DDD MIDTERMS -Nevertheless, due to high attrition rates, especially during clinical phases of

drug development, more attention is being focused early in the drug design
DRUG DESIGN process on selecting candidate drugs whose physicochemical properties are
predicted to result in fewer complications during development and hence more
-often referred to as Rational Drug Design or simply Rational Design likely to lead to an approved, marketed drug
-inventive process of finding new medications based on the knowledge of a
biological target
-in the most basic sense, drug design involves the design of molecules that are
complementary in shape and charge to the biomolecular target with which they
interact and bind to it
-drug is most commonly an organic small molecule that activates or inhibits the
function of a biomolecule such as protein, w/c in turn results in a therapeutic
benefit to the patient
-Drug design frequently but not necessarily relies on computer modeling
techniques
-most fundamental goal in drug design is to predict whether a given molecule
will bind to a target and if so how strongly
-Molecular mechanics or molecular dynamics is most often used to estimate the
strength of the intermolecular interaction between the small molecule and its COMPUTER-AIDED DRUG DESIGN (CADD)
biological target
-type of modeling is sometimes referred to as computer-aided drug design -COMPRISES A BROAD RANGE OF THEORETICAL AND
-finally, drug design that relies on the knowledge of the three- dimensional COMPUTATIONAL APPROACHES THAT ARE PART OF MODERN DRUG
structure of the biomolecular target is known as structure- based drug design DISCOVERY
-in addition to small molecules, biopharmaceuticals including peptides and -CADD METHODS HAVE MADE KEY CONTRIBUTIONS TO THE
especially therapeutic antibodies are an increasingly important class of drugs DEVELOPMENT OF DRUGS THAT ARE IN CLINICAL USE OR IN CLINICAL
and computational methods for improving the affinity, selectivity, and stability of TRIALS
these protein-based therapeutics have also been developed -SUCH METHODS HAVE EMERGED AND EVOLVED ALONG WITH
-the phrase "drug design" is to some extent a misnomer EXPERIMENTAL APPROACHES USED IN DRUG
-more accurate term is ligand design (i.e., design of a molecule that will bind -CADD IS AN EXCITING AND DIVERSE DISCIPLINE WHERE VARIOUS
tightly to its target) ASPECTS OF APPLIED AND BASIC RESEARCH MERGE AND STIMULATE
-although design techniques for prediction of binding affinity are reasonably EACH OTHER
successful, there are many other properties, such as bioavailability, -IN THE EARLY STAGE OF A DRUG DISCOVERY PROCESS,
metabolic half-life, side effects RESEARCHERS MAY BE FACED WITH LITTLE OR NO STRUCTURE
-that first must be optimized before a ligand can become a safe and efficacious ACTIVITY RELATIONSHIP (SAR) INFORMATION
drug
-these other characteristics are often difficult to predict w/ rational design -FURTHERMORE, IN VITRO EXPERIMENTS COMPLEMENTED WITH
techniques COMPUTATION METHODS ARE INCREASINGLY USED IN EARLY DRUG
DISCOVERY TO SELECT COMPOUNDS WITH MORE FAVORABLE ADME
(ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION) AND
TOXICOLOGICAL PROFILES
-CADD HAS BEEN CREDITED TO THE MODERN PATTERNS IN
COMPOUND CHARACTERIZATION IN DRUG DISCOVERY FOLLOWING
ITS INCEPTION IN 1981
-IT REPRESENTS AN ADVANCEMENT WHEN COMPARED TO HTS AS IT
REQUIRES MINIMAL COMPOUND DESIGN OR PRIOR KNOWLEDGE, BUT
CAN YIELD MULTIPLE HIT COMPOUNDS AMONG WHICH PROMISING
CANDIDATES HAVE BEEN ELECTED
-THE TYPICAL ROLE OF CADD IN DRUG DISCOVERY IS TO SCREEN OUT
LARGE COMPOUND LIBRARIES INTO SMALLER CLUSTERS OF
PREDICTED ACTIVE COMPOUNDS, ENABLING OPTIMIZATION OF LEAD
COMPOUNDS BY IMPROVING THE BIOLOGICAL PROPERTIES (LIKE
AFFINITY AND ADMET) AND BUILDING CHEMOTYPES FROM A
NUCLEATING SITE BY COMBINING FRAGMENTS WITH OPTIMIZED
FUNCTION
-CLUSTERING HAS BEEN APPLIED AS A MEANS TO SELECT
REPRESENTATIVES FROM SCREENING LIBRARIES
-SCREENING HITS INCLUDE MOLECULES THAT SPECIFICALLY BIND TO
THE TARGET IN ADDITION TO A GREATER NUMBER OF NONSPECIFIC
COMPOUNDS REQUIRING A TRIAGING PROCESS TO FILTER THESE
OUT THUS, SUCH A LARGE LIBRARY THAT CONTAINS A NUMBER OF
POSSIBLE HITS IS FURTHER DOWNSIZED AND CLUSTERED INTO
SERIES
-COMPUTATIONAL CHEMISTRY ALGORITHMS HAVE BEEN DEVELOPED
TO GROUP HITS BASED ON STRUCTURAL SIMILARITY, WHICH IS
NECESSARY TO ENSURE THAT COMPOUNDS ARE ADEQUATELY
SORTED OVER A BROAD SPECTRUM OF CHEMICAL CLASSES
-THUS, SELECTION OF HITS WOULD BE BASED ON CHEMICAL CLUSTER,
POTENCY, AND FACTORS SUCH AS LIGAND EFFICIENCY (WHICH GIVES
AN IDEA OF HOW WELL A COMPOUND BINDS FOR ITS SIZE)
-THE INCREASING APPLICATION OF DIVERSE COMPUTERIZED
METHODS IN DRUG DISCOVERY HAS ENABLED A BETTER HANDLING
OF DATA ASSOCIATED WITH A LARGE NUMBER OF COMPOUNDS
SCREENED AGAINST THE TARGET MOLECULES OR PROTEINS- FOR
LEADS
-COMPUTATIONAL TOOLS HELP TO DEFINE AND ELABORATE THE
STRENGTH OF INTERACTION BETWEEN LIGANDS AND TARGETS, AND
HAVE BEEN INSTRUMENTAL IN THE IDENTIFICATION OF LEAD
MOLECULES FROM DATABASES NEVERTHELESS, THE LACK OF
SPECIFICITY LEADS TO LOW HIT RATE FOR HTS, WHICH COULD LIMIT
ITS APPLICABILITY AND EFFICIENCY IN SCREENING LARGE
COMPOUND LIBRARIES
-CADD IS A MORE TARGETED APPROACH TO THE GENERATION OF
"HITS" WHEN COMPARED WITH TRADITIONAL HTS, IT ENABLES THE
ELUCIDATION OF THE MOLECULAR BASIS OF THERAPEUTIC ACTIVITY
AND POSSIBLE DERIVATIVES, AND THOSE VARIABLES THAT COULD BE
APPLIED OR IMPROVED FOR GENERATING AN OPTIMAL DRUG
COMPOUND THUS LEADING TO PRIORITIZATION OF THE ACTIVES
WITHOUT REQUIRING EXTENSIVE DEVELOPMENT AND VALIDATION
PRIOR TO USE, AS IN THE CASE OF ASSAY HTS
-THE CADD APPROACH HAS PLAYED A VITAL ROLE IN THE SEARCH
AND OPTIMIZATION OF POTENTIAL LEAD COMPOUNDS WITH A
CONSIDERABLE GAIN IN TIME AND COST
-IT HAS BEEN APPLIED DURING VARIOUS STAGES IN DRUG DISCOVERY
TARGET IDENTIFICATION, VALIDATION, MOLECULAR DESIGN, AND
INTERACTIONS OF DRUG CANDIDATES WITH TARGETS OF INTEREST
-CADD CAN BE STRUCTURE OR LIGAND BASED STRUCTURE-BASED
CADD SEEKS THE KNOWLEDGE OF THE TARGET PROTEIN STRUCTURE
IN THE DETERMINATION OF INTERACTION LEVELS OF ALL
COMPOUNDS BEING EXAMINED. LIGAND-BASED CADD RELIES ON THE
CHEMICAL SIMILARITY CRITERIA, AND THE PREDICTIVE,
QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP (QSAR) MODELS
THAT IT CREATES FROM THE MOLECULES TO DETERMINE THE KNOWN
ACTIVE AND INACTIVES
-OSAR MODELING ENABLES UNDERSTANDING OF THE INFLUENCE OF
STRUCTURAL FACTORS ON BIOLOGICAL ACTIVITY, USING THE
MODELS AND THE UNDERSTANDING TO CONSTRUCT COMPOUNDS
WITH IMPROVED AND OPTIMAL BIOLOGICAL PROFILES
-OTHER METHODS FOR QUANTITATIVE DESCRIPTION OF STRUCTURAL
CHANGE ARE COMPARATIVE MOLECULAR FIELD ANALYSIS AND GRID
STRUCTURE-BASED CADD
-IS A PREFERRED CHOICE FOR SOLUBLE PROTEINS THAT COULD BE
CRYSTALLIZED, WHILE LIGAND-BASED CADD IS BETTER SUITED FOR
COMPOUNDS WITH HIGH BINDING AFFINITY TO THE TARGET, DEVOID
OF OFF-TARGET EFFECTS, AND THAT COULD BE DESIGNED WITH
MINIMAL FREE ENERGY, FAVORABLE DRUG METABOLISM, AND
PHARMACOKINETIC/ADMET PROPERTIES
-IN GENERAL, CADD IS BETTER SUITED FOR OCCASIONS WHERE
SPARSE STRUCTURAL INFORMATION IS AVAILABLE. THIS IS USUALLY
THE CASE FOR MEMBRANE PROTEIN TARGETS
COMPUTER-AIDED DRUG DESIGN (CADD)
-HELPS SCIENTISTS IN MINIMIZING THE SYNTHETIC AND BIOLOGICAL
TESTING EFFORTS BY FOCUSSING ONLY ON THE MOST PROMISING
COMPOUNDS
-BESIDES EXPLAINING THE MOI ECTILAR BASIS OF THERAPEUTIC
ACTIVITY, IT ALSO PREDICTS POSSIBLE DERIVATIVES THAT WOULD
IMPROVE ACTIVITY
CADD ENTAILS
1. DRUG DISCOVERY AND DEVELOPMENT PROCESSES BEING
STREAMLINED BY THE USE OF COMPUTING POWER
2. IDENTIFICATION AND OPTIMIZATION OF NEW DRUGS USING
LEVERAGE OF CHEMICAL AND BIOLOGICAL INFORMATION
ABOUT TARGETS AND/OR LIGANDS
3. IN SILICO DESIGNING OF FILTERS FOR THE ELIMINATION OF
UNDESIRABLE COMPOUNDS WITH PROPERTIES LIKE POOR
ACTIVITY AND/OR POOR ABSORPTION, DISTRIBUTION,
METABOLISM, EXCRETION AND TOXICITY, ADMET WHICH
FACILITATE SELECTION OF THE MOST PROMISING CANDIDATES
ADVANTAGES OF CADD
THE MAIN ADVANTAGES OF DRUG DISCOVERY THROUGH CADD
ARE:
1. FOR EXPERIMENTAL TESTING, SMALLER SET OF COMPOUNDS
ARE SELECTED FROM LARGE COMPOUND LIBRARIES.
2. DRUG METABOLISM AND PHARMACOKINETICS (DMPK)
PROPERTIES LIKE ABSORPTION DISTRIBUTION, METABOLISM,
EXCRETION AND THE POTENTIAL FOR TOXICITY (ADMET) ARE
INCREASED BY OPTIMIZATION OF LEAD COMPOUNDS.
3. DESIGNING OF NOVEL COMPOUNDS CAN BE ACHIEVED EITHER
BY "GROWING" STARTING MOLECULES ONE FUNCTIONAL
GROUP AT A TIME OR BY PIECING TOGETHER FRAGMENTS INTO
NOVEL CHEMOTYPES
4. TRADITIONAL EXPERIMENTATION WHICH REQUIRES ANIMAL
AND HUMAN
MODELS CAN BE REPLACED BY CADD, SAVING BOTH TIME AND
COST
5. REDUCES THE CHANCES OF DRUG RESISTANCE AND THUS
WOULD LEAD TO
PRODUCTION OF LEAD COMPOUNDS WHICH WOULD TARGET
THE CAUSATIVE
FACTOR
6. CADD ALSO LEADS TO THE CONSTRUCTION OF HIGH QUALITY
DATASETS AND LIBRARIES THAT CAN BE OPTIMIZED FOR HIGH
MOLECULAR DIVERSITY OR SIMILARITY
TYPES OF CADD
THE CHOICE OF CADD APPROACHES TO BE EMPLOYED IS
DETERMINED BY THE AVAILABILITY OF THE EXPERIMENTALLY
DETERMINED 3D STRUCTURES OF TARGET PROTEINS
THERE ARE TWO MAJOR TYPES OF DRUG DESIGN
1. LIGAND-BASED DRUG DESIGN AND
2. STRUCTURE-BASED DRUG DESIGN
LIGAND-BASED (INDIRECT DRUG DESIGN)

