Drug Development Process

• Introduction
• Early drug discovery

Contents •
•
Preclinical research
Clinical research
• Regulatory review and approval
• Post- Marketing Safety Surveillance
 Stages of Drug Development

1. Discovery and Development

2. Preclinical research
3. Investigational New Drug (IND) Application
4. Clinical research
Clinical trial phase studies
The IND process
FDA IND approval
FDA review: NDA
Final FDA approval
FDA Post-Market Safety Monitoring
• Discovery
• Target Identification and Validation: Identify a molecular target (e.g., a protein, gene)
associated with a disease.
• Compound Screening: Screen thousands of compounds to find potential candidates that
affect the target.
• Preclinical Testing
• In Vitro Studies: Test the candidate drugs on cells or tissues in a laboratory setting.
• In Vivo Studies: Conduct animal studies to evaluate the safety, efficacy, and
pharmacokinetics (how the drug moves through the body).
2. Investigational New Drug Application (IND)
• Before human trials, a company must submit an IND application to the regulatory
authorities (e.g., FDA in the US).
• The IND includes data from preclinical studies, the proposed clinical trial protocols, and
manufacturing information.
• Approval of the IND allows the drug to enter clinical trials.
3. Clinical Trials
• Clinical trials are conducted in phases to ensure the drug's safety and efficacy.

• Phase I: Safety and Dosage

• Objective: Assess the safety, tolerability, and pharmacokinetics in a small group of
healthy volunteers or patients.
• Participants: 20-100
• Phase II: Efficacy and Side Effects
• Objective: Evaluate the drug's efficacy, determine optimal dosing, and identify side
effects.
• Participants: 100-300 patients with the disease/condition.
• Phase III: Confirmation and Monitoring
• Objective: Confirm efficacy, monitor side effects, compare with commonly used
treatments, and collect data for drug labeling.
• Participants: 1,000-3,000 patients.
4. New Drug Application (NDA)/Biologics License Application (BLA)
• After successful clinical trials, a company submits an NDA (for drugs) or BLA (for biologics) to
regulatory authorities.
• The application includes comprehensive data from preclinical and clinical studies, proposed
labeling, and manufacturing details.
5. Regulatory Review and Approval
• Regulatory authorities review the NDA/BLA to ensure the drug's safety, efficacy, and quality.
• This review can involve advisory committee meetings, additional studies, or clarifications.
6. Post-Market Surveillance (Phase IV)
• After approval, the drug enters the market but continues to be monitored for long-term
safety and effectiveness.
• Phase IV trials may be conducted to gather additional information about the drug's risks,
benefits, and optimal use.
 Various approaches to drug discovery
1. Pharmacological
2. Toxicological
3. IND application
4. Drug characterization
5. Dosage form
Pharmacological

Target Identification Identify and validate biological targets

Lead Compound
Find molecules that interact with the target
Identification

Lead Optimization To obtain candidate compound that are suitable for further investigation

Test in vitro and in vivo. Methods: ADME studies, toxicology, efficacy testing.
Preclinical Studies Importance: Assess safety and biological activity.

Testing for effect on liver enzymes, specific ion channels, unrelated target
Pharmacological
where interaction might happen
testing
Toxicological
Initial Toxicology
In vitro studies (cell culture models, genotoxicity assays)
Studies

Acute Toxicity Testing Single dose studies in rodents (LD50). Importance: Identifies acute hazards and
safe starting doses.

Subacute and Repeated dose studies in rodents and non-rodents for up to 90 days. Endpoints:
Subchronic Toxicity Clinical signs, body weight, hematology, necropsy, histopathology. Target organ
Testing toxicity.

Long-term studies (6 months to 2 years).Data on long-term safety and

Chronic Toxicity Testing carcinogenicity.

Reproductive and Fertility, prenatal, postnatal studies.

Developmental Toxicity

Carcinogenicity Testing Long-term studies in rodents

Investigational New Drug (IND) Application

Once all of the scientific, manufacturing, and technical hurdles have been overcome, an organization must gain approval before
they will be authorized to move forward with human studies. Government agencies such as the Food and Drug Administration
(U.S.), the European Medicines Agency (European Union), the Pharmaceuticals and Medical Devices Agency (Japan), Health
Canada, Health Science Authority (Singapore), Ministry of Food and Drug Safety (South Korea), National Medical Products
Administration (China), and similar agencies across the globe oversee the drug approval process.

