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Guidance for industry on pharmacovigilance requirements for biological productsPage 1 of 71Guidance for industry on PharmacoviGilance requirements for BioloGical Products PREFACE this is in consonance with the objective of the drugs & cosmetics act 1940 and rules 1945 there under and other functions of cdsco wherever applicable. these guidelines are intended for the guidance of the marketing authorization holders (mahs) i.e. manufacturers and importers of biological products. the procedure set out to facilitate the industry to submit the documents as per the requirements of drugs and cosmetics act and rules. Guidance documents may be amended from time to time as per requirements after obtaining necessary approval from the competent authority. 2FOREWORD the central drugs standard control organization (cdsco), being the apex regulatory authority for approval of drugs in india, is committed to safeguard and enhance the Public health by assuring the safety, efficacy and quality of drugs, cosmetics and medical devices. india has extensive Pharmacovigilance activities for vaccines as part of post licensure submissions in form of Psurs, Pms studies, aefi case reports and individual case safety reports (icsrs) received by PvPi at iPc. the present document is developed to provide the guidance to all the stakeholders including the marketing authorization holders on the coordinated activities of the various departments within the ministry of health and family Welfare to work together and enhance the pharmacovigilance of vaccines. the guidance document has been prepared in line with the recommendation of the nra assessment 2012 to provide guidance for the mah to perform specific safety study throughout the product life cycle and to define the roles and responsibilities of all the stake holders namely cdsco, PvPi at iPc, immunization division, mah, private and public practitioners and outlines the risk minimization action Plan. this could provide guidance to the manufacturers and importers of vaccines in the country to strengthen their adr monitoring and pharmacovigilance department to ensure patient safety. 3Guidance for industry on PharmacoviGilance requirements for BioloGical Products C s o t n n te AbbREviAtiOns 1. introduction 1.1 objective 1.2 Background 1.3 rationale 1.4 scope 2. roles and resPonsiBilities of authorities 2.1 cdsco 2.2 iPc 2.3 aefi secretariat, immunization division of ministry of health and family Welfare 2.4 Pharmacovigilance division (human vaccine) at cdsco 3. PharmacoviGilance Plan 3.1 Pharmacovigilance methods 3.1.1 Post marketing surveillance/ Periodic safety update report 3.1.2 Post marketing trials (Phase – iv) 4. roles and resPonsiBilities of marketinG authorization holder 5. develoPment and use of risk minimization action Plans 6. definitions 7. references 8. aPPendices 4AbbREviAtiOns: ade adverse drug event adr adverse drug reaction aefi adverse event following immunization cdl central drugs laboratory cdsco central drugs standard control organisation crf case report form dcG(i) drugs controller General (india) dio district immunization officer dov date of vaccination ePi expanded Programme on immunization fcif final case investigation form GcP Good clinical Practices GmP Good manufacturing Practices GlP Good laboratory Practices icsr individual case safety reports iPc indian Pharmacopoeia commission itsu immunization technical supportive unit mah marketing authorization holder ncc national coordinating centre nra national regulatory authority PBrer Periodic Benefit risk evaluation report Pcif Preliminary case investigation form Psur Periodic safety update report Phfi Public health foundation of india PvPi Pharmacovigilance Programme of india sePio state ePi officer uiP universal immunization Programme 5Guidance for industry on PharmacoviGilance requirements for BioloGical Products 1. intRODuCtiOn: over the last three decades, india has become a vibrant hub of vaccine manufacturing units with state-of-the-art facilities at par with the international manufacturing standards. today every third child in the world is administered with the vaccine of indian origin. india can now boast of producing safe, effective and affordable vaccine products which safe guard millions of children in domestic and international market. this responsibility warrants additional effort of constant vigilance of vaccine products moving in the market. the pre-market mandatory clinical trial has little scope to assess the inherent risks associated with the nature of antigens /excipients formulation or that cropping up due to specific manufacturing process and raw materials used risk assessment during product development should be conducted in a thorough and rigorous manner; however, it is impossible to identify all safety concerns during clinical trials. once a product is marketed, there is generally a large increase in the number of patients exposed, including those with co-morbid conditions and those being treated with concomitant medical products. therefore, post marketing surveillance which may be passive or stimulating have major role to assess the actual safety aspects of the vaccine product. safety data collection and risk assessment based on observational data are critical for evaluating and characterizing a product’s risk profile and for making informed decisions on risk minimization. this guidance document focuses on pharmacovigilance activities on a vaccine product circulating in the market throughout its life cycle post licensure period. this guidance uses the term pharmacovigilance to mean all scientific and data gathering activities relating to the detection, assessment, and understanding of adverse events. Pharmacovigilance principally involves the identification and evaluation of safety signals. in this guidance document, safety signal refers to a concern about an excess of adverse events compared to what would be expected to be associated with a product’s use. signals can arise from post marketing data and other sources, such as preclinical data and events associated with other products in the same pharmacological class. it is possible that even a single well documented case report can be viewed as a signal, particularly if the report describes a positive re-challenge and de-challenge or if the event is extremely rare in the absence of drug use. signals generally indicate the need for further investigation, which may or may not lead to the conclusion that the product caused the event. after a signal is identified, it should be further assessed to determine whether it represents a potential safety risk and whether other action should be taken. 