-RELIES ON KNOWLEDGE OF OTHER MOLECULES THAT BIND TO THE
BIOLOGICAL TARGET OF INTEREST. THESE OTHER MOLECULES MAY
BE USED TO DERIVE A PHARMACOPHORE MODEL THAT DEFINES THE
MINIMUM NECESSARY STRUCTURAL CHARACTERISTICS A MOLECULE
MUST POSSESS IN ORDER TO BIND TO THE TARGET
-IN OTHER WORDS, 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 (QSAR), IN WHICH A CORRELATION BETWEEN
CALCULATED PROPERTIES OF MOLECULES AND THEIR
EXPERIMENTALLY DETERMINED BIOLOGICAL ACTIVITY MAY BE
DERIVED. THESE QSAR RELATIONSHIPS IN TURN MA WITY OF NEW
ANALOGS
STRUCTURE-BASED (DIRECT DRUG DESIGN)
-RELIES ON KNOWLEDGE OF THE THREE DIMENSIONAL STRUCTURE
OF THE BIOLOGICAL TARGET OBTAINED THROUGH METHODS SUCH AS
X-RAY CRYSTALLOGRAPHY OR NMR 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
-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 AND THE INTUITION OF A MEDICINAL CHEMIST
-ALTERNATIVELY VARIOUS AUTOMATED COMPUTATIONAL
PROCEDURES MAY BE USED TO SUGGEST NEW DRUG CANDIDATES
-STRUCTURE-BASED CADD USES OUR KNOWLEDGE OF THE TARGET
PROTEIN STRUCTURE TO CALCULATE INTERACTION ENERGIES,
WHEREAS IN LIGAND-BASED CADD, CHEMICAL SIMILARITY SEARCHES
OR CONSTRUCTION OF PREDICTIVE, QUANTITATIVE
STRUCTURE-ACTIVITY RELATIONSHIP (QSAR) MODELS EXPLOITS OUR
KNOWLEDGE OF KNOWN ACTIVE AND INACTIVE MOLECULES
-STRUCTURE BASED CADD COMBINES INFORMATION FROM SEVERAL
FIELDS, FOR EXAMPLE, X-RAY CRYSTALLOGRAPHY AND/OR NMR,
SYNTHETIC ORGANIC CHEMISTRY, MOLECULAR MODELLING, QSAR,
AND BIOLOGICAL EVALUATION
-THROUGH STRUCTURE BASED CADD, WE AIM TO DESIGN
COMPOUNDS WITH STRONG BINDING AFFINITY WITH THE TARGET,
THEREBY EXHIBITING PROPERTIES LIKE REDUCED FREE ENERGY,
IMPROVED DMPK/ADMET PROPERTIES AND TARGET SPECIFICATION
LE, REDUCED OFF-TARGET
-VIRTUAL HIGH-THROUGHPUT SCREENING (VHTS) ALSO KNOWN AS
SCREENING OF VIRTUAL COMPOUND LIBRARIES IS ONE OF THE MOST
COMMON APPLICATIONS OF CADD
-DRUG DISCOVERY PROCESS USUALLY STARTS WITH AN ANALYSIS OF
BINDING SITES IN TARGET PROTEINS OR AN IDENTIFICATION OF
STRUCTURAL FEATURES COMMON TO ACTIVE COMPOUNDS
-THE PROCESS ENDS WITH THE GENERATION OF SMALL MOLECULE
"LEADS" SUITABLE FOR FURTHER CHEMICAL SYNTHETIC WORK.
-IT IS A RECENT AND EMERGING DISCIPLINE THAT USES SEVERAL
BIOINFORMATICS TOOLS AND RELATED FIELDS LIKE CHEMI
INFORMATICS AND COMBINATORIAL CHEMISTRY
-CADD USES COMPUTATIONAL CHEMISTRY TO DISCOVER, ENHANCES
OR STUDY OF DRUGS AND RELATED BIOLOGICALLY ACTIVE
MOLECULES
ROLE OF CADD
-THE TARGET OF COMPUTER ASSISTED DRUG DESIGN (CADD) IS NOT
TO FIND THE IDEAL DRUG BUT TO IDENTIFY AND OPTIMIZE LEAD
COMPOUNDS AND SAVE SOME EXPERIMENTS
-THE PARAMETERS EXPECTED FROM A DRUG ARE SAFETY
EFFICIENCY. STABILITY. SOLUBILITY SYNTHETIC VIABILITY. NOVELTY
-DRUG DISPENSING APPROACHES:
THERE ARE 4 BASIC APPROACHES FOR DRUG DESIGNING
1. LIGAND BASED APPROACH
2. TARGET BASED APPROACHES
3. DE NOVO APPROACHES
 4. SBDD
LIGAND BASED APPROACH
-THESE ARE USED WHEN THE RECEPTOR IS NOT KNOWN
-LIGAND BASED APPROACHES TRY TO IDENTIFY CHARACTERISTICS
COMMON TO KNOWN LIGANDS TO USE IN SCREENING FOR NEW OR
IMPROVED DRUGS
-IF A SET OF ACTIVE LIGAND MOLECULES IS KNOWN FOR THE
MACROMOLECULAR TARGET, BUT LITTLE OR NO STRUCTURAL
INFORMATION EXISTS FOR THE TARGET LIGAND BASED
COMPUTATIONAL METHOD BE EMPLOYED
THERE ARE TWO METHODS TO DO THIS:
1. QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIP QSAR)
METHOD
2. PHARMACOPHORE METHOD - IS THE SPECIFIC 3-D ARRANGEMENT
OF FUNCTIONAL GROUPS WITHIN A MOLECULAR FRAMEWORK THAT
ARE SPECIFICALLY BIND TO A MACROMOLECULE OR AN ENZYME
ACTIVE SITE
-IDENTIFICATION OF A PHARMACOPHORE IS AN IMPORTANT STEP IN
THE INTERACTION BETWEEN A RECEPTOR AND A LIGAND
TARGET BASED APPROACHES
-TARGET BASED DRUG DESIGN METHODS BASED ON THE STRUCTURE
OF THE BIOLOGICAL TARGET EITHER BOUND OR UNBOUND TO AN
INHIBITOR OR SUBSTRATE
-TARGET BASED DESIGN METHODS ARE ALSO KNOWN AS STRUCTURE
BASED OR RATIONAL DESIGN METHODS
DOCKING
-REFERS TO THE ABILITY TO POSITION A LIGAND IN THE ACTIVE OR A
DESIGNATED SITE OF A PROTEIN AND CALCULATE THE SPECIFIC
BINDING AFFINITIES.
-DOCKING ALGORITHMS CAN BE USED TO FIND LIGANDS AND BINDING
CONFORMATIONS AT A RECEPTOR SITE CLOSE TO EXPERIMENTALLY
DETERMINED STRUCTURES
-DOCKING ALGORITHMS ARE ALSO USED TO IDENTIFY MULTIPLE
PROTEINS TO WHICH A SMALL MOLECULE CAN BIND.
-INVOLVES SCANNING A DATABASE OF KNOWN MOLECULES FOR
THOSE LIKELY TO BIND WELL TO THE RECEPTOR
-IS USED TO GENERATE POSSIBLE BINDING GEOMETRIES AND CAN
EVALUATE USING A SCORING
-FUNCTION: THE METHOD MAY ALSO INVOLVE SOME REFINEMENT OF
THE INITIALLY GENERATED CONFORMATIONS BEFORE OR AFTER
SCANNING
DE NOVO APPROACHES
-DE NOVO DESIGN IS THE APPROACH TO BUILD A CUSTOMIZED LIGAND
FOR A GIVEN RECEPTOR
-THIS APPROACH INVOLVES THE LIGAND OPTIMIZATION
-LIGAND OPTIMIZATION CAN BE DONE BY ANALYZING PROTEIN ACTIVE
SITE PROPERTIES THAT COULD BE PROBABLE AREA OF CONTACT BY
THE LIGAND
-THE ANALYZED ACTIVE SITE PROPERTIES ARE DESCRIBED TO
NEGATIVE IMAGE OF PROTEIN SUCH AS HYDROGEN BOND,
HYDROGEN BOND ACCEPTOR AND HYDROPHOBIC CONTACT REGION
STRUCTURE BASED DRUG DESIGN
-STRUCTURE-BASED DRUG DESIGN (SBDD, ALSO KNOWN AS
RATIONAL DRUG DESIGN) IS A TECHNIQUE THAT ACCELERATES THE
DRUG DISCOVERY PROCESS BY UTILIZING STRUCTURAL
INFORMATION TO IMPROVE THE LEAD OPTIMIZATION PROCESS
-IT HAS BEEN ESTIMATED THAT SBDD CAN REDUCE THE COST FROM
TARGET IDENTIFICATION TO INVESTIGATIONAL NEW DRUG(IND)
FILLING BY 50%
-THE TECHNIQUE REQUIRES HIGH RESOLUTION 3-D STRUCTURE OF
THE INHIBITOR BOUND TO THE TARGET OBTAINED USING X-RAY
CRYSTALLOGRAPHY

