Issues in Reporting Adverse Drug Reactions (ADRs)

India is becoming a hub in the field of clinical research and a center for drug discovery and development and this advancement has created an urgent need to strengthen the current drug safety measures. Pharmacovigilance has emerged as an important field of science related to activities regarding detection, assessment, understanding detection and prevention of adverse drug reactions (ADRs) and other drug related issues. The current pharmacovigilance system is not fully able to address these issues because of certain “challenges” being posed to it. While major advancements of the discipline of pharmacovigilance have taken place in the West, not much has been achieved in India. Some of the important challenges to our existing pharmacovigilance activities are: under-reporting, lack of knowledge, proper training, education, attitude and motivation, confusion regarding terminology and definitions used in pharmacovigilance. Increasing use of biologics and herbal medicines in current medicine practice further pose challenges to our pharmacovigilance systems. There is lack of information about the active principle, efficacy, adverse effect profile, quality assurance/quality control, informal selling & interaction potential in case of herbal drugs. On the other hand, a complex production process, limited predictability of preclinical to clinical data, high potential for immunogenicity & possibility of an underlying exaggerated pharmacology in case of biologics further grieve the situation. Also there is need to improve the spontaneous reporting and causality assessment scales with high quality data submission.

KEY WORDS: Pharmacovigilance, India, ADRs, AEs, Challenges

INTRODUCTION

India is an emerging hub in the field of clinical research and a destination for drug discovery and development. Several new drug entities, new dosage forms, vaccines etc. are being introduced in the country challenging the monitoring of adverse drug reactions over a large population base. The monitoring of both known and unknown side effects of medicines is important even if the drug is in use for several years so that the safety profile of the drug can be ascertained. This has paved the way for pharmacovigilance. Pharmacovigilance may be defined as the pharmacological science relating to the detection, assessment, understanding and prevention of adverse drug reactions or any other possible drug related problems (1), particularly long term and short term side effects of medicines. While major advancements of the discipline of pharmacovigilance have taken place in the West, not much has been achieved in India. Although in India, pharmacovigilance has progressed from the situation as it was in past, but for different types of problems and limitations progress is yet not very rapid. (2)

The current review focuses on a number of elusive issues which require attention & addressal:

Under-reporting: India specific causes & possible solutions

Under-reporting is a major limitation of spontaneous reporting systems for suspected adverse drug reactions (ADRs) in India. It is both a technical and a psychological issue. Under-reporting may lead to failure to recognize an unacceptable risk associated with a particular drug. Furthermore, differences in reporting between different drugs may lead to apparent differences in the toxicity which may be spurious. It can lead to delay in signal detection and underestimation of the magnitude of the problem.

There is a long & exhaustive list focusing on the causes of under-reporting:

Lack of awareness

There is a general lack of awareness among health care professionals in terms of increasing health burden of ADRs. Those who are aware of this fact, fail to recognize the logistics of ADR reporting like who all can report, where to report & what to report.

Lack of knowledge & attitude

A large proportion of studies have found that the knowledge and attitudes of health care professionals appear to be strongly related with reporting. This result may have important implications in terms of public health, if knowledge and attitude are viewed as potentially modifiable factors. (5, 6)

Lack of motivation

Due to the passive nature of collection of reports, data collection is not exhaustive as it depends upon the attitude & motivation of the clinicians. Hence, some ADRs even if observed are not likely to be reported. Some feel that reporting a single ADR wont help much in contributing!

Fear of litigation & loss of reputation

Sometimes healthcare professionals fear that the acknowledgement of adverse reactions may reflect negatively on their competence or put them at risk of litigation. There is also a general fear of loss of reputation among the medical fraternity & patients.

Misconceptions about what to report

Some are reluctant to report adverse reactions because of doubts regarding the causal role of the drug. There is a uncertainity in majority of the cases regarding the drug causing the particular adverse drug reaction.

Unfriendly ADR reporting forms & hassel of posting of the forms

Some health care professionals fail to report due to the complexity of ADR reporting form. At any given instance of time all the information required to be filled is not available. Even after filling the form still there remains a hassel of posting of the forms. So, one always prefers to stay away from the problem. At times, difficulties in accessing the forms also contribute.

Lack of time to report

Excessive patient load in the health care set up in a developing country like India further worsen the situation.

The other factors which contribute towards under-reporting include hesitation & lack of confidence.