Although these agencies are controlled by the governments under which they operate, the nongovernmental organization the
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) was established
in 1990 as part of an effort to harmonize the rules and guidelines associated with the new drug approval (NDA) process. In
general, these agencies must receive and approve clinical plans before a potential therapy can be tested in human populations
 s
t
Investigational New Drug (IND) Application
a
n
c
• IND (US): Investigational New Drug application e
• CTA (EU): Clinical Trial Authorization a
n
• CTN (EU): Clinical Trial Notification d
p
r
o
1. Animal Pharmacology, Safety, and Toxicology d Data from animal studies
u
c Includes pharmacological profile and toxicological
t
s
data
t Ensures safety and biological activity before
a
b human trials
i
l
2. Chemistry, Manufacturing, and Controls (CMC) i
t
Details on drug composition, manufacturing
y process, and quality control
- Information on drug substance and product
E
n stability
s Ensures consistency and quality of the drug
u
r
3. Clinical Trial Protocols e Detailed plan of the clinical trials, including
s objectives, design, methodology, and statistical
c
o considerations
n
s
Information on investigators conducting the trials
i Ensures that trials are scientifically sound and
s
t ethically conducted
e
FDA does not respond to the IND by granting approval. “Approval” is a passive response. Instead, once submitted,
a sponsor must wait 30 days to allow FDA to make an assessment of the safety of the proposed trials.
If FDA raises no objections, the sponsor is allowed to begin the proposed clinical trial.

Before submitting the IND to the FDA, the sponsor has the option of scheduling a pre- IND meeting.
Pre-IND meetings are often held from 6 months to 1 year before filing the IND.
The sponsor submits a Pre-IND Information Package prior to the pre-IND meeting.
This Package describes the chemical structure of the drug, the proposed dosages, the
proposed indications and studies, and other information

INDs may be classified into two broad categories: commercial or noncommercial.

Commercial INDs (e.g. exploratory INDs) are submitted primarily by companies whose goal is to obtain marketing
approval for a new product.
Noncommercial INDs includes investigator, emergency use, and treatment INDs. These are filed for
noncommercial research.
Investigational new drug application: Clinical trial protocols, including investigator information

An IRB (in US), also referred to as an independent ethics committee or ethical review board (in EU), is a committee tasked with
ensuring that clinical trials are run in an appropriate manner. The IRB/EC has the responsibility to protect research participants
and has the right to disapprove the study protocol or require changes before approving the planned clinical trials and allowing
any participants to enroll. This process includes the development of appropriate informed consent documents, which will be
required from all clinical trial participants. They are formally charged with the tasks of monitoring, reviewing, and approving all
aspects of the clinical programs. This includes any changes to protocols that may be required as a result of new data that emerges
through the course of the trials. Risk-to-benefit analysis may also be performed by the IRB as the clinical trials move forward in
order to determine whether or not it is safe to continue the trials.

Investigator’s Brochure (IB)

The investigator’s brochure (IB) is a compilation of the clinical and nonclinical data on the investigational product(s) that are
relevant to the study of the product(s) in human subjects. Its purpose is to provide the investigators and others involved in the
trial with the information to facilitate their understanding of the rationale for, and their compliance with, many key features of
the protocol, such as the dose, dose frequency/interval, methods of administration: and safety monitoring procedures.
Compounds that exhibit cytotoxicity are capable of killing otherwise healthy cells. Fortunately, in vitro screening methods have been
designed to identify cytotoxic compound early in the drug discovery process. The 3- [4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium
bromide (MTT) human hepatotoxicity assay is one commonly used method. In this assay, changes in cell viability are monitored by
measuring the rate of conversion of the yellow dye MTT into purple formazan derivative.
This reaction occurs in the mitochondria of cells at a known rate, and concentrations of both MTT and formazan can be measured
spectroscopically. Cytotoxic compound will decrease the rate of conversion, making it possible to screen for
this potential safety issue. In addition, since this assay The lactate dehydrogenase (LDH) assay and the neutral red assay are also popular
methods of identifying compounds that represent a cytotoxicity risk. Both of these assays can be run with hepatocytes, preserving the ability
to identify compounds that produce cytotoxic metabolites in the liver. In the LDH assay the amount of LDH released by dead cells after an
incubation period with candidate compounds is used as an indicator of cytotoxicity
• carcinogenic compounds cause cancer through a variety of different mechanisms such as alteration in cellular metabolism or DNA damage
that cause uncontrolled proliferation of malignant cells. Compounds that are genotoxic damage the genetic information within a cell.
Changes to DNA created by genotoxic compounds can be in the form of single-stranded DNA breaks and double stranded DNA breaks or
mutation of the DNA. In some cases, genotoxicity leads to apoptosis (programmed cell death), but it can also lead to the formation of
malignant cells (cancer). Mutagenicity is a subset of genotoxicity in which the DNA is mutated. In this case, damage caused by a genotoxin
is improperly repaired, permanently altering the DNA
• Ames assay
• Micronucleus assay
• Chromosomal aberration assay
• Comet assay
• Teratogenicity refers to the potential of a substance to cause developmental malformations (birth defects) in a developing fetus