PRE FORMULATION STUDIES
-IS THE FOUNDATION OF DEVELOPING ROBUST FORMULATION
-IT CAN BE DEFINED AS A PHASE OF RESEARCH & DEVELOPMENT
PROCESS FOR AN INVESTIGATION OF PHYSICAL AND CHEMICAL
PROPERTIES OF NEW DRUG SUBSTANCE ALONE OR IN COMBINATION
WITH OTHER EXCIPIENTS IN ORDER TO DEVELOPMENT OF SAFE AND
EFFECTIVE DOSAGE FORM
-PHASE WHICH IS INITIATED ONCE THE NEW MOLECULE IS SEEDED
-IN A BROADER WAY, IT DEALS WITH STUDIES OF PHYSICAL, CHEMICAL,
ANALYTICAL AND PHARMACEUTICAL PROPERTIES RELATED TO
MOLECULE AND PROVIDES IDEA ABOUT SUITABLE MODIFICATION IN
MOLECULE TO SHOW A BETTER PERFORMANCE
-GROUP OF STUDIES THAT FOCUS ON THE PHYSICOCHEMICAL
PROPERTIES OF A NEW DRUG CANDIDATE THAT COULD AFFECT THE
DRUG PERFORMANCE AND THE DEVELOPMENT OF A DOSAGE FORM
-THIS COULD PROVIDE IMPORTANT INFORMATION FOR FORMULATION
DESIGN OR SUPPORT THE NEED FOR MOLECULAR MODIFICATION
EVERY DRUG HAS INTRINSIC CHEMICAL AND PHYSICAL PROPERTIES
WHICH HAS BEEN CONSIDER BEFORE
-IS THE STAGE OF DEVELOPMENT DURING WHICH THE
PHYSICOCHEMICAL PROPERTIES OF THE DRUG SUBSTANCE ARE
CHARACTERIZED AND ESTABLISHED KNOWLEDGE OF THE RELEVANT
PHYSICOCHEMICAL AND BIOPHARMACEUTICAL PROPERTIES
DETERMINES THE APPROPRIATE FORMULATION AND DELIVERY
METHOD FOR PRE-CLINICAL AND PHASE 1 STUDIES
OBJECTIVES OF PREFORMULATION STUDIES
1. TO GENERATE USEFUL DATA NEEDED IN DEVELOPING STABLE AND
SAFE DOSAGE FORMS THAT CAN BE MANUFACTURED ON A
COMMERCIAL SCALE
2. TO PROVIDE IN-DEPTH KNOWLEDGE AND UNDERSTANDING OF THE
PHYSICAL CHARACTERISTICS OF A CANDIDATE DRUG MOLECULE
PRIOR TO DOSAGE FORM DEVELOPMENT.
3. TO GENERATE USEFUL INFORMATION ON HOW TO DESIGN A DRUG
DELIVERY SYSTEM WITH GOOD BIOAVAILABILITY
GOALS OF PREFORMULATION STUDIES
1. TO ESTABLISH THE PHYSICOCHEMICAL PARAMETERS OF A
CANDIDATE DRUG MOLECULE.
2. TO DETERMINE THE KINETIC RATE PROFILE OF DRUG SUBSTANCES
3. TO ESTABLISH THE COMPATIBILITY OF A CANDIDATE DRUG
MOLECULE WITH COMMON EXCIPIENTS.
CLASSES OF PREFORMULATION STUDIES
-PREFORMULATION STUDIES CAN BE CLASSIFIED INTO:
1. FUNDAMENTAL PREFORMULATION STUDIES
THESE STUDIES ARE SPECIFIC TO CANDIDATE DRUG MOLECULES AND
IT INCLUDE SOLUBILITY ANALYSIS (EG, IONIZATION CONSTANT,
PARTITION COEFFICIENT SOLUBILIZATION, THERMAL EFFECT,
COMMON ION EFFECT, DISSOLUTION ETC.), SOLID STATE PROPERTIES
(EG., POLYMORPHISM, SOLVATED FORMS AND AMORPHOUS FORM)
STABILITY ANALYSIS (EG, SOLUTION-STATE STABILITY AND
SOLID-STATE STABILITY) AND PERMEABILITY STUDIES. THESE
STUDIES ARE DEPENDENT ON THE CHEMICAL STRUCTURE OF THE
CANDIDATE DRUG MOLECULE
2. DERIVED PREFORMULATION STUDIES
THESE STUDIES INCLUDE CHARACTERIZATION OF PARTICLE
PROPERTIES (EG, PARTICLE SIZE AND PARTICLE SHAPE), BULK
DENSITY, POWDER FLOW PROPERTIES. COMPACTION BEHAVIOUR
ETC.
THEY ARE CARRIED OUT ON THE INTENDED DOSAGE FORM
BEFORE EMBARKING ON PREFORMULATION STUDIES, SCIENTISTS
MUST CONSIDER:
1. THE AVAILABLE PHYSICOCHEMICAL DATA INCLUDING CHEMICAL 6) ISOMERIZATION
STRUCTURE, DIFFERENT SALTS, POTENCY RELATIVE TO THE
COMPETITIVE PRODUCTS AND THE DOSAGE FORM ETC. THE MAIN COMPONENTS OF PREFORMULATION STUDIES ARE:

