THIS CLASS IS IN BREIF FOR UNDERGRADUATE UNDERSTANDING AND EXAMINATION PURPOSE

1. Dr. RAGHU PRASADA M S
MBBS,MD
ASSISTANT PROFESSOR
DEPT. OF PHARMACOLOGY
SSIMS & RC.
1

2. Evidence-based medicine is the systematic, scientific
and explicit use of current best evidence in making
decisions about the care of individual patients
Therapeutic evaluation of drug
Quantification of benefit
Appropriate method-dosage, duration, patient selection
Surveillance of adverse effects
clinical trials
cohort studies
case control studies

4. Conduct
Clinical
Trial
Disease
Population Drug
Specific
Concern

5. Cost vs Health Outcomes Grid
Effectiveness -
Effectiveness +
Costs -
Costs +
?
Useless
Dominant
re we ready to
give up on
effectiveness for
lower costs?!
Costs
more but
does less
Costs more
and does
more
Costs less
but does
more
Costs less and does less

6. Based on: Appropriateness/Safety/ Efficacy and cost
 Genuine indication
 Minimum number of drugs
 Inexpensive and appropriate formulation
 Preferably oral route – avoid injections
 Monitor adverse drug Event
 Patient education related to drugs and disease

7.  Approval of the product, new drugs should be closely monitored
for their clinical safety once they are marketed. The applicants
shall furnish Periodic Safety Update Reports (PSURs) in order to-
 Report all the relevant new information from appropriate
sources;
 Relate these data to patient exposure;
 Summarize the market authorization status in different
countries and any significant variations related to safety; and
 Indicate whether changes should be made to produce
information in order to optimize the use of the product.

8. Title & Abstract
Introduction
General statement of purpose
Complete Preclinical results on animal study
Clinical data if available
Time frame
Goals: Primary & secondary objectives
Study Design:
Type of study
Recruitment criteria : Exclusion & Inclusion criteria
Randomisation criteria and Sample size
Duration of study
Data Analysis:
Case report forms, Statistical Analysis, Bibliography

9. Informed consent form:
Voluntary
Explained in simple nontechnical language
Translated in the native language of the subject
Comprehensive information regarding the trials
Benefit of new therapy over existing ones
Alternative treatments available
All possible adverse reactions
Freedom to withdraw from the trial
at any time,
without giving any reason

10.  Independent
 Competent
 5 – 7 members; 5 required for quorum.
 Member Sec from same Institution
 Others: A mix of medical non-medical,
scientific & non-scientific including lay public
 Multidisciplinary & Multisectorial

11. To protect the dignity, rights & well being of
patients / volunteers
Ensure a competent review of the protocol
Advise on all aspects of welfare & safety
Ensure scientific soundness of the proposal

12. It is a prospective ethically designed investigation in
human subject to objectively discover/verify/
compare/ the results of two or more therapeutic
measures(drugs)
Preclincal studiesmicrodosing studies
Phase I : First in man  safety
Phase II : First in patient dose, dosage form
Phase III : Efficacy, ADRs
Post marketing surveillance or Phase IV : Evaluation in
the real clinical setting

13. Objectives
To assess a safe & tolerated dose
To see if pharmacokinetics differ much from animal to man
To see if kinetics show proper absorption, bioavailability
To detect effects unrelated to the expected action
To detect any predictable toxicity
Inclusion criteria
Healthy volunteers : Uniformity of subjects: age, sex,
nutritional status [Informed consent a must]
Exception: Patients only for toxic drugs Eg AntiHIV, Anticancer
Exclusion criteria
Women of child bearing age, children

14. Methods
First in Man : Small number of healthy volunteers
First in a small group of 20 to 25
Start with a dose of about 1/10 to 1/5 tolerated animal
dose
Slowly increase the dose to find a safe tolerated dose
If safe  in a larger group of up to about 50 –75
No blinding
Performed by clinical pharmacologists
Centre has emergency care & facility for kinetics study
Performed in a single centre
Takes 3 – 6 months [ 70% success rate]

15. First in patient [ different from healthy volunteer]
Early phase [20 – 200 patients with relevant disease]
Therapeutic benefits & ADRs evaluated
Establish a dose range to be used in late phase
Single blind [Only patient knows] comparison with
standard drug
Late phase [ 50 – 500]
Double blind
Compared with a placebo or standard drug
Outcomes
Assesses efficacy against a defined therapeutic endpoint
Detailed P.kinetic & P.dynamic data
Establishes a dose & a dosage form for future trials
Takes 6 months to 2 years [ 35% success rate]

18. Age: Pediatric,Geriatric
Gender: Women
Physiology: Pregnancy, Nursing
Pathological states: renal failure, hepatic failure,
cardiac failure,
BMI: obese, lean
Ethnicity/Race
Vulnerability

