsors need to make sure that benefit for patients should overweigh risk to patients. Information sharing and a system for risk management throughout the lifecycle of drugs from preclinical, clinical, and post-marketing are crucial, and this is reflected in the development safety update report (DSUR) which had been proposed [5] and then taken forward by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) [6]. This emphasizes the importance of the principle of the benefit-risk balance, which is supported by

pharmacovigilance concepts which originally emerged in the post-marketing phase.

Drugs are approved based on the evidence of efficacy and acceptable level of harm that have been observed during clinical trials. Now, to tackle remaining unmet needs of patients globally, the regulatory schemes for supporting early access have been adopted, such as compassionate use, accelerated assessment by regulatory agencies, and conditional marketing authorization. If it is expected to have new medicines with conditional use, an applicant is allowed to provide comprehensive data after approval. Once such a new medicine is approved, definitely, there is little evidence of efficacy and safety in real-world practice, so that effective pharmacovigilance should produce the important data to supplement the evidence as well as cost savings for an applicant in the drug development. As we receive more applications of early access program, the more careful that we should be to pay attention with not to confusing "absence of evidence" with "evidence of absence" at approval. It is critical to detect precisely and promptly the harms potentially caused by an investigated drug (monitoring), to assess individual cases (qualitative evaluation) and comparative groups as planned (quantitative evaluation), and to finalize benefit-risk assessment at defined points in

How we can define "risk" then? According to the International Organization for Standardization, risk is the "effect of uncertainty on objectives" [7] and in terms of drug development, the objectives are patients' and public health. Another definition can be "combination of the probability of occurrence of harm and the severity of that harm" for medical devices and manufacturing medicinal products [8, 9]. As such, risks related to use of a drug is defined "any risk relating to the quality, safety or efficacy of the medicinal product as regards patients' health

**1.2. The latest strategy to promote marketing a new medicine**

istration (0.25–20 mg) [3].

time (**Figure 1**).

#### **1.1. What to do when any clinical safety problem happen in the development phase?**

Throughout the history, humans have used a variety of different therapies to treat injuries and diseases. During the nineteenth century, medicines were developed by separating, isolating, and extracting certain active ingredients from medicinal plants, e.g., morphine, quinine, and ephedrine. Then, in twentieth century, chemists discovered new chemicals, e.g., penicillin and streptomycin, from bacteria and synthesized better chemical substances of sulfonamides. In the first decades of twenty-first century, the development of drugs had been dramatically changed. Pharmaceuticals benefit from advances in all fields relating to medicine, e.g. pharmacology, physiology, and biochemistry, and were derived from synthetic compounds to target a certain site of action. For example, the progresses in medical science helped to reveal many of the mechanisms of the pathophysiological and pharmacological effects at the molecular level; for example, cimetidine and histamine-2 receptor blocker, which was a break through pharmacotherapy at that time for gastric ulcer. Molecular-targeted drugs now have been developed to treat various diseases, especially targeting specifically expressed molecules of cancer cells, e.g., imatinib.

Common to all pharmaceuticals is that they can bring both benefits and risks to humans. Thalidomide, which is now administered with dexamethasone to multiple myeloma patients, used to be first sold in West Germany as a sedative or hypnotic drug in 1950s, and then it was withdrawn from the market in 1961, because it was found to be responsible for teratogenic deformities in children based on reports of children of those mothers who took thalidomide during pregnancy. This tragedy was both a pre- and post-marketing landmark; countries recognized the need of adequate testing of medicines prior to marketing, the regulation of medicines, and the systems to identify the adverse effects of medicines as well as the potential relationship between marketing claims and safety [1, 2]. Because of the need for effective therapies in myeloma, thalidomide demonstrated sufficient benefit to achieve authorization and turned around the balance of benefit-risk from negative evaluation. This depended on effective risk minimization to prevent pregnancies in those who receive thalidomide.

International activities actively promoted regulations and empirical knowledge on clinical development in 1990s. However, in twenty-first century, one programme of an investigational medicinal product was withdrawn due to serious adverse reactions in the first-in-human clinical trial in 2006. This was known as TGN1412, a CD28 superagonist monoclonal antibody. Six volunteers were seriously afflicted by a cytokine-release syndrome requiring intensive care just after they received a bolus injection of TGN1412.

Although many new drugs implement a lifecycle risk management, another tragedy in clinical trial happened with a dose-finding study for BIA 10-2474, an experimental fatty acid amide hydrolase inhibitor for the treatment of anxiety disorder, Parkinson's disease, etc. An acute and rapid progressive neurologic syndrome developed on the fifth day of BIA 10-2474 administration (50 mg). The underlying mechanism of adverse drug reaction is still unknown regarding BIA 10-274, but it is supposed to be associated with drug accumulation as no clinical severe adverse events had been observed in single dose (0.25–100 mg) and 10-day administration (0.25–20 mg) [3].

The stories addressed above are extreme examples. However, a number of drug development programmes have been abandoned because of safety concerns or lack of efficacy. As mentioned in ICH Good Clinical Practice (GCP) [4], "A trial should be initiated and continued only if the anticipated benefit justifies the risks." Thus, sponsors need to make sure that benefit for patients should overweigh risk to patients. Information sharing and a system for risk management throughout the lifecycle of drugs from preclinical, clinical, and post-marketing are crucial, and this is reflected in the development safety update report (DSUR) which had been proposed [5] and then taken forward by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) [6]. This emphasizes the importance of the principle of the benefit-risk balance, which is supported by pharmacovigilance concepts which originally emerged in the post-marketing phase.

#### **1.2. The latest strategy to promote marketing a new medicine**

Furthermore, in this decade, the risk-based approach for application has been proposed to address and evaluate potential risks associated with the clinical use of medicines, with regard to quality, safety, and efficacy. While the risk-based approach is to be differentiated from the risk management system or the benefit-risk assessment for evaluating marketing authorization, the idea is very close to it. This chapter introduces pharmacovigilance in the clinical development phase, especially with the aim of stimulating discussion about identification of

Throughout the history, humans have used a variety of different therapies to treat injuries and diseases. During the nineteenth century, medicines were developed by separating, isolating, and extracting certain active ingredients from medicinal plants, e.g., morphine, quinine, and ephedrine. Then, in twentieth century, chemists discovered new chemicals, e.g., penicillin and streptomycin, from bacteria and synthesized better chemical substances of sulfonamides. In the first decades of twenty-first century, the development of drugs had been dramatically changed. Pharmaceuticals benefit from advances in all fields relating to medicine, e.g. pharmacology, physiology, and biochemistry, and were derived from synthetic compounds to target a certain site of action. For example, the progresses in medical science helped to reveal many of the mechanisms of the pathophysiological and pharmacological effects at the molecular level; for example, cimetidine and histamine-2 receptor blocker, which was a break through pharmacotherapy at that time for gastric ulcer. Molecular-targeted drugs now have been developed to treat various diseases, especially targeting specifically expressed

Common to all pharmaceuticals is that they can bring both benefits and risks to humans. Thalidomide, which is now administered with dexamethasone to multiple myeloma patients, used to be first sold in West Germany as a sedative or hypnotic drug in 1950s, and then it was withdrawn from the market in 1961, because it was found to be responsible for teratogenic deformities in children based on reports of children of those mothers who took thalidomide during pregnancy. This tragedy was both a pre- and post-marketing landmark; countries recognized the need of adequate testing of medicines prior to marketing, the regulation of medicines, and the systems to identify the adverse effects of medicines as well as the potential relationship between marketing claims and safety [1, 2]. Because of the need for effective therapies in myeloma, thalidomide demonstrated sufficient benefit to achieve authorization and turned around the balance of benefit-risk from negative evaluation. This depended on

effective risk minimization to prevent pregnancies in those who receive thalidomide.

International activities actively promoted regulations and empirical knowledge on clinical development in 1990s. However, in twenty-first century, one programme of an investigational medicinal product was withdrawn due to serious adverse reactions in the first-in-human clinical trial in 2006. This was known as TGN1412, a CD28 superagonist monoclonal antibody. Six volunteers were seriously afflicted by a cytokine-release syndrome requiring intensive care

risks associated with the clinical use of drugs qualitatively and quantitatively.

**1.1. What to do when any clinical safety problem happen in the development** 

**phase?**

10 Molecular Insight of Drug Design

molecules of cancer cells, e.g., imatinib.

just after they received a bolus injection of TGN1412.

Drugs are approved based on the evidence of efficacy and acceptable level of harm that have been observed during clinical trials. Now, to tackle remaining unmet needs of patients globally, the regulatory schemes for supporting early access have been adopted, such as compassionate use, accelerated assessment by regulatory agencies, and conditional marketing authorization. If it is expected to have new medicines with conditional use, an applicant is allowed to provide comprehensive data after approval. Once such a new medicine is approved, definitely, there is little evidence of efficacy and safety in real-world practice, so that effective pharmacovigilance should produce the important data to supplement the evidence as well as cost savings for an applicant in the drug development. As we receive more applications of early access program, the more careful that we should be to pay attention with not to confusing "absence of evidence" with "evidence of absence" at approval. It is critical to detect precisely and promptly the harms potentially caused by an investigated drug (monitoring), to assess individual cases (qualitative evaluation) and comparative groups as planned (quantitative evaluation), and to finalize benefit-risk assessment at defined points in time (**Figure 1**).

How we can define "risk" then? According to the International Organization for Standardization, risk is the "effect of uncertainty on objectives" [7] and in terms of drug development, the objectives are patients' and public health. Another definition can be "combination of the probability of occurrence of harm and the severity of that harm" for medical devices and manufacturing medicinal products [8, 9]. As such, risks related to use of a drug is defined "any risk relating to the quality, safety or efficacy of the medicinal product as regards patients' health

biased under restrictions of subjects' health background. As with post-marketing data collection, the data collection method is an essential element of the pharmacovigilance process during clinical trial with proper data collection to enable analysis of medical interpretation of the case narrative and the aggregated data. Evaluation of case information obtained in clinical trials is possible by use of the approaches cultivated in pharmacovigilance over years of experience.

Frameworks for Evaluating Qualitative and Quantitative Information on Adverse Drug Events…

http://dx.doi.org/10.5772/intechopen.76331

13

It is commonly known that not all hazards can be found before a drug is marketed. Pharmacovigilance is the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other possible drug-related problems [12]. It is now also more involved in pre-approval drug assessment as well-designated clinical trials in phase IV, referred to "the clinical safety activities throughout the lifecycle of a medicinal product" [13]. Drugs at approval have limited clinical information from clinical trials. For example, 16,000 subjects are needed to receive a drug to detect one adverse drug event out of 10,000 people with 80% probability, while clinical trials for most new drugs are conducted with 2000–3000 patients prior to approval. Therefore, rare adverse drug reactions are hardly detected, although relatively common adverse drug reactions (ADRs) are identified. Patients with complex conditions are excluded in order to eliminate factors that may affect efficacy of a tested drug. Most, but not all, ADRs occur in rather short time after administration. The short duration of observation, for example, 1 year or less in clinical trials is another limitation that will not observe late-onset ADRs. CIOMS VI [13] would help readers understand systematic approach for safety management during clinical development. Missing information at approval concerning clinical safety often refers to use in children, elderly, kidney disorders, drugs for oncology, HIV, vaccines, biologicals, and other advanced drugs as they will all mostly have a comparatively small number of subjects. All those limitations are to be addressed in pharmacovigilance plan for post-marketing. Clinical trials need to be monitored by the Data and Safety Monitoring Boards (DSMBs), also known as Data Monitoring Committees (DMC), who periodically review and evaluate the accumulated data from one or multiple clinical trials for safety of trial subjects. After DSMB evaluation, apparently obvious favorable or unfavorable results in the treatment group will lead to recommendations to discontinue a trial for the reason of negative benefit-risk in the treatment of the control group. However, the benefit-risk assessment continues throughout the drug development

**2.1. Characteristics of pharmacovigilance in clinical trials**

**2.2. Hazard data collection: planning and practical realization**

Although there are regulatory systems for both pre- and post-marketing individual case safety reports (ICSRs), the concept of cases to be reported is somewhat different between pre and post. After marketing, it is rather appropriate to pay more attention to unknown serious adverse reactions than known or non-serious ADRs, although the latter can provide useful supporting information about risk factors and nature of known ADRs. Clinical trials explore unknown properties and use of a medicine, and so taking ethics into account, all adverse events (AEs) must be collected and in addition, serious and unexpected adverse events are

lifecycle.

subject to expedited reporting.

**Figure 1.** Drug development process and clinical data review. The figure is arranged and restructured from some of slides provided with the kind permission of the Product Safety Culture Initiative in the Alliance for Clinical Research Excellence and Safety.

or public health and any risk of undesirable effects on the environment" [10]. In traditional pharmacovigilance, the concept of risk concerns adverse drug reactions [11], as described later, however EU regulations now emphasize that it is as been expanded to include ineffective use outside the label, misuse and abuse. In reality for pharmacovigilance, we propose to bear in mind other systematic factors impacting risks of medicines as well (such as facilities, procedures, computerized systems) that may cause medication errors. Those risks cannot be evaluated enough in drug development, therefore the plan is necessary to continue vigilance once marketed and take action once a potential harm is identified. Thus pharmacovigilance has become even more important to manage various safety problems with these new rapid access regulatory approvals.

Risk management encompasses "risk assessment" and "risk minimization" with the management cycle to assess, implement, evaluate, and modify safety measures; the former is to identify and characterize the nature, frequency, and severity of the risks associated with the use of a product, as focused in this chapter; the latter is to minimize or mitigate a product's risks through communication, education, and restriction of use while preserving its benefit.

#### **2. Pharmacovigilance in clinical trials**

Data obtained from clinical trials vary depending on the situation of an investigational substance and those are different from post-marketing data; the patient being administered can be perfectly observed, the number of patients is small, and the information on subjects can be biased under restrictions of subjects' health background. As with post-marketing data collection, the data collection method is an essential element of the pharmacovigilance process during clinical trial with proper data collection to enable analysis of medical interpretation of the case narrative and the aggregated data. Evaluation of case information obtained in clinical trials is possible by use of the approaches cultivated in pharmacovigilance over years of experience.

#### **2.1. Characteristics of pharmacovigilance in clinical trials**

or public health and any risk of undesirable effects on the environment" [10]. In traditional pharmacovigilance, the concept of risk concerns adverse drug reactions [11], as described later, however EU regulations now emphasize that it is as been expanded to include ineffective use outside the label, misuse and abuse. In reality for pharmacovigilance, we propose to bear in mind other systematic factors impacting risks of medicines as well (such as facilities, procedures, computerized systems) that may cause medication errors. Those risks cannot be evaluated enough in drug development, therefore the plan is necessary to continue vigilance once marketed and take action once a potential harm is identified. Thus pharmacovigilance has become even more important to manage various safety problems with these new rapid access

**Figure 1.** Drug development process and clinical data review. The figure is arranged and restructured from some of slides provided with the kind permission of the Product Safety Culture Initiative in the Alliance for Clinical Research

Risk management encompasses "risk assessment" and "risk minimization" with the management cycle to assess, implement, evaluate, and modify safety measures; the former is to identify and characterize the nature, frequency, and severity of the risks associated with the use of a product, as focused in this chapter; the latter is to minimize or mitigate a product's risks through communication, education, and restriction of use while preserving its benefit.

Data obtained from clinical trials vary depending on the situation of an investigational substance and those are different from post-marketing data; the patient being administered can be perfectly observed, the number of patients is small, and the information on subjects can be

regulatory approvals.

Excellence and Safety.