2. ANTICIPATED DOSE AND THE PROPOSED ROUTE OF DRUG 1) DEVELOPMENT OF A SUITABLE SPECTROSCOPIC ASSAY METHOD
ADMINISTRATION FOR DETERMINING CONCENTRATION AND PURITY

3. SUPPLY SITUATION AND DEVELOPMENT SCHEDULE
4. AVAILABILITY INDICATING ASSAY
EVALUATED PARAMETERS IN PREFORMULATION STUDIES
2) DETERMINATION OF SOLUBILITY AND DISSOLUTION RATES OF
PARENT COMPOUND AND SALTS IN WATER AND OTHER SOLVENTS
3) CHEMICAL STABILITY OF PARENT COMPOUND AND SALTS IN
SOLUTION AND SOLID STATE

A. PHYSICAL CHARACTERISTICS 4) DETERMINATION OF PKa AND PH DEPENDENCE OF SOLUBILITY AND

CHEMICAL STABILITY
1) ORGANOLEPTIC PROPERTIES OF THE CANDIDATE DRUG MOLECULE
E.G., COLOUR, ODOUR AND TASTE. 5) DETERMINATION OF LIPOPHILICITY (I.E OIL WATER PARTITION
COEFFICIENT, EXPRESSED AS Kd)
2) BULK CHARACTERIZATION E.G., PARTICLE SIZE AND SURFACE AREA,
POWDER FLOW PROPERTIES, DENSITY COMPRESSIBILITY, 6) DETERMINATION OF PARTICLE MORPHOLOGY, MELTING POINT AND
CRYSTALLINITY, POLYMORPHISM AND HYGROSCOPICITY SUITABILITY FOR MILLING

3) SOLUBILITY ANALYSIS EG. IONIZATION CONSTANT/ DRUG PKA, 7) CHARACTERIZATIONS OF IMPORTANCE FOR THE DOSAGE FORMS
PARTITION COEFFICIENT, SOLUBILIZATION, THERMAL EFFECT, OF CHOICE, E.G. BULK DENSITY, POWDER FLOW, ANGLE OF REPOSE
COMMON ION EFFECT (KSP) AND DISSOLUTION AND COMPRESSION PROPERTIES

