Pharmacovigilance in India: An Overview

Dr Viraj Suvarna
Medical Director
Boehringer Ingelheim India Pvt Ltd

Indu Nambiar
Senior Manager - Local Pharmacoviglance
LPVM, Boehringer Ingelheim India Pvt Ltd

The origin of pharmacovigilance in India goes back to 1986, when a formal ADR monitoring system consisting of 12 regional centers, each covering a population of 50 million, was proposed for India. This article provides a brief overview about the current situation and the future prospects of pharmacovigilance in India and analyses importance of implementing proper pharmacovigilance in the Indian context.

Pharmacovigilance in India has come a long way. A formal system for adverse drug reaction monitoring started in 1986. There were 6 regional centers then , viz., Mumbai, New Delhi, Kolkata, Lucknow, Puducherry and Chandigarh. Three institutes are linked to the Uppsala Monitoring Center of WHO, viz., KEM, AIIMS and AMU. In 2004 CDSCO or the Central Drug Standards Control Organization established the National Pharmacovigilance Program with sponsorship from WHO and the World Bank. There were 2 zonal, 5 regional centers and 24 peripheral centers. Due to lack of funding it folded up in 2008.

In July 2010, the PvPI or Pharmacovigilance Program of India began in AIIMS which was the National Coordination Center for reporting adverse drug reactions. Later it was shifted to the building of the Indian Pharmacopoeia Commission (IPC), Ghaziabad. Doctors in India get SMSes from PvPI from time to time alerting them to some clinically relevant adverse events reported with some drugs.

CDSCO expects companies to report to PvPI adverse events that occur, both during clinical trials, and during clinical practice (spontaneous adverse events). This practice helps in further characterizing a drug's safety profile. PV is a discipline which starts from the time a drug is discovered or invented, continues through its clinical development till it gets marketing authorization approval, and lasts for as long as the drug is in the market. In other words, PV is with you when you cross the road and even when you reach the other side (there could be potholes in the footpath).

So what exactly is meant by Pharmacovigilance? It is the science of being vigilant about a drug's safety profile. It is not enough to preach pharmacovigilance. One should practise what one preaches too. Over the years drugs have been made safer for patients. It is time to make patients safer for drugs. Pharmaceutical companies need to inform doctors about the benefits and risks of their products so that the doctor knows how to select the right patient for the right drug. In effect, they need to tell doctors where not to prescribe the drug too.

The locally approved prescribing information of a drug is available as a pack insert inside the pack of the product as a leaflet. However, this pack insert is with patients who buy the drug. The information in the pack insert is actually meant for the prescribing doctor looking at the way the language is so medically intensive. It is therefore imperative that the pharmaceutical company medical representative leaves behind the label of the drug with the prescribing doctor, as an LBL (Leave Behind Label). Ideally the medical representative should 'detail' salient features of the label (eg , dosage form/strengths, indications, contraindications, warnings and precautions, undesirable events and dosing recommendation) to the doctor and then leave it behind.

The doctor can sign and rate the medical representative on his/her detailing of the label on a tear-off that the medical representative can then send back to his/her company. This can also protect the company just in case the doctor uses the product in an off-label indication which has undesirable consequences for the patient. It is important that a company should never promote its products in offlabel indications. A doctor may prescribe a product in an off-label indication, only when there is no other alternative, there is a credible medical body of evidence that justifies its use, and the doctor conducts informed consent as a process.

There is nothing adverse about reporting an adverse event. Not reporting an event can have adverse consequences, especially for the pharmaceutical company as and when they are intimated about the event. Doctors can and should report in confidence and with confidence. The PvPI website has an adverse event reporting form, in different languages, separate for physicians and patients, that can be downloaded by anyone and used to report the event to PvPI.

The Oxford Textbook of Clinical Pharmacology, in its chapter on adverse events, starts with the maxim that, "unless a drug is capable of causing some harm, it is unlikely that it will have much of an effect." In other words, there is no drug which does not have a single adverse event. One can have adverse events even to a placebo, when it is sometimes called a nocebo. Let us all understand that when a doctor decides to prescribe a drug to a patient s/he has evaluated the benefit to risk ratio of the drug and found it to be positive.

What is an adverse event and how is it different from an adverse drug reaction? In the case of the former there is a temporal association of the event with the drug but it need not have a causal relationship. In the case of the latter, the causal relationship has been determined by a process which includes drug dechallenge when the event abates and drug re-challenge when the event recurs. For obvious reasons drug re-challenge is not always attempted.

A serious adverse event is one that results in death, or is life-threatening , or results in hospitalisation or prolongation of existing hospitalisation, or which leads to significant or persistent incapacity or disability or which results in a congenital anomaly. In addition, any important medical event may also be considered a serious adverse event if one has to take urgent medical or surgical measures to prevent one of the above five outcomes. In an investigator's opinion if the event is adjudicated to be a serious adverse event then it is also considered a serious adverse event.'

