DRUG DISCOVERY AND DEVELOPMENT

Sumerians, developed urban civilization around 4000BC in ancient mesopotamia.

In Greece, the god who gave mankind the give of medicine is Asklepios.
Caduceus, symbol of the god Hermes.
Temple of asklepios in Epidaurus, the first hospital in history.
Pharmakon, which in greek means both “poison” and “drug”
Hippocrates of Kos,
 most famous doctors of all time.Founder of modern medicine.It is a discipline finally free of theology and
philosophy.
 Primum non nocere!, “first, do not harm the patient”
 First medical practitioner who believe that disease are of natural origin, and not caused by astrological connections
or evil spirits.
 Supported humorism: blood, phlegm, yellow bile, black bile.
 Corpus hippocraticum, important reference through the middle ages. Collection of 70 medical treatises
 Hippocratic oath- documents the ethics of medical practice and constitute the most influential section of the
Corpus hippocraticum
 Asklepios to Aesculapios
Galen, most famous physician
 Galenic Corpus, Greek(elite language in Rome), 500 treatises, 1 million pages
 Materia Medica, a medical compendium widely employed in the West and based on Galen’s work.

Drug discovery and development process aims to make available medications that are safe and effective in improving
the length and quality of life and relieving pain and suffering. However, the process is very complex, time consuming,
and resource intensive, requiring multi-disciplinary expertise and innovative approaches.

Recent estimates suggest that it takes up to 13.5 years and 1.8 billion U.S. dollars to bring a new drug to the market.
There is a growing urgency to identify and develop more effective, efficient, and expedient ways to bring safe and
effective products to the market. The drug discovery and developmental process relies on utilizing relevant and robust
tools, methods, and models that are predictive of clinical effects in terms of diagnosis, prevention, therapy, and
prognosis. There is a growing emphasis on translational research, a bidirectional bench to the bedside approach. The all-
important predictivity depends on having robust, relevant, validated and qualified biomarkers for physiological and
pathological effects of interest.

Medicinal chemistry and pharmaceutics

play a crucial role from the beginning of the drug discovery and development process, involving chemical synthesis
(including compliance with current Good Manufacturing Practice, cGMP), characterization, purification, chemical
alteration, stability determination, and formulation of the drug candidate

Medicinal Chemistry
- relates to the design and production of compounds that can be used in medicine for the prevention, treatment or cure
of human and animal diseases.

Medicinal chemistry covers three critical steps:

1. A discovery step: consisting of the identification and production of new active substances usually called lead
compounds. Leads can originate from synthetic organic chemistry, from natural sources or from biotechnological
processes.

2. An optimization step: that deals mainly with the synthetic modification of the lead structure in order to improve
potency, selectivity and lessen toxicity. Its characteristics are the establishment and analysis of structure' -activity
relationships (SARs).

3. A development step consisting of the optimization of the synthetic route for bulk production. Modification of the
pharmacokinetic and pharmaceutical properties of the active substance to render it suitable for clinical use.

This may cover optimization of properties associated with: CSER

 Chemical formulation
 Solubility
 Elimination of unpleasant taste or irritation
 Reduction of pain at site of injection

DRUGS CAN BE CLASSIFIED UNDER THE FOLLOWING CATEGORIES: OMNCs

1. The origin of the drug
a. Minerals: iodine, phosphates, calcium, sodium , iron ipcsi
b. Animal kingdom: insulin, fish oils, biliary salts fib
c. Vegetable or plant origin: alkaloids, cardiac glycosides, anticancer agents alcaan
d. Genetic engineering and fermentation products

2. The mode of Action

 Medicine that treat the cause of the disease termed "true drugs" or etiological drugs. Antibacterials, antifungals,
antivirals and antiparasitics (chemotherapeutic drugs)bfvp. Activity resides in their selective toxicity or the ability to
destroy the invader without destroying the host. This includes also vaccines and preventive therapies.

3. The nature of illness

 The world health organization (WHO) in 1968 adopted this physiological classification which classifies drugs by the
body system on which they act.
EX. Cardiovascular, Diuretics, immunomodulators

4. The chemical structure

Disease has been recognized as an enemy of humankind since civilization began, and plagues of infectious diseases
arrived as soon as humans began to congregate in settlements about 5000 years ago. Early writings on papyrus and clay
tablets describe many kinds of disease, and list a wide variety of herbal and other remedies used to treat them. The
earliest such document, the famous Ebers papyrus, dating from around 1550BC, describes more than 800 such remedies.
Disease was in those times regarded as an affliction sent by the gods; consequently, the remedies were aimed partly at
neutralizing or purging the affliction, and partly at appeasing the deities. Despite its essentially theistic basis, early
medicine nevertheless discovered, through empiricism and common sense, many plant extracts whose pharmacological
properties we recognize and still use today; their active principles include opium alkaloids, ephedrine, emetine, cannabis,
senna and many others

The present medicinal system is dominated by the Allopathy or western medicine which is prominently taught and
practiced in most of the countries world wide. This system is still evolving and during last few decades focus was based
on chemical origin of most of the medicines. Thus majority of drugs in current practice are from synthetic origin.

Ayurveda, one of the oldest systems used by mankind for well being (Sharma 1995), originated in ancient India many
thousand years ago (about 4500 BC as agreed by most scientists).

Ayurveda literally means "science of life" in Sanskrit (Ayur: Life; Veda: Science). It is not only a medical system but a way
of life. Ayurveda aims at a holistic management of health and diseases. It is widely practiced in the Indian subcontinent
and is also one of the official systems of medicine in India. Its concepts and approaches are considered to have been
perfected between 2500-500 BC.

Charak Samhita and Sushrut Samhita (100-500 BC) are the two main Ayurvedic classics, wherein more than no plants
along with their classification, pharmacological and therapeutic properties have been described.

It is divided into eight major disciplines known as Ashtanga Ayurveda.

1. Kaaya Chikitsa (Internal Medicine)

2. Baala Chikitsa (Treatment of Children / Pediatrics)
3. Graha Chikitsa (Demonology / Psychology)
4. Urdhvaanga Chikitsa (Treatment of disease above the clavicle)
5. Shalya Chikitsa (Surgery)
6. Damstra Chikitsa (Toxicology)
7. Jara Chikitsa (Geriatrics, Rejuvenation)
8. Vrsha Chikitsa (Aphrodisiac therapy)

Kaya Chikitsa (Internal Medicine)

The word 'Kaya' represents 'Agni'—the digestive fire in the body. The discipline of Kaya Chikitsa deals with the
treatment of general ailments, like fever, diarrhea, cough, skin disorders, lung diseases, and bone disorders, by bringing
Agni back in balance.

Baala Chikitsa (Pediatrics)

Bala Chikitsa is the pediatric offshoot of Ayurvedic science for healing that details disorders, treatments, and dietary
recommendations, natural and herbal remedies for various diseases concerning children and infants such as digestive
disorders, teething problems, bone health, and nutritional requirements, among others. In covering the overlapping
subjects of gynecology and pediatrics, it also discusses the art of nursing, infertility, mental health of the mother and its
influence on the infant's well-being.

Graha Chikitsa (Psychology)

Graha Chikitsa is the psychic field of Ayurveda that deals with diseases and illnesses of the mind or diseases with
psychosomatic roots. Psychosomatic disorders are ones that do not have visible symptoms but are rooted in factors
related to mental health. This field talks about herbs and their applications as disinfectants and their abilities to bring
positivity in the atmosphere. It talks about herbs, diet, use of specific mantras, pranayama or breathing techniques,
meditation techniques and yogic therapies for healing the mind.

aUrdhvaang or Shalakya Chikitsa (EENT)

Shalakya Tantra deals with treating diseases and imbalances in body parts above the shoulders through holistic
treatments, cleanses and herbal formulations. Shalakya Tantra is the EENT (otorhinolaryngology) and ophthalmology
field equivalent of Ayurveda that deals with conditions of the eyes, ears, nose, lips, brain, central nervous system, skull
and throat. This field is further divided into:
 Nethrachiktsa (ophthalmology),
 Karnachikitsa (otology),
 Nasachikitsa (rhinology),
 Mukharogachikitsa (includes dentistry and laryngology), and
 Shirorogachikitsa (craniology).

