Moderator – Dr.Amitabh kumar , Professor
Presenter – Dr.Sriharsha Rayam
• Average time to develop new drug is 10 -12 years.
• On an average out of 10,000 – 30,000 potential
substances only 1 could make it to the market.
• As per 2006 estimates, the cost of bringing a new
drug could vary from 500 million to 2,000 million
unmet medical need;
new diseases ( AIDS, Alzheimer’s; obesity);
low efficacy (dementia, cancer);
side effects (antidepressants, antipsychotics)
cost of therapy; (Interleukins)
costs to individual/country; (Alzheimer’s; spinal
sustain industrial activity ( pharmaceutical industry
employs thousands and makes a massive contribution
to overseas earnings); patent expiry
WHY ARE NEW DRUGS NEEDED?
• Folk medicine - natural product remedies
• Early 19th century - extraction of compounds from plants
(morphine, cocaine )
History of Drug Discovery….
• James Lind – Citrus fruits – Scurvy – clinical trail
1909 - First rational drug design.
• Goal: safer syphilis treatment than Atoxyl.
• Paul Erhlich and Sacachiro Hata wanted to maximize toxicity
to pathogen and minimize toxicity to human (therapeutic
• They found Salvarsan (which was replaced by penicillin in the
• Mid to late 20th century
- understand disease states, biological structures, processes,
drug transport, distribution, metabolism.
Medicinal chemists use this knowledge to modify chemical
structure to influence a drug’s activity, stability, etc.
• procaine = local anaesthetic; Procainamide = antirhythmic
Drug development process – 3 main phases
• 1.drug discovery phase
• 2.preclinical phase
• 3.clinical trial phase
Drug discovery phase
1. Random screening
2. Serendipity ( By chance )
3. Rational drug designing
4. Designing of a prodrug or an active metabolite as a
• Blind hitting procedure where new chemical
entities are subjected to pharmacological
• Studies on animal models , isolated tissues etc
• It is time consuming, expensive, inefficient in
providing fruitful results ,burdensome
• Morphine, Atropine , digitalis, Quinidine,
2.SERENDIPITY (BY CHANCE / HAPPY
• New use from old drug or its side effects
• Lignocaine & Phenytoin
• Methotrexate – psoriasis
• Cyclophosphamide & Azathioprine – Graft rejection
1928, Fleming studied Staph, but contamination of plates with
airborne mold. Noticed bacteria were lysed in the area of mold.
A mold product inhibited the growth of bacteria: the antibiotic
3.RATIONAL DRUG DESIGNING
• A. compound centered approach
: from natural products – Pencillin,paclitaxel,cyclosporine
DA – complex molecules – difficult to synthesized
: from synthetic products – from pharmacological data
Ex: Based on proponolol structure- B blokers
H2 blockers - modifying structure of histamine
• Molecular modification ended up in molecular
New drugs are serving as me too drugs , no added
B. Target centered approach
* Biochemical or molecular targets
Ex: ACE blockers or AT II blockers
-Now a days large number of drugs this way
-Promising agents for lead optimisation
4. DESIGNING OF A PRODRUG OR AN
ACTIVE METABOLITE AS A DRUG
• Administered as the precursor of a drug and is converted
into active therapeutic agent Ex; Levodopa
• Paracetamol, an active metabolite of phenacetin
• N-acetyl procainamide, an active metabolite of
procainamide does not cause SLE
• After the synthesis or isolation of the compound =
• Purity by physico chemical and analytical studies
Then these are subjected to biological screening
LEAD COMPOUND - which have a potential of becoming
•compounds can elicit a positive response in a particular
assay, which is called a hit.
• “Lead” is a hit series for which the structure–activity
relationship is shown and activity demonstrated both in
vitro and in vivo
Leads are optimised with respect to
Pharmacodynamic properties-efficacy, potency,
Pharmacokinetic properties- metabolic stability and
Chemical optimisation-ease of chemical synthesis &
PRECLINICAL EVALUATION PHASE ( ANIMAL
Major areas are:
Pharmacodynamic studies In vivo in animals, In vitro
Absorption, distribution , elimination studies
Acute ,sub acute, chronic toxicity studies (toxicity profile)
Therapeutic index (safety & efficacy evaluation)
•Action relavent to proposed therapeutic use are
studied on animals
Ex: Antihypertensive activity – dogs,cats,rats
To find out – B.P
- ECG changes
- inotropic & chrinotropic efforts
- CO & t.p.r
•Once L.C exibits promising results – futhur studies at
•Receptor activity in vitro on cultured cells
•Further extended to molecular level to find out
receptor affinity & selectivity by performing in vitro
studies on cell membrane fractions from organs
•Graded response assy or Quantal assay - ED 50 of
New compounds subjected in several species of
Studies should establish
a) Relative bioavailability of the compound on oral or
b) Elimination half life for assessment of optimal dosage
Acute toxicity studies most commonly median lethal
i.e. LD50 is determined.