12 Molecular Insight of Drug Design

**2. Pharmacovigilance in clinical trials**

It is commonly known that not all hazards can be found before a drug is marketed. Pharmacovigilance is the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other possible drug-related problems [12]. It is now also more involved in pre-approval drug assessment as well-designated clinical trials in phase IV, referred to "the clinical safety activities throughout the lifecycle of a medicinal product" [13]. Drugs at approval have limited clinical information from clinical trials. For example, 16,000 subjects are needed to receive a drug to detect one adverse drug event out of 10,000 people with 80% probability, while clinical trials for most new drugs are conducted with 2000–3000 patients prior to approval. Therefore, rare adverse drug reactions are hardly detected, although relatively common adverse drug reactions (ADRs) are identified. Patients with complex conditions are excluded in order to eliminate factors that may affect efficacy of a tested drug. Most, but not all, ADRs occur in rather short time after administration. The short duration of observation, for example, 1 year or less in clinical trials is another limitation that will not observe late-onset ADRs. CIOMS VI [13] would help readers understand systematic approach for safety management during clinical development. Missing information at approval concerning clinical safety often refers to use in children, elderly, kidney disorders, drugs for oncology, HIV, vaccines, biologicals, and other advanced drugs as they will all mostly have a comparatively small number of subjects. All those limitations are to be addressed in pharmacovigilance plan for post-marketing. Clinical trials need to be monitored by the Data and Safety Monitoring Boards (DSMBs), also known as Data Monitoring Committees (DMC), who periodically review and evaluate the accumulated data from one or multiple clinical trials for safety of trial subjects. After DSMB evaluation, apparently obvious favorable or unfavorable results in the treatment group will lead to recommendations to discontinue a trial for the reason of negative benefit-risk in the treatment of the control group. However, the benefit-risk assessment continues throughout the drug development lifecycle.

#### **2.2. Hazard data collection: planning and practical realization**

Although there are regulatory systems for both pre- and post-marketing individual case safety reports (ICSRs), the concept of cases to be reported is somewhat different between pre and post. After marketing, it is rather appropriate to pay more attention to unknown serious adverse reactions than known or non-serious ADRs, although the latter can provide useful supporting information about risk factors and nature of known ADRs. Clinical trials explore unknown properties and use of a medicine, and so taking ethics into account, all adverse events (AEs) must be collected and in addition, serious and unexpected adverse events are subject to expedited reporting.

All serious adverse events must be assessed regardless of causality by the applicant at the time of application submission. Furthermore, what kind of AE data can be collected in the development phase depends on the clinical evaluation stage in the development process in which the investigational drug is as described in the protocol. The judgment as to whether a case is expected (known) or unexpected (unknown) is based on the labeling of the marketed drug, while in clinical trials, the reference safety information in the investigator's brochure is used. It is necessary for clinical trial sponsors to update the investigator's brochure at any time as needed, and the latest reference safety information receives close regulatory attention to ensure it is up to date for the judgment of known/unknown (or listed/unlisted) cases.

dropped out from a trial. A protocol needs to specify testing intervals and thresholds for evaluating data later. Discordance of coding interpreted from collected data will cause both false positives and false negatives. Issues of coding, if left unresolved, will worsen with mul-

Frameworks for Evaluating Qualitative and Quantitative Information on Adverse Drug Events…

http://dx.doi.org/10.5772/intechopen.76331

15

How data are presented influences the impression that an assessor would have. An appropriate approach should be selected among many options such as tables with strata according to, for example, dosage, duration of treatment with scatter plots for clinical chemical data, Kaplan-Meier plots for cumulative hazard clinical chemical data and outcome evaluation,

It is important to gain an understanding of the safety profile of a drug as early and as much as possible during development as possible as risks can be more easily controlled. Once the efficacy is proven at the end of clinical development, the benefit-risk profile of the drug is reviewed whether it is acceptable for approval. Both medical judgment (qualitative) and statistics including descriptive and inferential approach (quantitative) influence the evaluation of clinical safety during drug development. The same principles apply to post-marketing evaluation. It is more likely, however, that safety signal detection and assessment during clinical development depend as much on clinical judgment with case reports, especially for serious rare AEs. Such an approach is reasonable and necessary for small-size trials, since data accumulation is limited due to the small number of subjects. With accumulated data, statistical methods are possibly available for the evaluation of safety signals in clinical trials, especially for more commonly occurring adverse events, and it is certainly a practical option to use a database for the phase IV studies especially after conditional approval has been granted. Any approaches need to consider patient population characteristics including natural history of disease and current therapeutic standards for comparison, when evaluating safety. Safety evaluation is the basis of risk assessment as a whole, and it is required to report an unusual or worrying ICSR, especially for AE of special interest, routinely anytime and when a certain

Risk assessment as a part of pharmacovigilance in drug development requires analyzing and interpreting the safety profile. After risk assessment, investigator's brochure may be updated and risk management measures may be taken to minimize the risks, if necessary and medically significant. From perspectives of public health, risk assessment and decision-making

Although the clinical efficacy is steadily and iteratively demonstrated through phase I, II, and III, and then confirmed at the end of development, serious harm can occur at any stage of drug development. Thus pharmacovigilance in drug development may be more of a riskbased approach relating to any other drug-related issues that could affect patient safety and safe use of drug, including concerns about quality and efficacy as well as safety. In this sense, pharmacovigilance is consistent with a "risk-based approach" which to some extent can be

should be done at the right time rather to wait for punctual dataset for review.

ticenter research which will provide aggregate data for quantitative analysis.

evaluation milestone is reached such as with DSUR submissions.

found in regulatory guidances recently [15–17].

and so on.

**2.3. Safety profile and risk assessment**

In addition, since many of post-marketing ICSRs are spontaneous reports, there is a vast range in the quality of the information from rich cases to poor cases (e.g., age/gender, drug, and adverse event are minimum requirements for regulatory reporting), mostly without laboratory results and the exact size of the exposed population is unknown. Since laboratory test values of participants in a clinical trial are regularly collected, assessment of individual case safe report, described later in this chapter, should effectively utilize theses results for each subject as well as the corresponding case narratives. Clinical trials have detailed information on cases such as the AE development date and dose (details of which are often missing in post-marketing ICSRs) and the size of population is known, so it is possible to calculate the frequency of occurrence and the incidence of AE. Of course, efficacy is statistically evaluated in a prospective statistical analysis plan. Various designs of clinical investigation are available, not only clinical trials for the development of new drugs but also that for the extension of indication of existing drugs, development of new routes of administration, and changes in dosage regimen.

As regard to data collection of safety information in clinical trials, the Good Clinical Practice guideline [6] does not address details of standards for the types of data to be collected for safety monitoring although traditionally reliance has been placed mainly on AE case reporting to the regulatory agencies. While another guideline, ICH E2A [14], specify only the key data elements for inclusion in expedited reports of serious unexpected adverse drug reactions, it is prudent to collect more comprehensive safety data during development because poorly established safety profiles need to be clarified in greater detail with the collection of non-serious adverse events and essential laboratory data. Therefore, the study protocols should be well designed defining the data to be collected, which differs according to characteristics of a drug.

When collecting data, sponsors may prepare different procedures for targeted or untargeted AE detection. However, the methods are commonly used in the same manner such as questionnaires, patient diary cards, and medical records supplemented with serious adverse event (SAE) reporting forms. Safety outcomes can be presented using descriptive text or visual analogue scales for severity rating, based on subjective opinion, of adverse events during investigation, pre-, during-, and post-trial, since a participant was enrolled. Patients' opinions may not be scientifically presented, but an understanding of benefit and risk and impact of an AE on quality of life, thereby revitalizing patient-focused drug development, can be elaborated. Narratives are important information for in-depth investigation of suspected unexpected serious adverse drug reactions (SUSARs) and to understand the reasons why a participant has dropped out from a trial. A protocol needs to specify testing intervals and thresholds for evaluating data later. Discordance of coding interpreted from collected data will cause both false positives and false negatives. Issues of coding, if left unresolved, will worsen with multicenter research which will provide aggregate data for quantitative analysis.

How data are presented influences the impression that an assessor would have. An appropriate approach should be selected among many options such as tables with strata according to, for example, dosage, duration of treatment with scatter plots for clinical chemical data, Kaplan-Meier plots for cumulative hazard clinical chemical data and outcome evaluation, and so on.

#### **2.3. Safety profile and risk assessment**

All serious adverse events must be assessed regardless of causality by the applicant at the time of application submission. Furthermore, what kind of AE data can be collected in the development phase depends on the clinical evaluation stage in the development process in which the investigational drug is as described in the protocol. The judgment as to whether a case is expected (known) or unexpected (unknown) is based on the labeling of the marketed drug, while in clinical trials, the reference safety information in the investigator's brochure is used. It is necessary for clinical trial sponsors to update the investigator's brochure at any time as needed, and the latest reference safety information receives close regulatory attention to ensure it is up to date for the judgment of known/unknown (or listed/unlisted) cases.

In addition, since many of post-marketing ICSRs are spontaneous reports, there is a vast range in the quality of the information from rich cases to poor cases (e.g., age/gender, drug, and adverse event are minimum requirements for regulatory reporting), mostly without laboratory results and the exact size of the exposed population is unknown. Since laboratory test values of participants in a clinical trial are regularly collected, assessment of individual case safe report, described later in this chapter, should effectively utilize theses results for each subject as well as the corresponding case narratives. Clinical trials have detailed information on cases such as the AE development date and dose (details of which are often missing in post-marketing ICSRs) and the size of population is known, so it is possible to calculate the frequency of occurrence and the incidence of AE. Of course, efficacy is statistically evaluated in a prospective statistical analysis plan. Various designs of clinical investigation are available, not only clinical trials for the development of new drugs but also that for the extension of indication of existing drugs, development of new routes of administration, and changes in

As regard to data collection of safety information in clinical trials, the Good Clinical Practice guideline [6] does not address details of standards for the types of data to be collected for safety monitoring although traditionally reliance has been placed mainly on AE case reporting to the regulatory agencies. While another guideline, ICH E2A [14], specify only the key data elements for inclusion in expedited reports of serious unexpected adverse drug reactions, it is prudent to collect more comprehensive safety data during development because poorly established safety profiles need to be clarified in greater detail with the collection of non-serious adverse events and essential laboratory data. Therefore, the study protocols should be well designed defining the data to be collected, which differs according to characteristics of a drug. When collecting data, sponsors may prepare different procedures for targeted or untargeted AE detection. However, the methods are commonly used in the same manner such as questionnaires, patient diary cards, and medical records supplemented with serious adverse event (SAE) reporting forms. Safety outcomes can be presented using descriptive text or visual analogue scales for severity rating, based on subjective opinion, of adverse events during investigation, pre-, during-, and post-trial, since a participant was enrolled. Patients' opinions may not be scientifically presented, but an understanding of benefit and risk and impact of an AE on quality of life, thereby revitalizing patient-focused drug development, can be elaborated. Narratives are important information for in-depth investigation of suspected unexpected serious adverse drug reactions (SUSARs) and to understand the reasons why a participant has

dosage regimen.

14 Molecular Insight of Drug Design

It is important to gain an understanding of the safety profile of a drug as early and as much as possible during development as possible as risks can be more easily controlled. Once the efficacy is proven at the end of clinical development, the benefit-risk profile of the drug is reviewed whether it is acceptable for approval. Both medical judgment (qualitative) and statistics including descriptive and inferential approach (quantitative) influence the evaluation of clinical safety during drug development. The same principles apply to post-marketing evaluation. It is more likely, however, that safety signal detection and assessment during clinical development depend as much on clinical judgment with case reports, especially for serious rare AEs. Such an approach is reasonable and necessary for small-size trials, since data accumulation is limited due to the small number of subjects. With accumulated data, statistical methods are possibly available for the evaluation of safety signals in clinical trials, especially for more commonly occurring adverse events, and it is certainly a practical option to use a database for the phase IV studies especially after conditional approval has been granted. Any approaches need to consider patient population characteristics including natural history of disease and current therapeutic standards for comparison, when evaluating safety. Safety evaluation is the basis of risk assessment as a whole, and it is required to report an unusual or worrying ICSR, especially for AE of special interest, routinely anytime and when a certain evaluation milestone is reached such as with DSUR submissions.

Risk assessment as a part of pharmacovigilance in drug development requires analyzing and interpreting the safety profile. After risk assessment, investigator's brochure may be updated and risk management measures may be taken to minimize the risks, if necessary and medically significant. From perspectives of public health, risk assessment and decision-making should be done at the right time rather to wait for punctual dataset for review.

Although the clinical efficacy is steadily and iteratively demonstrated through phase I, II, and III, and then confirmed at the end of development, serious harm can occur at any stage of drug development. Thus pharmacovigilance in drug development may be more of a riskbased approach relating to any other drug-related issues that could affect patient safety and safe use of drug, including concerns about quality and efficacy as well as safety. In this sense, pharmacovigilance is consistent with a "risk-based approach" which to some extent can be found in regulatory guidances recently [15–17].

## **3. What can be done for "evaluating benefit-risk balance"?**

Many methods have been proposed and each of them gives us thoughts to some extent. So, do we need to apply all to our daily work? Those evaluation methods have been reviewed in terms of usefulness in benefit-risk assessment and reported by the European Medicines Agency, suggesting three quantitative methods for regulatory assessment use, Bayesian statistics, Decision trees and influence/relevance diagrams and Multi-criteria analyses, as well as qualitative approach [18]. They also pointed out some limitations, for example, Bayesian statistical model do not generally deal with multiple criteria, and some other approaches such as conjoint analysis may contribute to some specific cases. An assessment process, which includes many dimensions of public health to consider, will be enforced by the integration of methods/approaches. Authors make the point that quantitative methods/approaches are effectively adopted in practice only when a qualitative approach works.

Toward the end of development, all data pooled through clinical trials are reviewed. This may require meta-analysis of individual data of clinical trials as well as meta-analysis of published studies as well. It has been reported that no significant difference exists between metaanalysis of published data and of individual data, and using published data is still considered the norm [19]. From different studies, there needs to be a pooling of numerators (e.g., number of affected patients) and denominators (e.g., number of patients or patient years) for ADR frequency estimation; frequency expression as "number needed to treat to harm," pooling of

Frameworks for Evaluating Qualitative and Quantitative Information on Adverse Drug Events…

http://dx.doi.org/10.5772/intechopen.76331

17

After AE assessment, if necessary, a sponsor should update the investigator's brochure and continue developing the labeling and future surveillance plan. Accordingly, Core Safety Information of an investigator's brochure should be based on the Company Core Safety Information, which in turn will be transferred to the Summary of Product Characteristics. To extend development, phase IV studies are possible, for example, with registers for longterm follow-up, observational studies for safety in clinical setting or using the large clinical

Many algorithms and classification systems on causality have been proposed; however, none has been agreed and accepted by everyone. In recent years, it has been questioned whether it is worthwhile to spend much effort conducting causality assessment on individual suspected ADR reports. The reason why is that ICSRs are considered relatively weaker as an evidence for causality than compared to the frequency of events in the actively treated group with that of the comparative control group. If randomized controlled trials found significant differences with appropriate statistical power, it is likely that pharmacotherapy was the cause of event, that is, the medicinal product directly caused the event under certain conditions of use. It is important to ensure robustness and objectivity of the trial is preserved by blinding (as qualitative assessment of unblinded data is considered subjective). But can even the best conduct clinical trials replace spontaneous reporting? Clinical trials from the early development phase to phase IV cannot replace spontaneous ADR reporting systems for detecting very rare ADRs, and it is not realistic to conduct a large-scale epidemiological survey/study for each new drug. Large databases may consider a signal such a rare ADR as noise and so it may be missed. Therefore, even though information technology has evolved, it remains important to evaluate causal relationship qualitatively on ICSRs individually, using medical inference, taking into account the widely different circumstances in which they arise ranging from clinical

As a tool to assist qualitative evaluation, A to F ADR classes have been proposed and extended since the 1970s. It addresses the characteristics of how to categorize ADRs pharmacologically: Type A—augmented; Type B—bizarre; Type C—chronic; Type D—delayed; Type E—end of

In addition, the DoTS classification considering dose, time, and susceptibility was also proposed from the viewpoint of elements that are thought to affect how side effects become

within-study and between-treatment group differences.

database.