Shalya Chikitsa (Surgery)

Shalya Tantra details pre-operative procedures, post-operative procedures, general procedures, energy points (marmas),
and even anesthesia procedures along with the right type of instruments to use, bandages, or sutures to be used for the
specific procedures. Most of these instruments were made of stone, wood, bark, or thick leaves.

Damstra Chikitsa (Toxicology) Damstra Chikitsa or Agada Tantra is the branch of toxicology in Ayurveda that deals with
treatments and prevention of toxins in the body. It dealt with poisoning from animals, plants, vegetables, or metals or
man-made poison. But more importantly, this branch of Ayurveda also considered air and water pollution as a form of
poisoning that needed to be purified for health and well-being of man, as contamination would often lead to mass scale
epidemics. Ayurveda accords as much importance to purity of air, water, earth, and space as much as to the food,
environment and quality of life.

Rasayan/Jara Chikitsa (Geriatrics & Rejuvenation)

 This branch of Ayurveda deals with diseases and illnesses related to aging, as well as science of longevity and
rejuvenation.
 It deals with preventive healthcare, tips, treatments, herbal medicines (rasayana) to enhance quality of life and lead
a healthy, happy life full of vitality and vibrancy.

Jara chikitsa (jara meaning degeneration)

 also deals with degenerative disorders irrespective of ones age.
 This Ayurveda branch talks about different types of rasayanas like:
 Ausadha Rasayana (drug based),
 Ahara Rasayana (dietary), and
 Achara Rasayana (behavioral discipline).
 Jara Chikitsa includes healing modalities to achieve longevity, better memory, youthfulness, brightness, positive
emotions and virtues, strength, immunity and vitality.
 Rasayana works to improve dosha imbalances, rekindle digestive Agni and restore health with use Of diet and
herbal medication.
 Three sub branches of Rasayana Chikita
 Naimittika Rasayana (curative rejuvenation)
 Ajasrika Rasayana (promotion of health and a healthy lifestyle) and
 Kamya Rasayana (longevity, fertility and memory enhancement).

 Naimittika Rasayana is a curative discipline that examines and uses herbal drugs, formulations and their potency to
speed up recovery from existing diseases or illnesses.
 Ajasrika Rasayana is dedicated to the science of wellness and includes everything from diet, herbs, dairy, exercise
and practices to lead a spiritually, mentally and physically optimal life. It details the goodness and benefits of
everything that the nature provides for enhancing human health.
 Kamya Rasayana is the discipline that deals with the biochemistry of desire (kama), it also talks about the science of
prana or life force, memory and intellect and how these can be improved along with increasing lifespan.

Vrsha or Viijikarana Chikitsa (Aphrodisiac Therapy)

 This branch deals with promotion of sexual health of men and women and improvement in fertility. It focuses on
the health and illnesses of reproductive or genetic organs.
 It is a branch that talks about sex, virility, potency, strength, excitability, techniques, regimen, diet, herbal medicines,
and treatments to take care of reproductive organs, and diseases such as sexual dysfunctions, infertility, premature
ejaculation, and erectile dysfunction.
 The herbs and medicines administered under the Vajikarna sciences have qualitative and quantitative properties.
For example:
 to increase sperm count, medicines called Sukrala are recommended that include Asvagandha Musali, Sarkara,
Satavari;
 to improve ejaculation ingredients called SukraRecaka are administered that include milk, specific type of
meats, fruit pulps or amalaki;
 fruits like jatiphala constitute SukraStambhaka medicines that help in increasing the time of intercourse; and
 Sukrasosaka herbs like haritaki are the ones that help control excessive semen production.

DRUG DISCOVERY AND DEVELOPMENT AS A PROCESS

Overview and Definition

the complexity in drug development has increased manifolds over the past 40 years, requiring preclinical testing,
investigational new drug (IND) applications, and completed clinical testing before marketing approval from the FDA
generally, new drug applications (NDAS) or biologics license applications (BLA) are reviewed comprehensively before
approval, and then drug performance is resubmitted to regulatory agencies for post-marketing studies. the overarching
goal is to bring more efficient and safer treatments to the patients as quickly as possible after a thorough medical
evaluation.

Drug Discovery & Development

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

5 critical steps in the U.S. drug development process, including many phases and stages within each of them.
Drug Development
1. discovery and development
2. preclinical research
3. clinical development
4. FDA review
5. post-market monitoring

Phases Stages
Step 1: Discovery and Development
Step 2: Preclinical Research
Step 3: Clinical Development
Step 4: FDA Review
Step 5: FDA Post-market Safety Monitoring

Step 1: Discovery & Development

Drug discovery is how new medications are discovered. Historically, drugs were mostly found by identifying active
ingredients from traditional medicines or purely by chance. Afterward, classical pharmacology was used to investigate
chemical libraries including small molecules, natural products, or plant extracts, and find those with therapeutic effects.
Since human DNA was sequenced, reverse pharmacology has found remedies to existing diseases through testing.

 Disease processes, molecular compound tests, existing treatments with unanticipated effects, and new
technologies spur drug discovery through the cycle below.

 Today drug discovery involves screening hits, medicinal chemistry, and optimization of hits to reduce potential drug
side effects (increasing affinity and selectivity). Efficacy or potency, metabolic stability (half-life), and oral
bioavailability are also improved in this step of the drug development process.

Target Identification & Validation

Target identification finds a gene or protein (therapeutic agent) that plays a significant role in disease. When identified,
therapeutic characteristics are recorded. Targets are efficacious, safe, usable as drugs, and capable of meeting clinical
and commercial requirements. Researchers use disease association, bioactive molecules, cell-based models, protein
interactions, signaling pathways analysis, and functional analysis of genes to validate targets, or in vitro genetic
manipulation, antibodies, and chemical genomics. The Sanger Whole Genome CRISPER library and Duolink PLA are
excellent sources for drug discovery targets.

Hit Discovery Process

Following target validation, compound screening assays are developed.

Assay Development & Screening

Assays are test systems that evaluate the effects of the new drug candidate at the cellular, molecular, and biochemical
levels.
High Throughput Screening
High Throughput Screening (HTS) uses robotics, data processing/control software, liquid handling devices, and sensitive
detectors to rapidly conduct millions of pharmacological, chemical, and genetic tests, eliminating hours of painstaking
testing by scientists. HTS identifies active compounds, genes, or antibodies that affect human molecules.

Hit to Lead
In the Hit to Lead (H2L) process, small molecule hits from an HTS are evaluated and optimized in a limited way into lead
compounds. These compounds then move on to the lead optimization process.

Lead Optimization
In the lead optimization (LO) process, the lead compounds discovered in the H2L process are synthesized and modified
to improve potency and reduce side effects. Lead optimization conducts experimental testing using animal efficacy
models and ADMET tools, designing the drug candidate.

Active Pharmaceutical Ingredients

Active pharmaceutical ingredients (APIs) are biologically active ingredients in a drug candidate that produce effects. All
drugs are made up of the API or APIs and excipients. (Excipients are inactive substances that deliver the drug into the
human system.). High Potency Active Pharmaceutical Ingredients (HP APIs) are molecules that are effective at much
smaller dosage levels than standard APIs. They are classified based on toxicity, pharmacological potency, and
occupational exposure limits (OELs), and used in complex drug development involving more than ten steps. The drug
discovery process ends when one lead compound is found for a drug candidate, and the process of drug development
starts.

