Spontaneous Adverse Drug Reaction Reporting in the National Pharmacovigilance Programme
Dr. Manoj Swaminathan
Dissertation submitted in partial fulfillment of the requirement for the award of the degree of Master of Public Health
Achutha Menon Centre for Health Science studies Sree Chitra Tirunal Institute for Medical Sciences and Technology
Thiruvananthapuram- 695011, Kerala, INDIA
October 2007
DECLARATION
I hereby declare that this dissertation work titled "Spontaneous Adverse Drug Reaction reporting in The National Pharmacovigilance Programme" is the result of original research work and it has not been submitted for the award of any degree in any other institution.
Dr. Manoj Swaminathan Thiruvananthapuram, Kerala, India. October 2007.
Certificate
I hereby certify that the work embodied in this dissertation titled "Spontaneous Adverse Drug Reaction reporting in the National Pharmacovigilance Programme" is a bonafide record of original research work undertaken by Dr.Manoj Swaminathan, in partial fulfillment of the requirements for the award of the 'Master of Public Health' degree under my guidance and supervision.
Guide: Dr. V Raman Kutty Professor, Achutha Menon Centre for Health Science Studies, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Thiruvananthapuram, Kerala, India.
Acknowledgement
I wish to express my sincere gratitude to the following persons who have contributed in
varying degrees to the work resulting in this dissertation.
Dr. V Raman Kutty, Professor, AMCHSS, SCTIMST, for guiding me throughout the study
and motivating me regularly with his expertise.
Dr.Nilima Kshirsagar, the Coordinator of the south-west zonal pharmacovigilance centre and
the erstwhile Dean and Director (Medical Education and Health) at the Seth GS Medical
College and KEM Hospital, Mumbai for encouraging me and permitting me to carry out this
study.
I would like to specially thank Dr.Nithya J Gogtay, Associate Professor, Dept of Clinical
Pharmacology, KEM for motivating me to conduct the study and supporting me as and when
required;
Dr.Mala Ramanathan, for her expert guidance for performing the qualitative analysis;
Dr.Vijay Thawani, for helping me with the idea of e-discussion;
The faculty members of AMCHSS and the PhD scholars for their expert and valuable
suggestions during the presentations;
The support staff at AMCHSS for helping me whenever required and
the research scholars and the staff members at KEM who supported me at all times.
I express my sincere thanks to the members of the Technical Advisory committee and the
Institutional ethics committee for the approval of my study.
I am immensely grateful to Prof. K. Mohandas, Director of Sree Chitra Tirunal Institute of
Medical Sciences and Dr. K.R. Thankappan, Head of Department, AMCHSS, for enabling
me to complete this study.
This work would not have been possible without the contributions of the dedicated and the
committed healthcare professionals who reported adverse drug reactions.
Dr.Manoj Swaminathan
ABSTRACT
Background Adverse drug reactions (ADRs), which are associated with substantial morbidity and mortality, are the 4'h -6th leading causes of death in some of the developed countries. In India, ADRs are responsible
for 0.7 percent of the admissions, with 1 in 25 of the hospitalized patients experiencing an ADR out of which 1.8 percent has a fatal ADR. India, being the second most populated country with a large phannaceutical industry needs to have a well functioning pharmacovigilance system.
Objective To study the patterns of adverse drug reaction (ADR) reports in the south-west zonal centre of the National Pham1acovigilance Programme and explore the perspectives of the authorities and healthcare professionals with regards to the reporting practices of Adverse Drug Reactions.
Methods A descriptive study conducted at the south-west zonal pharmacovigilance centre of the national programme. All the ADRs reports of the years 2005 and 2006 were first computerized by entering into SPSS and then analyzed on the basis of the patient characteristics, sources of the reports, drug
class implicated causality, body system involved and the seriousness of the ADR. To understand the perspectives of the healthcare professionals involved in pharmacovigilance as well as the national programme, an intemet based e-discussion was caiTied out with the help of an internet based discussion group. A series of specific questions related to the programme were asked and the
participants were asked to respond as per their convenience, knowledge and position. The analysis was done manually; key emerging themes were identified and the interconnections between these themes that emerged were linked to develop a holistic conceptualization of perceptions
Results A total of 6105 ADRs were reported in the years 2005 and 2006 to the south-west zonal centre from the various reporting centres under the programme. The ADRs were mainly reported by the physicians (75.3percent); skin was the most commonly involved system in an ADR (33.2percent) and the anti microbial drugs are most commonly associated with an ADR (40.5percent). 0.9 percent ADRs resulted in death of the patient while 24.4 percent resulted in hospitalization of the patient.
Fourteen healthcare professionals participated in the e-discussion. They have varying perceptions regarding the effectiveness of programme, with the professionals within the programme perceiving that the programme is effective but the effectiveness varies at different levels and the outsiders perceiving that the programme is not effective. However, both are concemed about its sustainability
and they have different suggestions to improve the cuJTent status of the programme.
Conclusion In spite of a gradual increase in ADR reports over the years 2005 and 2006, there is gross under-reporting of ADRs in the national pharmacovigilance programme, the magnitude of which varies across regions. The patterns of the reported ADRs vary with the characteristics of the individuals as well as the characteristics of the drugs and the body systems involved. The need for the proper functioning and sustainability of the programme is recognized by the healthcare professionals.
List of Abbreviations
ADR
AE
AIIMS
BJMC
BCPNN
CDS CO
CIOMS
CME
CNS
cvs DPT
HBV
IGMC
IVRS
KEM
MEAR
NPVP
NSAID
OPV
OTC
SPSS
TB
TT
UMC
WHO
SEARO
Adverse Drug Reaction
Adverse Event
All India Institute of Medical Sciences
Behramji Jijibhoy Medical College
Bayesian Confidence Propagation Neural Network
Central Drug Standard Control Organization
Council for International Organizations of Medical Sciences
Continuing Medical Education
Central Nervous System
Cardio Vascular System
Diphtheria Pertussis Tetanus
Hepatitis B Vaccim~
Indira Gandhi Medical College
Interactive Voice Recording system
King Edward Memorial
Minimum Estimated ADR Reports
National Pharmacovigilance Programme
Non Steroidal Anti Inflammatory Drug
Oral Polio Vaccine
Over The Counter
Statistical Package for Social Science
Tuberculosis
Tetanus Toxoid
Uppsala Monitoring Centre
World Health Organization
South-East Asian Regional Office
Declaration Certificate Acknowledgements Abstract
TABLE OF CONTENTS
List of Abbreviations
Chapter 1
Chapter 2
Chapter 3
Chapter 4
REFERENCES
APPENDIX
INTRODUCTION
Background
Rationale
Literature review
Objectives
Chapterization plan
METHODOLOGY
Study type
Analysis of ADR reports
e-discussion with healthcare professionals
Ethical considerations
RESULTS
Results from quantitative analysis
Results from qualitative analysis.
DISCUSSION
Conclusion
Strengths
Limitations
Recommendations
1
2
4
16
16
17
17
20
22
23
38
44
48
49
50
51
... 52
Chapter 1
INTRODUCTION
1.1.1. Background
India, with a population of over a billion 1 and with a pharmaceutical industry which is
globally ranked as fourth in terms of volume and thirteenth in terms of value2, had its
National Pharmacovigilance Programme (NPVP) launched only recently, towards the end of
the year 2004. 3
With a number of acquisitions (both domestic and overseas), the Indian
pharmaceutical industry is trying to catch up with its global peers. It is estimated that the
Indian pharmaceutical market will triple to US$20 billion by 2015 and move into the world's
top-10 pharmaceuticals market in terms of value.4
The development of any new drug is not only challenging but also an expensive
procedure, as it needs to consider quality, efficacy as well as safety. As far as safety is
concerned, there is a need for efficient post-marketing surveillance system, monitoring and
reporting of Adverse Drug Reactions (ADRs) to the new drug.
ADRs, which are associated with substantial morbidity and mortality, are the 41h-6th
leading causes of death in some of the developed countries.5 One in 16 hospital admissions
are due to ADRs6 and it occurs in 0.3 to 7 percent of all hospital admissions, with incidence
of serious ADRs as high as 6.7 percent.5 The percentage of hospital admissions due to
adverse drug reactions in some countries like Norway, France and UK is more than 11
percent.7
1
ADRs impose a high financial burden due to their high costs and some countries spend up to
15-20 percent of their hospital budget dealing with drug complications.8 However,
susceptibility of adverse reactions differs between the various ethnic groups.9
1.1.2. The National Pharmacovigilance Programme3
The national pharmacovigilance programme was launched on 23rd November 2004. Under
the program 26 peripheral centers, five regional centers and two zonal Centers were
established. The peripheral centers record the ADRs and send to the regional Centers. The
regional centers collate and scrutinize the data received from the Peripheral Centers and
submit to the zonal centers. The north-east zonal centre is located at AIIMS, New Delhi and
the south-west zonal centre is located at KEM hospital, Mumbai. The zonal centers analyze
the data and submit consolidated information to the national pharmacovigilance centre. The
zonal Centre also provides training, general support and coordinates the functioning of the
regional Centers.