4) STABILITY ANALYSIS EG, SOLUTION-STATE STABILITY TESTING, Preclinical Phase

SOLID-STATE STABILITY TESTING, AND DRUG EXCIPIENT -in drug development the preclinical phase (in vitro and in vivo) — also named
COMPATIBILITY STUDIES preclinical studies or nonclinical studies is a stage of research that begins
before clinical trials, and during which important feasibility, iterative testing and
drug safety data are collected
B. CHEMICAL CHARACTERISTICS
-most common challenges, faced by all Al start ups, in designing and running
1) HYDROLYSIS preclinical experiments, have to do with
2) OXIDATION 1) reducing time, money and uncertainty in planning preclinical experiments,
3) PHOTOSTABILITY 2) automating the selection, manipulation and analysis of cells, and
4) RACEMIZATION 3) automating sample analysis with robotic cloud laboratory
5) POLYMERIZATION
-in drug development, preclinical development, also named preclinical
studies and non clinical studies
-is a stage of research that begins before clinical trial (testing in humans) can
begin, and during which important feasibility iterative testing and drug safety
data are collected, typically in laboratory animals
•main goals of preclinical studies are to:
1) determine a starting, safe dose for first-in-human study and
2) assess potential toxicity of the product, which typically include new medical
devices, prescription drugs, and diagnostics
• On average, only one in every 5,000 compounds that enters drug
discovery to the stage of preclinical development becomes an approved
drug
-each class of product may undergo different types of preclinical research
-for instance, drugs may undergo pharmacodynamics (what the drug does to
the body) (PD), pharmacokinetics (what the body does to the drug) (PK), ADME,
and toxicology testing
-data allows researchers to allometrically estimate a safe starting dose of the
drug for clinical trials in humans
-medical devices that do not have drug attached will not undergo these
additional tests and may go directly to good laboratory practices (GLP) testing
for safety of the device and its components
-some medical devices will also undergo biocompatibility testing which helps to
show whether a component of the device or all components are sustainable in a
living model
-most preclinical studies must adhere to GLPs in ICH Guidelines to be
acceptable for submission to regulatory agencies such as the Food & Drug
Administration in the United States
-typically, both in vitro and in vivo tests will be performed
-studies of drug toxicity include which organs are targeted by that drug, as well
as if there are any long-term carcinogenic effects or toxic effects causing illness
-FDA requires researchers to use good laboratory practices (GLP), defined in
medical product development regulations, for preclinical laboratory studies
-The GLP regulations are found in 21 CFR Part 58.1 Good Laboratory Practices
for Nonclinical Laboratory Studies
These regulations set the minimum basic requirements for:
-study conduct
-personnel
-equipment
-written protocols operating procedures
-study reports
-and a system of quality assurance oversight for each study to help assure the
safety of FDA-regulated product
-Usually preclinical studies are not very large. However, these studies must
provide detailed information on dosing and toxicity levels. After preclinical
testing, researchers review their findings and decide whether the drug should
be tested in people
IN VITRO:
-refers to a medical study or experiment which is done in the laboratory within
the confines of a test tube or laboratory dish
IN VIVO:
-refers to a medical test, experiment or procedure that is done on (or in) a living
organism, such as a laboratory animal or human
-Clinical trials or medical studies may be performed either in vivo or in vitro
-These approaches are similar in that they are both done in order to make
advances in the knowledge and treatment of illness and disease as well as
understanding "wellness” and normal bodily functions
-But there are also many important differences in how in vivo and in vitro
studies are conducted how they can be interpreted, and the practical
applications of any discoveries which are made
Preclinical Research
-before testing a drug in people, researchers must find out whether it has the
potential to cause serious harm to humans