Step 2: Preclinical Research

Once a lead compound is found, drug development begins with preclinical research to determine the efficacy and safety
of the drug. Researchers determine the following about the drug:
 Absorption, distribution, metabolization, and excretion information ADME
 Potential benefits and mechanisms of action
 Best dosage, and administration route
 Side effects/adverse events
 Effects on gender, race, or ethnicity groups
 Interaction with other treatments
 Effectiveness compared to similar drugs

Preclinical trials test the new drug on non-human subjects for efficacy, toxicity, and pharmacokinetic (PK) information.
These trials are conducted by scientists in vitro and in vivo with unrestricted dosages.

Absorption, Distribution, Metabolism, & Excretion (ADME) is a PK process of measuring the ways the new drug affects
the body. ADME involves mathematical descriptions of each effect.

Proof of Principle / Proof of Concept Proof of Principle (PoP) are studies that are successful in preclinical trials and early
safety testing. Proof of Concept (PoC) terminology is used almost interchangeably with PoP in drug discovery and
development projects. Successful PoP/PoC studies lead to program advancement to the Phase II studies of dosages

In Vivo, In Vitro & Ex Vivo Assays

These three types of studies are conducted on the whole, living organisms or cells, including animals and humans; or
using non-living organisms or tissue extract.
In vivo, preclinical research examples are the development of new drugs using mice, rat, and dog models.
In vitro is research conducted in a laboratory.
Ex vivo uses animal cells or tissues from a non-living animal.
Examples of ex vivo research assays are finding effective cancer treatment agents; measurements of tissue properties
(physical, thermal, electrical, and optical); and realistic modeling for new surgical procedures. In an ex vivo assay, a cell is
always used as the basis for small explant cultures that provide a dynamic, controlled, and sterile environment

In Silico Assays
In silico assays are test systems or biological experiments performed on a computer or via computer simulation. These
are expected to become increasingly popular with the ongoing improvements in computational power, and behavioral
understanding of molecular dynamics and cell biology.

Drug Delivery
New drug delivery methods include oral, topical, membrane, intravenous, and inhalation. Drug delivery systems are
used for targeted delivery or controlled release of new drugs. Physiological barriers in animal or human bodies may
prevent drugs from reaching the targeted area or releasing when they should. The goal is to prevent the drug from
interacting with healthy tissues while still being effective.

 Oral: Oral delivery of medications is reliable, cost-effective, and convenient for patients. Oral drug delivery may not
monitor precise dosages to the desired area but is ideal for prophylactic vaccinations and nutritional regimens.
Delayed action, stomach enzyme destruction, absorption inconsistencies, or patients with gastrointestinal issues or
upset can occur, and patients must be conscious during administration.

 Topical: Topical drug delivery involves ointments, creams, lotions, or transdermal patches that deliver a drug by
absorption into the body. Topical delivery is more useful for patient skin or muscular conditions — it is preferred by
patients due to noninvasive delivery and their ability to self-administer the medicine.
 Parenteral (IM, SC or IP Membrane): Parenteral drug delivery utilizes bodily membranes, including intramuscular
(IM), intraperitoneal (IP), or subcutaneous or (SC). It is often used for unconscious patients and avoids epithelial
barriers that are difficult for drugs to cross.

 Parenteral (Intravenous): Intravenous injection is one of the fastest drug delivery absorption methods. IV injection
ensures entire doses of drugs enter the bloodstream, and it is more effective than IM, SC, or LP membrane methods.

 Parenteral (Inhalation): Inhalation drug delivery gets the drug rapidly absorbed into the mucosal lungs, nasal
passages, throat, or mouth. Problems with inhalation delivery include difficulty delivering the optimum dosage due
to small mucosal surface areas and patient discomfort. Pulmonary inhalation drug delivery uses fine drug powders
or macromolecular drug solutions. Lung fluids resemble blood, so they can absorb small particles easily and deliver
them into the bloodstream.

Formulation Optimization & Improving Bioavailability

Formulation optimization is ongoing throughout pre-clinical and clinical stages. It ensures drugs are delivered to the
proper place at the right time and in the right concentration. Optimization may include overcoming solubility

Step 3: Clinical Development

Once preclinical research is complete, researchers move on to clinical drug development, including clinical trials and
volunteer studies to finetune the drug for human use.

Complexity of Study Design, Associated Cost & Implementation Issues

The complexity of clinical trial design and its associated costs and implementation issues may affect trials carried out
during this phase. Trials must be safe and efficacious and be completed under the drug development budget, using a
methodology to ensure the drug works as well as possible for its intended purpose. This rigorous process must be set up
correctly and enroll many volunteers to be effective.

Clinical Trials– Dose Escalation, Single Ascending & Multiple Dose Studies
Proper dosing determines medication effectiveness, and clinical trial examine dose escalation, single ascending, and
multiple dose studies to determine the best patient dosage

Phase I – Healthy Volunteer Study

This phase is the first time the drug is tested on humans; less than 100 volunteers will help researchers assess the safety
and pharmacokinetics, absorption, metabolic, and elimination effects on the body, as well as any side effects for safe
dosage ranges.

Phase II and Phase III – Studies in Patient Population

Phase II assesses drug safety and efficacy in an additional 100-500 patients, who may receive a placebo or standard drug
previously used as treatment. Analysis of optimal dose strength helps create schedules while adverse events and risks
are recorded. Phase III enrolls 1,000-5,000 patients, enabling medication labeling and instructions for proper drug use.
Phase III trials require extensive collaboration, organization, and Independent Ethics Committee (IEC) or Institutional
Review Board (IRB) coordination and regulation in anticipation of full-scale production following drug approval

Biological Samples Collection, Storage & Shipment

During clinical trials, biological samples are collected, stored, and shipped from testing sites according to global
standards and regulations. Transport containers of biological samples may include dry ice packs or other temperature
stabilizing methods. Different requirements apply to different types of biological samples.

Pharmacodynamic (PD) Biomarkers

PD biomarkers are molecular indicators of the drug ’ s effects on the target human area, and link drug regimen and
biological responses. This data can help select rational combinations of targeted agents and optimize drug regimens and
schedules. Rationality and hypothesis-testing power are increased through the use of PD endpoints in human trials.

Pharmacokinetic Analysis
Pharmacokinetic analysis is an experimental trial that determines the theory of how a new drug behaves in the human
body. The volume of distribution, clearance, and terminal half-life are defined through compartmental modeling.

Bioanalytical Method Development and Validation

Bioanalytical methods detect analytes and metabolites such as drug or biomarkers in biological or human samples to
determine drug efficacy and safety. The complete bioanalytical assay consists of sample collection, clean-up, analysis,
and detection.

Drug (Analyte) & Metabolite Stability in Biological Samples

Stability is important in determining human drug efficacy, and biological samples are required. Drug and drug
metabolites are susceptible to degradation, which can lower drug concentration over the life of the drug

Blood, Plasma, Urine & Feces Sample Analysis for Drug and Metabolites
Biological samples used in clinical trials include blood, plasma, urine, and feces to determine and analyze various
properties and effects of the drug and its metabolites on humans

Patient Protection – GCP, HIPAA, & Adverse Event Reporting

Human patients must always be protected during clinical trials, and Good Clinical Practices (GCP), the Health Insurance
Portability and Accountability Act (HIPAA), and adverse event reporting to IEC/IRB regulates and ensures their safety
Step 4: FDA Review
Once the new drug has been formulated for its best efficacy and safety, and the results from clinical trials are available,
it’s advanced forward for wholistic FDA review. At this time, the FDA reviews and approves, or does not approve, the
drug application submitted by the drug development company.