Correcting for under-reporting is difficult because the exact magnitude of under reporting is unknown. It has been seen that more number of ADRs are reported spontaneously usually after a reminder or following scientific workshops, conferences or other awareness programs and it decreases gradually over a period of time. So sustainability is an important factor for determining the spontaneous reporting of ADRs. (3) In addition, it has been found that serious, unexpected ADRs & those associated with newly marketed drugs are more likely to be reported.

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Easy access to ADR reporting forms, clarity of criteria for reporting, simple procedures and good motivational practices such as acknowledging the receipt of adverse drug reaction reports by personal letter or phone call, providing feedback to reporters in the form of articles in journals, adverse drug reaction bulletins or newsletters, organizing scientific workshops, trainings at regular intervals are all influential in addressing the problem. The periodic e-mail update on the safety of drugs represents an effective and inexpensive way to raise the awareness of clinicians on the importance of spontaneous ADR reporting. For continuous motivation there appears to be a need to adopt a policy of regular updates and educational strategies for health professionals. (4)

There is an urgent need for regular training of all health care personnel in the form of workshops, symposiums & scientific meetings. The training sessions must clarify the roles of the various healthcare professionals in pharmacovigilance. There should be closer relationship between the doctors and the pharmacovigilance centre’s. The paramedical staff should also be equally trained since they are in closer contact with the patients for a longer duration and can play an important role in making the pharmacovigilance programs more efficacious. Information analysis of the reported material is a highly specialized and complex job. It should be made as simple as possible by the use of appropriately trained staff, so that one may be able to provide an answer with greater certainty. Causality assessment scales are an example where there is need of improvement so that proper causal relationship between the drug and the adverse effect can be established. Appropriate training and education regarding Pharmacovigilance should also be introduced during the formal teaching of medical graduates as a welcome step. Unfortunately, this activity is missing in our existing medical education system. Though we are now involving many of the medical colleges as Pharmacovigilance centre’s but still most of the undergraduates are unaware of this process. (7) The reporting of adverse reactions needs continuous stimulation. Therefore, it seems necessary to hold awareness programmes at regular intervals to improve the ADR reporting. It is important to achieve the development of a positive attitude towards pharmacovigilance among healthcare professionals so that adverse reaction reporting becomes an accepted culture in India.

Vaccine Safety/Pharmacovigilance

The goal of pharmacovigilance of vaccines is the early detection and timely response to adverse events following immunization, in order to minimize negative effects to the health of individuals and lessen the potential negative impact on immunization of population. A stringent safety surveillance of vaccines is crucial since the majority of vaccines are administered not only to vulnerable children but also to healthy population. Moreover, vaccines are complex biological products, which may include multiple antigens, live organisms, adjuvants, and preservatives which can be responsible for the ADRs. e.g. lymphocyte meningitis after anti-mumps vaccine. (8) So, each component has unique safety implications, which is important to capture as compared to other drugs. (9) In addition, difficulties in causality assessment in case of vaccines makes the situation more worse. (10, 11)

Execution of Adverse Event Following immunization (AEFI) surveillance program in India is a challenge taking into account its large geographical area. Capacity to detect & respond to AEFIs needs improvement in India. A multipronged approach is the need of the hour to ensure effective vaccine safety surveillance.

Pharmacovigilance in clinical trials: A newer approach to patient safety in clinical trials

Safety monitoring of drugs during clinical trials is now recognized as one of the major concerns for new drug development due to the increasing complexity of clinical trials & involvement of large cohorts of participants. In a clinical trial, all adverse events experienced, irrespective of the causality should be monitored, accurately documented and adequately reported in a timely manner following the local regulatory requirements. Safety data from clinical studies is a key component that drug regulatory authorities consider in the decision-making as to whether to grant or deny market authorization for a drug. In addition, safety data from clinical trials helps not only in restricting harm at one centre but provides further vigilant action at other centres also. As per recent gazette notifications, Any unexpected serious adverse event (SAE) (as defined in GCP Guidelines) occurring during a clinical trial should be communicated promptly (within 14 calendar days) by the Sponsor to the Licensing Authority and to the other Investigator(s) participating in the study (Appendix XI In cases of any trial related injury, the safety data from clinical trials also serves as a basis for casuality aseessment for calculating compensation. Regarding reporting responsibilities of the investigators, Schedule Y states that:

Investigator(s) shall report all serious and unexpected adverse events to the sponsor within 24 h and to the Ethics Committee that accorded approval to the study protocol with 7 working days of their occurrence.