-the preclinical studies are conducted on animal models under laboratory
conditions
2 TYPES OF PRECLINICAL RESEARCH ARE:
IN VITRO: These experiments are conducted outside the animals in controlled
laboratory conditions
IN VIVO:These experiments are conducted inside the animals, usually
preclinical studies are not very large
-however, these studies must provide detailed information on dosing and
toxicity levels
-after preclinical testing, researchers review their findings and decide whether
the drug can be tested in people
The various experiments conducted during these studies include:
● Single dose toxicity studies
● Repeated dose studies
● Safety pharmacology studies
● Genotoxicity studies
● Carcinogenicity studies
● Reproductive toxicity studies
-In vitro studies are important in that they allow more rapid development of
new treatments many drugs can be studied at one time (and they can be
studied in a large number of samples of cells) and only those that appear to be
efficacious go on to human studies
-An absence of biokinetics (how the body transports and metabolized drugs
and toxins) is one of the significant drawbacks of in vitro studies
-This, as well as several other factors, can make it very difficult to extrapolate
the results of in vitro tests to what might be expected when the drug is used in
vivo
Sequential steps involved in design and conduct in vitro binding studies
-Method development and validation of bile acids/phosphate/Human serum
albumin (HSA) or Bovine serum albumin (BSA) using HPLC/IC/ICP-MS as per
USFDA published Bioanalytical guidelines
-Kinetic binding study is conducted for test and reference formulations with bile
acids/ phosphate/HSA or BSA concentrations and pH variation resembling the
gastrointestinal pH
-Free bile acids/phosphate/HSA or BSA concentration is determined and bound
concentration is computed
-Saturation binding with respect to time and binding similarity between test and
reference formulation is characterized
-Equilibrium binding study for test and reference formulations with appropriate
bile acids/ phosphate ranging 8 different concentrations and pH variation
resembling the GI pH
-Free bile acids/phosphate//HSA or BSA concentration is determined and
bound concentration is computed binding affinity (K1) and capacity (K2)
constants
-It's important to note that oftentimes in vivo studies are first done in non-
human animals such as mice
-These studies allow researchers an opportunity to see how a drug works amid
other bodily processes
-Mice and humans have important differences
-Sometimes a drug that is effective in mice will not be effective in humans (and
vice versa) due to inherent differences in the species
Our in vivo pharmacology capabilities include:
-Testing numerous medicinal entities, including small molecules, large
molecules and antibodies
-Inducing disease by multiple techniques - chemical, surgical and diet
-Dosing by commonly used administration routes - P.O, I.V. S.C and I.P
-Daily dosing including on weekends, at no additional cost
-Performing necropsies, histopathology, gene expression and clinical
pathology
-Executing standard or custom protocols
Preclinical studies
-before clinical trials are undertaken for a candidate drug, vaccine, medical
device, or diagnostic assay, the product candidate is tested extensively in
preclinical studies
-such studies involve in vitro (test tube or cell culture) and in vivo (animal
model) experiments using wide-ranging doses of the study agent to obtain
preliminary efficacy, toxicity and pharmacokinetic information
-such tests assist the developer to decide whether a drug candidate has
scientific merit for further development as an investigational new drug
-studies that are in vivo are those in which the effects of various biological
entities are tested on whole, living organisms or cells, usually animals, including
humans, and plants, as opposed to a tissue extract or dead organism
-this is not to be confused with experiments done in vitro, l.e., in a laboratory
environment using test tubes, Petri dishes, etc
-examples of investigations in vivo include: the pathogenesis of diseases
Phase 0
-Phase 0 is a recent designation for optional exploratory trials conducted in
accordance with the United States Food and Drug Administration's (FDA) 2006
Guidance on Exploratory Investigational New Drug (IND) Studies
-Phase 0 trials are also known as human microdosing studies and are designed
to speed up the development of promising drugs or imaging agents by
establishing very early on whether the drug or agent behaves in human
subjects as was expected from preclinical studies
-distinctive features of Phase 0 trials include the administration of single
subtherapeutic doses of the study drug to a small number of subjects (10 to 15)
to gather preliminary data on the agent's pharmacokinetics
-Phase 0 study gives no data on safety or efficacy, being by definition a dose
too low to cause any therapeutic effect
-Drug development companies carry out Phase 0 studies to rank drug
candidates in order to decide which has the best pharmacokinetic parameters
in humans to take forward into further development
-they enable go/no-go decisions to be based on relevant human models instead
of relying on sometimes inconsistent animal data
Phase I
-Phase I trials were formerly referred to as "first-in-man studies" but the field
generally moved to the gender-neutral language phrase "first-in-humans" in
the 1990s; these trials are the first stage of testing in human subjects
-they are designed to test the safety, side effects, best dose, and formulation
method for the drug
-Phase I trials are not randomized, and thus are vulnerable to selection bias
-normally, a small group of 20-100 healthy volunteers will be recruited
-these trials are often conducted in a clinical trial clinic, where the subject can
be observed by full-time staff
-these clinical trial clinics are often run by contract research organization
(CRO) who conduct these studies on behalf of pharmaceutical companies or
other research investigators
-the subject who receives the drug is usually observed until several half-lives of
the drug have passed
-this phase is designed to assess the safety (pharmacovigilance), tolerability,
pharmacokinetics and pharmacodynamics of a drug
-Phase I trials normally include dose-ranging, also called dose escalation
studies so that the best and safest dose can be found and to discover the point
at which a compound is too poisonous to administer
-the tested range of doses will usually be a fraction of the dose that caused
harm in animal testing
-Phase I trials most often include healthy volunteers
-however, there are some circumstances when clinical patients are used, such
as patients who have terminal cancer or HIV and the treatment is likely to make
healthy individuals ill
-these studies are usually conducted in tightly controlled clinics called CPUs
(Central Pharmacological Units), where participants receive 24-hour medical
attention and oversight
-in addition to the previously mentioned unhealthy individuals, "patients who
have typically already tried and failed to improve on the existing standard
therapies may also participate in phase I trials
-volunteers are paid a variable inconvenience fee for their time spent in the
volunteer center
-before beginning a phase I trial, the sponsor must submit an Investigational
New Drug application to the FDA detailing the preliminary data on the drug
gathered from cellular models and animal studies
Phase I trials can be further divided:
Single ascending dose (Phase Ia)
-in single ascending dose studies, small groups of subjects are given a single
dose of the drug while they are observed and tested for a period of time to
confirm safety > typically, a small number of participants, usually three, are
entered sequentially at a particular dose
-if they do not exhibit any adverse side effect, and the pharmacokinetic data are
roughly in line with predicted safe values, the dose is escalated, and a new
group of subjects is then given a higher dose
-if unacceptable toxicity is observed in any of the three participants, an
additional number of participants, usually three, are treated at the same dose
-this is continued until pre-calculated pharmacokinetic safety levels are reached,
or intolerable side effects start showing up (at which point the drug is said to
have reached the maximum tolerated dose (MTD)
-if an additional unacceptable toxicity is observed, then the dose escalation is
terminated and that dose, or perhaps the previous dose, is declared to be the
maximally tolerated dose
-this particular design assumes that the maximally tolerated dose occurs when
approximately one-third of the participants experience unacceptable toxicity
-variations of this design exist, but most are similar
Multiple ascending dose (Phase Ib)
-multiple ascending dose studies investigate the pharmacokinetics and
pharmacodynamics of multiple doses of the drug, looking at safety and
tolerability
-in these studies, a group of patients receives multiple low doses of the drug,
while samples (of blood, and other fluids) are collected at various time points
and analyzed to acquire information on how the drug is processed within the
body
-the dose is subsequently escalated for further groups, up to a predetermined
level
Food effect
-short trial designed to investigate any differences in absorption of the drug by
the body, caused by eating before the drug is given
-these studies are usually run as a crossover study with volunteers being
given two identical doses of the drug while fasted and after being fed
Phase II
-once a dose or range of doses is determined, the next goal is to evaluate
whether the drug has biological activity or effect

-Phase II trials are performed on larger groups (50-300) and are designed to
assess how well the drug works, as well as to continue Phase I safety
assessments in a larger group of volunteers and patients
-Generic testing is common, particularly when there is evidence of variation in
metabolic rate
-when the development process for a new drug fails, this usually occurs during
Phase II trials when the drug is discovered not to work as planned, or to have
toxic effects
-Phase II studies are sometimes divided into Phase Ila and Phase llb there is
no formal definition for these two sub-categories, but generally:
Phase Ila studies are usually pilot studies designed to demonstrate clinical
efficacy or biological activity ('proof of concept' studies)
Phase IIb studies determine the optimal dose at which the drug shows
biological activity with minimal side-effects ('definite dose-finding' studies)
TRIAL DESIGN
-some Phase II trials are designed as se, demonstrating a drug's safety and
activity in a selected group of participants
-other Phase II trials are designed as randomized controlled trials, where some
patients receive the drug/device and others receive placebo/standard treatment
Randomized Phase II trials have far fewer patients than randomized Phase III
Example: cancer design
-in the first stage, the investigator attempts to rule out drugs that have no or little
biologic activity
-for example, the researcher may specify that a drug must have some minimal
level of activity, say, in 20% of participants
-if the estimated activity level is less than 20%, the researcher chooses not to
consider this drug further, at least not at that maximally tolerated dose
-if the estimated activity level exceeds 20%, the researcher will add more
participants to get a better estimate of the response rate
-typical study for ruling out a 20% or lower response rate enters 14 participants
-if no response is observed in the first 14 participants, the drug is considered not
likely to have a 20% or higher activity level
-the number of additional participants added depends on the degree of
precision desired, but ranges from 10 to 20
-thus, a typical cancer phase II study might include fewer than 30 people to
estimate the response rate
Efficacy vs effectiveness
-when a study assesses efficacy, it is looking at whether the drug given in the
specific manner described in the study is able to influence an outcome of
interest (e.g. tumor size) in the chosen population (e.g. cancer patients with no
other ongoing diseases)
-when a study is assessing effectiveness, it is determining whether a treatment
will influence the disease
-in an effectiveness study, it is essential that participants are treated as they
would be when the treatment is prescribed in actual practice
-that would mean that there should be no aspects of the study designed to
increase compliance above those that would occur in routine clinical practice
-the outcomes in effectiveness studies are also more generally applicable than
in most efficacy studies (for example does the patient feel better, come to the
hospital less or live longer in effectiveness studies as opposed to better test
scores or lower cell counts in efficacy studies)
-There is usually less rigid control of the type of participant to be included in
effectiveness studies than in efficacy studies, as the researchers are interested
in whether the drug will have a broad effect in the population of patients with the
disease.
Success rate
-Phase II clinical programs historically have experienced the lowest success
rate of the four development phases