Regulatory Approval Timeline

The new drug regulatory approval timeline may be standard, fast track, breakthrough, accelerated approval, or priority
review depending on its applications and necessity for patients. If standard or priority review is required, the approval
timeline may be up to an year. Fast track, breakthrough, or accelerated approvals may occur sooner

IND Application
IND applications are submitted to the FDA before starting clinical trials. If clinical trials are ready to be conducted, and
the FDA has not responded negatively about the drug, developers may start the trials.

NDA / ANDA / BLA Applications

An NDA abbreviated new drug application (ANDA), or BLA is submitted to the FDA after clinical trials demonstrate drug
safety and efficacy. The FDA reviews study data and decides whether to grant approval or not. Additional research or
an expert advisory panel may be required before a final decision is made

Orphan Drug
An orphan drug is intended to treat disease so rare that financial sponsors are unwilling to develop it under standard
marketing conditions. These drugs may not be approved quickly or at all.
Accelerated Approval
New drugs may be granted accelerated approval if there is strong evidence of positive impact on a surrogate endpoint
instead of evidence of impact on actual clinical benefits the drug provides. Expedition of approval means the medication
can help treat severe or life-threatening conditions.

Reasons for Drug Failure

New drug applications may fail for a variety of reasons, including toxicity, efficacy, PH properties, bioavailability, or
inadequate drug performance.
 Toxicity: If the toxicity of a new drug is too high in human or animal patients, the drug may be rejected due to
safety concerns about its use following manufacture.
 Efficacy: If a new drug’s efficacy is not high enough or evidence is inconclusive, the FDA may reject it.
 PK Properties or Bioavailability: PK properties or poor bioavailability due to low aqueous solubility, or high first-
pass metabolism, may also cause a drug to fail FDA review. PK causes of drug failure include inadequate action
duration and unanticipated human drug interactions.
 Inadequate Drug Performance: If the new drug performs the desired function, but only at a shallow level, the FDA
may reject the application in favor of a formulation that performs better.

STEP 5: POST MARKET MONITORING

Following drug approval and manufacturing, the FDA requires drug companies to monitor the safety of its drug using the
FDA Adverse Event Reporting System (FAERS) database. FAERS helps FDA implement its post-marketing safety
surveillance program. Through this program, manufacturers, health professionals, and consumers report problems with
approved drugs

Here’s a summary of the FDA drug approval process discussed thus far.

Relevant Drug Development Concepts

 Drug Master File
A Drug Master File (DMF) is a submission to the FDA used to provide confidential, detailed information about facilities,
processes, or articles used in the manufacturing, processing, packaging, and storing of a human drug.

 Drugs for Pediatric Use

Drugs for pediatric use are intended for use in children or youth, generally under the age of 21. In some cases, the
American Academy of Pediatrics (AMA) may make exceptions if a pediatrician and family agree on an older age adult.
 Drugs for Veterinary Use Drugs for veterinary use are intended for use in animals, pets, and livestock. However,
some veterinary drugs get their start in humans and then change to human and animal drugs.

 Small Molecule vs. Biologics

Small molecules have a variety of applications or biological functions. Large molecules (also called biologics) are
proteins with a therapeutic effect. Small molecules work by cell signaling. Large molecule drugs are complex and may be
composed of over 1,300 amino acids. They are identical versions of human proteins.
small molecule drugs are chemically derived, biologics are extracted from living organisms.

Process Scale-up Differences & Difficulties

 Drug development involves generating progressively larger medicine batch sizes, and changes in processes for
different-sized batches may cause unexpected difficulties. Use of the right pharmaceutical equipment can be
helpful, as well as the discovery of parameters that affect critical process parameters (CPPs).

 New drug development is a highly regulated, complicated process that requires specialists and intense research and
development skill sets in the medical research community. All regulations and safety indications must be observed
carefully, and human and animal clinical trials subjects treated professionally and with the utmost care.

 The goal of drug development is to prevent human and animal pain and suffering whenever possible and find and
provide new drugs that we can depend on to improve our health and happiness

Computer aided drug design (CADD)

 is the inventive process of finding new medications based on the knowledge of a biological target
 it involves the design of molecules that are complementary in shape and charge to the biomolecular target with
which they interact and therefore will bind it

COMPUTER-AIDED DRUG DESIGN (CADD)

CADD represents computational methods and resources that are used to facilitate the design and discovery of new
therapeutic solutions

Drug design with the help of computers may be used at any of the following stages of drug discovery:
 hit identification using virtual screening (structure or ligand-based design)
 hit-to-lead optimization: optimization of other pharmaceutical properties while maintaining affinity

To change from:
 random screening against disease assays
 Natural products, synthetic chemicals

To:
 rational drug design and testing
 speed-up screening process
 efficient screening (focused, target directed)
 Denovo design (target directed)
 Integration of testing into design process
 Fail drugs fast (Remove hopeless ones as early as possible)

Types of drug design

1. Ligand-based drug design
2. Structure-based drug design

ligand-based drug design

 relies on knowledge of other molecules that bind to the biological target of interest.
 used to derive a pharmacophore model that defines the minimum necessary structural characteristics a molecule
must possess in order to bind to the target
 a model of the biological target may be built based on the knowledge of what binds to it and this model in turn
may be used to design new molecular entities that interact with the target
 Alternatively, a quantitative structure-activity relationship in which a correlation between calculated properties of
molecules and their experimentally determined biological activity, may be derived. These QSAR raltionships in turn
may be used to predict the activity of new analogs

structure-based drug design

 relies knowledge of the 3 dimensional structure of the biological target obtained through:
1.x-ray
2.nuclear magnetic resonance spectroscopy
 If an experimental structure of a target is not available, it may be possible to create a homology model of the target
based on the experimental structure of a related protein.
 Homology modeling, also known as comparative modeling of protein, refers to constructing an atomic resolution
model of the "target" and an experimental three-dimensional structure of a related homologous protein (the
"template")
 Using the structure of the biological target, candidate drugs that are predicted to bind with high affinity and
selectivity to the target may be designed using:
 interactive graphics
 Intelligence of a medicinal chemist.
  various automated computational procedures may be used to suggest new drug candidates

1) Virtual screening: The first method is identification of new ligands for a given receptor by searching large databases
of 3D structures of small molecules to find those fitting the binding pocket of the receptor using fast approximate
docking programs.
2) de novo design of new ligands: In this method, ligand molecules are built up within the constraints of the binding
pocket by assembling small pieces in a stepwise manner. These pieces can be either individual atoms or molecular
fragments. The key advantage of such a method is that novel structures can be suggested.
3) optimization of known ligands by evaluating proposed analogs within the binding cavity

binding site indentification

 It is the first step in structure based design.
 relies on identification of concave surfaces on the protein that can accommodate drug sized molecules that also
possess appropriate "hot spots" (hydrophobic surfaces, hydrogen bonding sites, etc.) that drive ligand binding.