**3.2. Qualitative data: case narrative**

trials, registries, to spontaneous reports.

use; and Type F—failure of therapy [20, 21].

#### **3.1. Basic processes of adverse event evaluation**

The identification of a potential safety issue for a drug requires processes to distinguish adverse reactions from unrelated adverse events. These cases can be found in reports submitted to regulatory authorities or published articles/posts through journals, media and even through social media and Internet. As a basic reference for risk assessment, the evaluation result of each individual case of suspected ADRs, as well as adverse events, is important because even one ADR case can be sufficient by evidence itself of a risk serious enough to stop a clinical trial. Therefore, the first step of the process is the assessment of individual case observations, and the difficulties of causality assessment are addressed further in the next Section 3.2. Case evaluation needs to consider clinical significance, seriousness, severity (continuous variables), and expectedness based on the latest investigator's brochure, causality, place and time of occurrence, dosage, and predisposing factors of trial subject. AEs based on laboratory data need to be interpreted as to whether they are of value as surrogate markers, whether testing intervals are adequate and whether such surrogate markers can be correlated with or help predict harmful endpoints.

Detection of specific ADRs as harmful properties of a medicine itself has an obvious purpose. These can be grouped or aggregate cases with features in common or a case series where the number of cases, individual causalities, inter-case consistency, and severity/seriousness can all be assessed. Plausibility of causal relationship between a drug and event can be discussed on the ground of causal assessment of each case or of a group of cases as an aggregate.

The next stage for attributing causality is to review the statistical quantification of safety data from individual studies. Biostatisticians can prepare and present data with tables and graphics as well as quantities of continuous/discrete variables. Points to consider include epidemiological morbidity and subjects' background data (bias and confounders), investigational comparators, randomization or not, primary/secondary/surrogate endpoint, dropouts and missing data, and data dependency on dose and time (hazard function). All aspects of statistical testing may play a critical role when applying a statistical analysis plan: types of test, probability threshold (p-level), adjustment for multiple testing and confounders, power of test, and confident intervals.

Toward the end of development, all data pooled through clinical trials are reviewed. This may require meta-analysis of individual data of clinical trials as well as meta-analysis of published studies as well. It has been reported that no significant difference exists between metaanalysis of published data and of individual data, and using published data is still considered the norm [19]. From different studies, there needs to be a pooling of numerators (e.g., number of affected patients) and denominators (e.g., number of patients or patient years) for ADR frequency estimation; frequency expression as "number needed to treat to harm," pooling of within-study and between-treatment group differences.

After AE assessment, if necessary, a sponsor should update the investigator's brochure and continue developing the labeling and future surveillance plan. Accordingly, Core Safety Information of an investigator's brochure should be based on the Company Core Safety Information, which in turn will be transferred to the Summary of Product Characteristics. To extend development, phase IV studies are possible, for example, with registers for longterm follow-up, observational studies for safety in clinical setting or using the large clinical database.

#### **3.2. Qualitative data: case narrative**

**3. What can be done for "evaluating benefit-risk balance"?**

effectively adopted in practice only when a qualitative approach works.

**3.1. Basic processes of adverse event evaluation**

16 Molecular Insight of Drug Design

Many methods have been proposed and each of them gives us thoughts to some extent. So, do we need to apply all to our daily work? Those evaluation methods have been reviewed in terms of usefulness in benefit-risk assessment and reported by the European Medicines Agency, suggesting three quantitative methods for regulatory assessment use, Bayesian statistics, Decision trees and influence/relevance diagrams and Multi-criteria analyses, as well as qualitative approach [18]. They also pointed out some limitations, for example, Bayesian statistical model do not generally deal with multiple criteria, and some other approaches such as conjoint analysis may contribute to some specific cases. An assessment process, which includes many dimensions of public health to consider, will be enforced by the integration of methods/approaches. Authors make the point that quantitative methods/approaches are

The identification of a potential safety issue for a drug requires processes to distinguish adverse reactions from unrelated adverse events. These cases can be found in reports submitted to regulatory authorities or published articles/posts through journals, media and even through social media and Internet. As a basic reference for risk assessment, the evaluation result of each individual case of suspected ADRs, as well as adverse events, is important because even one ADR case can be sufficient by evidence itself of a risk serious enough to stop a clinical trial. Therefore, the first step of the process is the assessment of individual case observations, and the difficulties of causality assessment are addressed further in the next Section 3.2. Case evaluation needs to consider clinical significance, seriousness, severity (continuous variables), and expectedness based on the latest investigator's brochure, causality, place and time of occurrence, dosage, and predisposing factors of trial subject. AEs based on laboratory data need to be interpreted as to whether they are of value as surrogate markers, whether testing intervals are adequate and whether such surrogate markers can be correlated with or help predict harmful endpoints. Detection of specific ADRs as harmful properties of a medicine itself has an obvious purpose. These can be grouped or aggregate cases with features in common or a case series where the number of cases, individual causalities, inter-case consistency, and severity/seriousness can all be assessed. Plausibility of causal relationship between a drug and event can be discussed on the ground of causal assessment of each case or of a group of cases as an aggregate.

The next stage for attributing causality is to review the statistical quantification of safety data from individual studies. Biostatisticians can prepare and present data with tables and graphics as well as quantities of continuous/discrete variables. Points to consider include epidemiological morbidity and subjects' background data (bias and confounders), investigational comparators, randomization or not, primary/secondary/surrogate endpoint, dropouts and missing data, and data dependency on dose and time (hazard function). All aspects of statistical testing may play a critical role when applying a statistical analysis plan: types of test, probability threshold (p-level),

adjustment for multiple testing and confounders, power of test, and confident intervals.

Many algorithms and classification systems on causality have been proposed; however, none has been agreed and accepted by everyone. In recent years, it has been questioned whether it is worthwhile to spend much effort conducting causality assessment on individual suspected ADR reports. The reason why is that ICSRs are considered relatively weaker as an evidence for causality than compared to the frequency of events in the actively treated group with that of the comparative control group. If randomized controlled trials found significant differences with appropriate statistical power, it is likely that pharmacotherapy was the cause of event, that is, the medicinal product directly caused the event under certain conditions of use. It is important to ensure robustness and objectivity of the trial is preserved by blinding (as qualitative assessment of unblinded data is considered subjective). But can even the best conduct clinical trials replace spontaneous reporting? Clinical trials from the early development phase to phase IV cannot replace spontaneous ADR reporting systems for detecting very rare ADRs, and it is not realistic to conduct a large-scale epidemiological survey/study for each new drug. Large databases may consider a signal such a rare ADR as noise and so it may be missed. Therefore, even though information technology has evolved, it remains important to evaluate causal relationship qualitatively on ICSRs individually, using medical inference, taking into account the widely different circumstances in which they arise ranging from clinical trials, registries, to spontaneous reports.

As a tool to assist qualitative evaluation, A to F ADR classes have been proposed and extended since the 1970s. It addresses the characteristics of how to categorize ADRs pharmacologically: Type A—augmented; Type B—bizarre; Type C—chronic; Type D—delayed; Type E—end of use; and Type F—failure of therapy [20, 21].

In addition, the DoTS classification considering dose, time, and susceptibility was also proposed from the viewpoint of elements that are thought to affect how side effects become manifested rather than the pathology of side effects in isolation (**Table 1**). [21] The authors recognize absorption/distribution/metabolism/elimination to be included as susceptibility factors and, in addition, propose to consider these factors as contributing to medication error (contribution of human factors and other causal and predisposing factors).

**3.3. Quantitative data: statistical approach**

handle enormous amounts of data.

**medicine's properties and potential**

Statistics are widely used in the drug development as "biostatistics" to validate the efficiency of investigational products entity. What about the application of statistics to assess safety?

Frameworks for Evaluating Qualitative and Quantitative Information on Adverse Drug Events…

http://dx.doi.org/10.5772/intechopen.76331

19

In the mid-1980s, the term "pharmacoepidemiology" was used for the first time, which often refers to the academic field of study, drug use and safety on a group level. As you can imagine from the phrase "epidemiology," the "group of subjects" or "population" studied by pharmacoepidemiology is a larger patient group than that of the clinical trial numbering up to tens of thousands or even an entire national population. This academic field has greatly expanded in the 1990s which is underpinned by the increased use of computerized databases including prescription records and clinical outcomes to investigate safety issues quickly and efficiently, as well as sophisticated computer technology, which enables high-enough performance to

More recently, the design of pharmacoepidemiologic studies has turned to using big data. No matter the size of study subjects, the most challenging aspect of pharmacoepidemiology is its research design as with clinical trials. The place of "chance" that may lead statistically significant difference, "Bias" by systematic error, and "Confounding" as a third factor associated with both drugs and events, all may contribute to a direct association between drugs and events, which should be considered when designing the research plan and considering their results. Studies on drug safety are often performed further in the post-marketing phase observationally. Because, a double-blind trial to verify whether a serious adverse event will occur to a patient can be ethically dubious as patients cannot be denied an approved effective medicine, and in order to mitigate weakness and strengthen observational studies, pharmacoepidemiological researches inevitably consider new designs. In this academic domain, study designs and statistical techniques have been evolved, such as self-controlled case series, new user design, etc., handling bias and confounding that are classic and common in cohort and case-control studies. Frequently used study designs in pharmacoepidemiology are described

New designs seem to be developed and used mainly for retrospective observational database studies. For the question of interest, there is still needs to conduct a traditional epidemiological study design for post-approval, phase IV study. As with the example of Brigham and Women's Hospital epidemiological studies, it may be necessary to plan for a cohort study to assemble from the beginning of development. Recently, many large-scale databases are becoming available and it is prudent to first make use of them. When choosing a database, you should make sure that prescription records, event data, and health-related information, such as gender and age, are available. If you can reconcile patient ID, separate databases may

Based on the principle of ICH E2E, risk management plans have become a part of a new drug approval document to be submitted to the regulatory authorities in many countries/regions.

further in the regulatory guidelines and the academic proposals [27–29].

be combined. However, this requires epidemiological knowledge and experience.

**3.4. Much to do in the post-marketing phase to fully develop and define a** 

WHO-Uppsala Monitoring Center advises that evaluation of causality can be categorized into six stages, such as certain, probable, possible, unlikely, conditional/unclassified, and unassessable/unclassifiable [22], and for that the following major four aspects are to be considered [23]. (1) temporal relationships: What is the temporal relationship between treatment initiation and the beginning of the event? How has the event changed after discontinuing treatment? (negative dechallenge) Did it recur after re-administration? (positive rechallenge) (2) Alternative causes: Have there been exposure factors other than complications, concomitant medications, or medicines that can explain the event occurrence? (3) Nature of the event: Some clinical events are often caused immediately by drugs (e.g., swelling in injection site). (4) Plausibility: Is the reaction already recognized by this medicine? (Is it a known side effect with this class?) Can the explanation for mechanism of event be derived from its known pharmacological action?

As a more specific evaluation criterion, nine criteria by Hill [24] and a number of scoring algorithms such as that devised by Naranjo et al. [25] can be used and applied to as part of causality assessment. Effective use of all these causality techniques requires practical knowledge about how to blend clinical, medical, and pharmacological sciences, which it means it is necessary to have suitably qualified persons with such knowledge actively leading and involved in the assessment team. Behavioral competencies for effective performance in pharmacovigilance have been discussed elsewhere [26].

As will be described later, it is not uncommon for elucidation of the mechanism of the development of ADR after many years following new drug approval often linked to advances in in scientific technology and research. Benefit-risk assessment that involves scientific review should be considered as standard operational procedures with structured framework to achieve feasible decision-making. However, as there are no perfect causality criteria, we should always bear in mind and not ignore clinical significant events regardless of causality unless there is overwhelming evidence of other causal factors which are obvious.


**Table 1.** DoTS classification of adverse drug reaction.

#### **3.3. Quantitative data: statistical approach**

manifested rather than the pathology of side effects in isolation (**Table 1**). [21] The authors recognize absorption/distribution/metabolism/elimination to be included as susceptibility factors and, in addition, propose to consider these factors as contributing to medication error

WHO-Uppsala Monitoring Center advises that evaluation of causality can be categorized into six stages, such as certain, probable, possible, unlikely, conditional/unclassified, and unassessable/unclassifiable [22], and for that the following major four aspects are to be considered [23]. (1) temporal relationships: What is the temporal relationship between treatment initiation and the beginning of the event? How has the event changed after discontinuing treatment? (negative dechallenge) Did it recur after re-administration? (positive rechallenge) (2) Alternative causes: Have there been exposure factors other than complications, concomitant medications, or medicines that can explain the event occurrence? (3) Nature of the event: Some clinical events are often caused immediately by drugs (e.g., swelling in injection site). (4) Plausibility: Is the reaction already recognized by this medicine? (Is it a known side effect with this class?) Can the explanation for mechanism of event be derived from its known phar-

As a more specific evaluation criterion, nine criteria by Hill [24] and a number of scoring algorithms such as that devised by Naranjo et al. [25] can be used and applied to as part of causality assessment. Effective use of all these causality techniques requires practical knowledge about how to blend clinical, medical, and pharmacological sciences, which it means it is necessary to have suitably qualified persons with such knowledge actively leading and involved in the assessment team. Behavioral competencies for effective performance in phar-

As will be described later, it is not uncommon for elucidation of the mechanism of the development of ADR after many years following new drug approval often linked to advances in in scientific technology and research. Benefit-risk assessment that involves scientific review should be considered as standard operational procedures with structured framework to achieve feasible decision-making. However, as there are no perfect causality criteria, we should always bear in mind and not ignore clinical significant events regardless of causality unless there is overwhelming evidence of other causal factors which are

**Dose Time Susceptibility**

Time dependent (rapid, first dose, and early/intermediate/

Age Sex

Disease

Physiological variation Exogenous factors

Time independent

late/delayed)

**Table 1.** DoTS classification of adverse drug reaction.

(contribution of human factors and other causal and predisposing factors).

macological action?

18 Molecular Insight of Drug Design

obvious.

Toxic Collateral

Hypersusceptibility

macovigilance have been discussed elsewhere [26].

Statistics are widely used in the drug development as "biostatistics" to validate the efficiency of investigational products entity. What about the application of statistics to assess safety?

In the mid-1980s, the term "pharmacoepidemiology" was used for the first time, which often refers to the academic field of study, drug use and safety on a group level. As you can imagine from the phrase "epidemiology," the "group of subjects" or "population" studied by pharmacoepidemiology is a larger patient group than that of the clinical trial numbering up to tens of thousands or even an entire national population. This academic field has greatly expanded in the 1990s which is underpinned by the increased use of computerized databases including prescription records and clinical outcomes to investigate safety issues quickly and efficiently, as well as sophisticated computer technology, which enables high-enough performance to handle enormous amounts of data.

More recently, the design of pharmacoepidemiologic studies has turned to using big data. No matter the size of study subjects, the most challenging aspect of pharmacoepidemiology is its research design as with clinical trials. The place of "chance" that may lead statistically significant difference, "Bias" by systematic error, and "Confounding" as a third factor associated with both drugs and events, all may contribute to a direct association between drugs and events, which should be considered when designing the research plan and considering their results. Studies on drug safety are often performed further in the post-marketing phase observationally. Because, a double-blind trial to verify whether a serious adverse event will occur to a patient can be ethically dubious as patients cannot be denied an approved effective medicine, and in order to mitigate weakness and strengthen observational studies, pharmacoepidemiological researches inevitably consider new designs. In this academic domain, study designs and statistical techniques have been evolved, such as self-controlled case series, new user design, etc., handling bias and confounding that are classic and common in cohort and case-control studies. Frequently used study designs in pharmacoepidemiology are described further in the regulatory guidelines and the academic proposals [27–29].

