Interview

Making drugs safer

India has become a major hub for clinical trials. However, whether patients in India receive safe drugs or not is still very much in question. Sushmi Dey finds out more about pharmacovigilance and pharmacoepidemological practices and the status in India, in conversation with Dr Pipasha Biswas, Managing Director of Symogen

What is the role of pharmacovigilance in clinical trials?

Pharmacovigilance refers to the science and activities related to the detection, assessment, understanding and prevention of adverse effects or any other medicine-related problem both long term and short term side-effects of medicines; thereby improving the safety of medicines in use. The goal of pharmacovigilance is the safer use of medicines and this is usually achieved by dissemination of accurate, timely and clinically relevant information. Thus, the objectives of pharmacovigilance are concerned with identifying, validating, quantifying and evaluating adverse reactions associated with the use of drugs.

Pharmacovigilance is therefore instrumental in continuously monitoring unwanted effects and other safety aspects of drugs that are already in the market. The central agency can then combine reports from many sources to produce a more informative safety profile for the drug product than could be done, based on one or a few reports from healthcare professionals.

Why is pharmacovigilance and reporting adverse drug reactions (ADRs) important?

There is an immense need for pharmacovigilance and post-marketing surveillance, as medicines are evaluated for toxicity in a limited group of patients before marketing. The limitations of clinical trials mean that when a drug is first marketed, much may be known about its efficacy, while relatively little may be known about its safety. For example, at least 30,000 people need to use a medication in order to identify, with 95 percent power, an adverse reaction with an incidence of one in 10,000. Hence, the information about the new drugs clinical safety is incomplete. After a new drug is marketed, it is used in very different populations from those included in clinical trials. Consequently, we rely almost totally on post-marketing surveillance to get more information on the adverse effects and safety of a new drug, as it is used in routine medical practice. Also, for example, a relative lack of widespread clinical trials for medicines to treat children means that many drugs are initially only licensed for use in adults, which can leave no alternative to the prescriber than to use "off-label" and unauthorised products in this population. Thus, the need for post-marketing surveillance can be seen as a means to identify drug safety problems not picked up by pre-marketing tests and promulgate any necessary advice and/or regulatory action to prescribers and users.

What is the ideal approach to pharmacovigilance?

Various methods are used throughout the life cycle of the product (from all phases of clinical trials and post-marketing) to evaluate new information that comes in routinely. This is called signal detection. Signal detection is one of the most important objectives of pharmacovigilance. The whole process of risk/benefit evaluation depends on effective detection of signals. Methods for signal detection include observations by clinicians and patients, case reports in the literature, assessment of individual case reports or clusters of reports that are received from healthcare professionals, patients and consumers etc, data from formal studies, e.g. clinical trials, epidemiological studies like cohort studies and case control studies.

The detection of signals require clinical assessment assisted by epidemiological and statistical analysis. Information technology tools also help in the generation of signals and enhancing its effectiveness. Automated signal generation is used by many MNCs, where reported safety profile of a particular product is compared with other products in the database using simple statistical methods like proportional reporting rates (PRR). Apart from PRR, which is very popular, there are other statistical tools used for signal detection that are used like incidence rates, frequency of adverse events and trend analysis.

What is pharmacoepidemology and how is it related to clinical safety of drugs?

Pharmacoepidemiology is the study of the utilisation and effects of drugs in large numbers of people. Pharmacoepidemiology borrows from both clinical pharmacology and epidemiology. Thus, pharmacoepide-miology can be called a bridge science spanning both clinical pharmacology and epidemiology. It complements pharmacovigilance and both go hand in hand, as mostly pharmacoe-pidemiological studies are needed for good pharmacovigilance plans. Pharmacoepidemiology helps in detecting adverse events sooner. In the process, it can protect the public's health, decreasing the time to removal of drugs that are causing public health problems and protecting access to useful drugs.

Both pharmacovigilance and pharmacoepidemiology are carried out by pharmacos on their products and by regulatory agencies on all medicinal products. Healthcare professionals have a role too, in reporting suspected side-effects of medicines to governmental regulatory agencies or pharmaceutical companies.

What are the infrastructure requirements in practising pharma-covigilance and pharmacoepi-demology?

Good pharmacovigilance practice is based on acquiring complete data from spontaneous adverse event reports, also known as case reports. The reports are used to develop case series for interpretation. Effective pharmacovigilance is dependent on the availability of information on the clinical effects of medicines in representative populations, as used in normal practice. For this to happen, it requires a robust pharmacovigilance system, which includes a system of collecting and monitoring suspected ADRs and processes for reviewing the data to decide whether further investigations are necessary.