Docking & Scoring

 Docking attempts to find the "best" matching between two molecules It includes finding the Right Key for the Lock
To place a ligand (small molecule) into the binding site of a receptor in the manners appropriate for optimal
interactions with a receptor.
 To evaluate the ligand-receptor interactions in a way that may discriminate the experimentally observed mode
from others and estimate the binding affinity

Components of Docking
I- pre- and/or during docking:
Representation of receptor binding site and ligand

II- during docking:

Sampling of configuration space of the ligand receptor complex

III- during docking and scoring:

Evaluation of ligand-receptor interactions

Advantages of CADD
 Time
 Cost
 Accuracy information about the disease
 screening is reduced
 Database screening less manpower is required

Success stories of CADD

> K+ ion channel blocker
structural based discovery

> Ca2+ antagonist / T-channel blocker

chemical descriptor based discovery

> Glyceraldehyde-phosphate DH inhibitors (anti-trypanosomatid drugs)

combinatorial docking

> Thrombin inhibitor

docking, de-novo design

Computational Tool For Drug Designing

Categories of software
 Databases & Draw Tools
 Molecular Modeling & Homology Modeling
 Binding site prediction & Docking
 Ligand design Screening - QSAR
 Binding free energy estimation
 ADME Toxicity

DATABASES
 ZincDatabase, Zinc 15Database
 ChEMBL
 JChemforExcel
 ProteinDataBank(PDB)
 BindingMOAD(MotherOfAllDatabase)
 PDBbind
 STITCH,SMPDB

DRUG SAFETY EVALUATION

What is Drug Safety Evaluation?

All medicinal products carry risks in addition to their possible benefits. For developing a new medicine, a decision can
only be made if both benefits & risks are addressed. Risk associated with the drug is minimized when medicines of good
quality, safety & efficacy are used rationally by an informed health professional & by patients. Guidelines were
developed to monitor drugs, foods & environmental contaminants for adverse reactions & toxicity. Pharmacovigilance
helps in reducing the risk of harm by ensuring use of good quality medicines approprietely.

In beginning, guidelines were restricted to local needs. In clinical trilas, critical efficacy endpoints are identifies in
advance & sample sizes are estimated for assessment of effectiveness.

DRUG SAFETY EVALUATION (TOXICITY STUDIES)

In biology, the term "in situ" means that the examination and observation of a rare occurrence take place where it
occurs. Subjects are examined on position and are not moved to another or channel. An example is an observation of
dolphins at sea. they observed where they are found and are not moved to an aquarium or other container which is
more convenient. In cell science, in situ can mean something in between in vivo and in vitro.

IN VIVO
 "in vivo" is a latin word which means "within the living."
 it is the experiment or observations done on the living tissue of the whole living organism in a controlled
environment.
 in vivo experiments are done in the organism's natural environment or in the organism itself.
 precise cellular conditions are presented in these studies.
one example is a clinical testing or a clinical trial which can be controlled testing of a new drug or device on
human subjects. the subjects are given the drugs and are observed for a certain period of time
 another is animal testing which is an experiment that is done in animals usually rats, birds, frogs, and other animals
where the drugs are directly injected into the body. so in vivo experiments, conditions are not manipulated or
controlled.
 it is found to be more suited on experiments done on organisms that are alive
 in medicine, clinical trials and animal testing are performed in vivo to analyze the overall effects of the experiments.
 in vivo experiments, living cells, or animal models are used. in vivo studies are crucial for the development of
medical devices, surgical instruments, procedures and novel therapeutics.

IN VITRO

 "in vitro" is a latin word that means "within the glass." therefore the studies which are done outside the living
organism,inside glass (test tubes or petrishishes) are known as in vitro studies.
 it is the experiment or observations done on the tissue outside of the living organism in a controlled environment,
usually using petri dishes and test tubes.
 the term in vitro is used in cell biology to explain the techniques which are performed on a controlled environment
outside a living cell or organism
 most experiments in cellular biology are done through in vitro studies and are not conducted in the organism's
natural environment. this results in the limited success of the experiments in simulating the actual conditions inside
an organism and make its outcome less precise.
 compared to in vivo experiments, it is less epensive and provides quicker results.
 most of the cellular, biochemical experiments are carried out in vitro in the labs to test.
 in vitro methods are widely used in the pharmaceutical industry to produce large scale pharmaceuticals using
microorganisms due to its ease of production and economic benefits.

"Methods and principles underlying various toxicological tests.”

CURRENT METHODS: GENERAL CONSIDERATIONS

 Toxicity studies are required to assess potential hazards to humans through the acute, subchronic, and chronic
exposure of laboratory animals to pesticides. The more specific types of toxicity that are determined include
carcinogenicity; developmental (including teratogenicity in offspring) and reproductive toxicity; mutagenicity; and
neurotoxicity

 Detailed information on the metabolism or biotransformation of the pesticide is also obtained. Consideration is
given to testing individual metabolites in animals, and in or on pesticide-treated plants to which humans could
exposed through their diet. The extent of metabolite testing required depends on the level of potential toxicity and
environmental persistence of the metabolite. With the exception of the acute toxicity tests, most tests are
conducted to determine the nature of any toxicity that can be produced by repeatedly dosing animals over an
extended period. The results enable toxicologists to estimate the safety of a material of humans

Weil (1972) published the following set of guidelines, which reflected a consensus among toxicologists.
These should be considered before initiating a toxicity test:

1. Use, wherever practical or possible, one or more species that biologically handle the material qualitatively and/or
quantitatively as similarly as possible to man. For this, metabolism, absorption, excretion, storage and other
physiological effects might be considered.

2. Where practical, use several dose levels on the principle that all types of toxicologic and pharmacologic actions in man
and animals are dose-related. The only exception to this should be the use of a single, maximum dosage level if the
material is relatively nontoxic.
3. Effects produced at higher dose levels (within the practical limits discussed in 2) are useful for delineating the
mechanism of action, but for any material effect, some dose level exists for man or animal below which this adverse
effect will not appear.

4. Statistical tests for significance are valid only on the experimental units that have been mathematically randomized
among the dosed and concurrent control groups.

6. Effects obtained by one route of administration to test animals are not a priori applicable to effects by another route
of administration to man. The routes chosen for administration to test animals should, therefore, be the same as those
to which man will be exposed. Thus, for example, food additives for man should be tested by admixture of the material
in the diet of animals.

SUBCHRONIC TOXICITY STUDIES

 Most subchronic toxicity studies monitor clinical or behavioral (neurological) signs of toxicity, body weight, food
consumption, eye effects, certain plasma or serum and urine parameters, organ weights, and gross and microscopic
pathology. Clinical and behavioral signs of toxicity are observed and recorded daily. They can consist of activity, gait,
excreta, hair coat, and feeding and drinking patterns. Body weight and food consumption data are routinely
recorded throughout the study at intervals (usually weekly) determined by the length of the study.
Ophthalmoscopic examinations are conducted at the beginning of the study and, typically, just before it terminates.

CHRONIC TOXICITY STUDIES

 Information derived from chronic studies is used to assess potential hazards resulting from prolonged and repeated
exposure to a pesticide over a large portion of the human life span. These studies usually last 12 to 24 months. Of
particular importance are long- term carcinogenicity studies, the purpose of which is to observe the test animals for
the development of neoplastic lesions after a lifetime of exposure at dose levels up to and including the MTD
determined from subchronic testing.

 The emphasis of the carcinogenicity study is the detection of tumors in animals. For these studies, both concurrent
and historical control data are used to evaluate the relevance of tumors. Historical control data should be derived
from studies in the same species and strain and, preferably, in the same laboratory as used in the study under
consideration.

DEVELOPMENTAL TOXICITY STUDIES

 Developmental toxicity studies are designed to assess the potential of developmental effects in offspring resulting
from the mother's exposure to the test substance during pregnancy. These effects include death of the developing
organism, structural abnormalities, altered growth, and functional deficiencies. In addition to the classic teratology
(now called developmental toxicity) study, a postnatal study is required by the EPA on a case-by-case basis. It is in
this study that functional deficiencies are best studied.

 The EPA prefers that the rat and the rabbit be used in these studies; however, hamster and mouse are also
acceptable. Doses should be administered over the period of major organogenesis (major visceral and skeletal
formation) in the fetus. The maternal animals only are dosed in this study and only for specified periods. When day
0 is the day that evidence of mating was observed, the rat and mouse are dosed on days 6 through 15; the rabbit,
days 6 through 18; and the hamster, days 6 through 14.

