Review on Modern Drug Discovery Process

 

Ms. Shraddha P. Amrutkar1*, Mr. Paresh A. Patil2*, Ms. Rajshri S. Patel3*

1R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Dhule.

2Ahinsa Institute of Pharmacy, Dondaicha, Shindkheda, Dhule. (MS) 425408 India.

3Parul Institute of Pharmacy and Research, Vadodara, Gujarat.

*Corresponding Author E-mail: rcp.pareshpatil@gmail.com

 

ABSTRACT:

Drug discovery is a process, which aims at identifying a compound therapeutically useful in treating and curing a disease. Developing a new drug from original idea to the launch of finished product is a complex process which can take 12-15years and cost in excess of $1 billion. The process of drug discovery involves the identification of candidates, synthesis, characterization, screening and assays for therapeutic efficacy. Once a compound has shown its value in these tests, it will begin the process of drug development prior to clinical trials. Drug discovery and development is an expensive process due to high cost of R & D and human clinical tests.

 

KEYWORDS: IND, NDA, Clinical study, HIT.

 

 


INTRODUCTION:

MODERN DRUG DISCOVERY (3)

·         In the past most drug have been discovered either by identifying the active ingredient from traditional medicines or by serendipitous discovery

·         At present a new approach is being tried to understand how disease and infections are controlled at the molecular and physiological level and to target specific entities based on this knowledge

·         Drug discovery process operates on target-based approach, in which organism is seen as series of genes and pathways and the goal is to develop drugs that affect only one gene or molecular mechanism in order to selectively treat the deficit causing the disease without producing side effects

 

STEPS INVOLVED IN MODERN DRUG DISCOVERY PROCESS (1):

1.       Target identification

2.       Target validation

3.       Hit and lead discovery

4.       Lead optimization

5.       Pre clinical testing

6.       Chemical testing and new drug application (NDA)

7.       Food and drug administration (FDA) approval

 

PHASES OF DRUG DISCOVERY and DEVELOPMENT:

1.       Pre -discovery

2.       Drug discovery

3.       Drug development

 

PRE-DISCOVERY:

·         Understanding the disease

·         Knowledge of physiological, biochemical and pathological mechanism of disease

·         Example- Parkinson disease

·         In Parkinson disease decrease level of dopamine in nigro-striatal pathway

·         Loss of dopaminergic neurons

·         The presence of characteristics intracellular aggregates called lewis bodies which is made up of mutated version of protein are called alpha-synuclein

·         Why only dopaminergic neurons affected?

·         Molecular mechanism of dopamine?

·         Reason for mutation of alpha-synuclein

 

TARGET IDENTIFICATION (2):

·         Target identification is the first key stage in the drug discovery pipeline

·         A drug target is the specific binding site of a drug in vivo through which the drug exerts its action

·         A drug target is the biomolecules, also a biomolecule involved in a transduction pathway

·         The change in the biomolecule structure various physiological response occurs and induce regulation of the cell, organ, tissue and body status

·         The physiological response triggered by the changes in biomolecule structure plays a major role in complex regulation and have a therapeutic effect on pathological conditions

 

TARGET VALIDATION (5):

·         New target validation is the basis of completely new drug exploration and initial step of drug discovery

·         After the drug has been identified, a rigorous evaluation needs to occurs that modulation of the target will have the desired therapeutic effect

·         In the drug discovery process, the major bottleneck is the target validation

·         Target validation might be of great help not only to new drug research and development but also provide more insight into the pathogenesis of target related disease

·         Validation technique range from in vitro tools through the use of whole animals’ models, to modulation of a desired target in disease patient

 

Target validation process might include six steps

1.       Discovering a biomolecule of interest

2.       Evaluating its potential as a target

3.       Designing a bioassay to measure biological activity

4.       Constructing a high-throughput screen

5.       Performing screening to find a hits

6.        Evaluating the hits

 

HIT AND LEAD DISCOVERY:

·         Identification of small molecule ‘hit’ as a starting point for the hit-to-lead process

·         The identification of small molecule modulators of protein function and the process of transforming these into high content lead series are key activities in modern drug discovery

·         A hit as being a compound which has the desired activity in a compound screen and whose activity is confirmed upon retesting

·         The “hit-to-lead” phase is usually the follow up of high-throughput screening (HTS)

·         Hits can be identified by one or more of several technology-based approaches like high-throughput biochemical and cellular assays, assays of natural products, structure-based design, peptides and virtual screening

 

LEAD OPTIMIZATION:

·         Lead optimization is the complex, no-linear process of refining the chemical structure of a confirmed hit to improve its drug characterisiticswith the goal of producing drug candidate

·         Lead optimization is a process that begins with a compound that displays an interesting biological action and ends with the identification of the best analogue

·         Lead structures are optimized for target affinity and selectivity

·         Leads are characterised with respect to pharmacodynamic properties such as efficacy and potency in vitro and in vivo, physiochemical properties, pharmacokinetic properties and toxicological aspects

 

Preclinical and Clinical Testing (4)

·         Clinical trial is defined as “systematic study of new drug in human subject to generate data for discovering or verifying the clinical, pharmacological and adverse effects with the objective of determining safety or efficacy of new drug.