A culture of learning about pharmacovigilance should start early in the professional training of healthcare students so that reporting of ADRs after marketing can be actively encouraged amongst all concerned doctors, pharmacists, nurses, patients and pharmaceutical companies This will help healthcare professionals to understand the subject and also create awareness by giving adequate information to patients at the start of any treatment about the potential benefits and risks of the therapy.

What are the tools used in post-marketing pharmacovigilance?

The various methods and resources used in post-marketing pharmacovigilance are data from healthcare professionals, marketing authorisation holders, regulatory authorities, world wide published literature and academic institutes. Several methods exist for studying adverse drug reactions in marketed medicines, including spontaneous reporting, prescription event monitoring, pharmacoepidemiological studies like cohort studies, case control studies, disease registries and various other automated databases.

Do you think there is a need for Indian pharma industry to implement pharmacovigilance?

Proactive pharmacovigilance is the way forward in India. By this, I mean a properly working pharmacovigilance system is essential, if medicines are to be used safely in India. It will benefit all parties, including healthcare professionals, regulatory authorities, pharmaceutical companies and the consumers. It helps pharmaceutical companies to monitor their medicines for risk and to devise and implement effective risk management plans to save their drugs in difficult circumstances.

Pharmacovigilance is an important and integral part of clinical research. Both clinical trials safety and post-marketing pharmacovigilance are critical throughout the product life cycle. With more and more clinical trials and other clinical research activities being conducted in India, there is an immense need to understand the importance of pharmacovigilance and how it impacts the life cycle of the product. This will enable integration of good pharmacovigilance practice in the processes and procedures to help ensure regulatory compliance and enhance clinical trial safety and post-marketing surveillance.

What is the status of pharma-covigilance in India?

Pharmacovigilance is still in its infancy in India and there exists very limited knowledge about the discipline. While major advancements of the discipline of pharmacovigilance have taken place in the Western countries, not much has been achieved in India. Even after joining the Uppsala Monitoring Centre for Adverse Drug Reactions programme in 1997, there has hardly been any improvement in the pharmacovigilance scenario in India. There have been two attempts to secure the pharmacovigilance programme in India through World Bank funds, but nothing much has happened. While some centres are trying their best to collect ADRs, that is not enough. However, with a number of recent high-profile drug withdrawls, the pharmaceutical industry and regulatory agencies have raised the bar.

Why is India lagging behind in implementing pharmacovigilance practices?

Pharmacovigilance impacts the life cycle of the product and it is important to understand its need. However, there are several reasons for why it is not happening in India. There is a lack of practical knowledge and proper training to staff at the centres. Besides, the Indian industry lacks substantial funds and human resource in this area. The industry here also suffers from a laid back attitude, which keeps it away from implementing such practices.

However, weak regulations of reporting ADRs and no mandatory rules and regulations governing pharmacovigilance is a major hurdle in implementation of pharmacovigilance in India. The DCGI should act quickly to improve pharmacovigilance so as to integrate good pharmacovigilance practice into the processes and procedures to help ensure regulatory compliance and enhance clinical trial safety and post-marketing surveillance.

Pharmacovigilance is a complex process and robust systems are essential to undertake the activity. The foundation for building a robust pharmacovigilance system has to be done by the DCGI staff and also by the Indian pharmacos. However, the system needs to be refined with the help of pharmacovigilance experts in collaboration with information technology.

What are your plans and strategies for implementation of pharmaco-vigilance and pharmacoepidemology in India?

We propose to build and maintain a robust pharmacovigilance system in India, which will include creating a single country-specific adverse event reporting form to be used by all. We also propose to create a clinical trial and post-marketing database for serious adverse events (SAEs)/suspected unexpected serious adverse reactions (SUSARs) and adverse drug reactions (ADRs) for signal detection and access to all relevant data from various stakeholders. For drugs already in the market, type and frequency of all adverse events (serious and non-serious) should be submitted in periodic safety update reports (PSURs) and also added to the summary of product characteristics (SPCs). We will list all new drugs/indications by maintaining a standard database for every pharmaco. Our strategies include making pharmacovigilance reporting mandatory and introducing pharmacovigilance inspections in the country. We also plan to pursue high-level discussions with various stakeholders to make them understand the importance of pharmacovigilance and strengthen DCGI office with trained scientific and medical assessors for pharmacovigilance. Education and training of medical students, pharmacists and nurses in the area of pharmacovigilance is also amongst our priorities. When I look at the advancement of this field in the West, I feel that India should also be well trained in this area, and to do that, I first thought of educating and training young minds which can really make a difference in the long run.

sushmi.dey@expressindia.com