Drug is given in graded doses to at least 2 animal
species by at least 2 routes.
To minimize biological variation, animal groups should
Percentage of animals dying in each group within
specified time (24 hrs) is plotted against the dose.
Other toxic symptoms suffered also recorded.
Sub acute toxicity
To identify target organs susceptible to drug toxicity.
Laboratory studies like hematology, renal ,hepatic
function test are carried out.
Animals are maintained at max. tolerated dose for 4 wks
– 3 months & killed for HPE.
If drug intended for chronic use in humans.
2 species of animals ,1 rodent and 1 non rodent are
Drug administered for many months (6-24
months),detailed biochemical & histological
measurements are made.
To evaluate cumulative toxicity
To assist carcinogenic potential
Study may run simultaneously with clinical trial.
Test for fertility & reproductive performance
Carried out in rats, treated with new drug before & after
Effects on early & late stages of embryonic & fetal
development are studied .
Carried out in 2 animal species to assess the effects of
drug on organogenesis.
Drugs given after mating
Fetuses are carefully examined for abnormalities.
It is invivo – invitro test conducted to detects
compounds which induces genetic damage directly or
The following standard test is generally expected to be
1. A test for gene mutation in bacteria – AMES test
2. An invitro test with cytogenetic evaluation of chromosome
damage with mammalian cells
3. In vivo test for chromosomal damage using rodent
Frequency of damage cells ,Total number, types and
frequency of metaphase chromosomal aberration
• for all drugs that are expected to be clinically used
for six months as well as for drugs used frequently in
an intermittent manner in the treatment of chronic or
• Animals :
rodent 2 animal species , same dose of chronic study,
for 2 years.
• Parameters :
Autopsy and detailed Histopathology of organ and
These studies are required when the new drug is proposed
to be used by some special route in human.
Rectal tolerance test
1. Dermal toxicity:
Animals: rabbit & rat
Parameters: erythema & edema
2. Vaginal toxicity:
Animals: rabit & dog
Parameters: swelling, closure of introitus & histopathology
of vaginal wall.
3. Rectal tolerance test-
Animals: rabbit & dog
Parameters: sign of pain, blood/mucus in faeces,
histopathology of rectal mucosa.
4. Ocular toxicity-
Parameters: Slit Lamp Test & Fluroscent Dye Test
Relative margin of safety of a drug
• Maximum Tolerated Dose
• No Adverse Effect Dose
• Human Equivalent Dose
• About 2.6m animals/y used in procedures in UK (11.6m in Europe)
• Likely to increase; more research, more targets, genetic capability
• 3Rs -- 3Rs -- 3Rs
• REPLACEMENT: use non-animal tests if possible (cheaper, less
trouble, less variable but not possible for everything at this time)
• REDUCTION: get the statistics right, don’t replicate work
unnecessarily, don’t overbreed
• REFINEMENT: reduce suffering and severity of procedure, pay
attention to housing, stress, husbandry and rich environments,
proper analgesia and pre- and post- operative care
CLINICAL TRIAL PHASE(HUMAN PHASE)
• To determine safety & efficacy of a new drug in humans
• Good clinical practices (GCP) by international Conference on
Harmonization (ICH) and declaration of Helsinki.
• It provides details about – designing the trail
- collection of data
- recording of information
- statistical analysis
- documentation & reporting
• When the new compound passes the preclinical phase ,
manufacturer may file a Investigational New Drug (IND)
application to authorized drug control body
• In INDIA - drugs controller general,Govt.of india,Delhi
• It contains information about the test drug –
- source,structure,manufacturing data
- preclinical data
- dosage forms,investigational protocol
- details about investigators
- agreement from the sponsers
- certification that Informed Consent will be
obtained from volunteers
Eight basic elements of informed consent
purpose of the research
risks or discomforts
any benefits to the subject which may reasonable be expected from
Any alternative procedures or treatment that may be available to the
confidentiality of records identifying the subject will be maintained
any compensation and whether any medical treatments are
available if injury occurs
An explanation of whom to contact for answers to questions about
the research and research subjects’ rights
A statement that participation is voluntary
Ethics committee & its
• At the institutional level – independent E.C to ensure
rights & welfare of the participants
- review protocol
- safeguard the rights , safety of trail subjects
- periodical review – SOPs
• 7 members – Member secretary
- chair person (outside)
- medical & non medical persons
ROLE OF PLACEBO
• Placebo controls – on healthy volunteers – Appetite
stimulant or new vaccine
• No place – Pt suffering from a disease – effective drug
• Ethics – consent is taken
PHASES OF CLINICAL TRIALS
• 4 phases
PHASE 1 CLINICAL TRIALS :
• Begins after 30 days of filing IND.