1.2. Rationale
Spontaneous ADR reporting is one of the simplest10 and effective methods for monitoring
ADRs. As regards India, the second most populated country with a large pharmaceutical '
industry needs to have a well functioning pharmacovigilance system. In India, ADRs are
responsible for 0.7 percent of the admissions, with one in 25 of the hospitalized patients
experiencing an ADR out of which 1.8 percent has a fatal ADR. 11 About 28-50 percent
ADRs in India are preventable. 12
2
India is one of the 98 countries that are associated with the WHO Programme for
International Drug Monitoring. 13 There are studies showing the well functioning
pharrnacovigilance systems and activities in many countries. 1415 There are no studies from
India conducted to understand the functioning of the National Pharmacovigi1ance
Programme with regards to the estimates of the ADRs reported and the patterns of the
reported ADRs.
1.3. Literature Review
1.3.1. Definitions
A side effect is "any unintended effect of a pharmaceutical product occurnng at doses
normally used in humans which is related to the pharmacological properties of the drug" .16
An adverse drug reaction is "a response to a drug which is noxious and unintended, and
which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of
disease, or for the modification of physiological function" .17
An adverse event (AE) is "any untoward occurrence that may present during treatment with
a pharmaceutical product but which does not necessarily have a causal relation to it" .10
An unexpected adverse reaction is "an adverse reaction, the nature or severity of which is not
consistent with domestic labelling or market authorization, or expected from characteristics
for the drug". 16
3
The terms "adverse reaction" and "adverse effect" are interchangeable, except that the
adverse reaction is seen from the patient point of view and the adverse effect from the point
of view of the drug. 10
A serious adverse effect is "any untoward medical occurrence that at any dose results in
death, requires hospital admission or prolongation of existing hospital stay, results in
persistent or significant disability/incapacity, or is life threatening". 10
Table 1.1 CLASSIFICATION OF ADVERSE DRUG REACTIONS 10
Type of Reaction Mnemonic Features A Dose-related Augmented Common
Related to a pharmacological action of the drug
Predictable Low mortality
B Non-dose-related Bizarre Uncommon Not related to a pharmacological action
of the drug
U npredictab ]e High mortality
c Dose-related& Chronic Uncommon Time-related Related to the cumulative dose
D Time-related Delayed" Uncommon Usually dose-related Occurs/becomes apparent sometime after
the use of the drug E Withdrawal End of use Uncommon
Occurs soon after withdrawal of the drug F Unexpected failure of Failure Common
therapy Dose-related Often caused by drug interactions
4
1.3.2. Causality Assessment of ADRs
It is necessary to find out whether an ADR is due to a particular drug(s). Before performing
the causality assessment, it is necessary to assess the following: 10
1. Temporal association between the use of the drug and the occurrence of the reaction
2. Pattern of the adverse reaction
3. Relevant investigations [for example plasma concentration, biopsies, organ function
tests, etc]
1.3.2.1. World Health Organization-Uppsala Monitoring Centre [WHO-
UMC] Causality Categories18
CERTAIN
A clinical event, including laboratory test abnormality, that occurs in a plausible time
relation to drug administration, and which cannot be explained by concurrent disease or
other drugs or chemicals. The response to withdrawal of the drug (de-challenge) should be
clinically plausible. The event must be definitive pharmacologically or phenomenologically,
using a satisfactory re-challenge procedure if necessary.
PROBABLE/LIKELY
A clinical event, including laboratory test abnormality, with a reasonable time sequence to
administration of the drug, unlikely to be attributed to concurrent disease or other drugs or
chemicals, and which follows a clinically reasonable response on withdrawal (De-challenge).
Re-challenge information is not required to fulfill this definition.
5
POSSIBLE
A clinical event, including laboratory test abnormality, with a reasonable time sequence to
administration of the drug, but which could also be explained by concurrent disease or other
drugs or chemicals. Information on drug withdrawal may be lacking or unclear.
UNLIKELY
A clinical event, including laboratory test abnormality, with a temporal relationship to drug
administration which makes a c~usal relationship improbable, and in which other drugs,
chemicals or underlying disease provide plausible explanations.
CONDITIONAL/ UNCLASSIFIED
A clinical event, including laboratory test abnormality, reported as an adverse reaction, about
which more data is essential for a proper assessment or the additional data are under
examination.
UNASSESSIBLE/ UN CLASSIFIABLE
A report suggesting an adverse reaction that cannot be judged, because information is
insufficient or contradictory and cannot be supplemented or verified.
6
1.3.3. Clinical Trials and ADRs
Clinical trial reports generally fail to provide details of defining and recording of ADRs,
making comparative evaluation of adverse effects rates between trials potentially
unreliable. 19 A minimum of 3000 patients at risk are needed to detect ADR with incidence of
111000 with 95 percent certainty _2
Limitations of most clinical trials in highlighting a drug's safetl1
Homogeneous populations.
Most trials assess relatively healthy patients with only one disease and mostly exclude
specific groups such as pregnant women, children and elderly people.
Sample size.
Small sample size (up to 1,000 patients) reduces the chance of finding rare adverse
effects.
Limited duration.
Trials of short duration preclude the discovery of long-term consequences such as
cancer.
Inability to predict the real world.
Drug interactions can be substantial in a population as patients may take drugs
concomitantly, a situation that can almost never be predicted from clinical trials.
7
1.3.4.1. Monitoring and Reporting of ADRs
"Monitoring, evaluating and communicating drug safety is a public-health activity with
profound implications that depend on the integrity and collective responsibility of all parties
- consumers, health professionals, researchers, academia, media, pharmaceutical industry,
drug regulators, governments and international organizations- working together".22
It was first developed in early 1960s when the possible association between thalidomide and
phocomelia was published by McBride, eventually leading to the withdrawal of thalidomide
from the market.23
Benefits of ADR Monitoring Programme24
An ongoing ADR-monitoring and reporting program can provide benefits to the
organization, pharmacists, other health care professionals, and patients. These benefits
include (but are not limited to) the following:
1. Providing an indirect measure of the quality of pharmaceutical care through
identification of preventable ADRs and anticipatory surveillance for high-risk drugs or
patients.
2. Complementing organizational risk-management activities and efforts to minimize
liability.
3. Assessing the safety of drug therapies, especially recently approved drugs.
4. Measuring ADR incidence.
5. Educating health care professionals and patients about drug effects and increasing their
level of awareness regarding ADRs.
6. Providing quality-assurance screening findings for use m drug-use evaluation
programs.
7. Measuring the economic impact of ADR prevention as manifested through reduced
hospitalization, optimal and economical drug use, and minimized organizational liability.
8
I 1.3.4.2. WHO Programme for International Drug Monitoring25 "The WHO Programme, which was established in 1968, consists of a network of the National Centers, WHO Headquarters, Geneva and the WHO Collaborating Centre for
International Drug Monitoring, the Uppsala Monitoring Centre, in Uppsala, Sweden. Within
the Programme, individual case reports of suspected adverse drug reactions are collected and
stored in a common database, presently containing over 3.7 million case reports.
Functions of the WHO Programme for International Drug Monitoring include:
Identification and analysis of new adverse reaction signals from the case report
information submitted to the National Centers and from them to the WHO
database. A data-mining approach (BCPNN) is used at the UMC to support the
clinical analysis made by a panel of signal reviewers
Provision of the WHO database as a reference source for signal strengthening
and ad hoc investigations. Web-based search facilities and customized services are
available
Information exchange between WHO and National Centers, mainly through
'Vigimed', an e-mail information exchange system
Publication of periodical newslette~s, (WHO Pharmaceuticals Newsletter and
Uppsala Reports), guidelines and books in the pharmacovigilance and risk
management area
Supply of tools for management of clinical information including adverse drug
reaction case reports. The main products are the WHO Drug Dictionary and the
WHO Adverse Reaction Terminology
9
Provision of training and consultancy support to National Centres and countries
establishing pharmacovigilance systems
Computer software for case report management designed to suit the needs of
National Centres (VigiFlow)
Annual meetings for representatives of National Centres at which scientific
and organizational matters are discussed
Methodological research for the development of pharmacovigilance as a
science".
Presently 98 countries are associated with the WHO Programme for International Drug
Monitoring. 13 This includes 96 percent of the high income countries in the Organization for
Economic Cooperation and Development [OECD]?6 However, less than 27 percent of lower
middle income and low income economies have national pharmacovigilance systems
registered with the WHO programme.26
1.3.5.1. Pharmacovigilance
Pharmacovigilance is defined as the detection, assessment and prevention of adverse drug ~
reactions in humans. 27
Major aims of pharmacovigilance28 are:
1. Early detection of hitherto unknown adverse reactions and interactions
2. Detection of increases in frequency of (known) adverse reactions
3. Identification of risk factors and possible mechanisms underlying adverse reactions
4. Estimation of quantitative aspect'S of benefit/risk analysis and dissemination of
Information needed to improve drug prescribing and regulation.