19. Guidance for Industry, investigators and
Reviewers; Exploratory IND Studies, Jan
2006,US FDA

20. Phase III A: up to NDA submission
End of Phase III A studies must include special patient
populations and pharmacoeconomic data collection
At least one placebo controlled trial
Phase III B:
Ongoing at time of NDA submission
Undertaken after NDA submission but before NCE is marketed
New indications may be included
New patient populations may be included
Special features explored e.g. drug interactions
20PLS-2012

21. Objectives
To assess overall and relative therapeutic value of the new drug
Efficacy, Safety and Special Properties
To determine optimal dosage schedule for use in General Practice
The dosage schedule in C.T.’s should be as close as possible to
its anticipated clinical use
Data obtained is Major component of NDA submissions-Regulatory
inputs are important i.e. what comparative drug to use
Marketing Department inputs i.e. information on most widely
Prescribed treatment
21PLS-2012

22. Large Sample Size: Multicentric, ↑Variability
Fewer exclusion criteria (stable concomitant disease allowed)
Longer duration of treatment: Weeks/Months
Study design
Parallel
Cross over
Investigator’s Brochure
Study Protocol (Investigator’s meeting)
All investigators agree to follow
Case Record forms
Same at all centers
Study monitoring especially recruitment rate
Study monitors
Clinical research associates
Drug supplies
22PLS-2012

23. After Marketing Permission
(Real World Use of the New D
Thousands/Lakhs of patients now use the drug
G.P.’s, Little medical supervision
Co morbidities/other drugs taken (Herbals)
Non adherence to treatment rampant (> 50%)
Long duration of treatment
Self-medication rampant
- Prescription drugs
- OTC drugs
PLS-2012 23

24. Phase IV C.T.: Special Characteristics
1. Very large sample size
2. No or little supervision: Physician shopping
3. Fewer data collected from each patient
4. Fewer Exclusions (Contraindications only)
5. Longer drug administrations
6. Expensive
7. Comorbidities and co-medications
8. Non adherence to treatment: Common
9. Self-medication common
PLS-2012 24

25. To obtain information on Unsupervised use of Registered Drug
in the Community under daily routine conditions
PMS: Legally fulfill this Regulatory Requirement
Mandatory for Fast Track Approvals
Does not influence diagnostic/therapeutic procedures of
Participating physicians. Uses Specific Record Forms
Enrolled patients are not subjected to any disadvantage or
additional risk
Data collected provides an unbiased picture of daily routine Use
of drug, allowing Realistic assessment of Benefit-Risk ratios

26. 1. Comparative long term Benefit-Risk assessment
2. Drug usage in the community
3. QOL Assessment
4. Dose-refinement
5. Rare ADR’s and long term safety
6. Benefit-Cost assessment
7. Improvement in Primary End-points of disease

27. 1. Spontaneous Voluntary Reporting
2. Case Control Studies
3. Intensive Hospital Monitoring
4. Prescription Event Monitoring
5. Literature Surveys
6. Prospective population based studies for rare ADR’s
7. Automated patient Data Banks
(Useful for retrospective studies)

28. CDSCO, HQ
National Coordination Centre
IPC Ghaziabad, UP
Steering
Committee
Working
Group
Signal Review Panel
CoreTraining Panel
Quality Review Panel
M O N
A
I
D
T
R
O R I N G
IMMUNIZATION
PROGRAMMES
Pharmaceutical
Industry ADRs
originating in
India
PROFESSIONAL BODIES
HOSPITALS
MEDICAL COLLEGES
Stakeholders
Patients, Health Care
Professionals, Pharma
Industry
CDSCO ZONAL/SUBZONAL
OFFICES
North
Ghazi
abad
Chan
digar
h
South
Chenn
ai,Hyd
eraba
d,
Bangl
ore
East
Kolkata
West
Mumb
ai
Ahma
dabad
1
3
4
c
A
D
E
B
PHARMACOVIGILANCE
28

29.  It is the pharmacological science relating to the
collection, detection, assessment, monitoring, and
prevention of adverse reaction with Pharmaceutical
products.
It is the study of the safety of marketed drugs under
the practical conditions of clinical use in large
communities
It is concerned with the development of science and
regulation in the area of drug safety.

32. Restrictive inclusion/exclusion criteria limits
generalizability
Conflict between results observed in controlled experiment
versus use in real life
Too expensive
Single intervention, single-dose-though there is increasing
use of factorial design
Ethical considerations
Bias in what interventions are studied and what studies are
published
Translation of large sample derived risks and outcomes to
individual patients

33. 1. Not dependent on large resources or research
infrastructure
2. Can be interesting, accessible and readily digestible
for readers
3. Convey the ‘art’ of medicine
4. Not all research questions are amenable to RCT
5. An expedient way of communicating new ideas,
syndromes, treatments and adverse reactions

34. “All substances are poisons;
there is none which is not a poison.
The right dose differentiates a poison from a remedy.”
Paracelsus (1493-1541)
THANKYOU
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