Pharmacovigilance: Need of Indian Pharma Industries

Mr.Sohan S.Chitlange

It is related to the surveillance of drugs once they are released for use in the community (post marketing surveillance) and relies on voluntery reporting, prescription monitoring, medical records and statistical studies in the population.

Since very few new drugs were discovered in India and hardly any new drug was launched for the first time in India in the past, there was no major compulsion to have a strong Pharmacovigilance system to detect adverse reactions of marketed drugs. The experience from the markets where the drug was in use for several years before introduction in India, was used by the Companies and the Regulatory Agencies to assess the safety parameters and take corrective actions , such as the withdrawal or banning of the drug in question. With the Indian Companies'' capacity to develop and market new drugs out of their own research efforts, it is important that adequate Pharmacovigilance standards are introduced to monitor adverse reactions of products, first launched in India.

Introduction:

WHO defines Pharmacovigilance as the Science and activities relating to the detection, assessment, understanding and prevention of adverse drug reactions.¹ Generally speaking, Pharmacovigilance is the science of collecting, monitoring, researching, assessing and evaluating information from healthcare providers and patients on the adverse effects of medications, biological products, herbalism and traditional medicines with a view to identifying new information about hazards associated with medicines preventing harm to patients.^2,3 It is the process of identifying and responding to the issues of drug safety through effects usually adverse.⁴

Continuous monitoring of their effects, side effects, contraindications and outright harmful effects which can result in a high degree of morbidity and in some cases, even mortality, is essential to maximize benefits and minimize risks. No degree of care and caution at the pre-clinical and clinical testing stages can guarantee absolute safety, when a drug is marketed and prescribed to large populations across the Country and outside.Because clinical trials involve several thousand patients at most; less common side effects and ADRs are often unknown at the time a drug enters the market. Even very severe ADRs, such as liver damage, are often undetected because study populations are small. Postmarketing pharmacovigilance uses tools such as data mining and investigation of case reports to identify the relationships between drugs and ADRs.The drug regulatory agencies have the responsibility of having a well-established pharmacovigilance system to monitor adverse reactions of drugs. During the drug development phase and later during the life time of a marketed drug.⁵

Need for Pharmacovigilance Systems

To be eternally vigilant to ensure that medicines, which are developed for treatment of diseases, actually do not do more harm than good, is one of the important pre-requisites for the progress of medicine. Already, at least in the U.S.A., figures as high as 3 to 5% of hospital admissions have been attributed to iatrogenic diseases, that is., those caused by drugs. The science and systems used for systematically identifying and correlating drugs and side-effects and taking corrective actions fall under the discipline of Pharmacovigilance.⁵     

Pharmacovigilance Process

Finding the risks of drugs

Medicines have helped to bring improved health and longer life to human beings. Medicines affect the lives of hundreds of millions of people every day. But they are not without risk, and have caused, do cause and will continue to cause harm to many people. There are also large numbers of people who experience no evident effect at all from the drugs they take.^{2, 3}

Clinical Trials

Pharmaceutical companies are required by law in all countries to perform clinical trials, testing new drugs on people before they are made generally available. The manufacturers or their agents usually select a representative sample of patients for whom the drug is designed — at most a few thousand — along with a comparable control group. The control group may receive a placebo and/or another drug that is already marketed for the disease.^{2, 3}

Clinical trials do, in general, tell us a good deal about how well a drug works and what     potential harm it may cause. They provide information which should be reliable for larger populations with the same characteristics as the trial group - age, gender, state of health, ethnic   origin, and so on.^{2, 3}

Pharmacoepidemiologic Studies

Pharmacoepidemiology is defined as “the study of effects of and use of drugs in large populations. It is the use of epidemiological methods to address issues from clinical pharmacology, usually questions about the balance between beneficial and adverse effect of drugs.” ^6,7,11 It also takes into account patient compliance and other factors that apply when drug is used under real-life conditions.¹² They are not experimental but observational in nature. Pharmacoepidemiologic studies can be of various designs, including cohort (prospective or retrospective), case-control, nested case-control, case-crossover, or other models.^{8, 9}

Cohort study:Cohort study compares exposed to unexposed patients and evaluates differences in outcome over time.