·         For any new drug to enter in clinical trial, it must pass preclinical studies

·         Pre-clinical studies involves in vitro (i.e., test tube or laboratory) studies and trials on animal population

 

In vitro:

Subcellular components (Ribosomes, mitochondria) Cellular/ subcellular extracts (wheat germ, reticulocyte extract) Purified molecules (DNA, RNA)

 

In vivo:

·         Rodent/non rodent

•Metabolic profile • Toxicology • Drug interaction

·         Animal models of disease states

·         Test conditions involving induced disease or injury similar to human conditions.

·         Behavioural Studies Functional Imaging

 

Ex vivo:

·         tissue in an artificial environment outside the organism with the minimum alteration of natural condition

·         tissue properties • Realistic models for surgery

 

WHY PRECLINICAL TESTING? (1)

·         Screening test

·         Test on isolated organ, bacterial culture

·         General observational test

·         Tests on animal models of human disease

·         Confirmatory tests and analogue activities

·         Mechanism of action

·         Quantitative test

·         Pharmacokinetics-ADME

·         Toxicity test

·         Systemic toxicity studies

·         Single and repeated dose toxicity studies

·         Male fertility study

·         Female reproductive and developmental toxicity studies

·         Teratogenicity study

·         Perinatal study (in pregnant animal)

·         Local toxicity

·         dermal toxicity study

·         Photo-allergy or dermal photo-toxicity

·         Vaginal toxicity

·         Inhalation toxicity

·         Allergenicity/hypersensitivity

·         Genotoxicity

·         Carcinogenicity

·         Gross observation and microscopy of >30 internal organ

 

INVESTIGATIONAL NEW DRUG (2):

·         Drug developers, orsponsors, must submit an IND application to FDA before beginning clinical research

·         IND application is the result of successful preclinical development

·         An IND application is a submission to FDA requesting permission to initiate the study of new drug product

·         The documentation required in an NDA is supposed to tell the detailed information about new drug product including what happened in clinical tests, what are the active ingredients, the result of animal studies, pharmacokinetic and pharmacodynamic properties of drug and how it is manufactured, proceed and packaged

 

The NIH organizes clinical trials into 5 different types:

1.       Treatment trials: test experimental treatments or a new combination of drugs

2.       Prevention trials: look for ways to prevent a disease or prevent it from returning

3.       Diagnostic trials: find better test or procedures for diagnosing a disease

4.       Screening trials: test methods of detecting diseases

5.       Quality of life trials: explore ways to improve comfort and quality of life for individuals

 

Clinical trials are commonly classified into 4 phases.(1)

Phase 0

Phase I: Human/ Clinical Pharmacology trial

Phase II: Exploratory trial

Phase III: Confirmatory trial

Phase IV: Post-Marketing Surveillance

 

Phase 0:

·         Recent designation for exploratory, first in human trials conducted in accordance with the U.S.F.D.A. 2006 on exploratory,

·         Administration of single sub therapeutic doses of the study drug to of a small number of subjects (10-15) to gather preliminary data on the agents pharmacokinetics and pharmacodynamics

 

Phase I:

·         Initial safety in terms of safe dose range and biological effects including adverse effects

·         Metabolism and kinetics

·         Heathy volunteers (20-80) in number except for life threatening disease such as cancer, AIDS, where actual patients only are included

 

Phase II:

·         To find whether or not the drug possesses the actual therapeutic potential

·         Its identified the therapeutic efficacy of the drug with the dose range, kinetics as well as metabolism

·         It follows the RCT type with binding of treatment

·         Healthy volunteers (100-300 in number)

·         To find out the therapeutic index and adverse effects of the drug

·         Safety – Efficacy – Drug Toxicity – Drug Interaction

 

Phase III:

·         Evaluate safety and efficacy at large

·         It is to confirm the effectiveness of the drug or treatment, to monitor side effects

·         Large number of patients (1000-3000 in number)

·         Once the drug passes this phase successfully, it is licenced for commercial use

·         Phase 3 of trial is a key study forming the primary basis for regulatory approval of an intervention and I often referred as pivotal trial

 

Phase IV:

·         It is carried out after the drug is released in the market for therapeutic use

·         It is mainly to detect uncommon but significant adverse effects

·         The FDA requires continued evaluation after release to evaluate safety sign that may affect the benefit-risk ratio

·         The focus of trials is on how drugs work in the real world

·         Once the drug enters the market, it will be utilized by many more patients having other co-morbidity and co-existing disease in addition to the diseased for which the drug is indicated and licenced

·         To provide critical information on drug-drug interactionor iatrogenic disease

 

TYPES OF CLINICAL STUDY (4):

Experimental study:

Randomized study:

·         Randomized, controlled clinical trials (RCTs), human subjects(either healthy volunteers or patients) do not choose the therapy being studied or compared

·         RCTs are based on randomization

·         When a new drug successfully passes the pre-clinical studies,it is challenged to clinical experiments that follow random assignment of subjects to two or more groups one of which behaves as control group and therefore,such clinical experiments are called as RCTs

·         Several components to be considered include

1.       Study design

2.       Patient population

3.       Control group

4.       Randomization

5.       Blinding or non blinding/open labelling

6.       Treatment consideration

7.       Outcome measures

 

Non- randomized study:

·         Patients are selected on the basis of selection criteria

·         They are not randomized to the particular treatment and are given a treatment depending upon course of disease.

