1. Spontaneous Reporting of ADRs
Dr. Manish Barvaliya,
Assistant Professor,
Department of Pharmacology,
GMERS Medical College,
Dharpur, Patan.
Mobile:

2. What will the session cover
ADRs - pre-marketing stage
Post marketing (Pharmacovigilance methods)
What is Spontaneous Reporting of ADR
What to Report, Whom to Report, Why to Report
What Happens to the Report
Under-reporting : a serious issue
August 5, 2019
Pharmacovigilance CME : Bhavnagar

3. Shouldn’t ADRs be picked up before marketing?
Why should we be vigilant even after drug is in market?
Preclinical studies Phase I, II & III clinical trials
August 5, 2019
Pharmacovigilance CME : Bhavnagar

4. Pharmacovigilance CME : Bhavnagar
Limitation of preclinical drug evaluation
Animal data cannot be extrapolated to man
Limitation of pre-marketing clinical evaluation
Number of patients too few
Patients too selective
Artificial therapeutic environment
Period of exposure too short
Before a medicine is licensed it will be tested in clinical trials. The trials are carried out in a relatively small number of patients(1, ,000) and under strict conditions with strict inclusion and exclusion criteria. In everyday clinical practice the medicine is available to be taken by millions of patients.
Only patients receive a medicine before it is marketed
Common adverse effects identified in clinical trials are mentioned in Prescribing Information
Unusual adverse effects occurring in only 1 in 5,000 or 1 in 10,000 patients will not have been seen
The more unusual ADRs occurring in small numbers of patients
e.g. 1 in 5,000 or 1 in 10,000 patients, will probably not have been seen in the clinical trials. This is why continued monitoring of every medicine on the market is essential.
Useful information
At least 30,000 people will need to be treated with a drug to discover, with 95% certainty, at least 1 patient with an ADR with an occurrence of 1 in 10,000.
August 5, 2019
Pharmacovigilance CME : Bhavnagar

5. Pharmacovigilance CME : Bhavnagar
Rule of 3
If no specific adverse reaction (drowsiness) occurs in N patients during clinical trials
Approximate frequency of adverse reaction in post marketing surveillance is = 3/N
100 patients: max frequency 3/100= 3%.
2000 patients: max frequency 3/2000= 0.15%
3000 patients: max frequency 3/3000= 0.1%
August 5, 2019
Pharmacovigilance CME : Bhavnagar

6. Pharmacovigilance CME : Bhavnagar
Statistical Concerns
Expected incidence of adverse reaction
Number of patients required to be treated for occurrence of following numbers of adverse reactions
1 in 100
1 in 200
1 in 1000
1 in 2000
1 in 10000
300
600
3000
6000
30000
480
900
4800
9600
48000
650
1300
6500
13000
65000
August 5, 2019
Pharmacovigilance CME : Bhavnagar

7. Topics to be studied after drug is marketed
Assessment of side effects
detection of unexpected adverse effects and interactions
identification of risk factors
quantitative measurement of (un)safety
long term safety/toxicity
Study of potential risk groups (children/elderly, pregnant women etc)
Detection of unexpected beneficial effects
fine tuning of dosage recommendations
August 5, 2019
Pharmacovigilance CME : Bhavnagar

8. Pharmacovigilance Methods
Passive surveillance:
Spontaneous Reporting
Case series
Stimulated Reporting
Active surveillance:
Record Linkage : Prescription Event Monitoring
National morbidity and mortality statistics
[Cancer register, malformation register, medical birth register, registry of severe cutaneous adverse reaction etc]
Amongst them Spontaneous is the best… studies all types of patients without any discrepencies in real world scenario,,,follow up is equal to usage/ dosage regimen
Stimulated reports: motivated prompted induced (questioning health care professional by company or regulatory authority)
August 5, 2019
Pharmacovigilance CME : Bhavnagar

9. Pharmacovigilance Methods
Comparative Observational Studies:
Cross sectional study
Case- control study
Cohort study
Targeted Clinical Investigations
Descriptive Studies:
Drug utilization study
August 5, 2019
Pharmacovigilance CME : Bhavnagar

10. Spontaneous Reporting of ADRs
Spontaneous or voluntary reporting involves a doctor or patient describing his or her own clinical observation of a suspected ADR with a marketed drug
Unsolicited communication by health care professional to a company, regulatory authority or ADR monitoring center that describes one or more ADRs in a patient who was given one or more drugs.
Voluntary in nature.
Initiated by health care professionals on suspicion of any adverse reaction.
August 5, 2019
Pharmacovigilance CME : Bhavnagar

11. Pharmacovigilance CME : Bhavnagar
Why to Report
Identify new causal relations
The clinical spectrum of a drug-AE pair.
The patient subtypes and medical circumstances associated with a product- induced adverse reaction.
Clues to the mechanism of action by which product exposure leads to an adverse reaction 
So now that we have seen that spontaneous adverse event reporting can make a big diff in the way we prescribe or the way we use medicine, but still there is underreporting.
Many cuntries have made in mandatory while in India it is still Voluntry.
I tried to figure out various reasons why Indian doctors do not report….
August 5, 2019
Pharmacovigilance CME : Bhavnagar

