REULATORY AFFAIRS

1. 1

2. CONTENTS:
1.HISTORY
2.AIMS
3.RESPONSIBILITIES
4.NEED OF PHARMACOVIGILANCE
5.GOVERNING BODIES
6.METHODS OF PHARMACOVIGILANCE
7. PHARMACOVIGILANCE INSPECTION
8.ADVERSE DRUG REACTION
9.APPLICATION OF PHARMACOVIGILANCE
10.POST MARKETING SURVEILLANCE
11. REFERENCES
2

3.  Thalidomide Disaster:
 Tranquilizer launched – 1957
 First reports of birth defects – 1959
 13 reports of birth defects - 1961
 Withdrawn shortly afterward
 10000 infants affected by Phocomelia.
 No teratogenicity detected in testis during
clinical trials and prior to launch.
3

4. Pharmacovigilance(Pv) also called as drug safety
Pharmakon-------in greek----drug
vigilance ---------in latin------to keep watch
Pharmacovigilance is the science &activities
relating to the detection , assessment, understanding
and prevention of adverse effects or any other medicine
related problems.
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5. AIMS
 To improve patient care and safety
 To improve public health and safety
 To contribute to the assessment of benefit, harm
effectiveness and risk of medicines
 To promote education and clinical training
 To promote rational and safe use of medicines
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6. RESPONSIBILITIES
Timely collection of data ,recording and
notification
Appropriate assessments (data completeness ,
seriousness)
Expedited and periodic reporting
Creates appropriate structures for communication
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7. Why do we need
Pharmacovigilance?
7

8.  Humanitarian concern
 Insufficient evidence of safety
from clinical trials, Animal
experiments & Phase 1 – 3 studies
prior to marketing authorization
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9. 9

10.  Small number of patients studied
 Restricted populations (age,
sex, ethnicity)
 Narrow indications
 Short duration of drug
exposure
10

11.  Medicines are supposed to
save lives
 Dying from a disease is
sometimes unavoidable;
dying from a medicine is
unacceptable.
11

12. ADRs are expensive !!
• Cost of drug related morbidity
and mortality exceeded
$177.4 billion in 2000
• ADR related cost to
the country exceeds
the cost of the medications
themselves.
12

13. Promoting rational use of
medicines and adherence
 Reason 5:
Ensuring public confidence
 Reason 6:
Ethics To know of something that is harmful
to another person who does not know, and
not telling, is unethical
13

14.  because of differences in:
• Drug production
• Distribution and use ( e.g.
indications, dose, availability)
• Genetics, diet, traditions of the
people (e.g. use of herbal
remedies, etc.)
• Pharmaceutical quality and
composition (active/inactive
ingredients )
14

15. • Started 1968
• Located in Uppsala,
Sweeden
• Collaborating centre for
maintaining global ADR
database - Vigibase
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16. • Identify early warning signals of serious adverse
reactions to medicines
• Evaluate the hazard
• Undertake research into
the mechanisms of action
to aid the development of
safer and more effective medicines
16

17.  The pharmaceutical industry
 Regulatory authorities
 WHO collaborating centre for international drug
monitoring
 CIOMS(Council for International Organization
of Medical Sciences )
17

18.  serious ADR
• Life-Threatening
• Hospitalization (initial or prolonged)
• Disability
• Death
• Congenital Anomaly
• Medically important event or reaction
Cause Cancer
 OTHER WISE ADR IS NON-SERIOUS
18

19. • Identifiable patient
• Identifiable drug (pharmaceutical product)
• Identifiable reaction
• Identifiable reporter
19

20. • Who should report?
• Healthcare Professionals
• Marketing authorization holder (MAH)
• Patients & their relatives
• Nurses
• Pharmacists
20

21. METHODS 0F PHARMACOVIGILANCE
1.Individual case safety reports
2.Clinical review of case reports
3.Cohort event monitoring
4.Longitudinal electronic patient records
5.Spontaneous reporting
6.Periodic Safety Update Reports (PSUR)
7.Expedited report
8.Record linkage
21

22. 1.INDIVIDUAL CASE SAFETY REPORTS:
-Like yellow card system of the Pharmacovigilance
section of the U.K.
-Their strength in signaling causal associations
depend on the skill and experience of the reporter and
the documentation and characteristics of the event.
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23. 23

24. 24

25. 25

26. 26

27. 27

28. 2.CLINICAL REVIEW OF CASE REPORTS:
-The quality of reports is variable , large national and
international organizations collect hundreds of thousands of
reports each year , every one which can’t possibly be
reviewed by the available experts.
-Even if each report could be reviewed , important
reporting patterns would be missed.
-Computational have therefore been developed to help
highlight the most urgent problems .
28

29. 3.COHORT EVENT MONITORING:
-Cohort Event Monitoring (CEM) systems for intensified
follow up of selected medicinal products.
-The main limitations are its restriction to small subset of
medicinal products , the relatively small fraction of the
population covered .
29