ETHICAL CONSIDERATIONS IN HUMAN AND ANIMAL EXPERIMENTATIONS

A LOOK BACK TO HISTORY

During the Second World War and the Holocaust, Nazi researchers committed mass-scale atrocities against Jews and
other prisoners under the name of medical research. The largest German Nazi concentration camp, Auschwitz,
witnessed Josef Mengele’s egregious experiments performed on Gypsy children, twins, dwarfs, and people with
abnormalities. When the research came to an end, they were killed and their organs autopsied and analyzed.
It took two years after the end of the war for 16 German physicians to be found guilty of nefarious crimes against
humanity. The Nazi doctors’ trial exposed torture, deliberate mutilation, sterilization, and murder. Their trial led to the
1947 drafting of the Nuremberg Code, a set of guidelines governing research on humans, which included 10 principles
focused on patient consent and autonomy. The Nuremberg Code, the first of its kind, was created to prevent a
recurrence of the horrors committed in Nazi Germany, and it paved the way for the development of medical ethics and
greatly influenced the evolution of human rights law.

The use of properly controlled clinical trials in medical experimentation has been of vital importance to the progress of
medical science. At the same time, the new form of experimentation has also generated some of our most difficult and
perplexing moral dilemmas. The solutions to the many complicated ethical problems involved in human experimentation
are not straightforward, and despite numerous books, articles, codes, guidelines, and declarations, many specific issues
of right and wrong in human experimentation have not yet been definitively resolved.
Society today has an obligation greater than ever to control, regulate, and enforce properly balanced codes of human
experimentation in order to minimize the unacceptable ethical problems and maximize the desired results of moderm
human experimentation. These, however, are not sufficient. The patient's greatest safeguard in experimentation is a
skillful, intelligent, and conscientious physician and investigator. Thus, the investigator bears great responsibility in
balancing between the common good and the individual's rights. In this article the relevant secular and Jewish ethical
principles and rules concerning human experimentation are specified and methodologically organized. Particular
emphasis is placed on the elucidation and evaluation of the ethical controversies surrounding randomized clinical trials

DEFINITION OF HUMAN EXPERIMENTATION

A subject is defined as an individual who is observed or experimented with by an investigator; an investigator is a
qualified individual who conducts research.

GENERAL STATEMENT
Medical and related research using human beings as subjects must necessarily ensure that:
The PURPOSE, of such research is that it should be directed towards the increase of knowledge about the human
condition in relation to its social and natural environment

 Such research is CONDUCTED under condition that no person or persons become a mere means for the betterment
of others and that human beings who are subject to any medical research or scientific experimentation are dealt
with in a manner conductive to and consistent with their dignity and well being.
 Such research must be subjected to a regime of EVALUATION at all stages of the proposal, i.e., research design, and
experimentation, declaration of results and use of the results.
 Each such evaluation shall bear in mind the objects to be achieved, the means by which they are sought to be
achieved , the potential uses and abuses of the experiment and its results

STATEMENT OF GENERAL PRINCIPLES

Principles of essentiality
Project involving human subjects can be performed only after if it gets approval from an authorized person, who checks
the essentiality of the project, whether it is useful or harmful for the society & the person who checks the essentiality
should be an external body of the project

Principles of voluntariness and community agreement

 Subjects which are going under such projects should be informed about the project & its benefits & its risk factors.
In shortly, volunteer should know everything in briefly about the project.
 If volunteer feels any risk at any stage of the project he/she can abstain from further participation & no legal
authority can stop him from doing so.
 Research involving any community or a group of persons as a research subjects these principles of voluntariness
shall apply to all members of community.

Principles of non-exploitation
 Research subject are paid for their involvement in the research or experiment, without seeing his/her economic or
social status or literacy or educational levels.
 Subjects should bear the knowledge of all dangers arising in & out of the research project. If during experiment
subject suffers from any side effects or toxic effects, he or she should be treated & rehabilitated as soon as possible.

Principles of privacy and confidentiality

 The identity of subject keep confidential until & unless it has to be disclosed for any valid scientific & legal reasons
& it should have written permission from the respective human subject to disclose it.

Principles of precaution and risk minimization

 Precaution should be taken at all stages of research & subject should not get affected by any adverse effects in
simple terms, he/she should bear minimal risks.

Principles of accountability and transparency

 The research or experiment should be conducted in fair, honest, impartial & transparent manner so, that there
should not be any arising of conflicts. Research data should be reserved for a prescribed period of time

Principles of the maximization of the public interest and of distributive justice

 Research should be benefited to all human kind & not just for people who are socially & economically better.

Principles of institutional arrangements

 All persons connected to research should ensure that all procedure & all institutional arrangements should fully
made in a bonafide & transparent manner.

Principles of public domain

 Results emerging from such research or experiments should bring in to the public domain & its results should
generally made known through scientific & other publications.

Principles of compliance
 Persons conducting, associated or connected anyhow with this research project involving human subject should
ensure that these guidelines are carefully observed

ETHICAL REVIEW PROCEDURES

 It is mandatory that all proposals on biomedical research involving human subjects should be cleared by an
appropriately constituted Institutional Ethics Committee (IEC), also referred to as Institutional Review Board (IRB).
 The Ethics committees are entrusted not only with the initial review of the proposed research protocols prior to
initiation of the projects but also have a continuing responsibility of regular monitoring for the compliance of the
ethics of approved programmes till the same are completed.

BASIC RESPONSBILITIES
 The basic responsibility of an IEC is to ensure a competent review of all ethical aspects of the project proposals
received.
  To protect the dignity, rights and well being of the potential research participants.
 To ensure that universal ethical values and international scientific standards are expressed in terms of local
community values and customs.
 To assist in the development and the education of a research community responsive to local health care
requirements

Animals in research
 VACCINATION
 ANTIBIOTICS
 ANESTHESIA
 NUMEROUS MEDICAL TREATMENTS FOR VARIOUS DISEASES

Today there exists a wide spectrum of views on this subject, ranging from those concerned with animal 'rights' to those
who view animals only as a resource to be exploited. All of these viewpoints have contributed to the development of
ethical principles of animal use is a term used to describe human-animal relationships and how animals ought to be
managed and treated.

The subject matter includes

 ANIMAL RIGHTS
 ANIMAL WELFARE
 WILDLIFE CONSERVATION
 ANIMAL LAW ANIMAL COGNITION
 MORAL STATUS OF NON HUMAN ANIMALS\

Ethical considerations in animal and experimentation clinical research advances the understanding of science and
promotes human health. Howver, it is important to remember the individuals who volunteer to participate in research.

ANIMALS ARE USED IN RESEARCH OR EXPERIMENTATION IN PLACE OF HUMAN SUBJECTS FOR VARIOUS REASONS.
ANIMALS ARE USED MOST OFTEN IN THE FOLLOWING CASES:
 DISEASE TREATMENT
 PREVENTION TREATMENT OF INJURIES
 BASIC MEDICAL TESTING
 MEDICAL DIAGNOSIS

Ethics and Experiments on Animals

The ethical assessments related to the use of animals in research are wide-ranging. It is generally thought that it
may be necessary to use laboratory animals in some cases in order to create improvements for people, animals or the
environment. At the same time, the general opinion is that animals have a moral status, and that our treatment of them
should be subject to ethical considerations. Such views are reflected in the following positions:
1. Animals have an intrinsic value which must be respected.
2. Animals are sentient creatures with the capacity to feel pain, and the interests of animals must therefore be taken
into consideration.
3. Our treatment of animals, including the use of animals in research, is an expression of our attitudes and influences us
as moral actors.