New designs seem to be developed and used mainly for retrospective observational database studies. For the question of interest, there is still needs to conduct a traditional epidemiological study design for post-approval, phase IV study. As with the example of Brigham and Women's Hospital epidemiological studies, it may be necessary to plan for a cohort study to assemble from the beginning of development. Recently, many large-scale databases are becoming available and it is prudent to first make use of them. When choosing a database, you should make sure that prescription records, event data, and health-related information, such as gender and age, are available. If you can reconcile patient ID, separate databases may be combined. However, this requires epidemiological knowledge and experience.

#### **3.4. Much to do in the post-marketing phase to fully develop and define a medicine's properties and potential**

Based on the principle of ICH E2E, risk management plans have become a part of a new drug approval document to be submitted to the regulatory authorities in many countries/regions. Most of the processes for evaluating ADRs are similar in the pre- and post-authorization phases, although differences are found in data source for evaluation which impact on the quality and meaning of an adverse event case. One of the significant differences is that the spontaneous reporting system plays a critical role in post-authorization for both qualitative and quantitative analysis, especially for the identification of potential safety issues as soon as possible. This requires the process for quality management of spontaneous reporting so that spontaneous reporting to be improved [30].

Data management and statistical methods draw attention to the need to press forward by improving the efficiency of data analysis. However, it is hard for database analyses to identify issues such as dependency problems of medicines such as benzodiazepines and many delayed side effects unless they are flagged as a safety problem by patients' complaints in the

Frameworks for Evaluating Qualitative and Quantitative Information on Adverse Drug Events…

http://dx.doi.org/10.5772/intechopen.76331

21

Phase IV studies, either interventional or observational studies, have to be appropriately designed, according to the purpose/hypothesis about drug efficacy, effectiveness, or safety. To say that "the medicine is safe" in regulatory science means that the probability of hazard is low and acceptable, as compared to the disease to be treated and the benefit expected by the drug. In that sense, the safety concerns of the marketed drug are always linked to the benefit of the drug which has been accepted in the approval process. Unlike "efficacy" review, observational studies prevail in drug safety due to ethical reasons. Clinical trials are designed to reduce a statistical erroneous conclusion that efficacy exists when it really does not (Type I error). It defines "efficacy" to be tested, and statistical analysis is planned on the basis of a single hypothesis of the efficacy, thus the testing of multiple hypothesis within a single study is discouraged. However, there are a lot of potential types of ADRs that would be inappropriate to examine in a randomized trial. This is another reason for using surveillance to catch any signs of hazard and using prospective/retrospective longitudinal observational studies and pharmacoepidemiological database studies to assess the occurrence of ADRs. In addition, population-based design is of significance to compensate limited generalizability in clinical trials. "Effectiveness" in real-world clinical settings of a drug is scrutinized normally by non-interventional study or trial where the drugs are prescribed as per usual based on the terms of a drug marketing license. Definition of "effectiveness" may be prone to chance of subjective variation of the prescribing physician, which would make

Some registration systems provide an overview of clinical trials and studies: purpose, study type, intervention, recruitment criteria, etc. One such system in regulatory use is ClinicalTrials. gov, where information on phase II to IV studies of drugs, biological products, and medical devices regulated by the FDA is submitted [32–34]. Approximately 20,000 phase IV studies, over a half of which were interventional, have been registered in ClinicalTrials.gov; among over 250,000 studies in 203 countries, noticeably, registered phase IV studies include studies without drugs and observational studies [35, 36]. Those interventional studies examine various aspects of efficacy, pharmacodynamics, pharmacokinetics and other pharmacological aspects. Safety is often focused along with efficacy as described above, and 4392 of 4722 safety studies were aimed at efficacy as well as safety from 2004 to 2014. Of those which were interventional studies, 226 (68.5%) of them recruited less than 300 patients. Again, from a public health view point of generalizability, safety profile cannot be efficiently informed through clinical studies alone.

**4. Remaining issues and the future for pharmacovigilance**

first place through spontaneous reporting.

**4.1. Characteristics of phase IV studies**

designing a study difficult.

One of major challenges of ICSR reporting is its quality variation over time and between different geographical regions, depending on reporting cultures and regulations. This means it is to be expected that the databases of aggregated ICSRs can vary between countries/regions and indicate different drug-event combinations as safety signals. To illustrate these differences, a comparison study was performed on ICSRs databases between the United States and Japan, namely, FDA Adverse Events Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) [31]. The ICSR elements and their definitions defined by ICH have been implemented by countries/regions. It is expected that a case should be recorded in the same manner in different countries, however, not in reality. In the study, although both databases limitedly open the data elements, there were discrepancies in the type of reported AEs, reported drugs, reporter type, seriousness, and average number of reported events per case, between the JADER and FAERS. For example, the average number of AEs per case was 1.6 (SD = 1.3, max = 37) in the JADER and 3.3 (SD = 3.5, max = 62) for the Japanese cases in the FAERS; "drug exposure during pregnancy," "no adverse events," and non-serious cases are present in FAERS, but as these are not mandatory for electronic submission in Japan, few reports from non-professionals were found in the JADER.

These differences are mostly due to regulations and customs. In addition to these, social factors and healthcare systems also have a considerable impact. Interstitial lung disease (ILD) is an example of how an AE can be differently reported in Japan based on social-induced reporting bias. Japan has experienced serious social concerns with ILD related to several drugs and simultaneously, diagnosis with x-ray imaging is available in Japanese clinics and hospitals so it would appear that ILD could be more efficiently detected than other countries. Coding rules also may affect ICSRs data, because medical terminologies of ICSRs are submitted using codes inputted by a reporting company, where the company culture may have been embedded in the process so that bias may arise. All these unresolved biases threaten internal and external validity of the ICSR databases.

Nevertheless, the ICSR database is still very useful for review in the post-approval phase. It gives an opportunity to detect any safety signal (a combination of a medicine and an event considered to require more detailed examination) that would require a closer scrutiny. Collecting individual cases in the post-approval phase is said to be particularly suited for capturing suspected cases of serious and rare adverse drug reactions; however, if healthcare professionals, especially physicians, do not report the event, the potential safety risk cannot be noticed. In order to complement this, those who evaluate actively post-marketing data are extending their activities to include looking for signals from a large amount of information, which is out of scope of this chapter.

Data management and statistical methods draw attention to the need to press forward by improving the efficiency of data analysis. However, it is hard for database analyses to identify issues such as dependency problems of medicines such as benzodiazepines and many delayed side effects unless they are flagged as a safety problem by patients' complaints in the first place through spontaneous reporting.

#### **4. Remaining issues and the future for pharmacovigilance**

#### **4.1. Characteristics of phase IV studies**

Most of the processes for evaluating ADRs are similar in the pre- and post-authorization phases, although differences are found in data source for evaluation which impact on the quality and meaning of an adverse event case. One of the significant differences is that the spontaneous reporting system plays a critical role in post-authorization for both qualitative and quantitative analysis, especially for the identification of potential safety issues as soon as possible. This requires the process for quality management of spontaneous reporting so that

One of major challenges of ICSR reporting is its quality variation over time and between different geographical regions, depending on reporting cultures and regulations. This means it is to be expected that the databases of aggregated ICSRs can vary between countries/regions and indicate different drug-event combinations as safety signals. To illustrate these differences, a comparison study was performed on ICSRs databases between the United States and Japan, namely, FDA Adverse Events Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) [31]. The ICSR elements and their definitions defined by ICH have been implemented by countries/regions. It is expected that a case should be recorded in the same manner in different countries, however, not in reality. In the study, although both databases limitedly open the data elements, there were discrepancies in the type of reported AEs, reported drugs, reporter type, seriousness, and average number of reported events per case, between the JADER and FAERS. For example, the average number of AEs per case was 1.6 (SD = 1.3, max = 37) in the JADER and 3.3 (SD = 3.5, max = 62) for the Japanese cases in the FAERS; "drug exposure during pregnancy," "no adverse events," and non-serious cases are present in FAERS, but as these are not mandatory for electronic submission in Japan, few

These differences are mostly due to regulations and customs. In addition to these, social factors and healthcare systems also have a considerable impact. Interstitial lung disease (ILD) is an example of how an AE can be differently reported in Japan based on social-induced reporting bias. Japan has experienced serious social concerns with ILD related to several drugs and simultaneously, diagnosis with x-ray imaging is available in Japanese clinics and hospitals so it would appear that ILD could be more efficiently detected than other countries. Coding rules also may affect ICSRs data, because medical terminologies of ICSRs are submitted using codes inputted by a reporting company, where the company culture may have been embedded in the process so that bias may arise. All these unresolved biases threaten internal and

Nevertheless, the ICSR database is still very useful for review in the post-approval phase. It gives an opportunity to detect any safety signal (a combination of a medicine and an event considered to require more detailed examination) that would require a closer scrutiny. Collecting individual cases in the post-approval phase is said to be particularly suited for capturing suspected cases of serious and rare adverse drug reactions; however, if healthcare professionals, especially physicians, do not report the event, the potential safety risk cannot be noticed. In order to complement this, those who evaluate actively post-marketing data are extending their activities to include looking for signals from a large amount of information,

spontaneous reporting to be improved [30].

20 Molecular Insight of Drug Design

reports from non-professionals were found in the JADER.

external validity of the ICSR databases.

which is out of scope of this chapter.

Phase IV studies, either interventional or observational studies, have to be appropriately designed, according to the purpose/hypothesis about drug efficacy, effectiveness, or safety. To say that "the medicine is safe" in regulatory science means that the probability of hazard is low and acceptable, as compared to the disease to be treated and the benefit expected by the drug. In that sense, the safety concerns of the marketed drug are always linked to the benefit of the drug which has been accepted in the approval process. Unlike "efficacy" review, observational studies prevail in drug safety due to ethical reasons. Clinical trials are designed to reduce a statistical erroneous conclusion that efficacy exists when it really does not (Type I error). It defines "efficacy" to be tested, and statistical analysis is planned on the basis of a single hypothesis of the efficacy, thus the testing of multiple hypothesis within a single study is discouraged. However, there are a lot of potential types of ADRs that would be inappropriate to examine in a randomized trial. This is another reason for using surveillance to catch any signs of hazard and using prospective/retrospective longitudinal observational studies and pharmacoepidemiological database studies to assess the occurrence of ADRs. In addition, population-based design is of significance to compensate limited generalizability in clinical trials. "Effectiveness" in real-world clinical settings of a drug is scrutinized normally by non-interventional study or trial where the drugs are prescribed as per usual based on the terms of a drug marketing license. Definition of "effectiveness" may be prone to chance of subjective variation of the prescribing physician, which would make designing a study difficult.

Some registration systems provide an overview of clinical trials and studies: purpose, study type, intervention, recruitment criteria, etc. One such system in regulatory use is ClinicalTrials. gov, where information on phase II to IV studies of drugs, biological products, and medical devices regulated by the FDA is submitted [32–34]. Approximately 20,000 phase IV studies, over a half of which were interventional, have been registered in ClinicalTrials.gov; among over 250,000 studies in 203 countries, noticeably, registered phase IV studies include studies without drugs and observational studies [35, 36]. Those interventional studies examine various aspects of efficacy, pharmacodynamics, pharmacokinetics and other pharmacological aspects. Safety is often focused along with efficacy as described above, and 4392 of 4722 safety studies were aimed at efficacy as well as safety from 2004 to 2014. Of those which were interventional studies, 226 (68.5%) of them recruited less than 300 patients. Again, from a public health view point of generalizability, safety profile cannot be efficiently informed through clinical studies alone.

#### **4.2. Utilizing and making sense of new data sources**

Real world data (RWD) refers to all the data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources [37]. They are collected under day-to-day circumstances and not through international trials with a control or comparative group. This means data are outside the controlled constraints of conventional randomized clinical trials. Especially occurring in the post-approval setting, the data can be used to evaluate what happens when a medicine is used in normal clinical practice. Such data can arise from a number of sources, not only in the clinical settings, but also social settings. Therefore, RWD can be found in electronic health records (EHRs), claims and billing activities, product and disease registries, patient-related activities in out-patient or in-home use settings, healthmonitoring devices and even blogs if possible [38]. In addition, RWD can include data on outcomes (both clinical and patient-reported), resource use (medical institutions, patient, and societal), treatment pathways, service models, patient preference, experience, and compliance. Secondary research data derived from routinely collected data is also applicable. Realworld evidence in drug development is, in turn, the clinical evidence regarding the usage and potential benefits or risks of a medical product derived from the analysis of all of this RWD.

companion diagnostic agents often as personalized medicine. As the tragedy of thalidomide was one milestone, the lessons learned after gefitinib's marketing in Japan can be considered a further milestone for molecular targeted drugs. Gefitinib was the second molecular-targeted drug that was launched in Japan ahead of the world in July 2002 based on the approved indication of lung cancer. Some years later, it was confirmed that the effectiveness is valid for small cell lung cancer patients with EGFR gene mutation (L858R or Exon 19 deficiency), and that the mutation of the ATP binding site is more common in Oriental women such as Japan and China [41]. In terms of safety, many adverse reaction cases of Interstitial Lung Disease were reported at the time of clinical trials, but the mechanism of action that caused such an

Frameworks for Evaluating Qualitative and Quantitative Information on Adverse Drug Events…

http://dx.doi.org/10.5772/intechopen.76331

23

However, there remains a huge question about the feasibility for a company being obliged to obtain even more data during development by investing in post-marketing safety studies and effectiveness studies. In recent years, regulatory authorities have streamlined reviews for approval, such as FDA's Accelerated Approval Program, and there are increasing numbers of applications requiring post-approval safety measures at the time of approval. It is considered as one possible solution to replace conducting many phase IV studies and in vitro studies with utilizing RWD, as described above. However, it should be noted that profiles of each database vary so much that they produce different results even if you study with the same objective, for example, pioglitazone [42]. Therefore, it is necessary to sufficiently clarify the risk minimization actions in a RMP, and to keep these in mind when choosing a database for quantitative assessment.

Pharmacovigilance can be defined as a multidisciplinary science consisting of systematic activities and processes relating to the detection, assessment, understanding, and prevention of adverse effects or any other problems related to medical healthcare products and their handling throughout their lifecycle, thus mitigating risk and maximizing benefits for patients. These activities include those required to monitor and assess a quality system embedded in a just and fair culture that facilitates reporting, communication, and organizational learning to demonstrate that the system is performing according to guiding safety principles agreed by all stakeholders. What has been learned from the history of various medicines is that the balance between benefit and risk can change from time to time based on the obtained experience and information, and that taking multiple approaches to a certain safety research objective can often result in different answers. Therefore, pharmacovigilance is a challenging and evolving multidisciplinary science that has to be applied logically throughout drug lifecycle. This chapter presented what are available in practice to assess and profile safety with a central aspect of adverse drug event/reaction throughout the development phase to the post-marketing phase.

adverse reaction had not yet been elucidated.

**5. Conclusions**

**Conflict of interest**

No potential conflict of interest was reported by the authors.

RWD and RWE may not be the best thing for collecting efficacy data, and interventional trials are essential and inevitable to prove efficacy of medicinal entity. The methodology to utilize RWD would elaborate the better use of RWD for the monitoring of safety information in the post-approval phase to add further information on benefit-risk balance [39]. As of today, the majority of studies with RWD are safety-focused, and real-world pharmacovigilance is one of the main drivers currently for collection of RWD for many companies, based on post-authorization requirements for safety evaluation in real-world patients. It is reported that registries, in the form of a cohort study, have not sufficiently enrolled participants [40], and it should bear in mind that any type of data source has difficulties and limitations in collection and quality of its data.