30. 4.LONGITUDINAL ELECTRONIC PATIENT
RECORDS:
 It is extremely valuable but underused.
 They cover large populations, provide detailed information
on both exposed and unexposed patients.
Information is extracted directly from the computer systems in
which physicians store patient’s data.
 Privacy protection for patients and physicians is of the utmost
importance.
30

31. 5.SPONTANEOUS REPORTING:
The reporting might be directly to the company ,
or it could be to the regulatory authority.
Main limitation is under reporting.
However , their main purpose is not the
quantification of the frequency, but identification of
signals.
31

32. When becoming aware of a serious adverse drug
reaction , health care providers, pharmacies,
pharmaceutical companies shall report to the health
authority.
 Time frame of reporting , report within a specific time
frame(ex:7days) upon knowing of any serious ADR.
32

33.  REPORTING METHODS AND TEMPLATE : shall submit
reports by post, fax or internet .
A verbal report is acceptable in urgent situations, but written
sbmission should be completed before the deadline.
Additional information on a serious ADR report, not available
at the time of the initial report , should be provided in follow
up reports.
33

34. 6.PERIODIC SAFETY UPDATE REPORTS(PSUR):
 Pre marketing clinical trials may not be sufficient to
reflect the product safety profile.
Therefore medically advanced countries impose the
“post marketing drug safety monitoring period ” on
new drugs.
License holders shall proactively collect post
marketing safety data, prepare PSUR and submit them
to the health authority.
34

35.  According to the “regulation of medical products
under safety monitoring” ,If pharmaceutical companies
fail to submit PSUR as required , then the health
authority may reassess the safety of the concerned
product.
The last PSUR should be submitted before the
expiration of the drug safety monitoring period.
The “summary bridging report” provides summarized
information of the PSURs.
35

36. 7.EXPEDITED REPORT:
 If there has been spontaneous reporting of a suspected
ADR to a pharmaceutical company , there are legal
obligations on the company to report serious reactions
within a specified time frame to the regulatory authority.
Based on the results of drug safety assessment , license
holders shall report to the health authorities in an
expedited manner
36

37. 8.RECORD LINKAGE:
 Bring together a variety of patient records .
 A specific example is prescription event
monitoring scheme.
 It is less expensive but time consuming method.
37

38. PHARMACOVIGILANCE INSPECTION
Two types -
1.Routine inspection
2.Targeted inspection
1.Routine inspections
To make sure that pharmaceutical companies have the
ability in performing Pharmacovigilance activities.
38

39. 2.Targeted inspections
a) Inspections irrelevant to drug safety
-Companies that have not yet been inspected
-Companies that launch their first product
-Companies which are newly merged
b) Inspections relevant to drug safety
-Companies that delay or fail to take their obligations on
safety monitoring
-Companies that delay to submit or submit incomplete
periodic safety update reports
-Companies that failed to report drug safety related issues
(like drug withdrawal with out reporting )
39

40. ADVERSE DRUG REACTIONS
An ADR is a harmful response in the patient caused
by the drug itself given in the recommended manner
(dose,frequency, route, administration technique)
Examples include allergic reaction, effects from
withdrawal, or reaction caused by interactions with
other medications.
40

41. TYPES OF ADR
Non immunological
a) TYPE A (or) predictable
b) TYPE B (or) unpredictable
Immunological a) TYPE -I (Ig E mediated)
b) TYPE -II (cytotoxic)
c) TYPE -III (immune complex)
d) TYPE -IV (cell mediated)
Miscellaneous a) Jarisch - herxheimer reaction
b) infectious mononucleosis
41

42. NON IMMUNOLOGICAL
TYPE A (or) predictable
1.Side effects
2.Secondary effects
3.Toxic effects
4.Mutagenicity&carcinogenicity
5.Drug interactions
6.Teratogenicity
7.Nonimmunological activation of effector
pathways
8.Exacerbation of disease
9.Metabolic alterations
10.Drug induced chromosomal damage
11.Effect on spermatogenesis
42

43. TYPE B (or) unpredictable
1. Intolerance
2. Idiosyncrasy
43

44. Type A
1.Side effects :
- Undesirable and unavoidable effects of drugs due
to their pharmacological property at recommended
doses.
Ex-Dry mouth from atropine therapy
2.Secondary effect:
-Indirect effects of drug due to its principal action.
Ex-Occurrence of TB in corticosteroid therapy.
44

45. 3.Toxic effect:
-It is a pharmacological action due to over dosage
or prolonged usage.
Ex-coma with barbiturates
4.Mutagenicity & carcinogenicity:
-Metabolites from drugs can cause structural
changes in chromosomes to produce mutations.
Ex-Anti cancer drugs
45

46. 5.Drug interactions:
-Can occur before its absorption into systemic
circulation .
Ex- Phenobarbitone inhibits griseofulvin absorption
from intestine
6.Teratogenicity:
-Fetal abnormalities produced due to drug intake by
the pregnant woman
Ex-Androgens cause virilization of fetus
46