·         Phase 4 of clinical trials follow this way

·         In many experimental studies in humans, randomization is not possible

·         Many of surgical experiments have evolved with specific indication and application

·         They have a focused patient group and therefore randomization is not possible or is unethical

·         Example-patients with the both kidneys failed require undergoing kidney transplantation, Although dialysis is an available option is not comparable with the renal transplantation and hence the patients cannot be randomized to such option

 

Observational study (3):

·         The subject to be observed chooses whether or not to take the drug or to have a surgery being studied.

·         Errors that are likely to occur include the differences in profile of the subjects since variables such as age, family history of disease, cause and severity of disease etc may not be defined

·         Example –two patient suffering from headache, one because of migraine and the other because of common cold. these two patients cannot be compare for the analgesic activity of one drug since the cause and severity of headache and hence the analgesic activity of the drug would vary greatly

·         Observational studies can never be blinded, hence biases from patients, observer and experimenter may result into systematic and random errors

·         Mainly two types

1.       Aggregate observation studies

2.       Individual observation studies

 

Aggregate observational studies:

Pandemic and epidemic studies on communicable diseases and their treatments are generally carried out as aggregate observation studies.

Example- occurrence and effective treatment of malaria and its relapse in particular geographical area

 

Individual observational studies (3):

·         The patients are individually observed and they are assembled in groups on the basis of outcome or exposure or both.

·         Depending on the basis of the grouping, the individual observational study is sub classified into 3 class.

      Cohort

      Case –control study

      Cross-sectional

 

Cohort:

·         Groups are assembled on the basis of exposure

·         Here the exposure is well-defined but outcome is variable

·         Thus it allow study of one exposure with many more outcomes

·         Cohort study can be retrospective where in the groups are defined in past or it can be prospective where in the groups are defined in present

·         The retrospective cohort correlates the exposure occurred in the past with the outcome resulted just in recent past

·         If the patients have been treated with different treatments to control outcome-related variables, it limits the correlation between exposure and one outcome only

·         Quick and expensive method

·         retrospective cohort study suffices the requirements of prospective study with additional advantage of less time and money consumption

 

Case-control (4)

·         Case-control study involves assembling of subjects in groups on the basis of the outcome found in those subjects

·         It compares the subjects with outcome in question (the group behaves as a case group) with the subjects without the outcome (the group acts as a control) e.g. occurrence or nonoccurrence of myocardial infarction (MI) in patients with hypertension (HT)

·         It generally follows the retrospective design and evaluates how the exposure is related to the well-defined outcome using control group

·          It is quick and inexpensive

·         patients with rare outcome can be assembled in a group to study oetioes, pathophysioes and prognosis of a disease.

·          Results are generally expressed in terms of odds ratio (OR) and risk ratio/ relative risk (RR)

·         Cross-sectional (5)

·         Cross-sectional study assesses both the exposure and outcome concurrently

·          Generally it is survey- or review based

·          Cross-sectional study is, therefore, good for prevalence research

·         However, it is not suitable for causal outcome assessment

 

REFERENCES:

1.        Gandhi, P., 2011. Clinical Research Methodology. Indian J Phar Edu Res, 45(2), pp.199-209

2.        Rao, V.S. and Srinivas, K., 2011. Modern drug discovery process: an in silico approach. Journal of Bioinformatics and Sequence Analysis, 2(5), pp.89-94

3.        Prakash, N. and Devangi, P., 2010. Drug Discovery. J. Antivir. Antiretrovir, 2(4)

4.        Hughes, J.P., Rees, S., Kalindjian, S.B. and Philpott, K.L., 2011. Principles of early drug discovery. British Journal of Pharmacology, 162(6), pp.1239-1249

5.        Thorat, S.B., Banarjee, S.K., Gaikwad, D.D., Jadhav, S.L. and Tharat, R.M., 2010. Clinical trial: a review. International Journal of Pharmaceutical Sciences Review and Research [Internet], 1(2), pp.101-6.

 

 

Received on 24.06.2020         Modified on 11.07.2020

Accepted on 21.07.2020       ©A&V Publications All right reserved

Res.  J. Pharmacology and Pharmacodynamics.2020; 12(3):137-141.

DOI: 10.5958/2321-5836.2020.00025.7