61.1 ObjECtivE: this document intends to be an aid to the marketing authorization holders (mah) and other allied stake holders who play active role in launching, distribution and bringing the vaccine products to its end users. the main focus of this guideline is to identify the risks, formulate the risk profile of a vaccine and its administration programme, design of appropriate pharmacovigilance plan to mitigate such risks and to explore the missing critical information which did not emerge during pre- market phase-i/ii/iii trials and therefore safety profile had not been established. 1.2 bACkgROunD the decision to approve a drug is based on its having a satisfactory balance of benefits and risks within the conditions specified in the product labeling. this decision is based on the information available at the time of approval. the knowledge related to the safety profile of the product can change over time through expanded use in terms of subject characteristics and the number of patients exposed. in particular, during the early post marketing period the product might be used in settings different from clinical trials and a much larger population might be exposed in a relatively short timeframe. once a vaccine is marketed, new information might emerge, which may have an impact on the benefits/risks ratio of the product. evaluation of this information should be a continuing process in consultation with regulatory authorities. detailed evaluation of the information generated through pharmacovigilance activities is important for all products to ensure their safe use. the benefit- risk balance can be improved by reducing risks to patients through effective pharmacovigilance that can enable information feedback to the users of medicines in a timely manner. 1.3 RAtiOnAlE this document rationally place guidance that all marketing authorization holder (mah) of human vaccines(importers and manufacturers)should establish an appropriate pharmacovigilance system with adequate number of qualified, trained, experienced manpower to collect, collate all aefi (minor, severe and serious). this pharmacovigilance system within the company should conduct decisive causality analysis of the collated aefi cases, after due investigation and prepare case closure report. in a comprehensive Psur, all such information shall have to be placed as per the norms stipulated in schedule-y of drugs & cosmetics act 1940 and rules 1945 and submitted to the licencing authority i.e dcG(i) in cdsco (hq) in a timely manner. cdsco shall convene the meeting of Psur committee within a reasonable time period and give opportunities to the concerned marketing authorization holder (mah) to present their case and Psur in general. Based on the recommendation of the Psur committee the vaccine licensing authority i.e. dcG(i) will take appropriate regulatory action in accordance with drugs & cosmetics act 1940 and rules 1945, so as to monitor the safety and effectiveness of human vaccine in the market. mahs must have a system in place that enhances the overall quality of the receipt, processing and reporting of ade while ensuring that accurate and complete pharmacovigilance information is provided to cdsco. 1.4 sCOPE this document has been framed in compliance with the provisions made under schedule-y of drugs & cosmetics act 1940 and rules 1945 and Good clinical Practices (GcP) Guidelines of india to provide Guidance to marketing authorization holders (importers and manufacturers of human vaccine) india to establish their pharmacovigilance system to collect all aefi 7Guidance for industry on PharmacoviGilance requirements for BioloGical Products cases pertaining to their vaccine products across the domestic and export market, after due investigation & causality analysis at their end and collate all such cases in Psur for periodic reporting to the licensing authority i.e. dcG(i) in cdsco. this document does not include all other new drugs and animal vaccine moving in the market. this document is designed to facilitate compliance by the industry and to enhance consistency in the implementation of the regulatory requirements regarding Good Pharmacovigilance Practices. this document would provide adequate information in a systematic manner for reporting serious adverse event or adverse event when the product is in the market and would enable the systematic sharing of information between cdsco, Pharmacovigilance Programme of india (PvPi) and the expanded Programme on immunization (ePi), ministry of health and family Welfare. the roles and responsibilities of the cdsco are as per the drugs and cosmetics act 1940 and rules 1945. the Pharmacovigilance Programme of india has the responsibility to collate the data received by them and to share the adverse reaction reported for vaccines to (i) district immunization officer (dio), (ii) state aefi committee and (iii) the national aefi committee for examination and recommendation. the results of the cases discussed in the signal review Panel of the Pharmacovigilance