#### **4.3. Necessity of pharmacovigilance for the development of pharmaceuticals**

Access to new therapies in oncology has depended on the results of post-approval RWD. There are some drugs approved based on progression-free survival using Kaplan-Meier survival analysis with no difference in overall survival time. Can the data of progression-free survival really support a clinically meaningful effect of anticancer drugs? Would not data about the overall survival period be better? It may be agreed with regulators that data on the overall survival time derived from post-approval observational research be evaluated with the results fed back to healthcare professionals through updates to the package insert, etc. Such an approach may well lead to increase in utilization of conditional approvals.

Beginning with imatinib, the development of molecular-targeted drugs and utilization in clinical practice became popular especially in the twenty-first century. However, it has been noted in recent years that many genetic mutations are present in the signal transduction system and from this scientist can more easily predict outcomes concerning effectiveness and safety. Even though we cannot fully clarify molecular targeted drugs at the time of approval, research for confirming gene mutation should continue to be recommended after marketing by using companion diagnostic agents often as personalized medicine. As the tragedy of thalidomide was one milestone, the lessons learned after gefitinib's marketing in Japan can be considered a further milestone for molecular targeted drugs. Gefitinib was the second molecular-targeted drug that was launched in Japan ahead of the world in July 2002 based on the approved indication of lung cancer. Some years later, it was confirmed that the effectiveness is valid for small cell lung cancer patients with EGFR gene mutation (L858R or Exon 19 deficiency), and that the mutation of the ATP binding site is more common in Oriental women such as Japan and China [41]. In terms of safety, many adverse reaction cases of Interstitial Lung Disease were reported at the time of clinical trials, but the mechanism of action that caused such an adverse reaction had not yet been elucidated.

However, there remains a huge question about the feasibility for a company being obliged to obtain even more data during development by investing in post-marketing safety studies and effectiveness studies. In recent years, regulatory authorities have streamlined reviews for approval, such as FDA's Accelerated Approval Program, and there are increasing numbers of applications requiring post-approval safety measures at the time of approval. It is considered as one possible solution to replace conducting many phase IV studies and in vitro studies with utilizing RWD, as described above. However, it should be noted that profiles of each database vary so much that they produce different results even if you study with the same objective, for example, pioglitazone [42]. Therefore, it is necessary to sufficiently clarify the risk minimization actions in a RMP, and to keep these in mind when choosing a database for quantitative assessment.

#### **5. Conclusions**

**4.2. Utilizing and making sense of new data sources**

22 Molecular Insight of Drug Design

quality of its data.

Real world data (RWD) refers to all the data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources [37]. They are collected under day-to-day circumstances and not through international trials with a control or comparative group. This means data are outside the controlled constraints of conventional randomized clinical trials. Especially occurring in the post-approval setting, the data can be used to evaluate what happens when a medicine is used in normal clinical practice. Such data can arise from a number of sources, not only in the clinical settings, but also social settings. Therefore, RWD can be found in electronic health records (EHRs), claims and billing activities, product and disease registries, patient-related activities in out-patient or in-home use settings, healthmonitoring devices and even blogs if possible [38]. In addition, RWD can include data on outcomes (both clinical and patient-reported), resource use (medical institutions, patient, and societal), treatment pathways, service models, patient preference, experience, and compliance. Secondary research data derived from routinely collected data is also applicable. Realworld evidence in drug development is, in turn, the clinical evidence regarding the usage and potential benefits or risks of a medical product derived from the analysis of all of this RWD. RWD and RWE may not be the best thing for collecting efficacy data, and interventional trials are essential and inevitable to prove efficacy of medicinal entity. The methodology to utilize RWD would elaborate the better use of RWD for the monitoring of safety information in the post-approval phase to add further information on benefit-risk balance [39]. As of today, the majority of studies with RWD are safety-focused, and real-world pharmacovigilance is one of the main drivers currently for collection of RWD for many companies, based on post-authorization requirements for safety evaluation in real-world patients. It is reported that registries, in the form of a cohort study, have not sufficiently enrolled participants [40], and it should bear in mind that any type of data source has difficulties and limitations in collection and

**4.3. Necessity of pharmacovigilance for the development of pharmaceuticals**

an approach may well lead to increase in utilization of conditional approvals.

Access to new therapies in oncology has depended on the results of post-approval RWD. There are some drugs approved based on progression-free survival using Kaplan-Meier survival analysis with no difference in overall survival time. Can the data of progression-free survival really support a clinically meaningful effect of anticancer drugs? Would not data about the overall survival period be better? It may be agreed with regulators that data on the overall survival time derived from post-approval observational research be evaluated with the results fed back to healthcare professionals through updates to the package insert, etc. Such

Beginning with imatinib, the development of molecular-targeted drugs and utilization in clinical practice became popular especially in the twenty-first century. However, it has been noted in recent years that many genetic mutations are present in the signal transduction system and from this scientist can more easily predict outcomes concerning effectiveness and safety. Even though we cannot fully clarify molecular targeted drugs at the time of approval, research for confirming gene mutation should continue to be recommended after marketing by using Pharmacovigilance can be defined as a multidisciplinary science consisting of systematic activities and processes relating to the detection, assessment, understanding, and prevention of adverse effects or any other problems related to medical healthcare products and their handling throughout their lifecycle, thus mitigating risk and maximizing benefits for patients. These activities include those required to monitor and assess a quality system embedded in a just and fair culture that facilitates reporting, communication, and organizational learning to demonstrate that the system is performing according to guiding safety principles agreed by all stakeholders. What has been learned from the history of various medicines is that the balance between benefit and risk can change from time to time based on the obtained experience and information, and that taking multiple approaches to a certain safety research objective can often result in different answers. Therefore, pharmacovigilance is a challenging and evolving multidisciplinary science that has to be applied logically throughout drug lifecycle. This chapter presented what are available in practice to assess and profile safety with a central aspect of adverse drug event/reaction throughout the development phase to the post-marketing phase.

#### **Conflict of interest**

No potential conflict of interest was reported by the authors.

#### **Author details**

Kaori Nomura<sup>1</sup> \* and Brian David Edwards<sup>2</sup>


#### **References**

[1] Pirmohamed M, Park K. Adverse drug reactions: Back to the future. British Journal of Clinical Pharmacology. 2003;**55**:486-492

[10] Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community Code Relating to Medicinal Products for Human Use. (as amended) [Internet]. Available from https://ec.europa.eu/health/sites/health/files/files/eudralex/ vol-1/dir\_2001\_83\_consol\_2012/dir\_2001\_83\_cons\_2012\_en.pdf [Accessed: Feb 1, 2018]

Frameworks for Evaluating Qualitative and Quantitative Information on Adverse Drug Events…

http://dx.doi.org/10.5772/intechopen.76331

25

[11] Lindquist M. The need for definitions in pharmacovigilance. Drug Safety. 2007;**30**(10):

[12] World Health Organization. The Importance of Pharmacovigilance – Safety Monitoring

[13] Council for International Organizations of Medical Sciences. Report of CIOMS Working Group VI: Management of Safety Information from Clinical Trials. Geneva: Council for

[14] International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting [Internet]. 1994. Available from: https://www. ich.org/fileadmin/Public\_Web\_Site/ICH\_Products/Guidelines/Efficacy/E2A/Step4/E2A\_

[15] European Medicines Agency. Guideline on the Risk-based Approach According to Annex I, Part IV of Directive 2001/83/EC Applied to Advanced Therapy Medicinal Products [Internet]. Feb 11, 2013. Available from: http://www.ema.europa.eu/docs/en\_ GB/document\_library/Scientific\_guideline/2013/03/WC500139748.pdf [Accessed: Feb 1,

[16] European Medicines Agency. Reflection Paper on Risk-based Quality Management in Clinical Trials [Internet]. Nov 18, 2013. Available from: http://www.ema.europa.eu/docs/ en\_GB/document\_library/Scientific\_guideline/2013/11/WC500155491.pdf [Accessed:

[17] Food and Drug Administration. Guidance for Industry Oversight of Clinical Investigations – A Risk-based Approach to Monitoring [Internet]. August 2013. Available from: https://www.fda.gov/downloads/Drugs/Guidances/UCM269919.pdf [Accessed:

[18] European Medicines Agency. 2010. European Medicines Agency. Benefit-risk Methodology Project Work Package 2 Report: Applicability of Current Tools and Processes for Regulatory Benefit-risk Assessment [Internet]. Aug 31, 2013. Available from: http:// www.ema.europa.eu/docs/en\_GB/document\_library/Report/2010/10/WC500097750.pdf

[19] Angelillo IF, Villari P. Meta-analysis of published studies or meta-analysis of individual data? Caesarean section in HIV-positive women as a study case. Public Health. 2003

[20] Rawlins MD. Clinical pharmacology: Adverse reactions to drugs. British Medical Journal. 1981;**282**:974-976 [Internet]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/

Sep;**117**(5):323-328. DOI: 10.1016/S0033-3506(03)00105-7

PMC1504743/pdf/bmjcred00650-0048.pdf [Accessed: Feb 1, 2018]

of Medicinal Products. Geneva: World Health Organization; 2002

825-830. DOI: 0114-5916/07/0010-0825/\$44.95/0

International Organizations of Medical Sciences. 2005

Guideline.pdf [Accessed: Feb 1, 2018]

2018]

Feb 1, 2018]

Feb 1, 2018]

[Accessed: Feb 1, 2018]


[10] Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community Code Relating to Medicinal Products for Human Use. (as amended) [Internet]. Available from https://ec.europa.eu/health/sites/health/files/files/eudralex/ vol-1/dir\_2001\_83\_consol\_2012/dir\_2001\_83\_cons\_2012\_en.pdf [Accessed: Feb 1, 2018]

**Author details**

24 Molecular Insight of Drug Design

Kaori Nomura<sup>1</sup>

**References**

\* and Brian David Edwards<sup>2</sup> \*Address all correspondence to: kaori.nomura@jikei.ac.jp

[1] Pirmohamed M, Park K. Adverse drug reactions: Back to the future. British Journal of

[2] Waller P. An Introduction to Pharmacovigilance. Chichester: John Wiley & Sons Ltd.;

[3] Kerbrat A, Ferre JC, Fillatre P, et al. Acute neurologic disorder from an inhibitor of fatty acid amide hydrolase. The New England Journal of Medicine. 2016;**375**:1717-1725. DOI:

[4] International Conference on Harmonisation of the Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline E6 Guideline for Good Clinical Practice [Internet]. 1996. Available from: https://www. ich.org/fileadmin/Public\_Web\_Site/ICH\_Products/Guidelines/Efficacy/E6/E6\_R1\_

[5] Council for International Organizations of Medical Sciences. Report of CIOMS Working Group VII: The Development Safety Update Report (DSUR): Harmonizing the Format and Content for Periodic Safety Reporting During Clinical Trials. Geneva: Council for

[6] International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline E2F Development Safety Update Report [Internet]. 2005. Available from: http://www.ich.org/ fileadmin/Public\_Web\_Site/ICH\_Products/Guidelines/Efficacy/E2F/Step4/E2F\_Step\_4.

[7] International Organization for Standardization. ISO31000:2009 Risk Management – Principles and Guidelines. [Internet] 2009. Available from: https://www.iso.org/obp/

[8] International Organization for Standardization. ISO14971:2007 Medical Devices – Application of Risk Management to Medical Devices. [Internet] 2007. Available from: https://www.iso.org/obp/ui/#iso:std:iso:14971:ed-2:v2:en:sec:H [Accessed: 15 April 2018] [9] International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Q9 Quality Risk Management [Internet]. 2005. Available from: http://www.ich.org/fileadmin/Public\_Web\_Site/ICH\_Products/Guidelines/

1 Jikei University School of Medicine, Tokyo, Japan

Clinical Pharmacology. 2003;**55**:486-492

2010. 3 p. DOI: 10.1002/9781444316766

Guideline.pdf [Accessed: Feb 1, 2018]

International Organizations of Medical Sciences; 2006

ui/#iso:std:iso:31000:ed-1:v1:en [Accessed: 15 April 2018]

Quality/Q9/Step4/Q9\_Guideline.pdf [Accessed: Feb 1, 2018]

10.1056/NEJMoa1604221

pdf [Accessed: Feb 1, 2018]

2 NDA Regulatory Science Ltd, London, UK


[21] Aronson JK, Ferner RE. Joining the DoTS: New approach to classifying adverse drug reactions. British Medical Journal. 2003;**327**:1222-1227. DOI: 10.1136/bmj.327.7425.1222

[34] Tse T, Williams RJ, Zarin DA. Update on registration of clinical trials in ClinicalTrials.

Frameworks for Evaluating Qualitative and Quantitative Information on Adverse Drug Events…

http://dx.doi.org/10.5772/intechopen.76331

27

[35] U.S. National Library of Medicine. [Internet]. Available from: https://clinicaltrials.gov

[36] Zhang X, Zhang Y, Ye X, et al Overview of phase IV clinical trials for postmarket drug safety surveillance: A status report from the ClinicalTrials.gov registry. BMJ Open.

[37] Food and Drug Administration. Real World Evidence. 2018. Available from: https:// www.fda.gov/scienceresearch/specialtopics/realworldevidence/default.htm

[38] Sherman, RE, Anderson, SA, Dal Pan, GJ et al. Real-world evidence – What is it and what can it tell us?. The New England Journal of Medicine; 2016:**375**(23):2293-2297p. DOI:

[39] Goldman M. The Valuable World of Real World Evidence [Internet]. 2014. Available from: http://www.pharmafile.com/news/196159/valuable-world-real-world-evidence. [Accessed: Feb 14,

[40] Bouvy JC, Blake K, Slattery J, et al. Registries in European post-marketing surveillance: A retrospective analysis of centrally approved products, 2005-2013. Pharmacoepidemiology

[41] Morita S, Okamoto I, Kobayashi K, et al. Combined survival analysis of prospective clinical trials of gefitinib for non-small cell lung cancer with EGFR mutations. Clinical

[42] Filipova E, Uzunova K, Kalinov K, Vekov T. Pioglitazone and the risk of bladder cancer: A meta-analysis. Diabetes Therapy. 2017;**8**(4):705-726. DOI: 10.1007/s13300-017-0273-4

Cancer Research. 2009;**15**(13):4493-4498. DOI: 10.1158/1078-0432.CCR-09-0391

and Drug Safety. 2017;**26**(12):1442-1450. DOI: 10.1002/pds.4196

gov. Chest. 2009;**135**:304-305. DOI: 10.1378/chest.09-1219

2016;6:e010643. DOI: 10.1136/bmjopen-2015-010643

[Accessed: Feb 14, 2018]

10.1056/NEJMsb1609216

2018]


[34] Tse T, Williams RJ, Zarin DA. Update on registration of clinical trials in ClinicalTrials. gov. Chest. 2009;**135**:304-305. DOI: 10.1378/chest.09-1219

[21] Aronson JK, Ferner RE. Joining the DoTS: New approach to classifying adverse drug reactions. British Medical Journal. 2003;**327**:1222-1227. DOI: 10.1136/bmj.327.7425.1222

[22] Uppsala Monitoring Center. The Use of the WHO-UMC System for Standardised Case Causality Assessment [Internet]. Available from: http://www.who.int/medicines/areas/ quality\_safety/safety\_efficacy/WHOcausality\_assessment.pdf [Accessed: Feb 1, 2018]

[23] Waller P. An Introduction to Pharmacovigilance. Chichester: John Wiley & Sons Ltd.;

[24] Hill AB. The environment and disease: Association or causation? Proceedings of the

[25] Naranjo CA, Busto U, Sellars EA, et al. A method for estimating the probability of adverse drug reactions. Clinical Pharmacology and Therapeutics. 1981;**30**:239-245. DOI:

[26] Edwards B, Tilson HH, West SL. Defining the competencies of those conducting pharmacovigilance. Pharmacoepidemiology and Drug Safety. 2006;**15**(3):193-198. DOI: 10.1002/

[27] FDA. Structured Approach to Benefit-Risk Assessment in Drug Regulatory Decision-Making [Internet]. 2013. Available from: https://www.fda.gov/downloads/forindustry/

[28] European Medicines Agency. The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) Guide on Methodological Standards in Pharmacoepidemiology (Revision 6) [Internet]. 2010. Available from: http://www.encepp.eu/standards\_ and\_guidances/documents/ENCePPGuideofMethStandardsinPE\_Rev6.pdf [Accessed: Feb 14,

[29] International Society for Pharmacoepidemiology. Guidelines for Good Pharmacoepidemiology Practices (GPP) [Internet]. 2015. Available from: https://www.pharmacoepi.org/

[30] Prabhakar U, Edwards B. Postmarketing safety surveillance issues with data collection for postmarketing pharmacovigilance. Pharmaceutical Medicine. 2010;**24**(6):343-348.