10
';- ~c~, >-
- - --------------"--~
The ultimate goals of pharmacovigilance are:
rational and safe use of medical drugs
. assessment and communication of the risks and benefits of drugs in the market
educating and informing of patients
1.3.5.2. Surveillance methods in pharmacovigilance
The main source of information in pharmacovigilance is by spontaneous reporting28
[voluntary reporting by health professionals I manufacturers of suspected adverse drug
reactions].
Other methods10'29
1. Post-marketing surveillance [Phase IV of clinical drug development]
2. Intensive in-patient monitoring
3. Prescription event monitoring
4. Case reports I Case series
5. Analysis of secular trends
6. Case control studies
7. Cohort studies
8. Randomized controlled trials [RCTs]
9. Record linkage
10. Anecdotal reporting [for example, in journals]
11. Meta-analysis
11
1.3.6.1. Who can report ADRs?
Healthcare professionals (for example doctors, dentists, nurses, and pharmacists) are the
preferred source of information in Pharmacovigilance?8 Even the pharmaceutical
manufacturers need to ensure that suspected adverse reactions to their products are reported
to the competent authority?8 In some countries, even the patients are allowed to report
ADRs.3031 Studies have shown that involvement of patients for reporting of ADRs has more
potential benefits than drawbacks.32 However, in India, only the Doctors, dentists, nurses and
pharmacists are allowed to report ADRs. 3
Though the reporting of adverse drug reactions is voluntary in most countries, in
some countries some legal reporting obligations on healthcare professionals have been
established and in many countries it is mandatory for pharmaceutical companies to report
suspected adverse drug reactions to the health authorities.28
1.3.6.2. Pharmacovigilance in other countries: who is reporting ADRs?
(i) Canada30
In the year 2006 Health Canada received a total of 10,518 domestic ADR reports. The
reports were mainly from the physician [3077 (29.2percent)], followed by patients [2544
(24.2percent)], pharmacists [2396 (22.8percent)], unknown health professionals [1281
(12-fpercent)], and nurses [806 (7.7percent)].
(ii) United States31
In the year 2005, the FDA-Medwatch's Adverse Events Registering System [AERS]
received a total of 326,626 ADR reports.
12
The reports were mainly from the healthcare professionals (41.61percent; 29.77percent by
the physicians and 11.84percent by other healthcare professionals) followed by consumers
(20percent), lawyers (7.65percent) and pharmacists (6.06percent).
(iii)lreland33
In 2005, the Irish Medicines Board (IMB) received a total 1,861 suspected adverse drug
reaction (ADR) reports that occurred in Ireland from healthcare professionals and
pharmaceutical companies. The reports were mainly from the marketing authorization
holders [856( 45.99percent)], general practitioners [322(17 .3percent)], community care
doctors [183(9.83percent)], hospital doctors [152(8.16percent)J, clinical trials
[127(6.82percent)J, nurses [110(5.9lpercent)J hospital pharmacists [60(3.22percent)]
community pharmacists [45(2.41percent)J and the dentists [6(0.3percent)].
(iv) Malaysia34
In 2005, the National Pharmaceutical Control Bureau received 2363 ADR reports. The
reports were mainly from the government doctors [1179 ( 49.89percent)], general
practitioners/private specialists
(25 .64percent) ], pharmaceutical
[153(6.47percent)J
(v) Singapore35
[157(6.64percent)], pharmacists & dentists [606
compames [368 (15.57percent)] and universities
In the year 2005, the Pharmacovigilance Unit of Health Sciences Authority (HSA) received a
total of 1,171 local spontaneous ADR reports. The reports were mainly from health care
professionals from the public hospitals (63.6percent), followed by national specialty
centers/government clinics (16.8percent), private clinics/specialist clinics (7 .7percent),
13
private hospitals (6.5percent), pharmaceutical companies (4.7percent) and community retail
pharmacies (0.6percent).
1.3.7. National Pharmacovigilance Programme
1.3.7.1. Specific aims: 3
contribute to the regulatory assessment of benefit, harm, effectiveness and risk of
medicines, encouraging their safe, rational and more effective (including cost
effective) use
improve patient care and safety in relation to use of medicines and all medical and
paramedical interventions
improve public health and safety in relation to use of medicines
promote understanding, education and clinical training in pharmacovigilance and its
effective communication to the public.
1.3.7.2. Objectives of the National Pharmacovigilance Programme3
Short-term: To foster a culture of notification
Medium-term: To engage several healthcare professionals and NGOs in the drug
monitoring and information dissemination processes.
Long-term: To achieve such operational efficiencies that would make Indian National
Pharmacovigilance Programme a benchmark for global drug monitoring endeavors.
14
Figure 1.1 NATIONAL PHARMACOVIGILANCE NETWORK 3
Pharmacovigilance Centres [Other Countries]
WHO-UMC Uppsala, Sweden
CDSCO India (New Delhi) National Phannacovigilance Centre
Zonal Pharmacovigilance Centre 1 [North-East] AIIMS
Zonal Pharmacovigilance Centre 2 [South-West] KEMMumbai (GS Medical College)
Peripheral Pharmacovigilance Centres (26 in India)
Phannacovigilance Centres [Other Countries]
Doctors Nurses Dentists Pharmacists
In addition to this, there is also ADR reporting at the zonal and the regional centres.
15
I 1.4. Objectives 1. To study the patterns of adverse drug reaction (ADR) reports in the south-west zonal centre of the National Pharmacovigilance Programme.
2. To explore the perspectives of the authorities and healthcare professionals with
regard to the reporting practices of Adverse Drug Reactions (ADRs).
1.5. Chapterization Plan
This dissertation consists of four chapters. The current chapter deals with the introduction to
the study, the rationale the objectives and literature review. Chapter two describes the
methodology used for performing the study. Chapter three deals with the results and findings
of the study and the last chapter deals with the discussion, conclusion, strengths and
limitations of the study and the recommendations.
16
'.--
' J I Chapter 2. Methodology 2.1. Study type
This is a descriptive study designed in two parts
1. Analysis of the ADR reports that have reached the Zonal Pharmacovigilance centre from
west and south India.
2. e-discussion with the healthcare professionals involved in pharmacovigilance.
The methodologies of the two sections have been explained separately.
2.1.1. Analysis of ADR reports
2.1.1.1. Study setting
The South-West zonal pharmacovigilance centre is located at the Department of Clinical
Pharmacology, Seth GS Medical College and KEM Hospital, Mumbai, India. It is also a
"WHO Special Centre for Adverse Drug Reactions Monitoring".36
The Centre, in addition to its own ADR monitoring centre, receives ADR reports from the
three regional centres.
2.1.1.2. Sample
All the ADRs reported in the years 2005 and 2006 and present at the south-west zonal
centre.
2.1.1.3. Data collection techniques.
The following important details/variables were selected from the ADR reporting form
[Appendix 1] of the CDSCO which i~ commonly used by various centres for reporting
ADRs.
17
1. ADR report number: This was done so that the ADR report, if needed later could
be traced/referred later.
2. Event date and report date
3. Year of ADR report
4. Source of the report with reference to the (i) zonal/regional centre, (ii) peripheral
centre, (iii) city/ district and the (iv) state where the reporting centre was located.
5. Patient details with regards to the age and sex
6. Profession of the reporting healthcare personnel
7. Causality of the reported ADR: The causality of the reported ADR is verified and
rectified at the regional or the zonal centre. So the final causality was selected.
8. Seriousness of the ADR
9. Details of the drug(s) that had caused ADR with regards to the brand/generic name,
the class to which it belongs and the route by which it is administered
10. Diagnosis for which the drug was used,
11. The body system which is involved jn the ADR.
The variables were coded with numbers as per convenience depending on the data. For
example, in case of sex of the patient, males were coded as 1 and females as 0. In cases of
body system involved, if more than one system is involved, then it was separately coded as
multi-system involvement. Similarly coding was done for all the other variables. [Appendix
2]
18
The information on the variable was directly entered with the code number into the SPSS
spreadsheet. In case of missing values for a particular variable, no code was entered.
In this way, each of the ADR report was entered in the form of codes and a complete
database of ADRs reported to the south-west zonal centre in the years 2005 and 2006 was
prepared.
2.1.1.4. Study duration
15th June 2007 to 15th September 2007
2.1.1.5. Analysis
The analysis of the data for the years 2005 and 2006 was done using SPSS Version 14. For
some of the variables, the analysis was done for the years 2005 and 2006 separately and for
most of the variables, the two years' combined data was used for analysis. Detailed analysis
was also carried out for certain drugs and age-groups which are associated with a significant
public health importance.