In a clinical trial, the investigator is asked to decide whether the event is related or not related to the trial or drug used in the trial. There is a third box which the investigator can tick if s/he is not sure whether the event is related or not related to the drug. This is taken to mean that the event might be related to the drug and is clubbed with those events marked as related to the drug; only to be on the safer side.

Also, if any adverse event happens in the 28-30 day period after the last dose of the study drug, it is still taken to mean that the event could be related to the drug as it takes about five half-lives of a drug to fully exit a patient's body, and sometimes the effect of a drug may outlast its physical presence in the body (hit and run drugs, eg, aspirin irreversibly acetylates platelet cyclo-oxygenase, and even if aspirin is no longer in the patient's body, the platelet cyclo-oxygenase enzyme is irreversibly inhibited so the effect of aspirin lasts much longer, viz., about 2 weeks, till new platelets are synthesized; platelet life span is 8-11 days).

In short, during clinical trials, conscientious companies take a lot of pains to ensure safety of the study participants. When translated to the less standardised world of clinical practice the safety profile may change and hence it is important that one continues this safety surveillance for as long as a drug is on the market. No matter how well a drug is studied in the controlled environment of a premarketing randomized clinical trial, postmarketing surveillance (observational, non-interventional, naturalistic setting) will always be needed to unearth rare adverse events.

When a doctor asks a pharmaceutical company how many adverse events have been reported on the company's product, the answer is always accompanied by a disclaimer that one cannot use this information to estimate the incidence of the adverse event because at any point in time one does not know whether all adverse events of that nature have been reported, at any point in time one does not know how many patients have received the drug, and one is not always able to assess the causal relationship of the drug with the event. Though, in the case of spontaneous adverse events on marketed drugs in the real world, causality is taken to be implied.

It is not always that an adverse event is harmful. Sometimes it could just be a side effect, eg, dryness of mouth and nose with anti-histaminic drugs that also have anticholinergic properties. At times the side effect can be developed into an indication as happened with Viagra (sildenafil citrate) which was developed as an anti-anginal and then when patients in the trial experienced an erection as a side effect, it was developed as a treatment for erectile dysfunction. Sometimes as with some targeted therapy in cancer, development of a side effect may indicate that the drug will be more effective in that patient, eg, skin rash and cetuximab or hypertension and sunitinib.

All this is fine but do patients, doctors and pharmaceutical companies in India report all adverse events? There is certainly scope for improvement. Doctors sometimes believe that if they report an adverse event they might get into trouble. Especially, if they use the product, not per its prescribing information. Or they feel that the event is only to be expected, eg, diarrhea with antimicrobials, as it is listed in the product's locally approved prescribing information. But all events need to be reported so that one can fully characterize the safety profile of a product. It might lead to changes in the prescribing information and can even lead to withdrawal of a product. It was an astute doctor who first observed the gray baby syndrome with chloramphenicol. And then he traveled the length and breadth of his country and tracked many more such events to make all aware of this adverse event.

Pharmaceutical company medical representatives are sometimes scared to report events thinking it might lead to loss of sales. However, they should realize that not reporting events can have this end result. The doctor may stop writing the product, stop writing other products of the company or even tell his/her other colleagues about it, telling them not to write the company's products.

Reporting the event shows the doctor that the company is serious about its commitment to doctors and patients. The PV professional and medical affairs colleagues, based in head office and in the field, get in touch with the doctor, provide him with information on similar adverse events, and with this wealth of safety data, from both RCTs and in the real world, the doctor is reassured about the safety profile, and continues prescribing the product .

The pharmaceutical company can come out with patient profiles where the drug should not be used. Or an eligibility score which can then be validated in the real world. Even within a drug's label, there could be patients who respond to a drug optimally, in terms of safety, efficacy or both. And there could be some patients within the label who do not respond optimally. The pharmaceutical company can delve into its clinical trials database and try and correlate response of patients to clinical characteristics. Ideally the company should communicate this information to doctors so that they in turn can use this information to ensure the best patient is selected who can get optimal benefit from the drug. This enhances credibility.

The PV team can use this market intelligence to feedback to the brand teams at regular core committee on safety monitoring meetings, where risk management is also discussed. The PV team can facilitate drug utilization evaluation studies in the real world. Sometimes a risk management plan may need to be in place as demanded by the regulator. At times the regulator may ask for a risk minimization action plan (MAP), for products that are extremely critical but have serious adverse events associated with their use . Basically, a risk MAP ensures that the benefit to risk ratio is always positive.

The PV team must do field work which will help gain customer insight (eg, a drug safety poster can be a useful item to grace the wall of a doctor's clinic) and bring the doctor closer to the company as PV is also a core competence. It is in effect the seat belt of a company, not coming in the way of fast paced growth, but protecting the company from accidents.

PV is not just about reporting an adverse event on time and with due quality and completeness (initial and follow up). It is more than this. The PV professional must interact with her/his medical affairs and medical information colleagues and provide the reporting doctor with the requisite information that helps the doctor choose the right patient for the right drug.