Case control study: This compares individual with disease to individual without disease. ¹⁰

Case Report

FDA recommends that sponsors make a reasonable attempt to obtain complete information for case assessment during initial contacts and subsequent follow-up, especially for serious events and encourages sponsors to use trained health care practitioners to query reporters. Good case reports include the following elements:

· Description of the adverse events

· Suspected and concomitant product therapy details

· Patient characteristics

· Documentation of the diagnosis of the events

· Clinical course of the event and patient outcomes⁹

Developing a Case Series

FDA suggests that sponsors initially evaluate a signal generated from postmarketing spontaneous reports through a careful review of the cases and a search for additional cases.  Additional cases could be identified from the sponsor’s global adverse event databases, the published literature, and other available databases, such as FDA’s Adverse Event Reporting System (AERS). FDA suggests that sponsors evaluate individual case reports for clinical content and completeness, and follow up with reporters, as necessary.⁹

Analysis of a Case Series

In the event that one or more cases suggest a safety signal warranting additional investigation, FDA recommends that a case series be assembled and descriptive clinical information be summarized to characterize the potential safety risk and, if possible, to identify risk factors.⁹ A case series commonly includes an analysis of the following:

• The clinical and laboratory manifestations and course of the event;
• Demographic characteristics of patients with events  
• Exposure duration
• Doses used in cases, including labeled doses, overdoses;
• Use of concomitant medications;
• The presence of co-morbid conditions
• The route of administration ⁹

Use of Data Mining to Identify Product-Event Combinations

At various stages of risk identification and assessment, systematic examination of the reported adverse events by using statistical or mathematical tools, or so-called data mining, can provide additional information about the existence of an excess of adverse events reported for a product.  By applying data mining techniques to large adverse event databases, , it may be possible to identify unusual or unexpected product-event combinations warranting further investigation.⁹

Spontaneous reporting

Spontaneous reporting is the core data-generating system of international pharmacovigilance, relying on healthcare professionals (and in some places consumers) to identify and report any suspected adverse drug reaction to their national pharmacovigilance centre or to the manufacturer. Spontaneous reports are almost always submitted voluntarily. One of this system’s major weaknesses is under-reporting, though the figures vary greatly between countries and in relation to minor and serious ADRs. Another problem is that overworked medical personnel do not always see reporting as a priority. If the symptoms are not serious, they may not notice them at all. And even if the symptoms are serious, they may not be recognised as the effect of a particular drug.^{2, 3}

Even so, spontaneous reports are a crucial element in the worldwide enterprise of pharmacovigilance and form the core of the World Health Organization Database, which includes around 3.7 million reports (September 2006), growing annually by about 250,000.^2,3

ther reporting methods In addition, spontaneous reporting of suspected adverse effects by the medical profession has resulted in investigations of ADRs. Other partners in the dispensing and usage of drugs including retailers and patients also are expected to report any unanticipated side effects during the treatment phase.^{2, 3} The two main system of Pharmacovigilance are in se in UK

-Yellow card system, in this Doctors reporting suspected serious adverse reaction directly to the                  

  (Medicines and Health services Regulatory Agency) MHRA.

 - This involves the systematic post marketing surveillance of recently marketed medicines.¹³

Some countries legally oblige spontaneous reporting by physicians. In most countries, manufacturers are required to submit reports they receive from healthcare providers to the national authority. Others have intensive, focused programmes concentrating on new drugs, or on controversial drugs, or on the prescribing habits of groups of doctors, or involving pharmacists in reporting. All of these generate potentially useful information. Such intensive schemes, however, tend to be the exception.^{2, 3}

 International collaboration

The principal of international collaboration in the field of pharmacovigilance is the principle basis for the WHO International Drug Monitoring Programme, through which over 80 member nations have systems in place which encourage healthcare personnel to record and report adverse effects of drugs in their patients. These reports are assessed locally and may lead to action within the country. Through membership of the WHO Programme one country can know if similar reports are being made elsewhere. (The European Union also has its own scheme.) ^{2, 3}

Member countries send their reports to the Uppsala Monitoring Centre where they are processed, evaluated and entered into the WHO International Database. When there are several reports of adverse reactions to a particular drug this process may lead to the detection of a signal — an alert about a possible hazard communicated to member’s countries. This happens only after detailed evaluation and expert review.^{2, 3}

Spin-Off from Pharmacovigilance

A very important contribution that a well-established Pharmacovigilance system can provide is the possibility of identifying the potential for using the ADR data to develop new indications and uses for a drug marketed for a specific indication. There are a number of cases where the observation of a side effect has led to the development of a new indication for an existing drug.⁵  

Observations of unexpected side effects led to the development of Minoxidil, the first ever drug for alopecia, of Carbamazepine for Epilepsy, and many other drugs. In order to successfully and effectively utilize this approach to develop new uses for existing drugs, it is important for the Clinicians and Patients supported by the innovating Company and te Regulatory Agency, to be on the look-out for unexpected effects of drugs administered to Patients. Only a prepared mind can see and logically correlate the cause-effect relationship in drug usage and drug effects. The benefits that can accrue from such evidence and observation based therapeutics can be enormous and perhaps can provide one of the most cost - effective approaches to new drug development, one of the important pre-requisites for successful modern drug development.⁵

Pharmacovigilance in India

Pharmacovigilance is fastest emerging as an important approach for the early detection of unwanted effects of the drugs and to take appropriate regulatory actions if necessary .This may ensure the safer use of drugs.¹⁴