12. Pharmacovigilance CME : Bhavnagar
Importance
Forms the core of the World Health Organization Database
Foundation of post-marketing surveillance programs largely because of 
The high volume of information they supply,
Their low maintenance costs
Quickly detect unexpected ADRs 
Cover all drugs during their whole life cycle
Cover the whole patient population, including special subgroups such as the elderly (Real world scenario)
Patient follow up possible
Does not interfere with prescribing habits
Helps in generating hypothesis which can be further investigated. Major role in in identification of safety signals once drug is marketed.
Database within country is important.
August 5, 2019
Pharmacovigilance CME : Bhavnagar

13. Pharmacovigilance CME : Bhavnagar
Who Should Report
Family physicians
Medical specialist
Dentists
Pharmacists
Nurses
Patients
August 5, 2019
Pharmacovigilance CME : Bhavnagar

14. Pharmacovigilance CME : Bhavnagar
Whom to Report
Spontaneous reporting can be made to
ADR Monitoring Cell
The regulatory authorities (DCGI, USFDA)
To the pharmaceutical company that markets the product
To medical or scientific journals
August 5, 2019
Pharmacovigilance CME : Bhavnagar

15. Pharmacovigilance CME : Bhavnagar
How to Report
Fill up an ADR form and
Report to the ADR Monitoring cell (AMC)
August 5, 2019
Pharmacovigilance CME : Bhavnagar

16. Pharmacovigilance CME : Bhavnagar
ADR form
The forms are provided to the clinicians to describe the details of suspected ADR. The form is generated by CDSCO working under Directorate General of Health Services (DGHS) Govt of India.
August 5, 2019
Pharmacovigilance CME : Bhavnagar

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How to Report
August 5, 2019
Pharmacovigilance CME : Bhavnagar

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ADR Drop box
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19. Pharmacovigilance CME : Bhavnagar
What to Report
Ideally
All the
Adverse Events
All the ADR but it is not possible for one doctor to record and report all the adverse drug events. The amount of paper work would be as much as writing prescriptions.
To begin with we should focus on some of the adverse events…..
August 5, 2019
Pharmacovigilance CME : Bhavnagar

20. Pharmacovigilance CME : Bhavnagar
What to report
Unknown unexpected ADR
Serious ADR (Seriousness and severity are different)
ADR of new drug
ADR in special population
Adverse reaction due to device, radio contrast, herbal medicines
For established drugs and vaccines all suspected reactions considered to be serious should be reported, even if the reaction is well recognised. For example GI bleeding with NSAIDs should be reported.
A reaction that
is fatal
is life threatening
is disabling
is incapacitating
results in hospitalisation
prolongs hospitalisation
August 5, 2019
Pharmacovigilance CME : Bhavnagar

21. Pharmacovigilance CME : Bhavnagar
What to Report
Adverse Reactions/ Events associated with
Biologicals
Blood transfusion
Blood product
Tissue organ
Cell therapy transplantation
Adverse events following Immunization
Biovigilance programme (BvPI) including Haemovigilance across the country under its Pharmacovigilance Programme of India ( PvPI 10th Dec 2012
August 5, 2019
Pharmacovigilance CME : Bhavnagar

22. What to Report Do you suspect an ADR? Yes Is it a serious reaction?No
Is the patient a child?
Report
Yes No
Report
Is it a New Drug (less than 4 years)
Yes No
You may skip reporting
August 5, 2019
Pharmacovigilance CME : Bhavnagar

23. Pharmacovigilance CME : Bhavnagar
If in Doubt
Fill the Form!
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Pharmacovigilance CME : Bhavnagar

24. What happens to the forms
ADR reports collected at the AMCs Dispatched to the coordinating centre Coordinating centre conducts causality assessment Upload the reports into vigiflow Uppsala Monitoring Center Signal detection
PvPI, India
August 5, 2019
Pharmacovigilance CME : Bhavnagar

25. Pharmacovigilance CME : Bhavnagar
Signal
Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously
Usually more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information Further analysis and regulatory action- revision of pack inserts and if serious adverse events are fount- withdrawl of drugs from the market
An AE signal is defined as a potential product-AE relation that deserves further attention. which includes developing more detailed information about an already known product-AE relation
August 5, 2019
Pharmacovigilance CME : Bhavnagar

26. Pharmacovigilance CME : Bhavnagar
Examples
Hepatotoxicity with the novel uricosuric diuretic tienilic acid,
Anaphylactoid reactions with zomepirac
Agranulocytosis with the antipsychotic agent clozapine
Multi-system toxicity with the antimalarial agent Fansidar
Zomepirac NSAID with antipyretic activity in 1980
Sulfadoxine and Pyrimethamine – SJS, TEN, Skin Reactions
Zimeldine- SSRI
emepromium bromide – anticholinergic used as antispasmodic
Benoxaprofen – Eli Liiy NSAID
Pharma Times 44;05:2012
August 5, 2019
Pharmacovigilance CME : Bhavnagar