[31] Nomura K, Takahashi K, Hinomura Y, et al. Effect of database profile variation on drug safety assessment: An analysis of spontaneous adverse event reports of Japanese cases. Drug Design, Development and Therapeutics. 2015;**9**:3031-3041. DOI: 10.2147/DDDT.

[32] Gillen JE, Tse T, Ide NC, McCray AT. Design, implementation and management of a web-based data entry system for ClinicalTrials.gov. Studies in Health Technology and

[33] Zarin DA, Keselman A. Registering a clinical trial in ClinicalTrials.gov. Chest.

Informatics. 2004;**107**(Pt 2):1466-1470. DOI: 10.3233/978-1-60750-949-3-1466

2007;**131**(3):909-912. DOI: https://doi.org/10.1378/chest.06-2450

userfees/prescriptiondruguserfee/ucm329758.pdf [Accessed: Feb 14, 2018]

resources/policies/guidelines-08027/. [Accessed: Feb 14, 2018]

2010. 25-27 p. DOI: 10.1002/9781444316766

Royal Society of Medicine. 1965;**58**(5):295-300

10.1038/clpt.1981.154

DOI: 10.1007/BF03256835

pds.1153

26 Molecular Insight of Drug Design

2018]

S81998


**Chapter 3**

**Provisional chapter**

**Integrated Approach to Nature as Source of New Drug**

**Integrated Approach to Nature as Source of New Drug** 

Classically, the development and launching of a new drug is a highly time consuming, tedious and expensive process involving following fundamental steps: (1) Identification of cause of Disease and Search for target site. (2) Search and Optimisation of active compound, that is, the Drug Lead. (3) Testing of Drug in Animals (pre-clinical phase). (4) Clinical Trials. (5) Approval of New Drug by Competent authority and availability of the drug. Drug discovery and development process involves around 10–15 years of investigation period and incredibly high cost and investment. This process also involves participation of experts from various disciplines and fields. Therefore, the new approaches are obligatory to be developed not only to expedite the process but also to ensure the launch of safer and effective drug. Over this background, the importance of experimental wisdom and holistic approach is intensifying to offer good base as an attractive discovery engine. Natural product drug discovery, ethno-pharmacology, traditional and attractive medicines are re-emerging as new strategic options. In the past decade, the number of new chemical entity (NCG) in drug development channel is declining markedly might have led to the rekindling of interest in emergence of natural product as new drug leads. The novel natural products can be optimised on the basis of their biological activities using highly sophisticated combinatorial biosynthetic techniques, microbial genomes

**Keywords:** natural products, drug leads, microorganism and marine source

Drug discovery and development is mainly concerned with new chemical entity with biological activity. It works on enhancing the properties of drugs used in the treatment of different

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

DOI: 10.5772/intechopen.74961

**Lead**

**Lead**

Seema Kohli

Seema Kohli

**Abstract**

and screening process.

**1. Introduction**

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.74961

#### **Integrated Approach to Nature as Source of New Drug Lead Integrated Approach to Nature as Source of New Drug Lead**

DOI: 10.5772/intechopen.74961

#### Seema Kohli Seema Kohli

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.74961

#### **Abstract**

Classically, the development and launching of a new drug is a highly time consuming, tedious and expensive process involving following fundamental steps: (1) Identification of cause of Disease and Search for target site. (2) Search and Optimisation of active compound, that is, the Drug Lead. (3) Testing of Drug in Animals (pre-clinical phase). (4) Clinical Trials. (5) Approval of New Drug by Competent authority and availability of the drug. Drug discovery and development process involves around 10–15 years of investigation period and incredibly high cost and investment. This process also involves participation of experts from various disciplines and fields. Therefore, the new approaches are obligatory to be developed not only to expedite the process but also to ensure the launch of safer and effective drug. Over this background, the importance of experimental wisdom and holistic approach is intensifying to offer good base as an attractive discovery engine. Natural product drug discovery, ethno-pharmacology, traditional and attractive medicines are re-emerging as new strategic options. In the past decade, the number of new chemical entity (NCG) in drug development channel is declining markedly might have led to the rekindling of interest in emergence of natural product as new drug leads. The novel natural products can be optimised on the basis of their biological activities using highly sophisticated combinatorial biosynthetic techniques, microbial genomes and screening process.

**Keywords:** natural products, drug leads, microorganism and marine source

#### **1. Introduction**

Drug discovery and development is mainly concerned with new chemical entity with biological activity. It works on enhancing the properties of drugs used in the treatment of different

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

medical conditions. Classically, the development and launching of a new drug is a highly timeconsuming, tedious and expensive process involving under mentioned fundamental steps:

Since ages the natural products have been the source of medicinal agents and will continue to play crucial role in the human health through the expanded investigation of world biodiversity. World Health Organization (WHO) reports that about 80% of the world's population depends on traditional medicine for their health care. Further, at least 119 important chemical

Integrated Approach to Nature as Source of New Drug Lead

http://dx.doi.org/10.5772/intechopen.74961

31

With the advent of theory of drug-receptor action, the scientists concluded that it is the isolated compound from the plant extract that is responsible for pharmacological action. This leads to new era in pharmacology and area of new drug research. The classical example is morphine (from opium) and digoxin (from *Digitalis purpurea*). A number of modern medicines have been obtained from natural resources such as plants, microorganisms, marine organisms and minerals. Nature continues to be a main source of molecular diversity, which through the pursuit of multidisciplinary, international collaborative research can result in the

Lead identification/optimisation is the one of the most important steps in drug development following the biological target identification. The properties of a drug can be enhanced or potentiated by making certain modifications/alterations in its chemical structure. Drug efficacy, potency, selectivity and pharmacokinetic parameters can be improved by making necessary structural changes. The chemical structure is the key to lead compound identification. After the lead compound identification, the next step is the study of ADMET that is absorption, distribution, metabolism, excertion and toxicology of the probable drug lead. If these studies are positive and satisfactory, the compound is nontoxic and nonmutagenic, then the compound is turned to be potential lead compound. This may then be developed as new drug. (**Figure 2**). Lead compound is a chemical compound that shows desired pharmacological activity and may initiate the development of new chemical entity, relevant compound. These are actually the starting molecule for the new drug. Newer techniques can be adopted to accelerate the enhancement in the compounds pharmacological

Recently, there has been a keen interest in natural product research as the traditional method of drug discovery failed to yield desired lead compound particularly in areas such as immunosuppressant, anti-infective and metabolic diseases. Natural product research continues to explore a variety of lead chemical structures that can be used as a template for new drug by the pharmaceutical industry. This is also evident that new approaches to enhance the joint drug discovery and development process would be expected to take place basically from

substances have been derived from 90 plant species [2].

development of promising lead compounds [3].

**2. Natural product as new drug lead**

The promising sources of lead compound and novel drugs are:

properties.

• Natural products • Chemical libraries

• Computational Medicinal Chemistry


Drug discovery leading to strong and doable lead candidate always remained exigent assignment for scientists. In fact experts accomplish the task by transforming the screening hit compound to a suitable drug candidate. The journey of new drug to the market is considerably long and takes about 10–15 years of investigation period. Therefore, the new approaches are obligatory to be developed not only to expedite the process but also to ensure the launch of safer and effective drug [1].

Over this background, the importance of experimental wisdom and holistic approach is intensifying to offer good base as an attractive discovery engine. Natural product drug discovery, ethno-pharmacology, traditional and attractive medicines are re-emerging as new strategic options. In the past decade, the number of new chemical entity (NCE) in drug development channel is declining markedly might have led to the rekindling of interest in the emergence of natural product new drug leads. The novel-natural products can be optimised on the basis of their biological activities using highly sophisticated combinatorial biosynthetic techniques, microbial genomes and screening process (**Figure 1**).

**Figure 1.** Complete process of drug discovery from plants.

Since ages the natural products have been the source of medicinal agents and will continue to play crucial role in the human health through the expanded investigation of world biodiversity. World Health Organization (WHO) reports that about 80% of the world's population depends on traditional medicine for their health care. Further, at least 119 important chemical substances have been derived from 90 plant species [2].

With the advent of theory of drug-receptor action, the scientists concluded that it is the isolated compound from the plant extract that is responsible for pharmacological action. This leads to new era in pharmacology and area of new drug research. The classical example is morphine (from opium) and digoxin (from *Digitalis purpurea*). A number of modern medicines have been obtained from natural resources such as plants, microorganisms, marine organisms and minerals. Nature continues to be a main source of molecular diversity, which through the pursuit of multidisciplinary, international collaborative research can result in the development of promising lead compounds [3].

#### **2. Natural product as new drug lead**

Lead identification/optimisation is the one of the most important steps in drug development following the biological target identification. The properties of a drug can be enhanced or potentiated by making certain modifications/alterations in its chemical structure. Drug efficacy, potency, selectivity and pharmacokinetic parameters can be improved by making necessary structural changes. The chemical structure is the key to lead compound identification. After the lead compound identification, the next step is the study of ADMET that is absorption, distribution, metabolism, excertion and toxicology of the probable drug lead. If these studies are positive and satisfactory, the compound is nontoxic and nonmutagenic, then the compound is turned to be potential lead compound. This may then be developed as new drug. (**Figure 2**). Lead compound is a chemical compound that shows desired pharmacological activity and may initiate the development of new chemical entity, relevant compound. These are actually the starting molecule for the new drug. Newer techniques can be adopted to accelerate the enhancement in the compounds pharmacological properties.

The promising sources of lead compound and novel drugs are:


**Figure 1.** Complete process of drug discovery from plants.

medical conditions. Classically, the development and launching of a new drug is a highly timeconsuming, tedious and expensive process involving under mentioned fundamental steps:

Drug discovery leading to strong and doable lead candidate always remained exigent assignment for scientists. In fact experts accomplish the task by transforming the screening hit compound to a suitable drug candidate. The journey of new drug to the market is considerably long and takes about 10–15 years of investigation period. Therefore, the new approaches are obligatory to be developed not only to expedite the process but also to ensure the launch of

Over this background, the importance of experimental wisdom and holistic approach is intensifying to offer good base as an attractive discovery engine. Natural product drug discovery, ethno-pharmacology, traditional and attractive medicines are re-emerging as new strategic options. In the past decade, the number of new chemical entity (NCE) in drug development channel is declining markedly might have led to the rekindling of interest in the emergence of natural product new drug leads. The novel-natural products can be optimised on the basis of their biological activities using highly sophisticated combinatorial biosynthetic techniques,

• Identification of cause of Disease and Search for target site

• Testing of Drug in Animals (pre-clinical phase)

microbial genomes and screening process (**Figure 1**).

• Clinical Trials

30 Molecular Insight of Drug Design

safer and effective drug [1].

• Search and Optimisation of active compound, that is, the Drug Lead

• Approval of New Drug by Competent authority and availability in market.

• Computational Medicinal Chemistry

Recently, there has been a keen interest in natural product research as the traditional method of drug discovery failed to yield desired lead compound particularly in areas such as immunosuppressant, anti-infective and metabolic diseases. Natural product research continues to explore a variety of lead chemical structures that can be used as a template for new drug by the pharmaceutical industry. This is also evident that new approaches to enhance the joint drug discovery and development process would be expected to take place basically from

**Figure 2.** Process of lead selections and identification.

Apart from comparing with other drug discovery methods, natural products are still providing their fair share of new clinical candidates and drugs. These said compounds were still a significant source of new drugs, especially in the anticancer, anti-infective, antihypertensive, immune-suppression and neurological disease therapeutic areas [4–7]. The natural products

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Plants are affluent source of pharmaceuticals as well as drug leads. They are the natural laboratories where the simple chemical skeleton is transformed to complex chemical structures. The natural metabolites are far better than the synthesised metabolites in biological efficacy. A survey of plant-derived drugs in countries that host the WHO—Traditional medicinal Centres indicated that out of 122 compound identified 80% were derived from 94 plant species. Some of the drugs obtained in this approach are: sodium cromoglycate, a bronchodilator from khellin (*Ammi visnaga*), Metformin, an antidiabetic from galegine (*Galega officinalis*), verapamil a antihypertensive from papaverine (*Papaver somniferum*), aspirin an analgesic from salicin (willow bark), atorvastatin from mevastatin (*Penicillium citrinum*), (**Figure 5**). Malaria remains one of the biggest challenges faced by the mankind, and there is a continuous search for an effective drug. The isolation of quinine from cinchona bark was reported in 1820 by the French pharmacists Caventou and Pelletier. Quinine formed the basis for the synthesis of the commonly used antimalarial drugs. Another antimalarial drug developed from plant lead is artemisinin obtained from *Artemisia annua*. There analogues are used in many countries for

Other noteworthy drugs developed from traditional medicinal plants are: Reserpine an antihypertensive drug from *Rauvolfia serpentina*, Ephedrine from *Ephedra sinica* used as the basis for the synthesis of the anti-asthmatic drug salbutamol and salmeterol, tubocurarine a muscle

used as drug lead are shown in **Figure 4**.

**Figure 4.** Natural products as drug leads.

**2.1. Plants**

the treatment of malaria.

**Figure 3.** Drug leads and drug development.

innovation in drug target elucidation along with lead structure discovery. There are new technologies like automated separation techniques, high throughput screening and combinatorial chemistry are powerful and revolutionising drug discovery. (**Figure 3**).

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**Figure 4.** Natural products as drug leads.

Apart from comparing with other drug discovery methods, natural products are still providing their fair share of new clinical candidates and drugs. These said compounds were still a significant source of new drugs, especially in the anticancer, anti-infective, antihypertensive, immune-suppression and neurological disease therapeutic areas [4–7]. The natural products used as drug lead are shown in **Figure 4**.

#### **2.1. Plants**

**Figure 3.** Drug leads and drug development.

**Figure 2.** Process of lead selections and identification.

32 Molecular Insight of Drug Design

innovation in drug target elucidation along with lead structure discovery. There are new technologies like automated separation techniques, high throughput screening and combinatorial

chemistry are powerful and revolutionising drug discovery. (**Figure 3**).