Guidelines
These guidelines have been prepared by the National Committee for Research Ethics in Science and Technology (NENT).
Their purpose is to provide ethical guidelines for researchers and other people who are considering experiments on
animals. The guidelines will be useful when planning projects, assessing them, and when reporting and publishing
findings and results. They are also intended to contribute to reflection on research ethics and the use of animals in
research in both research communities and in the public debate.

1. Respect for animals' dignity

Researchers must have respect for animals' worth, regardless of their utility value, and for animals' interests as living,
sentient creatures. Researchers must be respectful when choosing their topic and methods, and when disseminating
their research. Researchers must provide care that is adapted to the needs of each laboratory animal.
2. Responsibility for considering options (Replace)
Researchers are responsible for studying whether there are alternatives to experiments on animals. Alternative options
must be prioritised if the same knowledge can be acquired without using laboratory animals. If no good options are
available, researchers should consider whether the research can be postponed until alternative methods have been
developed. When justifying experiments on animals, researchers therefore must be able to account for the absence of
options and the need to acquire knowledge immediately.

3. The principle of proportionality: responsibility for considering and balancing suffering and benefit
Researchers must consider the risk that laboratory animals experience pain and other suffering (see guideline 5) and
assess them in relation to the value of the research for animals, people or the environment. Researchers are responsible
for considering whether the experiment may result in improvements for animals, people or the environment. The
possible benefits of the study must be considered, substantiated and specified in both the short and the long term. The
responsibility also entails an obligation to consider the scientific quality of the experiments and whether the
experiments will have relevant scientific benefits

4. Responsibility for considering reducing the number of animals (Reduce)

Researchers are responsible for considering whether it is possible to reduce the number of animals the experiment plans
to use and must only include the number necessary to maintain the scientific quality of the experiments and the
relevance of the results. This means, among other things, that researchers must conduct literature studies, consider
alternative experiment designs and perform design calculations before beginning experiments.

5. Responsibility for minimising the risk of suffering and improving animal welfare (Refine) Researchers are
responsible for assessing the expected effect on laboratory animals. Researchers must minimise the risk of suffering and
provide good animal welfare. Suffering includes pain, hunger, thirst, malnutrition, abnormal cold or heat, fear, stress,
injury, illness and restrictions on the ability to behave normally/naturally.

6. Responsibility for maintaining biological diversity

Researchers are responsible for ensuring that the use of laboratory animals does not endanger biological diversity. This
means that researchers must consider the consequences to the stock and to the ecosystem as a whole. The use of
endangered and vulnerable species must be reduced to an absolute minimum. When there is credible, but uncertain,
knowledge that the inclusion of animals in research or the use of certain methods may have ethically unacceptable
consequences for the stock and the ecosystem as a whole, researchers must observe the precautionary principle.

7. Responsibility when intervening in a habitat

Researchers are responsible for reducing disruption and any impact on the natural behaviour of individual animals,
including those that are not direct subjects of research, as well as of populations and their surroundings. Certain
research and technology-related projects, like those regarding environmental technology and environmental
surveillance, may impact on animals and their living conditions, for example as a result of installing radar masts,
antennas or other measurement instruments. In such cases, researchers must seek to observe the principle of
proportionality (see guideline 3) and minimise the possible negative impact.

8. Responsibility for openness and sharing of data and material

Researchers are responsible for ensuring that there is transparency about research findings and facilitating the sharing
of data and material from experiments on animals. Such transparency and sharing are important in order to avoid
unnecessary repetition of experiments. Transparency is also important in order to ensure that the public are informed
and is part of researchers' responsibility for dissemination.

9. Requirement of expertise on animals

Researchers and other parties who handle live animals must have adequately updated and documented expertise on
animals. This includes specific knowledge about the biology of the animal species in question, and a willingness and
ability to take care of animals properly.

10. Requirement of due care

There are national laws and rules and international conventions and agreements regarding the use of laboratory animals,
and both researchers and research managers must comply with these. Any person who plans to use animals in
experiments must familiarise themselves with the current rules.

Investigational New Drug Application

What is an IND ?
 An IND is a submission to the food and drug administration (FDA) requesting permission to initiate a clinical study
of a new drug product.
 The Federal Food, Drug and Cosmetic act requires that drugs have an approved marketing application before they
can be shipped in interstate commerce.
 The IND application allows a company to initiate and conduct clinical studies for their new drug products.

When Do I Need An IND ?

 An IND is required any time I want to conduct a clinical trial of an unapproved drug.
 An IND would be required to conduct a clinical trail if the drug is
 A new chemical entity , not approved for the indication under investigation in a new dosage form.
 Being administered at a new dosage level.
 In combination with another drug and the combination is not approved.

You Don’t Need An IND

An IND is not required to conduct a study if the drug :
 is not intended for human subjects , but is intended for in vivo testing or lab research animals (non clinical studies).
 is an approved drug and the study is within its approved indication for use.

CATEGORIES OF IND:
 COMMERCIAL IND : goal is to obtain marketing approval for a new product.
 NON-COMMERCIAL IND : It includes
 INVESTIGATOR IND : In this case ,the physician is both the sponsor and investigator.
 EMERGENCY IND : FDA authorize immediate dispensing of a non-approved drug in a life threatening situation
when no standard acceptable therapy is available.
 TREATMENT IND : FDA will permit investigational drug to be used to treat a serious or life threatening disease
or if there is no comparable alternative drug available.

Content of IND
In three broad areas:

1. Animal Pharmacology and Toxicology Studies –

o An assessment as to whether the product is reasonably safe for initial testing in humans
o Any previous experience with the drug in humans

2. Manufacturing Information
o composition, manufacturer, stability, and controls used for manufacturing the drug

3. Clinical Protocols and Investigator Information

o Commitments to obtain informed consent from the research subjects, to obtain review of the study by an institutional
review board (IRB), and to adhere to the investigational new drug regulations.

Once the IND is submitted, the sponsor must wait 30 days before initiating any clinical trials. During this time, FDA has
an opportunity to review the IND for safety to assure that research subjects will not be subjected to unreasonable risk

FORMAT OF IND
A. Cover sheet (Form FDA-1571)
o Name, address, telephone of sponsor
o Identification of phases o Commitment not to begin CT until IND approval
o Commitment by IRB- Form 56
o Commitment for conducting CT- accordance with regulations
o Name, title – Monitor
o Name, title – person(s) for reviewing
o Name, Address of CRO, if any
o Signature of sponsor
B. Table of contents
C. Introductory statement & general investigational plan
D. Investigators brochure
E. Study protocol
F. Investigator facilities & IRB data
G. Chemistry manufacturing & control data
H. Pharmacology & toxicology data
I. Previous human experience

INTRODUCTORY STATEMENT
 Description of the investigational drug
 All active ingredients
 Drug’s pharmacological classification
 Structural formula
 Route of administration
 Summary of previous human experience
 Formulation of dosage forms
 Objective and planned duration of proposed clinical investigation.

INVESTIGATIONAL PLAN
 Description of clinical studies planned for the experimental drug
 Purpose of the study
 Indication to be studied
 Types of trials to be initiated
 Number of study subjects
 Risks involved

INVESTIGATORS BROCHURE
 Structural formula of drug.
 Summary of pharmacological , toxicological , pharmacokinetic effects in animals.
 Safety and efficacy
 Purpose of study
 Dose / dose frequency
 Monitoring procedures
CLINICAL PROTOCOL
 a clinical protocol describes how a particular clinical trial is to be conducted
 It describes
 the objectives of study
 the trial design
 how subjects are selected
 how the trial is to be carried out

Clinical Trial Design

Clinical trial design is an important aspect of interventional trials that serves to optimize, ergonomise and economize
the clinical trial conduct. The purpose of the clinical trial is assessment of efficacy, safety, or risk benefit ratio.