2.1.1.6. MINIMUM ESTIMATED ADR REPORTS [MEAR]
Worldwide, pharmacovigilance studies from various countries have shown that ADRs occur
in 0.3 to 7 percent of all the hospital adrnissions5 A study from India shows that ADRs
occur in 4 percent of the hospitalized patients11
In India the average hospitalization rate per year is 2823 per 100,000 population.37
Considering the minimum value that is 0.3 percent of the hospital admissions, we have
derived the minimum estimated ADR reports [MEAR] for the states as,
MEAR = 0.3 x [Hospitalization rate] x [Population]
19
I 2.1.2. e-discussion with healthcare professionals
The quantitative aspect of this study only gives the information on the number as well as the
pattern of ADRs reported in the NPVP. In order to get an overview regarding the current
status of the NPVP, it is also essential to obtain the views of the healthcare professionals
who are directly or indirectly involved in the programme. This aspect is described in the
following section. The objective here is to explore the perspectives of the authorities and
healthcare professionals with regards to the reporting practices of Adverse Drug Reactions
(ADRs) in the National Pharmacovigilance Programme.
Thee-discussion method was chosen for the fulfilment of this objective. The other possible
options by which this objective could be fulfilled were in-depth interviews and focus group
discussions with the healthcare professionals involved in the programme and who are
located in the city of Mumbai where the whole study was conducted.
As the ADR reporting centres are spread out in different states of the country, it was
essential to include the perspectives in different regions and not Mumbai alone. So an
internet based e-discussion group was contacted for obtaining the perceptions of the various
healthcare professionals with regards to the NPVP. This e-discussion group conducts
discussions on current hot topics and has, since its inception, conducted e-discussions on
more than 27 topics.
20
The members in this e-discussion group are an active group of healthcare professionals from
various states of the country and are mostly pharmacologists, pharmacists, clinicians,
academicians, researchers or students interested in the rational use of medicines. As regards
to pharmacovigilance, the group consists of co-ordinators of various reporting centres, ADR
reporting professionals, pharmacovigilance officers, academicians and also researchers in
pharmacovigilance. The greatest advantage of this method was in getting the information
and perspectives of the healthcare professionals from various parts of the country.
The e-discussion was conducted from 21st to 301h July 2007. The group members were
explained the purpose and the objectives of the study. The consent form was e-mailed to
them and they were asked to participate only if they consented. A series of specific questions
related to the NPVP were asked and the participants were asked to respond as per their
convenience, knowledge and position in the NPVP. The group members who participated
were thanked for their participation and if needed, were asked to justify their answers.
In-case of a low response rate for specific questions, the questions were again put up in order
to remind them to respond. About fourteen people participated in thee-discussion and these
involved the co-ordinators of reporting centres under the NPVP, ex-pharmacovigilance
officer under the NPVP, pharmacologists, ADR reporting professionals, clinicians and
researchers in pharmacovigilance.
21
2.1.2.1. Analysis of Data
All the responses obtained by e-discussion were anonymized for the purpose of analysis.
The responses were then categorized in terms of the questions and the profession (or position
in NPVP) of the participant.
The analysis was carried out under the guidance of an experienced qualitative research
consultant. The complete transcript of thee-discussion was coded independently by both the
researcher and the qualitative research consultant. In cases of disagreement, the two coders
discussed the codes in order to reconcile the disagreement and obtain a set of mutually
agreed upon codes to cover the whole transcript. The developed code list was then linked
carefully to identify various categories that were similar. For example, a series of codes
represented various reasons for declaring the NPVP as ineffective. These were grouped
together under a broad theme of ineffectiveness of NPVP along with the underlying reasons.
Similarly, the other broad themes that emerged from the codes were grouped along with their
underlying reasons. The key emerging themes were identified and the interconnections
between these themes that emerged were linked to develop a holistic conceptualization of
perceptions regarding the healthcare professionals involved in pharmacovigilance.
2.2. Ethical Considerations
The study was approved by the Institutional Ethics Committee of Sree Chitra Tirunal
Institute for Medical Sciences & Technology, Thiruvananthapuram. No direct interviews/
interventions were planned. Permission was taken from the coordinator of the zonal
pharmacovigilance centre, who is also a member of the national pharmacovigilance advisory
committee.
22
Chapter 3. RESULTS
The findings of the study are presented in this chapter. The results will be presented in two
sections.
1. Results from quantitative analysis
2. Results from qualitative analysis.
Fig 3.1 FLOW OF ADR REPORTS TO THE SOUTH-WEST ZONAL
CENTRE
South West Zonal Centre SGS Medical College & KEM Hospital. Mumbai
KEM
Regional Centre 1 Regional Centre 2 Regional Centre 3 Hospital Nair Hospital, Mumbai IGMCNagpur JIPMER Pondicherry
+----{ Pondicherrv .--{ Nair Hosp 4 IGMC J rl Coimbatore
H Ootv
] .
J
J H Wardha J H Annamalai Nagar/Chidambaram . BJMC +--- +{ Karad
J Ahmedabad rl Bangalore ] H Mvsore l H Indore MP ) Karamsad
~ rl J Gujarat Manipal ~ Ujjain MP )
H Kolar J .___ Goa Hindu ~ Jabalpur MP 13 Pharmacy Kochi
The South-West Zonal Pharmacovigilance centre received a total of 6105 ADR reports in the
years 2005 and 2006.
Table 3.1 ADR Reports in 2005 and 2006
I ADR Reports 4254 1851
There is a more than 129 percent increase in the number of ADR reports in 2006 as
compared to 2005. The reports are from the hospital attached to the zonal centre as well as
the three regional centres which in-tum receive ADR reports from the 16 peripheral centres
as well as the regional centre themselves.
Fig 3.2 Quarterly Flow of ADR reports in 2005-06
1400 1333 1328
1200
1000
t 800 ... ~
600 1 ..... 400
200
0
Jan-Mar'OS Apr-Jun'05 Jul-5ep'05 Oct~De~.:'OS Jan-Mar'06 Apr-Jun'06 Jui-Sep'06 Oct-Dec'06
However, there has been a gradual incr~:;tse in the number of ADRs reported over the years
2005 and 2006 ever since the inception of the NPVP in October 2004. (Correlation
coefficient, r = 0.87)
24
3.1.1. SEX-WISE CLASSIFICATION OF THE DATA Out of the 6105 ADR reports, the information on sex was available in 6054 [99.2percent]
reports.
YEAR MALES FEMALES 2005 980 [53.5%] 851 [46.5%] n=1831 2006 2307 [54.6%] 1916 [45.4%] n=4223 TOTAL 3287 [54.3%] 2767 [45.7%] Table 3.2 Sex-wise classification of the data
3.1.2. AGE
The information on age was available for 6040 [98.9percent] reports. The mean age of the
patients was 35.8618.21, which was 36.7318.36 in the year 2005 and 35.4818.14 in the
year 2006. The mean age of the males was 36.0818.57 and that of the females was
35.6517.78.
Fig 3.3 ADRs in different Age-groups 1600 1442
29 3
010 21-30 31-40 4150 SHiO 61-70 71-SO 8190 91-100
Age-group (years)
25
3.1.3. MONTH-WISE REPORTING OF ADRs:
Fig 3.4 Month-wise ADR Reporting 800
-o 700 $ 600 ... 0 0.. 500 4;1 0::
400 "' tX Q 300 oe( J 200 {!, 100
0
~~ ~~ ~;s t:>:> &.;;> ~'I;
'\q; ~{I
Month
3.1.4. SOURCE OF ADR REPORTS
3.1.4.1. With reference to overall reporting centers
There are 20 reporting centres, which send reports to the zonal centre.
Fig 5 Month-wise reporting
"' 20.
i 18 16 Gl 14 u ~ 12 t: 10 & 8 Gl ... 6 ;:; 4. d 2 z
0
I I 17
U\ c 11$ ......
Fig 3.5 Month-wise reporting centres that reported ADRs
8 9
12 13 10
19
Months
However, in the years 2005 and 2006 there was not a single month when all the 20 centres
sent the ADR reports.
26
3.1.4.2. With reference to Regional/Zonal Centres
REGIONAL/ZONAL ADR REPORTS IN ADRREPORTS TOTAL CENTRE 2005 IN 2006 PONDICHERRY 563 [30.4%] 1530 [36%] 2093 [34.3%] NAIR 429 [23.2%] 1153 [27.1%] 1582 [25.9%] IGMC 538 [29.1%] 898 [21.1 %] 1436 [23.5%] KEM 321 [17.3%] 673 [5.8%] 994 [16.3%]
Table 3.3 Total ADR reports from Regional/Zonal Centres
It was found that ADR reporting is mainly from the southern region i.e., from the regional
centre at Pondicherry, which contributed to 34.3 percent of the overall ADR reports and
received ADR reports from the southern states of Karnataka, Tarnilnadu, Pondicherry, and
Kerala. The situation was found to be similar in the years 2005 and 2006 when this centre
contributed to 30.4 percent and 36 percent of the reports respectively.