27. Pharmacovigilance CME : Bhavnagar
Hepatotoxicity and pulmonary fibrosis with amiodarone
Guillain-Barre syndrome with the antidepressant zimeldine
Arthralgia with mianserin
Oesophageal ulceration with emepromium bromide
Severe gastrointestinal, liver, blood and skin reactions with benoxaprofen
August 5, 2019
Pharmacovigilance CME : Bhavnagar

28. Pharmacovigilance CME : Bhavnagar
Limitations
Under reporting
Missing data
Reporting fluctuates with the length of time drug has been on the market.
Delayed adverse reactions are difficult to detect.
According to Weber et al, total number of ADR report increases until 2 years after the introduction and declines thereafter.
Choloroquine induced ophthalmopathy
August 5, 2019
Pharmacovigilance CME : Bhavnagar

29. Pharmacovigilance CME : Bhavnagar
Why Under-reporting
August 5, 2019
Pharmacovigilance CME : Bhavnagar

30. Inmans Seven Deadly Sins
Br J Clin Pharmacol 1996
August 5, 2019
Pharmacovigilance CME : Bhavnagar

31. Pharmacovigilance CME : Bhavnagar
Fear of
Litigation
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Pharmacovigilance CME : Bhavnagar

32. Pharmacovigilance CME : Bhavnagar
Lethargy or indifference about contributing to the general advancement of knowledge
the belief that the single case an individual doctor might observe could not contribute to medical knowledge
August 5, 2019
Pharmacovigilance CME : Bhavnagar

33. Pharmacovigilance CME : Bhavnagar
Guilt-at having caused an adverse effect
August 5, 2019
Pharmacovigilance CME : Bhavnagar

34. Pharmacovigilance CME : Bhavnagar
Ignorance-of the need for reporting
August 5, 2019
Pharmacovigilance CME : Bhavnagar

35. Pharmacovigilance CME : Bhavnagar
Ambition-
to collect and publish a personal series of cases
August 5, 2019
Pharmacovigilance CME : Bhavnagar

36. Pharmacovigilance CME : Bhavnagar
Diffidence- about reporting a mere suspicion
the belief that reporting an ADR would only be done if there was certainty that it was related to the use of a particular drug;
Diffidence (Shy)
August 5, 2019
Pharmacovigilance CME : Bhavnagar

37. Pharmacovigilance CME : Bhavnagar
Complacency-
the mistaken belief that only safe drugs are licensed
the belief that very serious ADRs are well documented by the time a drug is marketed
Complacency (disapproval for situation)
August 5, 2019
Pharmacovigilance CME : Bhavnagar

38. Reasons for not reporting the ADRs (India)
Not aware of correct reporting centers
Did not have ADR reporting form
Feeling that ADR was well known
Was not sure about the drug causing ADR
Did not have set procedure of ADR reporting in their organization
Ind J Phar Pract 4;2:2011
August 5, 2019
Pharmacovigilance CME : Bhavnagar

39. Pharmacovigilance CME : Bhavnagar
Despite the limitations of SRS,
decision to withdraw the drug from market may have to be taken on basis of spontaneously reported cases to avoid risk of exposure of large population to the suspected drug
As there can be delay before the results of confirmatory studies are available.
August 5, 2019
Pharmacovigilance CME : Bhavnagar

40. When do Practitioners Report
A positive relationship between the PVG Centre and the reporter
Active personal and general feed-back
Encouragement from the Centre
Simple and readily available report forms
Pharmacoepidemiology and Drug Safety 1997;6:21-6
August 5, 2019
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41. Pharmacovigilance CME : Bhavnagar
Remember!
“All health-care professionals have a
responsibility to inform colleagues about
clinically important adverse drug reactions
that they detect, even if a well-recognised or causal link is uncertain.”
Lancet 2000; 356:
August 5, 2019
Pharmacovigilance CME : Bhavnagar

42. an evidence for absence of ADR. Pharmacovigilance CME : Bhavnagar
Remember!
Absence of evidence for ADR is not
an evidence for absence of ADR.
August 5, 2019
Pharmacovigilance CME : Bhavnagar

43. Do not assume someone else will report it!
If you suspect an ADR..
Do not assume someone else will report it!
Never assume someone else will report
It does not matter if someone else has reported, duplicates are picked up and usually complement each other.
It doesn’t matter if it turns out not to be an ADR. Don’t not report just because you are not sure.
August 5, 2019
Pharmacovigilance CME : Bhavnagar

44. Can We Make A Difference?
YES
August 5, 2019
Pharmacovigilance CME : Bhavnagar

45. THANK YOU..!! Please, Report an ADR.
"The person who takes medicine must recover twice, once from the disease and once from the medicine."
William Osler, M.D.
August 5, 2019
Pharmacovigilance CME : Bhavnagar