• Drug given to 20-100 healthy volunteers
• Duration could vary from 1 month to 1 year.
• Following is studied here :
• Drug absorption/Metabolism in human.
• Effect on organs and tissues. -Side affect of different
• Thus early evidences on effectiveness are achieved
*NON BLIND OR OPEN LABEL TRAIL
Phase I studies are carried out in 2 stages
Single rising dose
Each volunteer given a single dose of drug/placebo.
Dose-escalating study design.
Initial dose and route of administration decided from existing
8 -12 volunteers .
2-4 volunteers receive placebo and 6-8 volunteers receive drug
STAGE 1–SINGLE RISING DOSE
Started after single dose administration results
Drug / placebo given repeatedly for 1 or more weeks
E. g. Antibiotics given for 5-7 days
Anticonvulsants tested for 4 weeks or more
Interval between doses is usually one half life.
Kinetic data obtained from blood and urine sample
collected after 1st
and last dose
STAGE 2 REPEATED ADMINISTRATION
PHASE 2 CLINICAL TRIALS :
• Therapeutic exploratory trial
• First time in patients
• Less than 300 patients
• Doses are usually less than the highest doses
used in phase I
*SINGLE BLIND TRAIL
1. Efficacy in patients
2. Safety issues
3. Optimum dose finding
Dose efficacy relationship
Therapeutic dose regimen
Duration of therapy
Frequency of administration
PHASE II DIVIDED INTO EARLY & LATE
• EARLY PHASE II
small number of pts – upto 200
detail therapeutic benefited & ADR
idea to establish dose range
SINGLE BLIND STUDY
• LATE PHASE II
large number of pts – 200-400
DOUBLE BLIND STUDY
third party holds the code identifying studies
PHASE 3 CLINICAL TRIALS :
• By several physicians at many centres
• Large scale – 1000 to 5000 plus
• To further establish the safety & efficacy
• Long term side effects in patients
• Duration could vary from 5 years to 6 years.
• DOUBLE BLIND CROSS OVER design
• At end of trail statistical analysis of data is
Pts groups Week 1 Week 2 Week 3
PLACEBO NEW DRUG
PLACEBO NEW DRUG STANDARD
NEW DRUG STANDARD
Double-Blind Cross Over design
• NDA Refers to New Drug Application
• Formal proposal for the FDA to approve a new drug for
• Sufficient evidences provided to FDA to establish:
• Drug is safe and effective.
• Benefits outweigh the risks.
• Proposed labeling is appropriate.
• launched to the Market
• Post marketing surveillance – field trails
• No fixed duration
• To discover relatively rare side
effects(congenital effects) or drug interactions
• From hundreds to thousands of people
• Usually takes place after drug is approved to
provide additional information on the drug’s
risks, benefits and optimal use
PERIODIC SAFETY UPDATE REPORT
• Report any new information about the new drug & its
• Every 6 months for 2 yrs & annually next 2 yrs
Where the drug
Thalidomide was developed by German pharmaceutical company
Grünenthal. It was sold from 1957 to 1961 in almost 50 countries
under at least 40 names. Thalidomide was chiefly sold and
prescribed during the late 1950s and early 1960s to pregnant
women, as an antiemetic to combat morning sickness and as an aid
to help them sleep. Before its release, inadequate tests were
performed to assess the drug's safety, with catastrophic results for
the children of women who had taken thalidomide during their
From 1956 to 1962, approximately 10,000 children were born
with severe malformities, including phocomelia, because their
mothers had taken thalidomide during pregnancy. In 1962, in
reaction to the tragedy, the United States Congress enacted laws
requiring tests for safety during pregnancy before a drug can
receive approval for sale in the U.S.
Phocomelia presents at birth very short or absent long bones
and flipper-like appearance of hands and sometimes feet.