Historically, Indian market has always, except in very few cases, seen the launch of only products, which have been earlier approved and marketed in U.S.A., Western Europe or Japan. Until now, the time lag between the first marketing of a new drug in a foreign country and India has been on an average around 4 years, and hardly any new drug was introduced for the first time    in ndia. In that kind of scenario, it was not too critical that there was in place a system of pharmacovigilance inIndia, since reports of side-effects from outside India would have helped our regulatory agencies to assess the rationale of continuing the drug in the Indian market. Thus in the past, action on marketed drugs has been triggered on the basis of reports on the harmful effects of drugs marketed abroad. In a few cases, drugs, which have been banned or withdrawn in foreign markets, were allowed to be kept in the market in India. For example, Chloramphenicol, Phenyl Butazone, Clioquinol, Phenformin, Cisapride, all continue to be prescribed in India on the basis of a conscious decision by the Regulatory Agency that the benefit to risk ratio is in favour of the former.¹⁵

The evolution of a new Patent regime in the Indian Pharmaceutical Industry (the Post-2005 scenario) as a consequence of India being a founder member of WTO, and her obligations under Trade Related Intellectual Property Rights and Services (TRIPS), makes it incumbent that ndia can no longer copy patented products and market them without licence from the innovator company. The leading Indian companies realizing the compulsions of the new regime have already initiated investments of substantial resources for the discovery and development of new drugs needed for both Indian and International markets. This in turn means that during the coming years R&D by the Indian Pharmaceutical companies will hopefully lead to new drugs based on pre-clinical and clinical data generated mostly in ndia. In such cases, the Indian regulatory agencies cannot count on the experience of other markets to assess the incidence and prevalence of adverse reactions from drug usage, and therein lies the importance of a properly designed pharmacovigilance system in India. For an effective Pharmacovigilance system to be functional and efficient all the stakeholders need to be alert and attentive through out the lifetime of the drug in the market.¹⁵

National Pharmacovigilance Centre

The Central Drugs Standard Control Organization (CDSCO) has initiated a country-wide Pharmacovigilance programme under the aegis of DGHS, Ministry of Health & Family Welfare Government of India.¹⁵

 The programme is coordinated by the National Pharmacovigilance Centre at CDSCO. The National Centre is operating under the supervision of the National Pharmacovigilance Advisory Committee to recommend procedures and guidelines for regulatory interventions.¹⁵

 National Pharmacovigilance Programme

The National Pharmacovigilance Programme was officially inaugurated by the Honorable Health Minister Dr.Anbumani Ramadoss on 23 November, 2004 at New Delhi.¹⁵ The National Pharmacovigilance Programme for India, sponsored by the World Health Organization (WHO) and funded by the World Bank, became fully operational in January 2005.¹⁶

The Programme aims to foster the culture of ADR notification in its first year of operation and subsequently aims to generate broad based ADR data on the Indian population and share the information with global health-care community through WHO-UMC.¹⁵

The nation wide programme, sponsored and coordinated by the country’s central drug regulatory agency – Central Drugs Standard Control Organization (CDSCO) – to establish and manage a data base of Adverse Drug Reactions (ADR) for making informed regulatory decisions regarding marketing authorization of drugs in India for ensuring safety of drugs.¹⁵

Under the program 26 peripheral centers, 5 Regional Centers and 2 Zonal Centers were established. The Peripheral centers will record the Adverse Events (AE) and send to the Regional Centers.They in turn collate and scrutinize the data received from the Peripheral Centers and submit to the Zonal Centers. The Zonal Centers will analyze the data and submit consolidated information to the National Pharmacovigilance Centre. The Zonal Centre will also provide training, general support and coordinate the functioning of the Regional Center

Peripheral Pharmacovigilance Centres:

Primary pharmacovigilance centers. Relatively smaller medical institutions including individual medical practitioners’ clinics, private hospitals, nursing homes, pharmacies etc. First contact ADR data collection unit at a health care facility. They would be identified and coordinated by RPCs / ZPCs in consultation with CDSCO. ¹⁵ 

Regional Pharmacovigilance Centers (RPCs):

Secondary pharmacovigilance centers. Relatively larger healthcare facilities attached with medical colleges. They would act as second level centers in the administrative structure of the NPPI. They will function as first contact ADR data collection units also. They would be identified and coordinated by ZPCs in consultation with the CDSCO. ¹⁵

Zonal Pharmacovigilance Centre (ZPCs) :

Tertiary pharmacovigilance centers. Large healthcare facilities attached with medical colleges in metro cities identified by the CDSCO for the purpose. They would act as third level centers in the administrative structure of the NPPI. They will function as First contact ADE data collection units also.¹⁵