Plants are affluent source of pharmaceuticals as well as drug leads. They are the natural laboratories where the simple chemical skeleton is transformed to complex chemical structures. The natural metabolites are far better than the synthesised metabolites in biological efficacy. A survey of plant-derived drugs in countries that host the WHO—Traditional medicinal Centres indicated that out of 122 compound identified 80% were derived from 94 plant species. Some of the drugs obtained in this approach are: sodium cromoglycate, a bronchodilator from khellin (*Ammi visnaga*), Metformin, an antidiabetic from galegine (*Galega officinalis*), verapamil a antihypertensive from papaverine (*Papaver somniferum*), aspirin an analgesic from salicin (willow bark), atorvastatin from mevastatin (*Penicillium citrinum*), (**Figure 5**). Malaria remains one of the biggest challenges faced by the mankind, and there is a continuous search for an effective drug. The isolation of quinine from cinchona bark was reported in 1820 by the French pharmacists Caventou and Pelletier. Quinine formed the basis for the synthesis of the commonly used antimalarial drugs. Another antimalarial drug developed from plant lead is artemisinin obtained from *Artemisia annua*. There analogues are used in many countries for the treatment of malaria.

Other noteworthy drugs developed from traditional medicinal plants are: Reserpine an antihypertensive drug from *Rauvolfia serpentina*, Ephedrine from *Ephedra sinica* used as the basis for the synthesis of the anti-asthmatic drug salbutamol and salmeterol, tubocurarine a muscle

**Figure 5.** Drugs developed from plant lead molecule.

relaxant, from Curare species. A number of anticancer agents have been obtained from plants: vinblastine and vincristine from *Catharanthus roseus* and two clinically active compounds etoposide and teniposide, Paclitexel most exhilarating anticancer derived from Taxus species. (**Figure 6**).

In addition, recently, various other chemically active agents have gained attention and importantly placed in the arsenal of plant-derived anticancer agents. These are topotecan, irinotecan (CPT-11); belotecan and also their analogues 9-amino and 9-nitro camptochecin. These are semi-synthetic in nature, derived from camptochecin isolated from a Chinese ornamental tree camptotheca acuminate. One of the first plant-derived tubulin interactive compounds recently entered clinical trials, maytansine from the Ethiopian tree *Maytenus serrata*. This plant granted a new lease of life "warhead" (slightly modified), on a monoclonal antibody. The natural product chemists wondered if the compound was microbial in origin due to its similarity to the "ansa" antibiotic such as the rifamycins. Scientists at Takeda during 1977 reported very closely resembled the maytansinoids structure. Thereafter, compounds isolated from bacterium which was renamed as *Actinosynnema pretiosum* in fact similar to those isolated from other plant genera [8].

**2.2. Animals**

**Figure 6.** Plant-derived drugs.

Amphibians, reptiles and humans have been a fine source of drug. Epibatidine is a potent analgesic obtained from the skin of epipedobates tricolour (A frog). This drug is several times stronger than morphine. But the main snag is that the therapeutic dose of the drug is more close to its toxic dose that drives the development of synthetic analogue. Epibatidine has turned out to be important lead compound for potential novel painkillers. Teprotide isolated from the venom of the snake pit viper, *Bothrops jararaca* led to the design and synthesis of ACE inhibitor Captopril used in the management of hypertension. Another noteworthy finding

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**Figure 6.** Plant-derived drugs.

#### **2.2. Animals**

relaxant, from Curare species. A number of anticancer agents have been obtained from plants: vinblastine and vincristine from *Catharanthus roseus* and two clinically active compounds etoposide and teniposide, Paclitexel most exhilarating anticancer derived from Taxus species.

In addition, recently, various other chemically active agents have gained attention and importantly placed in the arsenal of plant-derived anticancer agents. These are topotecan, irinotecan (CPT-11); belotecan and also their analogues 9-amino and 9-nitro camptochecin. These are semi-synthetic in nature, derived from camptochecin isolated from a Chinese ornamental tree camptotheca acuminate. One of the first plant-derived tubulin interactive compounds recently entered clinical trials, maytansine from the Ethiopian tree *Maytenus serrata*. This plant granted a new lease of life "warhead" (slightly modified), on a monoclonal antibody. The natural product chemists wondered if the compound was microbial in origin due to its similarity to the "ansa" antibiotic such as the rifamycins. Scientists at Takeda during 1977 reported very closely resembled the maytansinoids structure. Thereafter, compounds isolated from bacterium which was renamed as *Actinosynnema pretiosum* in fact similar to those isolated from

(**Figure 6**).

34 Molecular Insight of Drug Design

**Figure 5.** Drugs developed from plant lead molecule.

other plant genera [8].

Amphibians, reptiles and humans have been a fine source of drug. Epibatidine is a potent analgesic obtained from the skin of epipedobates tricolour (A frog). This drug is several times stronger than morphine. But the main snag is that the therapeutic dose of the drug is more close to its toxic dose that drives the development of synthetic analogue. Epibatidine has turned out to be important lead compound for potential novel painkillers. Teprotide isolated from the venom of the snake pit viper, *Bothrops jararaca* led to the design and synthesis of ACE inhibitor Captopril used in the management of hypertension. Another noteworthy finding

unexplored. Marine environment characterises various diverse resources towards new drugs to fight most major diseases like malaria and cancer. Marine environment also signifies an ecological resource consisting of a variety of aquatic plants and animals. Such aquatic organisms are screened for immunomodulatory, antibacterial, antifungal, antiinflammatory, antimicrobial, neuroprotective, anticancer, analgesic and antimalarial properties. These aquatic organisms are used for new drug developments mostly all over the world. Thus, under the marine pharmacology, there is further scope for research on the drugs of marine origin [10]. Marine pharmacology can be classified on the basis of source

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• Chemicals produced by or found in marine organisms shown to have a wide variety of

Some of the drugs of marine origin approved for human use in different parts of the world

Given underneath are certain marine drugs that are now under Clinical Phase III trial (**Table 4**).

Antibacterial Eicosapentaenoic acid, isolated from *Phaeodactylum tricornutum* active against gram

Anti-inflammatory The extracts and other parts of a Mediterranean sponge species *Spongia officinalis* showed

Antiviral agents Exo-polysaccharide extracted from the *Celtodoryx girardae* has Anti-herpes simplex virus-1

Anticancer Bryostatin, obtained from the Bryozoan, *Bugula neritina*, some forms from sponges and

Antimicrobial The cephalosporins are well-known antimicrobial agents with a marine source of origin. Antimalarial activity Isonitrile containing antimalarial molecules have been extracted from the Acanthella sp.,

Neuroprotective Extracts of South Indian green seaweed Ulva reticulate having neuroprotective action. Antiparasitic Extracts of Sarcotragus sp. known as Tunisian sponge showed in-vitro anti-leishmanial

of the candidate drug:

are as follows (**Table 3**).

**Class Marine drugs**

**Table 2.** Classification of marine drugs.

• Genetically engineered marine organisms

applications as pharmaceuticals.

• Manufacture of pharmaceuticals and nutraceuticals of marine origin

Classification of marine drugs on the basis of their action (**Table 2**).

There are some marine drugs that are undergoing Phase II trial (**Table 5**).

positive and gram negative bacteria.

anti-inflammatory activity in vivo.

Few drugs are also undergoing Clinical Phase I trial (**Table 6**).

activity.

(HSV) activity.

a Japanese sponge.

tunicates have cytotoxicity.

Analgesic Ziconotide, first US FDA approved analgesic of marine origin.

**Figure 7.** Drug from snake venom.

was the isolation of exendin-4 from the venom of Gila monster, *Heloderma suspectum* that leads to the development of Byetta an injectable antidiabetic drug to control type 2 diabetes. In 2009, a notable peptide having closeness to Human GLP-1 was approved for similar indication in Europe and then in Japan, in 2010, in the USA, under the name liraglutide [9] (**Figure 7**).

#### **2.3. Micro organisms**

The discovery of Penicillin from *Penicillium notatum* in 1929 by Fleming steers a new era in medicine "The Golden Era of Antibiotics" and accelerated the investigation of nature for bioactive agents. The microorganisms are the productive source of dissimilar bioactive metabolites and have turned out to be a vital source of drugs in Pharmaceutical industry. These are antibacterial agents: Penicillin from Penicillium species, cephalosporins from *Cephalosporium acremonium*, tetracycline, chloramphenicol, aminoglycosides, rafamycin, and so on. In addition to this immunosuppressive agents like cyclosporins from trichoderma, cholesterol lowering drug such as mevastatin (compactin; from Penicillium species) and lovastatin from Aspergillus species, anthelmintics and antiparasitic drugs like ivermectins from Streptomyces species are all originated from microorganisms [9].

Among the anticancer drugs, anticancer antibiotics plays a significant role in the chemotherapy. These are given in **Table 1**.

#### **2.4. Marine organisms**

Seventy five percent of the earth surface has been covered by water, but there is limited research as far as pharmacology of marine organisms is concerned. Many of these are still


**Table 1.** Antitumor antibiotics.

unexplored. Marine environment characterises various diverse resources towards new drugs to fight most major diseases like malaria and cancer. Marine environment also signifies an ecological resource consisting of a variety of aquatic plants and animals. Such aquatic organisms are screened for immunomodulatory, antibacterial, antifungal, antiinflammatory, antimicrobial, neuroprotective, anticancer, analgesic and antimalarial properties. These aquatic organisms are used for new drug developments mostly all over the world. Thus, under the marine pharmacology, there is further scope for research on the drugs of marine origin [10]. Marine pharmacology can be classified on the basis of source of the candidate drug:


Classification of marine drugs on the basis of their action (**Table 2**).

Some of the drugs of marine origin approved for human use in different parts of the world are as follows (**Table 3**).

Given underneath are certain marine drugs that are now under Clinical Phase III trial (**Table 4**).

There are some marine drugs that are undergoing Phase II trial (**Table 5**).

Few drugs are also undergoing Clinical Phase I trial (**Table 6**).


**Table 2.** Classification of marine drugs.

**S.No. Anti-tumour antibiotic Source**

apy. These are given in **Table 1**.

**2.4. Marine organisms**

species are all originated from microorganisms [9].

**Table 1.** Antitumor antibiotics.

**2.3. Micro organisms**

**Figure 7.** Drug from snake venom.

36 Molecular Insight of Drug Design

1 Bleomycin Streptomyces verticillus 2 Mitomycin Streptomyces caespitosus 3 Daunomycin Streptomyces peucetius

4 Doxorubicin Streptomyces peucetius var. caesius.

was the isolation of exendin-4 from the venom of Gila monster, *Heloderma suspectum* that leads to the development of Byetta an injectable antidiabetic drug to control type 2 diabetes. In 2009, a notable peptide having closeness to Human GLP-1 was approved for similar indication in Europe and then in Japan, in 2010, in the USA, under the name liraglutide [9] (**Figure 7**).

The discovery of Penicillin from *Penicillium notatum* in 1929 by Fleming steers a new era in medicine "The Golden Era of Antibiotics" and accelerated the investigation of nature for bioactive agents. The microorganisms are the productive source of dissimilar bioactive metabolites and have turned out to be a vital source of drugs in Pharmaceutical industry. These are antibacterial agents: Penicillin from Penicillium species, cephalosporins from *Cephalosporium acremonium*, tetracycline, chloramphenicol, aminoglycosides, rafamycin, and so on. In addition to this immunosuppressive agents like cyclosporins from trichoderma, cholesterol lowering drug such as mevastatin (compactin; from Penicillium species) and lovastatin from Aspergillus species, anthelmintics and antiparasitic drugs like ivermectins from Streptomyces

Among the anticancer drugs, anticancer antibiotics plays a significant role in the chemother-

Seventy five percent of the earth surface has been covered by water, but there is limited research as far as pharmacology of marine organisms is concerned. Many of these are still


**Table 3.** Approved drugs of marine origin.



**3. Natural product drug discovery and development: an integrative** 

Enfortumab vedotin It is used in immunotherapy, and it is a combination of a fully human IgG1k antibody

An integrative approach comprising various discovery tools and novel discipline would definitely endow with an input in natural product drug discovery and development. Natural product can be envisaged to remain an indispensable component in the development of new drug. According to Lutz natural product not only complement synthetic molecule, they also exhibit drug-related features unsurpassable by any synthetic compound. An important attribute of natural product is their huge structure and chemical diversity. Another beneficial feature of natural product is their biological history. The natural products possess an inherent ability to interact with other molecules, which is a crucial precondition for making a drug. The natural product due to its sterically more complex structure exhibit advanced binding properly compared with synthetics. The natural products are perceived as "drug like-ness" and "biological friendliness" than totally synthetic molecule making them apposite lead

ILX-651 (tasidotin or synthadotin) A synthetic derivative of dolastatin-15 and it inhibits assembly of tubulin.

Pseudopterosins A leading class of diterpene glycosides primarily extracted from the

types of cancer.

process.

and monomethyl auristatin E.

also in metastatic renal cancer.

It is an orally active drug and has progressed to Phase II trials in different

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octocoral *Pseudopterogorgia elisabethae*. It is a strong phorbol myristate acetate inhibitor. In a double-blind, Phase II clinical trial, the drug was found to augment re-epithelialisation process in early wound repair

It is a peptide similar to Ziconotide and is undergoing Phase I trials for the treatment of

An antibody-drug conjugate, with monomethyl-auristatin F attached to the anti-CD70 monoclonal humanised antibody 1F6. This molecule is presently being evaluated for its value in relapsed and refractory non-Hodgkin's lymphoma in Phase I clinical trials and

The process of drug discovery involves the identification of candidates, synthesis, screening, characterisation and assays for therapeutic efficacy, which in fact is a very lengthy and tedious process. Considering the success of natural products as source of new drugs, new technologies have emerged to facilitate the process. These technologies are combinatorial chemistry, high throughput screening (HTS), bioinformatics, proteomics and genomics.

**approach**

**Marine drugs in clinical Phase II trial**

**Table 5.** Marine drugs in clinical Phase II trial.

**Table 6.** Marine drugs in clinical Phase I trial.

cancer.

**Marine drugs in clinical Phase I trial**

Leconotide (AM-336, ω-conotoxin CVID)

Vorsetuzumab mafdotin

(SGN-75)

candidates.

**Table 4.** Marine drugs in clinical Phase III trial.



**Marine drugs in clinical Phase II trial**

**Approved marine drug**

38 Molecular Insight of Drug Design

Cytarabine It is FDA approved and mainly used in different types of leukaemia, including acute myelocytic

Vidarabine It is FDA approved used in recurrent epithelial keratitis caused by HSV type 1 and 2, acute kerato-

Trabectedin A marine product extracted from Ecteinascidia turbinate. First anticancer molecule of marine

conjunctivitis, and also for superficial keratitis Ziconotide Ziconotide, FDA approved has shown potential as an analgesic.

apoptotic pathway.

pain related to the cancer.

ovarian cancer

**Table 3.** Approved drugs of marine origin.

**Marine drugs in clinical Phase III trial**

**Table 4.** Marine drugs in clinical Phase III trial.

**Marine drugs in clinical Phase II trial**

[3-(2,4-dimethoxybenzylidene) -anabaseine; GTS-21]

Eribulin mesylate (E7389) or halichondrin B

Soblidotin (auristatin PE

or TZT-1027)

DMXBA (GTS-21)

leukaemia, lymphocytic leukaemia, meningeal leukaemia, and chronic myelogenous leukaemia.

origin got approval in EU for use in soft-tissue sarcoma and in relapsed cases of platinum-sensitive

It is a polyether macrolide natural molecule originally extracted from marine sponges, with potent anticancer activity reported in preclinical animal models. Eribulin is a potent molecule which produces irreversible antimitotic activity leading to cell death by

Is a synthetic derivative of the dolastatin backbone from dolastatin 10. It is a vascular disrupting agent causing the collapse of the vasculature inside the tumour, in addition to its tubulin inhibitory activity. It is undergoing trials in clinical Phases I, II, and III and

tumour agent, currently in Phase III trials as analgesic against inadequately controlled

It is a synthetic imitative of anabaseine, an alkaloid found in many species of aquatic worms of phylum nemertea. It is reported to be beneficial for improving cognition and sensory gating deficiency in a variety of

It was primarily isolated from a tunicate *Aplidium albicans* found in the

Kahalalide family. It is now in Phase II with proof of antitumor potency

*funebris*) skin and mucus as well as from renieramiycins extracted from varieties of sponges and tunicates. Preclinical in vivo studies indicated high antitumor activity in cells of breast, prostate and renal cancers with a

originally derived from marine Aspergillus sp. CNC-139 and phenylahistin extracted from Aspergillus ustus. It inhibits the polymerisation of tubulin, resulting in destabilisation of the vascular endothelial cells of the tumour.