47. 7.Non immunological activation of effector
pathways:
-Some drugs cause release of mediators from mast
cells resulting in urticaria.
Ex-Radio contrast media
8.Exacerbation of disease :
-Barbiturates precipitate symptoms of porphyria
47

48. 9.Metabolic alterations :
Ex- Isotretinoin interferes with VLDL metabolism
and causes xanthoma
10.Drug induced chromosomal damage:
-Also called clastogens
Ex-Antibiotics, Anticonvulsants
11.Effect on spermatogenesis:
-Cytotoxic drugs causes oligospermia.
48

49. Type B
1.Intolerance:
-Appearance of toxic effects in a recipient to
therapeutic doses of drug
Ex- trifluperazine single dose causing muscle
dystonia in children
2.Idiosyncrasy:
-Uncertain reaction to a drug in a genetically defect
patient
Ex-chloramphenicol causes bone marrow
depression
49

50. IMMUNOLOGICAL
1.Type 1 (immediate or anaphylactic):
Ex:-penicillin, lignocaine
Mediators
urticaria
Earlier exposure
AB formed
AG:AB reaction
mast cells
Re exposure to the
same Drug (AG)
50

51. 2.Type 2 (cytotoxic):
Drug + particular tissue AB
(AG)
AG:AB reaction
complement
cytolysis
Ex: Blood transfusion reactions, cephalosporins
51

52. 3.Type 3 (retarded or arthus ):
Drug (AG) AB
AG :AB complex
Complement
Inflammatory reaction
Ex:- Acute interstitial nephritis with NSAIDs
52

53. 4.Type 4 (delayed hypersensitivity reactions ):
Ex:-Contact dermatitis
Prior sensitization T lymphocytes c receptors
(AB)
Re exposure of the drug
(AG)
Release of lymphokines
AG:AB reaction
Attracts granulocytes
Inflammatory response
53

54. MISCELLANEOUS
1.Jarisch-herxheimer reaction:
-This is seen when an infective disease is treated
with antimicrobials , due to release of active
substances from dead micro organisms and injured
tissue resulting in focal exacerbation of the lesions.
2.Infectious mononucleosis:
-Ampicillin induced morbilliform rash in patients
suffering from infectious mononucleosis.
54

55. Steps of ADR monitoring:
1.Identifying adverse drug reactions
2.Assessing causality
3.Documentation of ADR
4.Reporting serious ADRs to PV centres/ADR
regulatory authorities
55

56. 56

57. APPLICATION OF PHARMACOVIGILANCE
1. In national drug policy
2.In the regulation of medicines
3.In clinical practice
4.In disease control public health programmes
(problems are apparent in situations for the treatment
of tropical diseases)
57

58. Post marketing surveillance(PMS)
-Is the practice of monitoring the safety of a pharmaceutical
drug or medical device often it has been released on the market
and is an important part of the science of Pharmacovigilance.
-Since drugs are approved on the basis of clinical trials, which
involve relatively small numbers of people & do not have
other medical conditions.
Approaches are –Spontaneous reporting database
-Prescription event monitoring
-Electronic health records
-Patient registries
58

59. Uses-No fixed duration or patient population
Starts immediately after marketing
Report all ADRs
Helps to detect rare ADRs
PMS-Consists of 3 systems
1.ADR collecting and reporting system
2.Re-examination system
3.Re-evaluation system
59

60. Sources-Focus groups
- Customer surveys
- Customer complaints& warranty claims
- Literature reviews
- Media
Benefits-Improvement of medical device quality
-Verification of risk analysis
-Detection of chronic complaints
-Performance in different user
population
-Customer satisfaction
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61. Needs of PMS-
-To develop information about drug effects
-To find rare adverse events
-Assess to more patient data
Methods of surveillance-
-controlled clinical trials
-spontaneous recording
-cohort studies
-case control studies
-All adverse events occurring in a PMS should be
submitted to UMC in the form of fact sheet.
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62. Fact sheet should be-email to vigibase@whoumc.org
- Confirmation will be sent of received cases
within 3 days
-Case report format-ICH E2B
-Both serious and non serious cases should be
submitted
-Reporter qualification should be specified in the
ICSR
-ICSR on veterinary medicines , cosmetics should
not be submitted to UMC
-either of the two ADR terminologies WHOART
(or)MedDRA can be used .
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63. Monitoring and evaluation
1.Process indicators –
-Number of ADR monitoring centres
participating
-Number of personnel trained in a year
-Funds budgeted and spent
2. Out come indicators –
-Number of ADR reports received in year
-Number of ADR reports processed in year
-Number of ADR reports submitted to vigiflow
3. Impact indicators –
-Number of signals generated and confirmed
-Number of safety related alerts issued by
CDSCO
63

64.  Management sciences for health 2012,
part п pharmaceutical management, chapter 35.
pharmacovigilance, pg:no:35.2-35.19
 A Practical Guide on Pharmacovigilance for Beginners,
Dr.S.Gunasakaran,MBBS,MD, R.Satheeshkumar, M.Pharm
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65. Thankyou
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