Pharmacovigilance in clinical trials needs to be encouraged and fostered. The present scenario requires reform and needs recommendations for building a robust safety surveillance system for clinical trials in India.

Arora D. Pharmacovigilance obligations of the pharmaceutical companies in India. Indian J Pharmacol 2008 February , 40 (Suppl 1): S13-S16

Focused Pharmacovigilance

HIV/AIDS, Malaria & Kala-azar are major public health concerns in India. Adequate systems and infrastructure for ADR monitoring and risk management activities are largely absent in India, adequate national or regional quality and safety monitoring systems after drug distribution are also lacking. With increase in number of patients, availability of new drugs, generic fixed-dose combinations and the ignorance of pharmaceutical company sector in global pharmacovigilance activities, there is a great need of focused pharmacovigilance.

In India, a total of 2.4 million patients were suffering from HIV/AIDS in 2009 and about 200,000 new HIV-positive individuals are diagnosed each year. (12) Antiretroviral therapy reduces morbidity and mortality in people living with HIV infection, but adverse drug reactions remain a potential barrier to treatment success as they are an important cause of poor adherence due to inability to tolerate antiretroviral therapy. ADR monitoring and causality assessment in resource-limited countries like India remain major challenges.

In India, Post-marketing ADR monitoring often relies exclusively on spontaneous reporting which is a major issue. As of now there is no pre-existing surveillance system solely dedicated to ADR monitoring of anti- HIV/AIDS drugs in India. (13, 14) We can develop an HIV-focused pharmacovigilance program which can integrate both active and passive ADR surveillance for antiretroviral therapy (ART). Moreover integrating the HIV-focused pharmacovigilance program with the existing health care program of AIDS can go a long way. (15)

As per WHO report 2011-2012, South East Asian Region bears the second largest burden of malaria (13%), only second to African region (81%). Among South-East Asia region, India shares two-thirds of the burden (66%) followed by Myanmar (18%) and Indonesia (10%). (16)

Emerging chloroquine-resistance especially in P. falciparum is considered as one of the important contributing factors responsible for an increase in its occurrence in India. Because of this there is a wide scale use of Artemisinin based combination therapies (ACTs) and other new drug combinations. Our health systems have a very little experience with these new drugs. Pharmacovigilance for ACTs and other combination treatments in India is essential as malaria transmission is high and antimalarial drugs are used very frequently. Moreover, drugs can be obtained without a prescription. Informal use of antimalarial drugs may increase the risk of incorrect dosing, inappropriate treatment, and drug interactions which may impact negatively on drug safety. Furthermore, the administration of antimalarial treatments in patients with concomitant illness, including HIV/AIDs, tuberculosis and malnutrition, is a concern. So all these factors demand a focused pharmacovigilance activity to ensure safe use of antimalarial drugs especially the ACTs and other new drug combinations. (17, 18).

In India Kala azar cases are mostly concentrated in Bihar, Uttar Pradesh, West Bengal and Jharkhand with over 165.4 million people at risk (19). Sodium antimony gluconate (SAG) and miltefosine are the first line drugs for the treatment of kala-azar & are known to cause several side effects. Sodium antimony gluconate (SAG) has been known to cause anorexia, nausea, vomiting, abdominal pain, metallic taste in mouth, diarrhoea, pancreatitis, reversible elevation of liver enzyme activities, myalgia, arthralgia, proteinuria, ECG changes (T wave inversion,prolongation of QT interval, ST segment abnormalities), phlebitis, uveitis, optic atrophy, acute renal failure, hepatic necrosis and bone marrow hypoplasia. (20)

Miltefosine is known to cause mild adverse effects which are mainly gastrointestinal in which loss of appetite, nausea and vomiting were found to be the major dose-limiting side effects. Other frequently observed miltefosine-related toxicities are mainly associated with the kidneys and liver. (21) Teratogenicity is the main limitation to the use of miltefosine which calls for responsible surveillance & appropriate mechanisms to protect the women of child-bearing age. (22) In addition to the adverse-effects, quality of the generic products also need to be monitored. (23) In view of the current side effect profile & other related issues monitoring of adverse effects to anti-leishmanial drugs is utmost. Focused Pharmacovigilance for anti-leishmanials can be integrated with the National Vector Borne Disease Control Programme (NVBDCP) which is an umbrella programme for prevention and control of vector borne diseases.