-In 2010, the percentage of Phase II trials that proceeded to Phase III was 18%
and only 31% of developmental candidates advanced from Phase II to Phase III.
in a large study of trials conducted over 2006-2015
Phase III
-this phase is designed to assess the effectiveness of the new intervention and,
thereby, its value in clinical practice
-Phase III studies are randomized controlled multicenter trials on large patient
groups (300-3,000 or more depending upon the disease/medical condition
studied) and are aimed at being the definitive assessment of how effective the
drug is, in comparison with current gold standard treatment
-because of their size and comparatively long duration, Phase III trials are the
most expensive, time-consuming and difficult trials to design and run,
especially in therapies for chronic medical conditions
-Phase III trials of chronic conditions or diseases often have a short follow-up
period for evaluation, relative to the period of time the intervention might be
used in practice -this is sometimes called the "premarketing phase" because
it actually measures consumer response to the drug
-it is common practice that certain Phase III trials will continue while the
regulatory submission is pending at the appropriate regulatory agency
-this allows patients to continue to receive possibly lifesaving drugs until the
drug can be obtained by purchase
-other reasons for performing trials at this stage include attempts by the
sponsor at "label expansion" (to show the drug works for additional types of
patients/diseases beyond the original use for which the drug was approved for
marketing), to obtain additional safety data, or to support marketing claims for
the drug
-studies in this phase are by some companies categorized as "Phase IIIB
studies”
-while not required in all cases, it is typically expected that there be at least two
successful Phase III trials, demonstrating a drug's safety and efficacy, in order
to obtain approval from the appropriate regulatory agencies such as FDA (US),
or the EMA (European Union)
-once a drug has proved satisfactory after Phase III trials, the trial results are
usually combined into a large document containing a comprehensive
description of the methods and results of human and animal studies,
manufacturing procedures, formulation details, and shelf life
-this collection of information makes up the "regulatory submission "that is
provided for review to the appropriate regulatory authorities in different
countries
-they will review the submission, and if it is acceptable, give the sponsor
approval to market the drug
-most drugs undergoing Phase III clinical trials can be marketed under FDA
norms with proper recommendations and guidelines through a New Drug
Application containing all manufacturing, preclinical, and clinical data
-in case of any adverse effects being reported anywhere, the drugs need to be
recalled immediately from the market
-while most pharmaceutical companies refrain from this practice, it is not
abnormal to see many drugs undergoing Phase III clinical trials in the market
ADAPTIVE DESIGN
-the design of individual trials may be altered during a trial-usually during Phase
II or Phase III-to accommodate interim results for the benefit of the treatment,
adjust statistical analysis, or to reach early termination of an unsuccessful
design, a process called an “adaptive design”
-Examples are the 2020 World Health Organization Solidarity Trial, European
Discovery Trial and UK Recovery trial of hospitalized people with severe
COVID-19 infection, each of which applies adaptive designs to rapidly alter trial
parameters as results from the experimental therapeutic strategies emerge
-Adaptive designs within ongoing Phase II-II clinical trials on candidate
therapeutics may shorten trial durations and use fewer subjects, possibly
expediting decisions for early termination or success, and coordinating design
changes for a specific trial across its international locations
SUCCESS RATE
-for vaccines, the probability of success ranges from 7% for non-industry
sponsored candidates to 40% for industry-sponsored candidates
-2019 review of average success rates of clinical trials at different phases and
diseases over the years 2005-15 found a success range of 5-14%
-separated by diseases studied cancer drug trials were on average only 3%
successful, whereas ophthalmology drugs and vaccines for infectious diseases
were 33% successful
-Trials using disease biomarkers especially in cancer studies, were more
successful than those not using biomarkers
-2010 review found about 50% of drug candidates either fail during the Phase Il
trial or are rejected by the national regulatory agency
Phase II / III cost
-the amount of money spent on Phase lill trials depends on numerous factors,
with therapeutic area being studied and types of clinical procedures as key
drivers
-Phase II studies may cost as much as $20 million, and Phase Ill as much as
$53 million
PHASE IV
-Phase IV trial is also known as postmarketing surveillance trial or informally
as confirmatory trial
-Phase IV trials involve the safety surveillance (pharmacovigilance) and
ongoing technical support of a drug after it receives permission to be sold (eg.
after approval under the FDA Accelerated Approval Program)
- Phase IV studies may be required by regulatory authorities or may be
undertaken by the sponsoring company for competitive (finding a new market
for the drug) or other reasons (for example, the drug may not have been tested
for interactions with other drugs, or on certain population groups such as
pregnant women, who are unlikely to subject themselves to trials)
-the safety surveillance is designed to detect any rare or long-term adverse
effects over a much larger patient population and longer time period than was
possible during the Phase II-III clinical trials
-Harmful effects discovered by Phase IV trials may result in a drug being no
longer sold or restricted to certain uses examples include cerivastatin (brand
names Baycol and Lipobay) troglitazone (Rezulin) and rofecoxib (Vioxx)
COVID 19 drug development
-is the research process to develop preventative therapeutic prescription drugs
that would alleviate the severity of coronavirus disease 2019
-internationally by August 2020, several hundred drug companies,
biotechnology firms, university research groups, and health organizations were
developing over 500 potential therapies for COVID-19 disease in various stages
of preclinical or clinical research
-the World Health Organization, EUropean Medicines Agency, US Food and
Drug Administration, and the Chinese government and drug manufacturers
were coordinating with academic and industry researchers to speed
development of vaccines, antiviral drugs and post-infection therapies
-the International Clinical Trials Registry Platform of the WHO recorded 536
clinical studies to develop post-infection therapies for COVID-19 infections, with
numerous established antiviral compounds for treating other infections under
clinical research to be repurposed
-In March, the WHO initiated the "SOLIDARITY Trial" in 10 countries, enrolling
thousands of people infected with COVID-19 to assess treatment effects of four
existing antiviral compounds with the most promise of efficacy
-A dynamic, systematic review was established in April 2020 to track the
progress of registered clinical trials for COVID-19 vaccine and therapeutic drug
candidates
-Drug development is a multistep process, typically requiring more than five
years to assure safety and efficacy of the new compound
-Several national regulatory agencies, such as the EMA and the FDA approved
procedures to expedite clinical testing
By August, dozens of potential post-infection therapes, including favipiravir,
remdesivir, and lopinavir used in the international Solidarity trial, were in the
final stage of human testing-Phase III-IV-and 17 vaccine candidates had
entered the second or third stage of human safety, dosing and efficacy
evaluation, Phase II and Phase III
DRUG SAFETY EVALUATION
-Non-clinical drug safety evaluation, the assessment of the safety profile of
therapeutic agents through the conduct of laboratory studies in in vitro systems
and in animals, i an essential step in the progress of new pharmaceuticals
heading toward the ultimate goal of clinical trials and eventually, approval
-In Drug Safety Evaluation: Methods and Protocols, expert researchers detail a
compendium of analytical technologies with a focus on clarity and applicability
in real life laboratory practice
-These malicious contributions feature key topics such as acute to chronic
general toxicity studira, histopathology studies, reproductive toxicity studies,
genotoxicity studies, safely pharmacology studies, investigative toxicity studies,
and safety biomarker studies
-As a volume in the highly successful Methods in Molecular Biology senes,
include brief introductions to their respective subjects, lists of the necessary
materials, step-by-step readily reproducible protocols, and ups on
troubleshooting and avoiding known pitfalls
-Comprehensive and authoritative, Drug Safety Evaluation Methods and
Protools serves as an ideal guide to this field, helpful to pharmaceutical
scientists, toxicologists biochemists, and molecular biologists as well as
scientists from all other disciplines who wish to translate these thorough
methods into their own work
THE ANIMAL RIGHTS DEBATE