Necropsy (animal autopsy) is the examination of an animal’s body and organs after death to determine the cause of death and identify any
pathological changes.
 Drug Characterization
• Drug characterization involves finding of biological and physiochemical properties of potential drug molecules.
• Pre-formulation studies involve to characterize the drug in number of aspects.

Pre-formulation
• Phase of research and development in which preformulation studies characterize physical and chemical
properties of drug molecule in order to develop safe, effective and stable dosage form.

• Objectives
• To establish physico-chemical parameters of a new drug entity
• To determine its kinetic and stability
• To establish its compatibility with common excipients
• It provides insight into how drug products should be processed and stored to ensure their quality
• Types

1. Biological characterization
Interaction of drug molecule with biological system
eg., Receptor binding, Enzyme inhibition

2. Physiochemical characterization
Physical and chemical characteristics of potential drug
eg., solubility, NMR, IR
Major Area of Pre-formulation Research

Bulk characters Solubility analysis

Crystallinity and polymorphism Ionization constant-Pka
Hygroscopicity pH solubility
Fine particle characterization Common ion effect
Powder flow properties Thermal effect
Solubilization
Dissolution
Bulk stability
• Colour, odour, taste of new drug must be recorded
Dosage form
Dosage form: way in which a therapeutic agent is taken or administered (tablet, capsule, spray)

Dosage regimen: the schedule of doses per unit time ( no. of doses and interval)

Dosage regimen design is the selection of drug dosage, route, and frequency of administration in an informed
manner. At the same time, variability among patient in pharmacodynamic response demands individualized
dosing to assure maximum efficacy.
Clinical Data Management (CDM) involves various activities that handle the data outlined in clinical research protocols. It is
essential for ensuring the accuracy, reliability, and integrity of data collected during clinical trials
Data Management Activities in Clinical Research:
Data Collection: Gathering data from study participants through CRFs, electronic data capture (EDC) systems, and other sources.
Data Entry: Inputting collected data into databases, ensuring accuracy and completeness.
Data Validation: Checking data for errors, inconsistencies, and missing values to maintain data quality.
Data Cleaning: Correcting errors and resolving discrepancies in the data.
Data Storage: Safely storing data in compliance with regulatory requirements and ensuring its availability for analysis.
Regulations and Guidelines:
Good Clinical Practice (GCP): Ensures that the rights, safety, and well-being of trial participants are protected.
International Council for Harmonisation (ICH): Provides guidelines for the technical and regulatory aspects of clinical trials.
FDA Regulations: Includes requirements for data handling and reporting in clinical trials conducted in the United States.

A Case Report Form (CRF) is a critical data-reporting document used in clinical studies to systematically collect data from
each trial participant.
Components of a CRF:
Demographic Information: Basic participant information such as age, sex, and medical history.
Baseline Data: Initial health status and measurements taken before the intervention.
Intervention Data: Details of the treatment or intervention administered to the participant.
Follow-Up Data: Information collected at subsequent visits to monitor progress and outcomes.
Adverse Events: Documentation of any side effects or adverse reactions experienced by the participant.
Clinical Data Management System

The clinical trial data gathered at the investigator site in the

CRF are stored in the CDMS & this system employ various
means to verify the data to reduce possibility of error due to
human entry.
Types of CDMS:
1. Paper based system
2. Electronic data capturing system