3.1.4.3. With reference to States
There are 35 states in India.38 The South-west zonal centre received ADR reports from the
eight states of Maharashtra, Karnataka, Gujarat, Tamilnadu, Madhya Pradesh, Kerala,
Pondicherry and Goa in the years 2005 and 2006.All the ADR reports (lOOpercent) had the
information on the state from which the ADRs were reported
STATE ADR REPORTS IN ADR TOTAL 2005 REPORTS IN
2006
Maharashtra 891 [48.1%] 1996 [46.9%] 2887 [47.3%] Karnataka 424 [22.9%] 749 [17.6%] 1173 [19.2%] Gujarat 282 [15.2%] 481 [11.3%] 763 [12.5%] Tamilnadu 94[5.1%] 462 [10.9%] 556[9.1%] Madhya Pradesh 94 [ 5.1%] 125 [ 2.9%} 219 [ 3.6%] Kerala 30 [ 1.6%] 168 [ 3.9%] 198 [ 3.2%] Pondicherry 15 [ 0.8%] 151 [ 3.5%) 166 [ 2.7%] Goa 21 [1.1%] 122 [2.9%] 143 [2.3%] Total 1851 4254 6105
Table 3.4 Total ADR reports from each state
27
';.~ ~ "-~,
------~----~-~---~
Table 3.5 STATE-WISE MINUMUM ESTIMATED ADR REPORTS [MEAR]
ACTUAL No. OfADR REPORTS IN % ofADRs
STATE POPULATION38 MEAR*. 2006 Reported MAHARASHTRA 96,878,627 820465.1 1996 0.24 KARNATAKA 52,850,562 447591.4 749 0.17 KERALA 31,841,374 269664.6 168 0.06 TAMILNADU 62,405,679 528513.7 462 0.09 MADHYAPRADESH 60,348,023 511087.4 125 0.02 GUJARAT 50,671,017 429132.8 481 0.11 PONDICHERRY 974,345 8251.728 151 1.83 GOA 1,347,668 11413.4 122 1.07 TOTAL 357,317,295 3026120 4254 0.14
*MEAR = 0.3 x [Hospitalization rate] x [Population]
This shows that only about 0.14 percent of the estimated ADRs were reported in the year
2006. In terms of absolute numbers, Maharashtra leads with the maximum ADR reports in
2006 but as a proportion to MEAR, Pondicherry leads with the maximum ADRs being
reported.
3.1.4.4. With reference to Cities/Districts
All the ADR reports (lOOpercent) had the information on the city/district from where the
ADR was reported. The ADR reports from the four cities/districts- Mumbai, Nagpur,
Ahmedabad and Mysore contributed to more than 60 percent of the overall ADR reports.
CITY /District ADR REPORTS IN ADR REPORTS IN TOTAL[% ofTotal 2005 [% ofTotal 2006 [% of Total ADRs in years 2005 & ADRs in that year] ADRs in that year] 2006] n=1851 n=4254 n=6105
Mumbai 447 [24.1] 1223 [28.7] 1670 [27.4] Nagpur 387 [20.9] 664 [15.6] 1051 [17.2] Ahmedabad 228 [12.3] .. 384 [ 9.0] 612 [10.0] .q,.~' Mysore 184 [ 9.9] 381 [9.0] 565 [ 9.3] Others 605 [32.7%] 1602 [37.7%] 2207 [36.1%]
Table 3.6 Total ADR reports from City/ District
28
Though the total ADR reports have gone up by over 129 percent in the year 2006, the
proportionate contribution of these cities/districts to the overall ADR reports has remained
more or less the same.
Further analysis excludes ADRs due to unknown drugs.
3.1.5. BRAND NAMES AND GENERIC NAMES
The reporting healthcare professionals have the liberty of writing either the generic name,
brand/trade name or both while filling up the ADR report. It was found that 46.6 percent of
the total ADR reports had only the generic names of the drugs, 20.5 percent reports had only
the brand/trade names and 32.9 percent reports had both - generic as well as brand/trade
names.
T bl 3 7 R rts th b dJ .c/b th a e . epo WI ran rgenen 0 names 2005 n=1831 2006 n=4183 TOTAL n=6014
GENERIC NAME 851 [46.5%] 1952 [46.7%] 2803 [46.6%] BRAND/TRADE NAME 273 [14.9%] 957 [22.9%] 1230 [20.5%] BOTH 707 [38.6%] 1274 [30.5%] 1981 [32.9%]
Though the proportion of healthcare professionals who report the generic names has
remained more or less the same in the two.years, the proportion of healthcare professionals
who report the brand/trade names has gone up by more than 50 percent in 2006.
3.1.6. WHICH HEALTHCARE PROFESSIONALS REPORT ADRs?
As per the National pharmaGovigilance protocol, Doctors, pharmacists, dentists and the
nurses are allowed to report ADRs.3 Profession of the reporter was mentioned in 6011
(99.9percent) reports. It was found that 75,3 percent of the ADRs were reported by Doctors
and 24.6 percent of the ADRs by pharmacists. Only two ADRs were reported by dentists and
three by nurses.
29
T bl 38 ADR a e . f b d f t repor mg ase on pro esswn o repor er 2005 n=1829 2006 n=4182 TOTAL n=6011
Doctor 1553 [84.8%] 2973 [71.1%] 4526 [75.3%] Pharmacist 276 [15.1 %] 1204 [28.8%] 1480 [24.6%] Nurse Nil 3 [0.1 %] 3 [0.0%] Dentist Nil 2 [0.0%] 2 [0.0%]
3.1.7. BODY-SYSTEMS AFFECTED DUE TO ADR
The information on the system involved due to the ADR was available in 6007 [99.9percent]
ADR reports. Skin is the most commonly involved system in an ADR, followed by Gastro-
intestinal system and Central nervous system respectively, and the situation was similar in
2005 and 2006.
T bl 3 9 B d t U t dd t ADR a e . o ty sys em a ec e ue o SYSTEM 2005 n=1828 2006 n=4179 TOTAL n=6007 Skin 636 [34.7%] 1359 [32.5%] 1995 [33.2%] Gastro-Intestinal System 403 [ 22 %] 1041 [24.9%] 1444 [24 %] Central Nervous System 283 [15.5%] 672 [16.1 %] 955 [15.9%] Multi-System Involvement 160 [ 8.7%] 356 [ 8.5%] 516 [8.6%] Others (Cardiovascular, 346 [18.9%] 751 [ 18%] 1097 [18.2%] Renal, Musculoskeletal, Endocrine, Haematological etc)
3.1.8. DRUG CLASS IMPLICATED IN AN ADR
Antimicrobials are most commonly associated with causation of ADRs, followed by CNS
drugs, NSAIDs and CVS drugs respectively and the situation is similar in 2005 and 2006.
2005 n=1831 2006 n=4183 Total n=6014 Antimicrobials 698 [38.1 %] 1739 [41.6%] 2437 [40.5%] Dru~s actin~ on CNS 294 [16.1 %] 649 [15.5%] 943 [15.7%] Non-steroidal anti- 184 [10.0%] 492 [11.8%] 676 [11.2%] inflammatory drugs [NSAIDs] Drugs acting on CVS 142 [ 7.8%] 228 [ 5.5%] 370 [ 6.2%] Other drugs [Steroids, 513 [28.0%] 1075 [25.6%] 1588 [26.4%] Antidiabetics, Haematinics, Antineoplastic drugs, etc. Table 3.10 Drug class implicated in an ADR
30
3.1.9. CAUSALITY ASSESSMENT OF ADRs.
The information on causality was available for 5914 (98.3percent) of the ADR reports. In the
years 2005 and 2006, the information was available for 1766(96.5percent) reports and 4148
(99 .2percent) reports respectively.
The causality assessment of ADRs was done as per the WHO classification and the ADRs
were classified as certain, probable, possible, unlikely, conditional and unclassifiable.
Table 3.11 Causality assessment of ADRs 2005 n=1766 2006 n=4148 Total n=5914
Certain 16 [0.9%] 40 [1.0%] 56 [ 0.9%] Probable 802 [45.4%] 1886 [45.5%] 2688 [45.5%] Possible 880 [49.8%] 2060 [49.7%] 2940 [49.7%] Unlikely 51 [ 2.9%] 106 [2.6%] 157 [ 2.7%] Conditional Nil 26 [0.6%] 26 [0.4%] Unclassifiable 17[1%] 30 [0.7%] 47 [0.8%]
3.1.10. SERIOUSNESS OF ADRs
It was found that only 4486 (74.6percent) of the overall ADR reports had information on the
seriousness of the ADR. The situation was similar in both the years when 1332 (72.7percent)
ADR reports in 2005 and 3154 (75.4percent) ADR reports in 2006 had the information on
the seriousness of ADRs.