Mediterranean Sea. It is a highly potent apoptosis inducer.

companies are trying to use it as a weapon to specific monoclonal antibodies.

Tetrodotoxin Well-known "marine toxin", and highly substituted guanidine-derivative is not an anti-

laboratory animals.

Plitidepsin It is a natural marine depsipeptide, currently obtained by total synthesis.

Elisidepsin (PM02734) It is a novel cyclic peptide derived from marine sources belonging to the

with positive therapeutic index. PM00104 (Zalypsis) It is linked to jorumycin extracted from the Pacific nudibranch's (*Jorunna* 

Plinabulin (NPI-2358) It is a fully laboratory made analog of the natural product halimide

modest antitumor action on colon cancer cells.

**Table 5.** Marine drugs in clinical Phase II trial.


**Table 6.** Marine drugs in clinical Phase I trial.

## **3. Natural product drug discovery and development: an integrative approach**

An integrative approach comprising various discovery tools and novel discipline would definitely endow with an input in natural product drug discovery and development. Natural product can be envisaged to remain an indispensable component in the development of new drug. According to Lutz natural product not only complement synthetic molecule, they also exhibit drug-related features unsurpassable by any synthetic compound. An important attribute of natural product is their huge structure and chemical diversity. Another beneficial feature of natural product is their biological history. The natural products possess an inherent ability to interact with other molecules, which is a crucial precondition for making a drug. The natural product due to its sterically more complex structure exhibit advanced binding properly compared with synthetics. The natural products are perceived as "drug like-ness" and "biological friendliness" than totally synthetic molecule making them apposite lead candidates.

The process of drug discovery involves the identification of candidates, synthesis, screening, characterisation and assays for therapeutic efficacy, which in fact is a very lengthy and tedious process. Considering the success of natural products as source of new drugs, new technologies have emerged to facilitate the process. These technologies are combinatorial chemistry, high throughput screening (HTS), bioinformatics, proteomics and genomics. Other recently developed techniques are molecular diversity, compound library design, MMR based screening, QSAR and computer-aided drug design.

software, liquid handling devices and sensitive detectors making researchers to quickly conduct the biochemical, genetic or pharmacological tests. Employing HTS, it is comparatively trouble-free and swift to identify active compounds. HTS is hassle free technique that collects

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Genomics and proteomics in combination with combinatorial chemistry and high-throughput screening are helping to bring forward an unparalleled number of potential lead compounds. Proteomics includes technologies for protein mapping that is separating, distinguishing and quantifying the proteins in samples and also identification and characterisation of specific protein. The main protein mapping technology currently in use is two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) that can resolve up to 2000 proteins in single gel.

Genomics is an area within genetics that concerns the sequencing and analysis of an organism's genome. The genome is the entire DNA content that is present within one cell of an organism. Experts in genomics strive to determine complete DNA sequences and perform genetic mapping to help understand disease. Since many diseases occurs due to failure of genes to perform correctly, genomics help to identify the genes involved in responsiveness to

In spite of so many inherent advantages of these natural products for the synthesis of various molecules ranging from simple skeleton to highly complex chemical structures, they do have

• Drug discovery from natural products would eventually lead to its commercialisation. This may further burden the natural resource and consequently lead to undesirable environmental concerns. While synthesis of active molecule could be an option, not every molecule is amenable for complete synthesis. Hence, certain degree of dependence on lead resource would continue, for example, anticancer agent like etoposide, docetaxel, paclitaxel. It is expected that around 25,000 plant species would cease to exit by the end of this century.

• Another issue, the IPR protection related to the natural products is creating some confusion

These processes impede the pace of discovery process at various levels. Challenges in the new

because the lead compounds are based on some linkage to traditional uses.

**i.** Existing prototype for drug discovery in large pharmaceutical industries.

a given drug. Hence, genomics is an integral part of drug discovery [12].

large amount of experimental data in a relatively short time [11].

**3.3. Bioinformatics, proteomics and genomics**

**4. Challenges with natural products**

certain potential limitations.

drug developments are mainly due to:

**ii.** Technical limitation of natural products

#### **3.1. Combinatorial chemistry**

Combinatorial chemistry involves the rapid synthesis or the computer simulation of a large number of different but often structurally related molecules or materials. In a combinatorial synthesis, the number of compounds made increases exponentially with the number of chemical steps. In a binary light-directed synthesis, 2n compounds can be made in n chemical steps. Combinatorial chemistry is especially common in computer aided drug design (CADD) and can be done online with web-based software, such as mole inspiration.

#### *3.1.1. Principle of combinatorial chemistry*

Combinatorial chemistry is a technique by which large numbers of structurally distinct molecules may be synthesised in a time and submitted for pharmacological assay. The key of combinatorial chemistry is that a large range of analogues is synthesised using the same reaction conditions, the same reaction vessels. In this way, the chemist can synthesise many hundreds or thousands of compounds in one time instead of preparing only a few by simple methodology.

The conventional approach of synthesis is

**A + B → AB**

In contrast to this approach, combinatorial chemistry offer the potential to make every combination of compound A1 to An with compound B1 to Bn.

The range of combinatorial techniques is highly diverse, and these products could be made individually in a parallel or in mixtures, using either solution or solid phase techniques.

Combinatorial Chemistry is used to synthesise large number of chemical compounds by combining sets of building blocks. Each newly synthesised compound's composition is slightly different from the previous one. A traditional chemist can synthesise 100–200 compounds per year. A combinatorial robotic system can produce in a year thousands or millions compounds, which can be tested for potential drug candidates in a high-throughput screening process [11].

#### **3.2. High throughput screening**

High throughput screening is a standard method for hit discovery for scientific experimentation in drug discovery and allied field. HTS uses robotics, data processing and control software, liquid handling devices and sensitive detectors making researchers to quickly conduct the biochemical, genetic or pharmacological tests. Employing HTS, it is comparatively trouble-free and swift to identify active compounds. HTS is hassle free technique that collects large amount of experimental data in a relatively short time [11].

#### **3.3. Bioinformatics, proteomics and genomics**

Other recently developed techniques are molecular diversity, compound library design,

Combinatorial chemistry involves the rapid synthesis or the computer simulation of a large number of different but often structurally related molecules or materials. In a combinatorial synthesis, the number of compounds made increases exponentially with the number of chemical steps. In a binary light-directed synthesis, 2n compounds can be made in n chemical steps. Combinatorial chemistry is especially common in computer aided drug design (CADD) and can be done online with web-based software, such as mole

Combinatorial chemistry is a technique by which large numbers of structurally distinct molecules may be synthesised in a time and submitted for pharmacological assay. The key of combinatorial chemistry is that a large range of analogues is synthesised using the same reaction conditions, the same reaction vessels. In this way, the chemist can synthesise many hundreds or thousands of compounds in one time instead of preparing only a few by simple

**A + B → AB**

In contrast to this approach, combinatorial chemistry offer the potential to make every combi-

The range of combinatorial techniques is highly diverse, and these products could be made individually in a parallel or in mixtures, using either solution or solid phase techniques.

Combinatorial Chemistry is used to synthesise large number of chemical compounds by combining sets of building blocks. Each newly synthesised compound's composition is slightly different from the previous one. A traditional chemist can synthesise 100–200 compounds per year. A combinatorial robotic system can produce in a year thousands or millions compounds, which can be tested for potential drug candidates in a high-throughput screening

High throughput screening is a standard method for hit discovery for scientific experimentation in drug discovery and allied field. HTS uses robotics, data processing and control

MMR based screening, QSAR and computer-aided drug design.

**3.1. Combinatorial chemistry**

40 Molecular Insight of Drug Design

*3.1.1. Principle of combinatorial chemistry*

The conventional approach of synthesis is

nation of compound A1 to An with compound B1 to Bn.

inspiration.

methodology.

process [11].

**3.2. High throughput screening**

Genomics and proteomics in combination with combinatorial chemistry and high-throughput screening are helping to bring forward an unparalleled number of potential lead compounds. Proteomics includes technologies for protein mapping that is separating, distinguishing and quantifying the proteins in samples and also identification and characterisation of specific protein. The main protein mapping technology currently in use is two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) that can resolve up to 2000 proteins in single gel.

Genomics is an area within genetics that concerns the sequencing and analysis of an organism's genome. The genome is the entire DNA content that is present within one cell of an organism. Experts in genomics strive to determine complete DNA sequences and perform genetic mapping to help understand disease. Since many diseases occurs due to failure of genes to perform correctly, genomics help to identify the genes involved in responsiveness to a given drug. Hence, genomics is an integral part of drug discovery [12].

#### **4. Challenges with natural products**

In spite of so many inherent advantages of these natural products for the synthesis of various molecules ranging from simple skeleton to highly complex chemical structures, they do have certain potential limitations.


These processes impede the pace of discovery process at various levels. Challenges in the new drug developments are mainly due to:


According to Koehn and Carter, the unique feature/characters of the compound isolated from natural products are:

not much published, the marine-sourced fungi shall perform progressively significant role in the future. This role especially when given the impressive advances in the power of organic synthesis to report the supply problems intrinsic with this source material. With the arrival of genetic techniques that permit the isolation and expression of biosynthetic cases in the future, microbes and their marine invertebrate hosts might better be the new frontier towards natural

Integrated Approach to Nature as Source of New Drug Lead

http://dx.doi.org/10.5772/intechopen.74961

43

Forthcoming features of antibiotic discovery and development include somewhat from a different perspective, a significant number of issues referred to in this chapter. Together with these novel sources to refurbished phenotypic screens that employ high-content imaging systems and that can run in microliter volumes, it might enable investigators to speedily evaluate

products lead discovery. Plant endophytes also offer stimulating new resource.

Pharmacy Department, K.N. Polytechnic College Jabalpur, Madhya Pradesh, India

Bulletin of the World Health Organisation. 1985;**63**:965-981

[1] Lahlou M. The success of natural products in drug discovery. Pharmacology and Phar-

[2] Famsworth NR, Akerele O, Bingel AS, Soejarto DD, Guo Z. Medicinal plants in therapy.

[3] Ulrich-Merzenich G, Panek D, Zeiltor H, Velter H, Wagnes H. Drug development from natural products: Expoliting synergistic effects, Indian. The Journal of Experimental

[4] Pawar HA. Natural product as a source of lead to the design of new drugs. Natural Products Chemistry & Research. 2014;**2**(6):156. DOI: 10.4172/2329-6836.1000156

[5] Cragg GM, Newman DJ. Biodiversity: A continuing source of novel drug leads. Pure

[6] Patwardhan B, Vaidya ADB. Natural products drug discovery: Accelerating the clinical candidate development using reverse pharmacology approaches, Indian. The Journal of

[7] Bhutani KK, Gohil VSM. Natural products drug discovery research in India: Status and

appraisal. Indian Journal of Experimental Biology. 2010;**48**:199-207

the activity of individual agents and their potential.

Address all correspondence to: seemankohli@gmail.com

**Author details**

Seema Kohli

**References**

macy. 2013;**4**:17-31

Biology. 2010;**48**:208-219

and Applied Chemistry. 2005;**77**(1):7-24

Experimental Biology. 2010;**48**:220-227


It is presumed that large number of NP despite being biologically active and having favourable pharmacokinetic profile do not satisfy the criteria "drug likeness." The challenge is of building a physio-chemical tuned natural products library in line c the lead generation to promote natural products to their full potential. Therefore, ultimately, the biggest challenge is to find alternative drug ability criteria for the compound of natural origin, as they do not fit "rule of five" for to be drug like. As per rule of five propagated by Lipinski [14], a drug candidate should have:


#### **5. Conclusion**

Natural product drug discovery, ethno-pharmacology, traditional and attractive medicines are re-emerging as new strategic options. The chapter endeavoured that novel-natural products can be optimised on the basis of their biological activities using highly sophisticated combinatorial biosynthetic techniques, microbial genomes and screening process.

The chapter made efforts to provide short-lived imprint of the significance of natural products as bioactive molecules and also as pharmaceutical agents. On the advent of novel screening systems related to the discovery of genetic information accelerating the need to rapidly identify effective and novel lead structures as important necessity. It is certain that an important portion of these leads will remain to be resultant natural product.

As on today, comparative ease of access to plants now resulted in the discovery of a plantderived compounds, so far as the microbial sources are particularly important in the area of antibiotic. Further effort suggests, that marine organisms, and such group of organisms not much published, the marine-sourced fungi shall perform progressively significant role in the future. This role especially when given the impressive advances in the power of organic synthesis to report the supply problems intrinsic with this source material. With the arrival of genetic techniques that permit the isolation and expression of biosynthetic cases in the future, microbes and their marine invertebrate hosts might better be the new frontier towards natural products lead discovery. Plant endophytes also offer stimulating new resource.

Forthcoming features of antibiotic discovery and development include somewhat from a different perspective, a significant number of issues referred to in this chapter. Together with these novel sources to refurbished phenotypic screens that employ high-content imaging systems and that can run in microliter volumes, it might enable investigators to speedily evaluate the activity of individual agents and their potential.

#### **Author details**

#### Seema Kohli

According to Koehn and Carter, the unique feature/characters of the compound isolated from

**f.** Wider distribution of molecular properties, such as molecular mass, O/w partition coef-

It is presumed that large number of NP despite being biologically active and having favourable pharmacokinetic profile do not satisfy the criteria "drug likeness." The challenge is of building a physio-chemical tuned natural products library in line c the lead generation to promote natural products to their full potential. Therefore, ultimately, the biggest challenge is to find alternative drug ability criteria for the compound of natural origin, as they do not fit "rule of five" for to be drug like. As per rule of five propagated by Lipinski [14], a drug

Natural product drug discovery, ethno-pharmacology, traditional and attractive medicines are re-emerging as new strategic options. The chapter endeavoured that novel-natural products can be optimised on the basis of their biological activities using highly sophisticated

The chapter made efforts to provide short-lived imprint of the significance of natural products as bioactive molecules and also as pharmaceutical agents. On the advent of novel screening systems related to the discovery of genetic information accelerating the need to rapidly identify effective and novel lead structures as important necessity. It is certain that an important

As on today, comparative ease of access to plants now resulted in the discovery of a plantderived compounds, so far as the microbial sources are particularly important in the area of antibiotic. Further effort suggests, that marine organisms, and such group of organisms

combinatorial biosynthetic techniques, microbial genomes and screening process.

portion of these leads will remain to be resultant natural product.

natural products are:

42 Molecular Insight of Drug Design

**a.** Increased steric complexity

**e.** Molecular rigidity is high

candidate should have:

**iii.** Mol, wet >500 Da **iv.** PK of less than 5

**5. Conclusion**

**i.** Less than 10 H bond acceptors **ii.** Less than 5 H bond acceptors

**b.** Presence of large number chiral centres

**c.** Presence of greater number of oxygen atoms

ficient and diversity of ring system [13].

**d.** Ratio of aromatic ring atoms to total heavy atoms, that is, low

Address all correspondence to: seemankohli@gmail.com

Pharmacy Department, K.N. Polytechnic College Jabalpur, Madhya Pradesh, India

#### **References**


[8] Balunas MJ, Douglas Kinghorn A. Drug discovery from medicinal plants. Life Sciences. 2005;**78**:431-441

**Section 2**

**Specific Molecular Mechanism and Lead**

**Compounds for Drug Design**