• Pharmakon – a drug , vigilare – to be observant
• Continuous monitoring for unwanted effects & other
safety related aspects of marketed drugs
• Thalidomide, Isotretinoin ,
• Fenfluramine & Phentermine – PHTN & valvular H.D
• Troglitazone – liver toxicity
• WHO – safety monitoring of medical products -
setting a P.V centre in every country
• P.V – Detection,Assessment, Understanding and
Prevention (DAUP) of ADR
• INDIA ,National P.V centre – AIIMS, New Delhi by central
drug standard control organization (CDSCO)
• 2 zonal , 8 regional & 28 peripheral P.V centres
• Generated data – global P.V database at WHO-Uppsala
• Reporting ADR includes:
• Pharmaceutical companies are commercial enterprises
• Pharmaceutical companies will, therefore, tend to avoid
products with a small market (i.e. a disease which only
affects a small subset of the population)
• Pharmaceutical companies will also avoid products that
would be consumed by individuals of lower economic status
(i.e. a disease which only affects third world countries)
Choosing a Disease
Most research is carried out on
diseases which afflict “first world”
countries: (e.g. cancer,
depression, diabetes, flu, migraine,
Choosing a Disease
The Orphan Drug Act
• The Orphan Drug Act of 1983 was passed to encourage
pharmaceutical companies to develop drugs to treat
diseases which affect fewer than 200,000 people
• Because the cost incurred will not be recovered
• So rare diseases are left untreated – orphan diseases ,
drugs – orphan drugs
• Govt. offered tax relief and exclusive marketing rights
• > 300 drugs
Ex: factor XIII , Erythropoietin , Atravaquone ,
Antithrombin III , Miltefosine , Acetyl cysteine , Relaxin
New tools for drug screening
HIGH THROUGHPUT SCREENING
Screening large libraries of 2 lakh compounds
Rate of 1,00,000 compounds/day
In HTS chemicals are tested for their ability to modify a
Methods – screening of combinatorial chemistry
,genomics, proteomics & peptide
Drugs are tested for their activity on these molecules using
plates wherein a large number of compounds are
Screening depends on inhibition of enzymic products which
are detected using fluoroscopy or photometry
24 WELL PLATE.
96 WELL PLATE.
- COMPOUND STORAGE.
- COMBINATORIAL CHEMISTRY.
- SAMPLE COLLECTION.
384 WELL PLATES.
-DNA LIBRARY MANIPULATION.
1536 WELL PLATES.
Minimizing cost and maximizing patent life time.
Highly efficient development.
Availability Of Instruments.
HTS is a remarkable achievement in drug discovery process
to speed up preclinical discovery process. This automation in
the process is supported by the excellent software packages.
The goal of the HTS is to accelerate drug discovery by
screening large libraries at a rate that may exceed 50,000
compounds per week.
CASSETTE DOSING / N-IN-ONE DOSING
• Elegant, inexpensive , time intensive novel technique –
aim to rapidly assess P.K of large number of compounds
• Several compounds(5-10) to single animal & rapid sample
analysis by liquid chromatography or mass spectography
• Advantages – to reduce no. of animals
- increased quality of kinetics data
- reduce the amount of the drug
- time minimized
• Disadvantages – drug to drug interactions
- false positives
Micro dosing / First In Human( FIH) studies /
•Study of new drug in microdoses to derive PK information in
human before undertaking phase I studies is called PHASE 0
or lower of the expected therapeutic dose.”
A dose less than 100ug
•(The test compound has no pharmacologic effect at
• Microdosing approach in man could ‘accelerate’ drug
development without compromising clinical safety
• Microdosing helps researchers select better drug candidates
for clinical trials by providing early human PK and
• Reduced cost of development
• Reduced development time
Determine the pharmacokinetics
Determine a non -toxic dose range
Determine the safety of an chemical entity
? Predictive accuracy of microdosing
PK at microdose vs. therapeutic dose
False positive/ negatives
Compound metabolism and solubility (limited solubility
at higher doses; ? Microdose too small)
Study mainly based on PK parameters - not efficacy and
• 3rd world diseases?
• orphan drugs with few users?
• improve safety and efficacy records
• reduce animal utilisation (cell lines; early
human volunteers, )
• new diseases (AIDS; Alzheimer’s; CJ
disease;human BSE variant; obesity; cancer)
• new biology - (clone human receptors;
disease model by gene changes)
The future ?
• Pharmacological basis of Therapeutics – Goodman &
Gilman 12th Edition .
• Principles of pharmacology – HL Sharma & KK sharma 2nd
• Drug Screening methods – Gupta 2 nd edition
• Experimental Pharmacology – Bikash Medhi
• Text book of pharmacology – K. D. Tripathi.7th Edition.
• Basics & clinical pharmacology – Katzung 11th
• www.history of clinicaltrails.in