Table 3.12 Seriousness of ADRs 2005 n=1332 2006 n=3154 Total n=4486
Hospitalisation-Initial/Prolonged 348 [26.1 %] 745 [23.6%] 1093 [24.4%] Required Intervention to Prevent 82 [ 6.2%] 235 [ 7.5%] 317 [ 7.1%] Permanent Damage/Impairment Life Threatening 29 [ 2.2%] 57 [ 1.8%] 86 [ 1.9%] Disability 11 [ 0.8%] 192[6.1%] 203 [ 4.5%] Death 23 [ 1.7%] 16[0.5%] 39 [ 0.9%] Others - Discomfort/Continuing 839 [63%] 1909 [60.5%] 2748 [61.3%] medication/Recovering/Unknown
31
3.1.11. ROUTES OF ADMINISTRATION AND ADRs
The data regarding route of administration of the drug was available in 5992 (99.6percent)
ADR reports. In the year 2005 the information was available for 1827 (99.8percent) reports
and in the year 2006 for 4165 (99.6percent) reports.
Table 3.13 Route of administration of drug causing ADR 2005 n=1827 2006 n=4165 Total n=5992
Oral Route 1424 [77.9%] 3287 [78.9%] 4711 [78.6%] Intra-Venous Route 265 [14.5%] 619 [14.9%] 884 [14.8%] Intra-Muscular or 75[4.1%] 136 [ 3.3%] 211 [ 3.5%] Subcutaneous
Others (Topical, 63 [3.4%] 123 [2.9%] 186 [ 3.1 %] Inhalational, etc)
Most of the ADRs are caused due to drugs administered by the oral route, followed by
intravenous routes, intramuscular/subcutaneous routes and other routes respectively. The
situation was similar in both the years.
3.1.12. SPECIFIC ADRs
3.1.12.1. ADRs DUE TO DRUGS FROM THE COMPLEMENT ART AND ALTERNATIVE MEDICINE SYSTEMS
The drugs from the complementary and alternative systems of medicine constituted about 59
[!percent] ADR reports. The number of ADR reports due to these drugs more than doubled
from 17 in the year 2005 to 42 in the year 2006. Out of these reports, 52 [88percent] were
due to herbal drugs and 7[12percent] due to homeopathic drugs.
Out ofthe 59 reports, 34 [57.6percent] were among the females.
The mean age of these individuals [40.2216.26] was higher than the overall data
[35.8618.21].
All the Zonal/Regional centres and most of the states except Pondicherry and Madhya
Pradesh had reported atleast one ADR due to these drugs.
32
Skin was the most commonly involved system [23 cases (39percent)] followed by the
Gastro-Intestinal Tract [20 cases (33.9percent)].
In 56 [94.9percent] cases, the drug was administered by the oral route.
In terms of causality, 28 [47.5percent] of these ADRs were probable ADRs followed by 27
[45.8percent] possible ADRs.
In terms of seriousness, 9 [16.7percent] ADRs resulted in hospitalization (initial/prolonged)
of the patient and one patient [1.9percent] had a life-threatening complication. 2 [3.7percent]
patients required intervention to prevent permanent impairment/damage However, there
were no deaths reported due to these drugs.
3.1.12.2. ADRs DUE TO ANTITUBERCULAR DRUGS
The ADRs due to anti tubercular drugs contributed to 383 [6.4percent] reports. The number
of reports due to these drugs increased from 105 in the year 2005 to 278 in the year 2006.
Out of these reports, 207 [54percent] were of males. The mean age of these individuals
[34.7815.75] was similar to the overall data [35.8618.21]. All the Zonal/Regional centres
had reported ADRs due to Anti-TB drugs. 246 [64.2percent] of thes~ cases were reported
from the Maharashtra state, followed by Karnataka with 54[14.1percent] reports.
Gastro-Intestinal Tract was the most commonly involved system [219 cases (57.2percent)]
followed by the skin [76 cases (19.8percent)]; 371 [96.9percent] repo~s were due to oral
anti-TB drugs.
Causality assessment was available for 373 [97 .4percent] reports, out of which
206[55.2percent] were possible and 149 [39.9percent] were probable.
33
The seriousness of the ADRs was available for 285 [74.4percent] reports. There were 7
[2.5percent] ADR deaths due to Anti-TB dmgs. 140[49.1percent] ADRs resulted in
hospitalization (initial/prolonged) and 6[2.1 percent] had a life threatening complication.
18[6.3percent] patients required intervention to prevent permanent impairment/damage.
3.1.12.3. ADRs DUE TO ANTI-RETROVIRAL DRUGS
The ADRs due to anti retroviral drugs contributed to 162 [2.7percent] reports. The number
of reports due to these dmgs more than quadmpled from 32 in the year 2005 to 130 in the
year 2006. Out of these reports, 106 [65.8percent] were of males. The mean age of these
individuals [36.859.02] was similar to the overall data [35.8618.21].
All the Zonal/Regional centres had reported ADRs due to antiretroviral dmgs. 92
[56.8percent] of these cases were reported from the Gujarat state, followed by Maharashtra
with 55[34percent] reports. There were only 9[1.6] reports from Karnataka and 1 [0.6percent]
report from Tamilnadu.
Skin was the most commonly involved system [62 cases (38.3percent)] followed by the
Central Nervous System [36 cases (22.2percent)] and the Gastro-Intestinal Tract [27 cases
(17 .9percent)]
Causality assessment was available for 157 [96.9percent] reports, out of which
107[68.2percent] were possible and 26 [29.3percent] were probable.
The seriousness of the ADRs was available for 158 [98.1percent] reports. 22[13.8percent]
ADRs resulted in hospitalization (initial/prolonged) and 5[3.1 percent] had a life threatening
complication. 5[3.1 percent] patients required intervention to prevent permanent
impairment/damage. There were no ADR deaths reported due to anti retroviral drugs.
34
3.1.12.4. ADRs DUE TO ANTICANCER DRUGS
The ADRs due to anticancer drugs contributed to 209 [3.4percent] reports. The number of
reports due to these drugs increased from 74 in the year 2005 to 135 in the year 2006. Out of
these reports, 113 [54.3percent] were of females. The mean age of these individuals
[45.1517.53] was higher than the overall data [35.8618.21].
All the Zonal/Regional centres had reported ADRs due to anticancer drugs. Out of these
reports, 87 [41.6percent] were from the Maharashtra state, followed by Karnataka with
63 [30.1 percent] reports and Kerala with 29[13.9percent] reports.
Gastro-Intestinal Tract was the most commonly involved system [60 cases (28.8percent)]
followed by the haematological system [51 cases (24.5percent)] and the skin [40 cases
(19.2percent)]. The route of administration of the drug was available in 206 [98.6percent]
reports. 175[85percent] of the ADRs were due to intravenously administered anticancer
drugs, followed by the oral route with 23[11.2percent] reports.
Causality assessment was available for 208 [99.5percent] reports, out of which
125[60.1percent] were possible and 78 [37.5percent] were probable.
The seriousness of the ADRs was available for 173 [82.8percent] reports. 35[20.2percent]
ADRs resulted in hospitalization (initial/prolonged) and 2[1.2percent] had a life threatening
complication. 13[7 .5percent] patients required intervention to prevent permanent
impairment/damage. There were no ADR deaths reported due to anticancer drugs.
3.1.12.5. ADRs DUE TO V ACCINES/SERAffOXOIDS
The ADRs due to vaccines/sera/toxoids.
Table 3.14 ADRs due to vaccines/sera/toxoid VACCINE/SERUM/TOXOID TOTALADRs Anti-Snake Venom 42 [60percent ] DPT/OPV /HBV 22 [31.4percent] Inj.TT 3 [ 4.2percent] Anti Diphtheric Serum 2 [ 2.9percent] Anti Gas Gangrene Serum 1 [ 1.4percent]
Out of these reports, 46 [65.7percent] were of males. The mean age of these individuals
[20.1318.1] was lesser than the overall data [35.8618.21].
All the Zonal/Regional centres had reported . ADRs due to vaccines/seraltoxoids. 35
[50percent] of these cases were reported from the Maharashtra state, followed by
Pondicherry with 12[17.1percent] reports and Kamataka with 9[12.9percent} reports.
Skin was the most commonly involved system [24 cases (34.3percent)] followed by the
central nervous system [23 cases (32.9percent)].
The route of administration of the drug was available in 70 [1 OOpercent] reports.
45[64.3percent] of the ADRs were due to intravenously administered ones, followed by the
intramuscular route with 21 [30percent] reports.
Causality assessment was available for 57 [81.4percent] reports, out of which
25[43.9percent] were probable and 24 [42.1percent] were possible. ~
The information on seriousness of the ADRs was available for 57 [81.4percent] reports.
There were 3[5.3percent] deaths due to administration of Anti-Snake venom. Also,
21 [36.8percent] ADRs resulted in hospitalization (initial/prolonged) and 7[12.3percent] had
a life threatening complication. 10[17.5percent] patients required intervention to prevent
permanent impairment/ damage.
36
3.1.12.6. ADRs IN UNDER-5 AGEGROUP .
The ADRs in the under-5 age group children contributed to 225 [3.7percent] reports. The
number of reports due to these drugs more than tripled from 54 in the year 2005 to 171 in the
year 2006.