The National Pharmacovigilance Advisory Committee (NPAC):

Oversee the performance of various Zonal, Regional and Peripheral Pharmacovigilance centers as well as recommend possible regulatory measures based on the data received from various centers. It also oversees data collection and assessment, interpretation of data as well as publication of ADR monitoring data. The Committee also periodically evaluates their protocol compliance levels to ensure that the data received is homogenous and can be scientifically pooled for informed regulatory decisions. Wherever necessary, NPAC also seeks the opinion of experts in various specializations. ¹⁵    The specific aims of the Pharmacovigilance Programme are to:

• 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. 
• Monitoring medicines as used in everyday practice to identify previously
• unrecognized adverse effects or changes in the patterns of their adverse effects
• Assessing the risks and benefits of medicines in order to determine what action,
• if any, is necessary to improve their safe use
• Providing information to users to optimize safe and effective use of medicines
• Monitoring the impact of any action taken ¹⁵

Conclusion:

Pharmacovigilance required for systematically identifying and correlating drugs and side-effects and taking corrective actions, especially for the product launching first time in India. Due to the evolution of a new Patent regime in the Indian Pharmaceutical Industry it is critical to have a system of pharmacovigilance in India The Pharmacovigilance programme has been started from 23 November 2004 at New Delhi and the programme is coordinated by the Central Drugs Standard Control Organization, sponsored by the World Health (who)organization

References:

1. WHO Pharmacovigilance:ensuring the safe use of medicines. WHO policy perspective on medicines.Geneva:WHO;2004
2. The Importance of Pharmacovigilance, World Health Organization 2002
3. World Health Organization Technical Report No, 498 (1972)
4. R.S Satoskar, S.D  Bhandarkar, Nirmal N-Rege, Pharmacology and Pharmacotherapeutics, Popular Prakashan,Revised 9  edition,3
5. http://www.pharmabiz.com
6. Current Controversies in Pharmacoepidemiology “Basic and Clinical Pharmacology and  Toxicology” published by the Nordic Pharmacological Society, Distributor ,BLACKWELL MUNKSGAARD Volume 98,number 3,March 2006
7. Padmaja Udaykumar “Text Book of Medical Pharmacology” CBS publication, 2^nd edition, 4
8. F.S.K Barar,Essentials of Pharmacotherapeutics,2004,S,Chand and company Publiction,New Delhi, 110055,3  edition,59,60
9. U.S. FDA , Guidance for Industry Good Phramacovigilance Practices and      Pharmacoepidemiologic Assessment, Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Rockville,MD, March 2005
10. S.George Crruthers,Brain B.Hoffman,Kenneth L.Melmon,david W.Nierenberg, “Melmon and Morrellis, Clinical Pharmacology,MC GRAW HILL,4^th edition,1333,1334
11. Brain L.Storm, “Pharmacoepidemiology”WILEY,3^ed edition,22-25
12. H.P.Rang,M.M.Dale,J.M.Ritter,P.K.Moore,“Pharmacology”,CURCHILLLIVINGSTONE, 5^th edition,5
13. Derek G.Waller,Andrew G.Renwick,Keith Hillier, “Medical Pharmacology and      Therapeutics”ELSEVIER SAUNDERS, 2nd edition, 55, 56
14. National Pharmacovigilance programme, “Indian Journal of Pharmacology”Medknow       Publication, volume 37,issue 6,December 2005
15. National Pharmacovigilance Protocol, Ministry of Health and Family Welfare, Govt. of India
16. http://www.raps.org

About Authors:

Mr.Sohan S.Chitlange (M.Pharm. Pharmaceutical Chemistry)

Asst. Professor, Dept.of Pharm.Chemistry, Padm. Dr.D.Y. Patil Institute of Pharmaceutical Sciences & Research, Pimpri, Pune.
sohanchitlange@rediffmail.com

Mr. Amol A. Kulkarni (M.Pharm. Pharmaceutical Chemistry)

Lecturer, Dept.of Pharm.Chemistry, Padm. Dr.D.Y. Patil Institute of Pharmaceutical Sciences & Research, Pimpri, Pune.
amolkulkarni89@rediffmail.com

Mohammed Imran (M.Pharma. Sem.II Quality Assurance)

Dept.of Pharm.Chemistry, imransa99@rediffmail.com

Mr. Santosh S. Bhujbal (M.Pharm. Pharmacognosy)

Asst.Professor, Dept.of Pharmacognosy, Padm.Dr.D. Y. Patil  Institute of Pharmaceutical.Sciences &Resreach, Pimpri, Pune.

Dr. Avinash D. Deshpande (M.Pharm. PhD. Pharmacology)

Principal & Director of pharmacy, Padm.Dr.D. Y. Patil Institute of Pharmaceutical Sciences & Research, Pimpri, Pune.