There are several types of clinical trial design. These can be classified as follows:
 according to the method used to allocate participants into treatment or control groups (non-randomised or
randomised controlled trials)
 according to the awareness of either participants or researchers or both of which group participants are allocated
into (single or double-blind studies)
 according to the magnitude of difference between treatment and control groups that is expected (superiority or
non-inferiority trials)

Non-randomised controlled clinical trial designs

In non-randomised controlled trials, participants are allocated into treatment and control arms by the investigator. In
these trials, control groups can be concurrent controls or historical controls. When using a historical control, all subjects
in the trial receive the study medicine; the results are either compared to the patient’s history (for example, a patient
living with a chronic illness) or a previous study control group.

Randomised controlled clinical trial designs

In randomised controlled trials, trial participants are randomly assigned to either treatment or control arms. The process
of randomly assigning a trial participant to treatment or control arms is called ‘randomisation’. Different tools can be
used to randomise (closed envelopes, computer generated sequences, random numbers). There are two components to
randomisation: the generation of a random sequence and the implementation of that random sequence, ideally in a way
that keeps participants unaware of the sequence. Randomisation removes potential for bias.

There are different types of randomised trial designs.

Parallel group trial design
In parallel group randomisation, after randomisation each participant will stay in their assigned treatment arm for the
duration of the study. Parallel group design can be applied to many diseases, allows running experiments simultaneously
in a number of groups, and groups can be in separate locations.

Cross-over trial design:

Cross-over randomisation is when participants receive a sequence of different treatments (for example, the candidate
compound in the first phase and the comparator/control in the second phase). Each treatment starts at an equivalent
point, and each individual serves as his/her own control. It presents some advantages, such as low variance due to
treatment and control being the same participant, and the possibility of including a number of treatments. However,
there must be a sufficient time gap between the different treatment phases (washout period).

Matched pair trial design

In the matched-pair design, participants are first matched in pairs according to certain characteristics. Then, each
member of a pair is randomly assigned to one of the two different study subgroups. This allows comparison between
similar study participants who undergo different study procedures.

Stratification
Stratification also allows for comparison between similar study participants who undergo different study procedures. All
study participants are grouped according to one or more factors (for example, age, gender, lifestyle factors, concomitant
medication) before being randomised. This ensures balanced allocation within each combination.

Cluster sampling
Randomised trials can also use cluster sampling. In cluster sampling, suitable geographical areas are found (for instance,
city, region, etc.). A number of these geographical areas are then randomly chosen. For each of these chosen
geographical areas, a proportionate subsample from the members of the study sample in that area are chosen, and
these subsamples are then combined into a sample group.

Withdrawal trials
In a withdrawal trial, the participant receives a test treatment for a specified time and are then randomised to continue
either with the test treatment or a placebo (withdrawal of active therapy).

Factorial design
Factorial clinical trials test the effect of more than one treatment. This allows assessment of potential interactions
among the treatments.

There are a number of different types of comparison trials possible:

 Superiority to demonstrate that the investigational medicine is better than the control;
 Equivalence to demonstrate that the endpoint measure is similar (no worse, no better) than the control;
 Non-inferiority to demonstrate that the investigational medicine is not worse than the control;
 Dose-response relationship trials to determine various dose parameters, including starting dose and maximum dose.

Clinical Trial Core Documents

The Core Documents For Clinical Trials are as Follows:
 Investigator's Brochure
 Clinical Study Protocol
 Case Report Form (CRF)
 Informed Consent Form
 Clinical Study Reports

INVESTIGATOR'S BROCHURE (IB):

Contains pre-clinical and clinical information related to an investigational drug. The information should be presented in a
concise, simple, objective, balanced form that should be taken into account during translation.

 List of Abbreviations
 Contents & Summary
 Introduction provides the chemical name (and generic and trade names, if approved) of the investigational product.
 Physical, chemical and pharmaceutical properties and formulation of the medicinal product.
 Non-clinical studies & Clinical Studies and their results.
 Conclusions and Guidance for the Investigator
 References (at the end of each section)

CASE RECORD/REPORT FORM (CRF)

CRF is a paper or electronic document designed to record all the information for an individual study subject required by
the Study protocol.

All CRF's should include the following data:

 Study title and number;

 Investigator's name;
 Study subject/patient ID (number and initials);
 Inclusion / exclusion criteria;
 Demographic data;
 Detailed description of dosage regimens of investigational drug;
 Concomitant treatment;
 Adverse events (side effects and intercurrent diseases);
 Conclusion on subject's health;
 Investigator's signature and date.

Additionally, the CRF's should include special pages to record the following information:
 ·past medical history;
 ·results of physical examination;
 ·primary and secondary diagnoses;
 ·relevant previous treatment;
 ·baseline characteristics, results of interim assessments, evaluation of efficacy endpoints, laboratory tests,
description of study procedures etc.

All CRF's should be legible and suitable for duplication and possible additional sharing.

Clinical Study Protocols

The Guideline ICH E6 defines the protocol as, A document that describes the objective(s), design, methodology,
statistical considerations, and organization of a trial.

The Study Protocol should ensure adequate conduction of the clinical trials and collection and analysis of data that are
further submitted to the regulatory authorities for review and consideration.

Parts of Protocol
 Introduction/Abstract
 Objectives
 Background/Rationale
 Eligibility criteria
 Study design/methods (including drug/device info)
 Safety/adverse events
 Regulatory guidance
 Statistical section (including analysis & monitoring)
 Human subjects protection/informed consent

INFORMED CONSENT
-is a process by which a subject voluntary confirms his/her willingness to participate in one or another clinical trial, after
having been informed of all aspects of the study.
-Informed consent should be documented by means of a written, signed and dated Informed Consent Form (ICF). :

The Subject Should be Informed of the Following:

 the purposes of the trial;
 the methods of the trial;
 the study drug(s) and treatment regimens;
 available alternative treatment(s);
 the potential risks and benefits, and possible discomforts.

Clinical Trial Stakeholders

Clinical Research industry is a dynamic and interdependent industry. The industry works in collaboration with various
organizations.

The stakeholders of clinical research industry

All Stakeholders are bounded by three basic responsibilities
1. ETHICAL responsibilities
2. SCIENTIFIC responsibilities
3. Administrative responsibilities

Sponsors are primary stakeholders who intiates, organizes, finances clinical research. Sponsors can be an individual or
company or an organization. Usually, Sponsors are pharmaceutical company, biotechnology companies

Academic Institutions. Investigator and investigator team is appointed/hired by sponsor. The Investigator team is
constituted by co-investigator, sub-investigator, clinical research coordinator, study nurse, pharmacist, laboratory
personnel, research assistant and subject recruiter.

All team members should be qualified, experienced and trained to conduct assigned clinical research duties under
supervision of principal investigator. Clinical Research should be conducted in accordance with ethical principles that
have their origin in declaration of Helsinki and consistent with good clinical practice, standard operating procedures and
Applicable Regulatory Requirements.

Institutional review board or independent ethics committee IRB

is stakeholder at the clinical research site. Trial should be initiated at the site only after approval from the ethics
committee.

Ethics committee
is responsible for protecting rights safety and well being of trial subjects, Review of ongoing clinical trials, compensation
and payments to trial subjects.

Regulatory Authorities are the stakeholders responsible for giving permission to conduct clinical research in the country.
The sponsor submits the investigational new drug application or new drug application to the regulatory authorities for
review and approval. Once the sponsor obtains approval to initiate and continue the research, regulatory authorities
conduct audits and inspection upon serious non compliance, major violations.

Regulatory Authorities are also responsible for ensuring protection of public health by safeguarding rights, safety and
wellbeing of trial subjects.