Out of these reports, 140 [62.8percent] were of males. The mean age of these children
was 2.031.35 years. All the Zonal/Regional centres had reported ADRs in the under-5
children. 124 [55.1percent] of these cases were reported from the Maharashtra state,
followed by Karnataka with 47[20.9percent] reports. The anti-microbial drugs were
responsible for majority of ADRs [116 (51.6percent)] followed by the drugs acting on the
central nervous system [28(12.4percent)] and the vaccines/sera [23(10.2)].
Skin was the most commonly involved system [104 cases (46.4percent)] followed by
the Central Nervous System [36 cases (16.1percent)] and the Gastro-Intestinal Tract [35
cases (15.6percent)] Causality assessment was available for 199 [88.4percent] reports, out of
which 102[51.3percent] were possible and 86 [38.2percent] were probable.
The seriousness of the ADRs was available for 193 [85.8percent] reports. It was found that
5[2.6percent] ADRs resulted in the death of the child, 75[38.9percent] ADRs resulted in
hospitalization (initial/prolonged) and 4[2.1percent] had a life threatening complication and
13[6.7percent] children required intervention to prevent permanent impairment/damage.
37
3.2. RESULTS OF QUALITATIVE ANALYSIS
3.2.1.Current status of the NPVP
The participants in the e-discussion included the professionals involved in the NPVP as well
as the professionals outside the programme. Two clear strands with regard to the perceptions
emerged. Those not engaged with the NPVP perceived the programme to be ineffective
while those within the NPVP were more tolerant to its functioning. In general, those not
involved in the programme had an opinion that the NPVP is not effective. The insiders felt
that the programme is effective but the effectiveness varied across the institutions. However
both the groups had concerns about the sustainability of the NPVP. Thus these were the first
key themes identified.
NPVP NOT B"'f"B:J1VE
CX)N(E=NS AB:YJT SJSfAJNABIUlY a= "THE PR.:.X?RA.M ME
INSDER3 PEHE"'IIONS
VARYING B'"t"BB:ffV8'U:e3 OF NPVP
WAYS OF
IMPFOVING THE
SfATUS OF NPVP
FIG 3.6 PERCEPTIONS OF HEAL THCARE PROFESSIONALS ABOUT NPVP
38
,''
NPVP seen as ineffective [Outsider's perceptions]: The reasons for ineffectiveness
include lack of awareness about the programme, inadequate training and IEC activities,
absence of pharmacovigilance departments in most of the pharmaceutical companies,
inadequate supply of ADR forms and absence of reporting from the lower levels of the
health system and the independent healthcare providers.
NPVP seen as having varying effectiveness [Insider's perceptions]: The effectiveness of
NPVP varies across the various levels of healthcare units, which is mainly due to the poor
commitment at different levels, lack of involvement of independent healthcare providers and
the lack of reporting mechanisms at the primary and the secondary levels of healthcare
system.
3.2.2.Under-reporting of ADRs
Presently, the reporting of ADRs is inadequate mainly due to the lack of awareness
regarding NPVP, lack of commitment, lack of training and a shortage or absence of ADR
forms. There is an absence of a voluntary mporting culture. There were also situations when
ADRs were reported as caused due to poor quality of the drugs.
The ability to meet the targets for the reported ADRs is lacking and there is no mechanism
to check the validity of the reported ADRs, which is worsened, by a poor fo1low-up
mechanism. The ADR forms are not user friendly with problems of inadequate spacing and
absence of a logical sequencing.
There is an absence of a general reporting culture and a fear of legal implications and other
bad consequences due to reporting.
39
There is a lack of appreciation for reporting ADRs at every level of the healthcare system.
Reporting is not the responsibility of a specific person and there is a shortage of staff, time
and funds as well as delay in funding by the CDSCO especially with regards to the salaries
of the pharmacovigilance officers at the respective centres.
"Reasons are many, but the main reason is the apathy of the prescribers and lack of
.awareness about pharmacovigilance. The situation is similar as promoting rational use of
medicines. What the academics talk, most prescribers are not able to appreciate. It's only a
momentary motivation that is soon lost in the rigors of patient care and other influences.
Only a few committed ones are able to respond with the necessary enthusiasm and
commitment".
. ............... ... Pharmacologist cum ADR reporting professional
"Apathy, callousness, indifference, let-go attitude, unawareness, lack of zeal !missionary
spirit, lack of appreciation and reward for. good work, insensitive professionals, over work,
less staff, other pressing work, fear of legal involvement after reporting, etc. "
............... Senior Professor cum Pharmacologist
3.2.3. Sustainability of NPVP
Concerns regarding sustainability were reported by both the groups; those within the NPVP
and those outside the NPVP. These related to the need for second-line researchers becoming
involved in the programme. The lack of adequate number of reporting centres, lack of funds
and staff at the reporting centres and poor feedback mechanisms could affect the
sustainability of the programme.
40
"The salary is the biggest problem in the NPVP. The CDSCO pays Rs. 15,000 per month to
the Pharmacovigilance officer employed but the salary never reaches at right time.
Sometimes it takes around 6 months to get your salary in hand. There is need
for improvement in this aspect and at least for those who complete 1 year, the salary should
be increased. "
....... ex-Pharmacovigilance officer at a reporting centre
3.2.4. Improving the current status of NPVP
By way of improving the functioning of the NPVP and also giving it a better chance to
sustain itself, these were several suggestions for improvement:
1. Mandatory ADR reporting: ADR reporting should be made mandatory and there
should be mechanisms to monitor the reporting with regards to the quality of reports.
2. More ADR reporting centres: There should also be an increase in the number of
peripheral reporting centres.
3. Involving the professional bodies, media and publishers: In order to sustain the
NPVP, it is necessary to involve the various professional bodies and engage the
second-line researchers in pharmacovigilance. It is essential to analyze and publish
the ADR reports through the use of media and publishing houses. The information
needs to be disseminated to the various professional bodies of Medicine, Dentistry,
Nursing and Pharmacy.
4. Training the healthcare professionals: The healthcare professionals need to be
trained regularly with the help of CMEs and single page pulls should be distributed
regularly to them, which will serve as a feedback mechanism and also keep them
41
updated about ADRs. It IS also essential to train the independent healthcare
providers.
5. Imparting pharmacovigilance education to undergraduates: Pharmacovigilance
should be included in the undergraduate curriculum of the medical and allied fields.
The students should be taught how to report ADRs through practical training with the
use of simulated cases.
6. Enhancing the logistics: ADR reporting can be improved by enhancing the logistics
related to the availability of the ADR forms at all levels of the healthcare system.
7. Networking of professionals: There is a need for networking of the professionals
involved in pharmacovigilance which includes the researchers as well as experts in
this field.
8. Pharmacovigilance in tertiary hospitals and pharmaceutical companies: There is
a need for ADR monitoring activities in large tertiary care hospitals. There should be
an ongoing prescription event monitoring by the pharmaceutical companies for
estimating the ADRs.
9. Use of modern techniques: Modern techniques such as Interactive Voice Recording
Systems (IVRS) should be used for monitoring of ADRs.
10. Inclusion of Pharmacovigilance in the National Public Health Programmes:
Though the inclusion of pharmacovigilance in the National Public Health
Programmes will improve the scope for increasing awareness regarding NPVP, there
is a need for a competent authority for implementing the programme.
42
11. Involving the complementary and alternative medicine systems in NPVP: There
were two views regarding the inclusion of complementary and alternative medicine
systems in the NPVP. Firstly there is a need to respect these systems and secondly
increasing the awareness among the consumers/patients regarding the misconception
that these medicines are always safe and never cause any adverse reactions.
12. Patient involvement in ADR reporting: There is a need for patient involvement in
reporting ADRs which will minimize their exploitation to a great extent and thus
empower them.
"Having given them equal status, start involving them also. They have been neglected
so long so need more care and gentle incorporation so that resistance does not build up.
Unless the masses are educated, enlightened and informed, they cannot be empowered. If the
patients are considered as guinea pigs and have no power of sharing the decision making
about their own disease, expecting them to report the ADRs is far fetched.
Understand the scenario. It is patient's disease, suffering, loss of productivity. In India
most of the patients pay out of the pocket for getting medical treat1nent. Yet if they are made "
to suffer the ''preventable" ADRs, there is no accountability of therapeutic management; it is
sheer exploitation of patients. Just because the patients are not organized, they are at the
receiving end."
............... Senior Professor cum Pharmacologist
43
Chapter 4
4.1. Discussion
This is the first study of its kind on the reporting patterns of ADRs in the NPVP. However as
it has been only three years since the launch of the programme, it becomes too early to
decide whether the programme has been successful or not. Though there has been a gradual
increase in the number of ADR reports over a period of time, there is gross under-reporting
of ADRs in India when compared to the other countries.