Key members
The Key members involved in Data Management:
Clinical Data Manager
Database Administrator
Database Programmer
Clinical Data Coordinator
Clinical Data Associate
Data Extraction, Cleaning & Locking
Data Processing & Reporting
The primary tool for collecting data in clinical trials. CRFs can be either paper-based or electronic (eCRFs).
Manual Data: Data entered manually, often from paper CRFs or other non-electronic sources.
Electronic Data: Data entered directly into an electronic system, often through eCRFs or electronic health records (EHRs).
2. Data Types and Integration:
Raw Data: Initial, unprocessed data collected from various sources during the clinical trial. Raw data can come in both manual
and electronic forms.
Combining Data: The process of integrating raw data from different sources. This step involves reconciling manual and electronic
data to create a comprehensive dataset for analysis.
3. Data Approval Process: Before data can be used for final analysis, it must go through a review and approval process. This
ensures that all data is accurate, complete, and compliant with regulatory standards.
Data Capturing:
CRF: The Case Report Form is used to capture all the required data for the clinical trial. This form is designed based on the study
protocol and can be either paper-based or electronic.
Manual Data Entry: When data is captured on paper CRFs, it must be manually entered into the CDMS. This process can be time-
consuming and prone to errors.
Electronic Data Entry: Data captured electronically through eCRFs is directly entered into the CDMS, reducing errors and
increasing efficiency.
Data Integration: Raw Data: Both manual and electronic data are considered raw data when first collected. Raw data needs to be
processed and cleaned before analysis.
Combining Manual and Electronic Data: If a study uses both paper and electronic CRFs, the data from these sources must be
combined. This involves:Reconciliation: Ensuring that data from manual and electronic sources match and are consistent.
Validation: Checking for discrepancies and correcting errors to create a unified dataset.
Data Approval: Approval Process: Once the raw data is combined and cleaned, it must go through an approval process. This
typically involves:Data Review: Data is reviewed for accuracy and completeness by clinical data managers or other designated
personnel.Regulatory Compliance: Ensuring that the data complies with regulatory requirements such as Good Clinical Practice
Once the data are uploaded by side then data validation is done by data validation team if there is any discrepancy then alert is
send to the site to resolve it.
Data Extraction: This is the process of retrieving data from various sources, such as CRFs (paper or electronic) and other data
collection tools, to prepare it for cleaning and analysis.
2. Real-Time Query Management Real-Time Query: During data entry, queries may arise regarding the accuracy, completeness,
or consistency of the data.
No: If no real-time query is raised, the process moves forward without interruption.
Yes: If queries are raised, they must be answered. This involves verifying and correcting the data as needed.
Approval Required: Once the queries are resolved, the data needs approval before proceeding to the next step.
3. Data Cleaning Detecting & Diagnosing Errors: Identifying errors such as missing data, inconsistencies, or incorrect entries.
Editing Incorrect Data: Correcting any errors identified during the detection phase. This could involve modifying incorrect entries,
filling in missing values, and ensuring data consistency.
Integrated Data Passage: Ensuring that data flows seamlessly between different stages and systems, maintaining integrity and
consistency.
Outlier Determination: Identifying and examining data points that are significantly different from the rest of the data to
determine if they are errors or valid outliers.
Robust Estimation of Analytical Parameters: Using statistical methods to estimate parameters accurately, considering the
presence of outliers and other anomalies.
4. Data Locking Clean Data: Once the data has been cleaned and verified, it is considered "clean data." This data is now ready for
the final locking process.
Approval to Lock Data: Before locking the data, it must be reviewed and approved to ensure that all queries have been resolved
and the data is accurate and complete.
Can This Data Be Locked?:
Yes: If the data meets all the criteria, it is locked, preventing any further changes.
No: If the data cannot be locked (due to unresolved queries or issues), the cleaning process is repeated until the data meets the
function provided by CDM

1. Case report forms (CRFs) design

2. Database design
3. Database programming
4. 21 CFR part 11 compliant validation process
5. Loading, reconciliation and integration of external data
6. Medical coding
7. Status reporting
8. Forms management
9. Data entry and cleaning
10.Data locking
Safety monitoring in clinical
trials