•Two main questions about the ethics of animal testing are whether animals
have rights and, if they do, whether those rights should be protected
•A legal right is a law-based entitlement that applies to all members of a
particular group and is upheld by the justice system
•Those in favor of extending equal rights to animals argue that the suffering and
well-being of other species are just as important as the suffering and well-being
of humans and should be treated accordingly
•It is known that animals can feel pain and distress, and therefore many
consider the act of subjecting animals to pain, injury, or death for the sake of
science to be immoral
•Others argue against extending equal rights to animals, positing that human
interest should be placed above the well-being of animals
•Many argue that animal research has yielded substantial benefits to the human
race, and that these outweigh the negative effects on animals
CURRENT ANIMAL RESEARCH
•The Animal Welfare Act (AWA) of 1966 is the only federal law in the United
States regulating the treatment of animals in research; while some other laws
and policies may include additional species coverage or specifications for
animal care and use all refer to the AWA as the minimally acceptable standard
for animal treatment and care.
•Some of the animals covered under the AWA include any live or dead cat dog,
hamster, rabbit, nonhuman primate, or guinea pig
•Animals excluded from this act are birds, rats, mice, farm animals, and
cold-blooded animals
•Under the AWA all animal dealers, must be registered and licensed, and all
animal testing facilities in compliance with this act are required to establish a
special committee that includes at least one person trained as a veterinarian
and one person who is not affiliated with the facility
•These committees regularly assess animal care, treatment, and practices
during research
•In addition to compliance with the Animal Welfare Act, most research
Institutions have an institutional review board (IRB) which is a committee that
has been formally designated to approve, monitor, and review biomedical and
behavioral research involving humans. Most studies involving humans must
pass IRB approval before they can begin
• A variety of animals are used in experiment.
• While animals with shorter life spans and less sophisticated nervous systems
tend to be used, this is not always true
•Some advocate that there should be a hierarchy of animal rights, with more
rights granted to sophisticated species, while others argue that the same nights
should be awarded to all living beings
REPLACEMENT, REDUCTION, REFINEMENT
•Replacement reduction, and refinement (also referred to as "the three R's")
exist as guiding principles for more ethical use of animals in testing and
research
•These guidelines are intended to improve animal welfare and scientific quality
where the use of animals in experimentation cannot be avoided and are
implemented in many research labs worldwide
•REPLACEMENT refers to the preferred use of non-animal methods whenever
it is possible to achieve the same scientific goats as animal research
•REDUCTION refers to methods that enable researchers to obtain comparable
levels of information from fewer animals, or to obtain more information from the
same number of animals
•Methods of experimental REFINEMENT aim to alleviate or minimize potential
pain, suffering or distress and enhance the welfare of the animals used
The 3Rs stand for:
replacing the use of animals with non-animal methods where possible;
reducing the number of animals used to a minimum while still obtaining
scientifically valid results;
refining practices to minimize the stress and improve the welfare of study
animals used for regulatory purposes
ETHICAL GUIDELINES
•To protect the rights and well-being of research participants, and at the same
time discover meaningful results and insights into human behavior, virtually all
psychological research must pass an ethical review process
•At most colleges and universities, this is conducted by the IRB
•This group examines the proposed research to make sure that no harm is done
to the participants, and that the benefits of the study outweigh any possible
risks or discomforts to people taking part in the study
• Minors are more protected than adults in ethical guidelines, because a minor
is not considered to be able to give fully informed consent
RIGHT OR WRONG DECISION
•Ethical Guidelines help researchers make the night decisions, such as getting
informed consent from human subjects
•There is a duty to protect the rights of people in the study as well as their
privacy and sensitivity
•The confidentiality of those involved in the study must be maintained, keeping
their anonymity and privacy secure
•A process of informed consent is used to make sure that volunteers know what
will happen in the experiment and understand that they are allowed to quit the
experiment at any time
•Also, a debriefing is typically done at the conclusion of the experiment in order
to reveal any deceptions used and generally make sure that the participants are
unharmed by the procedures
•Today, most research in social psychology involves no more risk of harm than
can be expected as by routine psychological testing or normal daily activities
Institutional Animal Care and Use Committees (IACUCS)
•are centrally important in applying laws about animal research in the United
States
•Most research involving laboratory animals is funded by the United States
National Institution of Heath or, to lesser extents, other federal agencies
•The NIH Office of Laboratory Animal Welfare (OLAW) has been directed by
law to develop policies that describe the role of Institutional Animal Care and
Use Committees
•Every institution that uses certain animals for federally funded laboratory
research must have an Institutional Animal Care and Use Committee (IACUC) •
Each local IACUC reviews research protocols and conducts evaluations of the
institution's animal care and use, which includes the results of inspections of
facilities that are required by law
•The corresponding, parallel, and equivalent local ethical body responsible for
overseeing U.S. federally funded research involving humans is the Institutional
Review Board (IRB)
•The IACUC must have a minimum of three members, appointed by the Chief
Executive Officer of the research facility
•The appointed members must be qualified to regulate animal care at that
institution
•Membership requirements, an defined in 9 CFR 52 31, are as follows
1. The committee shall be composed of a Chairman and at least two other
members
2. One of these members must be a Doctor of Veterinary Medicine with training
or experience related to laboratory animal research
3. One member must have no relation with the institution except for serving on
the IACUC
•Additionally, if the committee consists of more than three members, more than
three members can not be from the same administrative unit of the facility
•Each local IACUC reviews research protocols and conducts evaluations of the
institution's animal care
•The evaluations include inspections of all animal use facilities every six months
•The IACUC reports to the NIH Office of Laboratory Animal Welfare (OLAW)
annually, and is issued an animal welfare assurance number by OLAW without
which no federally funded use of animais in research may occur
•The IACUC is required to report significant noncompliance with animal use
protocols to OLAW, as well as IACUC actions taken to correct the
noncompliance
PROTOCOL REVIEW
•Each animal use protocol (AUP) must be reviewed by full IACUC committee at
least once every three years, and can be reviewed more frequently if the
committee wishes
The protocol must cover at least these points:
a. Identification of the species and approximate number of animals to be used.
b. Rationale for involving animals, and for the appropriateness of the species
and numbers used.
c. A complete description of the proposed use of the animals
d. A description of procedures designed to assure that discomfort and injury to
animals will be limited to that which is unavoidable in the conduct of
scientifically valuable research, and that analgesic, anesthetic, and
tranquilizing drugs will be used where indicated and appropriate to minimize
discomfort and pain to animals
e. A description of any euthanasia method to be used.

In review, the IACUC is required to ensure that the proposed work falls within
the OLAW Animal Welfare Assurance, and that the following points are covered

a. Procedures with animals will avoid or minimize discomfort, distress, and

pain to the animals, consistent with sound research design,

b. Procedures that may cause more than momentary or slight pain or

distress to the animals will be performed with appropriate sedation
analgesia, or anesthesia, unless the procedure is justified for scientific
reasons in writing by the investigator

c. Animals that would otherwise experience severe or chronic pain or

distress that cannot be relieved will be painlessly killed at the end of the
procedure or if appropriate, during the procedure

d. The living conditions of animals will be appropriate for their species and
contribute to their health and comfort. The housing, feeding, and
nonmedical care of the animals will be directed by a veterinarian or
other scientist trained and experienced in the proper care handling, and
use of the species being maintained or studied