Table 4.1 COUNTRY WISE ANNUAL ADR REPORTS PER MILLION POPULATION 30,3t,33-3540
COUNTRY POPULATIONj, ANNUALADR ADRREPORTS REPORTS PER MILLION
POPULATION United States 303,004,000 326,626 1077.96 Ireland 4,301,000 1861 432.69 UK 60,587,300 20,000 330.1 Canada 33,041,100 10,518 318.33 Singapore 4,436,000 1171 263.98 Malaysia 27,278,100 2363 86.63 India 1,169,016,000 13,918"' 11.91
* Total ADR reports standardized for the population
The ADR reporting rate varies across different states. There is ADR reporting from all the
southern states except from the state of Andhra Pradesh; which must have been intentionally
kept out of the programme for the reasons not known. It can be expected that the state of
Kerala with such a huge per capita expenditure on the drugs41 needs to report more number
of ADRs. But this is not possible with only one reporting centre at Kochi, which is expected ... ---
to cater to the whole state of Kerala. There is a need for more and well functioning reporting
centers across the various states if we need to improve the overall ADR reporting rates.
44
The ADR reporting by the physicians is very high in India [75.3percent] as compared to the
other countries where the physicians contribute to 30-50 percent of the ADR reports.30313334
Even in a hospital based study from India it was found that 64.6 percent of the ADRs are
identified and reported by physicians and nurses.42 In India, the dentists and the nurses who
are also supposed to contribute to the overall reporting are hardly reporting any ADRs. It is
therefore necessary to involve the professional bodies of nursing and dentistry and there
should be activities to improve the awareness regarding the detection and reporting of
ADRs. The healthcare professionals need to be trained by experienced professionals in
pharmacovigilance through CMEs and regular distribution of single page pull-outs on
ADRs. A study from Portugal has shown that a targeted educational intervention improves
the quality of ADR reporting among the healthcare professionals.43
It is important to give feedback to the reporting professionals and the reporting centres at
every level of the national pharmacovigilance system. A properly given feedback influences
the reporting of ADRs by the healthcare professionals.44
In this study ADRs were found to be common in the 21-50 year age-groups. It can be
expected that the drug consumption is higher in the extreme age-groups and hence the
proportion of ADRs in the extreme age-groups should be higher than in the middle aged
people. It is possible that the ADRs in the children and the old people are not being reported.
Studies have shown that children constitute a vulnerable group to ADRs since a new drug
gets released to the market without the benefit of even limited experience in them.45
45
Anti-microbials are most commonly associated with an ADR, responsible for 40.5 percent of
the reports. This is in-line with other studies from India that have shown that the
antimicrobials are most commonly associated with ADRs, responsible for more than 36
percent of the overall ADRs reported. 11 42 This can be expected in India where the anti-
microbials constitute 21.8 percent, the highest of the overall market share of all the drugs.41
In this study, skin was found to be the most commonly involved system. This is in-line with
studies that show that skin ADRs affect more than two percent of the hospital admissions46;
antimicrobials being most commonly associated with the skin ADRs.4647 With Anti-
microbials being responsible for more that 40 percent of the ADRs in this study, this can be
expected.
ADRs due to anti Tb drugs constituted 6.4 percent of the reports, commonly involving the
gastrointestinal system [57.2 percent] with 2.5 percent ADRs resulting in death of the
subjects. In one of the studies from India, Anti-Tb drugs contributed to over 11 percent of
th~ overall ADRs reported. 11 In a study from Iran it was seen that ADRs occur in 53 percent
of the patients who are on anti-Tb drugs; the gastrointestinal system being the most
commonly involved system in 58 percent cases and the ADRs were responsible for the death
of 2.5 percent of the cases.48 As India has the highest incidence of Tb cases in the world49, it
is necessary to specially conduct the post-marketing surveillance of anti Tb drugs.
46
We found that 1.2 percent of the ADRs were due to vaccines/seraltoxoids, out of which more
than 30 percent of the ADRs were as a result of the routine immunization procedures in the
children. There were three deaths and 21 hospitalizations due to vaccines/seraltoxoids. This
is contrary to the common belief that vaccines are completely safe and effective. Hence there
is a need for monitoring ADRs in the national immunization programmes. A study from
France shows that the post-marketing surveillance of vaccines allows the detection of
possible rare and serious effects and for evaluating the real vaccination risk. However, it
must be intensive and systematic.50
On the basis of causality, most of the ADRs were found to be possible (49.7percent) or
probable (45.5percent). This finding is consistent with another study from India where 52.3
percent ADRs were found to be possible and 46.2 percent found to be probable.42 A lot of
vital information could not be captured due to incomplete filling of the ADR forms by the
healthcare professionals. Good data quality management in pharmacovigilance benefits the
whole pharmacovigilance system and it can reduce the negative impact of incomplete ADR
reports to a great extent. 51
An attitudinal survey conducted among the medical practitioners in Netherlands52 to study
the reasons for not reporting ADRs showed that 18 percent of the practitioners were not
aware of the need for reporting ADRs and 22 percent did not know how to report ADRs.
The reasons given for non or under-reporting of ADRs in India were similar to the studies
conducted in various countries 52-54, where the most common reasons include lack of
awareness of proper reporting procedure, clinical negligibility of the reactions and the ADR
being too well known.
47
The suggestions given by the healthcare professionals for improving the situation of the
programme were similar to that of a study conducted in ltaly53 and China54 where the
suggestions included the inclusion of pharmacovigilance in the academics, provision of
guidelines for ADR spontaneous reporting and of feed-back information to the reporters.
In India, the attitudes regarding NPVP are indicative that atleast amongst the net savvy
professionals, the need for effective pharmacovigilance is recognized in spite of the resource
crunches to the personnel working under the programme. However, our study shows that in
India, there are concerns that the NPVP should not degenerate into another "Paper
programme" of the Government. Therefore the requirement is that the NPVP should be
expanded but carefully.
4.2. Conclusion
1. There is a gradual increase in the ADR reports in the years 2005 and 2006, though it
is too early to say unless the upward trend continues in the future.
2. Overall, low proportions of the estimated ADRs are getting reported.
3. Antimicrobials are the most commonly associated with ADRs.
4. Low awareness among the healthcare professionals about the NPVP is perceived as
the main cause of under-reporting of ADRs.
5. Nurses and the dentists are hardly reporting any ADRs.
6. There are problems due to shortage of ADR forms and due to incomplete filling of
ADRforms.
7. There is low reporting of ADRs among the people of the extreme age groups
(children and the old).
48
8. The need for the proper functioning and sustainability of the NPVP is recognized by
the healthcare professionals.
9. There is a general resource crunch reflecting among the personnel working under the
NPVP.
10. The current status of the NPVP can be improved by commitment of the healthcare
professionals as well as the authorities at every level of the healthcare system of
India.
4.3.1. Strengths of the study
1. One among the few studies on pharmacovigilance in India and perhaps the first one
on the reporting patterns of ADRs in the NPVP.
2. A 'beginning' for creation of a computerized database of ADRs in the NPVP.
3. Use of an internet based method [e-discussion] for exploring the perspectives of the
healthcare professionals directly or indirectly associated with NPVP and who are
located in various parts of the country.
49
4.3.2. Limitations of the study
1. Denominator: Absence of the estimates of the exact numbers of ADRs occurring
every year in India, making it difficult to compare the actual yearly ADR numbers
though attempts were made using the estimates of MEAR [Mean estimated ADR
reports] for the states.
2. Availability of ADR reports: Only the ADR reports that have reached and
maintained by the zonal centre were analyzed as there may be some reports, that have
not reached the zonal centre mainly due to the problems of logistics with regards to
the transportation of ADR forms from various levels of the reporting system.
3. Validity of ADR reports: The available ADR reports could not be validated as
regards the quality of the information and reliability and the data was entered
assuming that the information was valid.
4. Generalizability of data: Due to non-availability of the ADR data from the
other zonal centre [North-east], theavailable results cannot be generalized as for the
whole country.
5. Potential important information on some variables [for example, seriousness of
ADR] could not be captured completely due to incomplete filling ofADR forms by
the healthcare professionals.
6. e-discussion: It is possible that another e-discussion group may have other ideas,
but these recommendations seems indicative of a deep understanding of the systems
and drugs; therefore, possible validity of the findings.
50
4.4. Recommendations
1. Efforts should be taken to improve the awareness among the healthcare professionals
about the programme and there should be a dedicated and competent governing
authority at each level of the programme
2. There should be proper management of resources under the programme and efforts
should be made by the higher centres to manage the data.
3. The number of the ADR reporting centres across the country should be increased and
the logistics of the ADR reporting forms should be improved in order to make them
available at all the reporting centres. Modern and user friendly techniques for ADR
reporting [for example, IVRS] should be adopted in order to increase the magnitude
of reports
4. ADR reporting should be made mandatory. It is the professional duty of all the
healthcare professionals to report all suspected ADRs which they come across during
their practice. However, they also need to fill each ADR report relevant information
legibly and completely in order to ensure quality of reporting
5. India should contribute significantly to the WHO programme for International drug
monitoring and there is a need for an online database of the country wide ADRs
There is need for more studies on pharmacovigilance from India and it is necessary to
study the awareness, patterns and cu},ture of ADR reporting at the other regions that were
not covered under this study.
51
. --- .. " ~ -- -----------------~-~-~-~
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