Programme of india (PvPi) will be shared with aefi secretariat and cdsco for regulatory action. the licensing authority may also advise the mah to conduct Phase iv trial in case of demonstration of product safety, efficacy and dose definitions. these trials may not be considered necessary at the time of new drug approval but may be required by the licensing authority for optimizing the product use. they may be of any type but should have valid scientific objectives, for example, epidemiological studies etc. similarly the immunization division under ministry of health and family Welfare collects information on adverse event related to vaccines on a regular basis. information on serious adverse events is collected in the case report form (crf) and details of the investigation of the reported event are collected in the Preliminary case investigation form (Pcif) and final case investigation form (fcif) in which the state aefi committee assigns the causality. the aefi secretariat will share limited linelist in excel format with cdsco for deaths and clusters on a weekly basis and all serious and severe cases on a monthly basis. limited linelist will be in excel format and will have state, age, sex, date of vaccination (dov), antigens administered, manufacturing details (name, batch number and expiry date) and reason for reporting. cdsco will share linelist details for vaccines relevant to the particular manufacturer with instructions that these are being shared with the mah for internal review and not for investigations in the field. aefi secretariat of the immunization division conducts a quarterly review of completely investigated aefi cases which are reviewed and classified by the national aefi committee (through the causality assessment sub-committee) to the immunization division of ministry of health and family Welfare. these assessment reports are shared with cdsco and based on the causality assessment report detailed inspection related to GmP, product quality assessment etc. and further regulatory action are initiated by the nra, in case the quality of the implicated vaccines are indicated to be responsible for the adverse events in the causality assessment report. 82. ROlEs AnD REsPOnsibilitiEs OF AuthORitiEs: 2.1 CEntRAl DRugs stAnDARD COntROl ORgAnizAtiOn: the central drugs standard control organization (cdsco) under dGhs in ministry of health and family welfare (Govt. of india) acts as the nodal agency (nra) for regulation of “drugs” as defined in section 3 (b) (i-iv) in drugs & cosmetics act 1940 to ensure the quality, safety, efficacy of all human vaccines (defined as drugs). cdsco is empowered under drugs & cosmetics act 1940 to grant permission, licenses for marketing within the country and foreign country as well. cdsco is also mandated by ministry of health and family Welfare, Govt. of india, to conduct a nation-wide pharmacovigilance programme in coordination with the indian Pharmacopoeia commission (iPc) located at Ghaziabad which is the national coordinating centre (ncc) of many adr monitoring centers established in various medical colleges across the country. the roles and responsibilities of cdsco are as per the drugs and cosmetics act and rules. cdsco is responsible to take appropriate regulatory decision and actions on the basis of recommendations of ncc-PvPi at iPc Ghaziabad and aefi programme of immunization division of ministry of health and family Welfare, new delhi. cdsco is also responsible to take regulatory decision on the basis of analysis of the Pms, Psur, aefi data done by expert committee of cdsco (hq). the Pharmacovigilance Programme of india has the responsibility to collate the data received by them from the various adverse drug reactions monitoring centers and share the adverse reaction reported for vaccines to (i) district immunization officer (dio), (ii) state aefi committee and (iii) the national aefi committee for examination and recommendation. the PvPi at iPc has established a signal review Panel signal identification/review from the committed individual case safety reports to World health organization–uppsala monitoring centre (Who-umc). the results of the cases discussed in the signal review Panel of the Pharmacovigilance Programme of india (PvPi) will be shared with aefi secretariat and cdsco. these results will be used as additional evidence during causality assessment by the ca sub-committee and finalised by the national aefi committee. as a part of the condition of the marketing authorization, the mah is also required to submit Pms/Psur after licensure of the product. the Psurs is to be submitted every six months for first two years of the approval and for subsequent two years annually. the licensing authority may extend the total duration of submission of Psurs if it is considered necessary in the interest of public health. the licensing authority may also advise the mah to conduct Phase iv trials which go beyond the prior demonstration of product safety, efficacy and dose definitions. these trials may not be considered necessary at the time of new vaccine approval but may be required by the licensing authority for optimizing the vaccine’s use. they may be of any type but should have valid scientific objectives. 2.2 PhARmACOvigilAnCE PROgRAmmE OF inDiA At iPC: the central drugs standard control organization (cdsco), directorate General of health services under the aegis of ministry of health & family Welfare, Government of india in collaboration with indian Pharmacopoeia commission, Ghaziabad has 9Guidance for industry on PharmacoviGilance requirements for BioloGical Products initiated a nation-wide Pharmacovigilance programme for protecting the health of the patients by assuring drug safety. the programme is coordinated by the indian Pharmacopoeia commission, Ghaziabad as a national coordinating centre (ncc). the centre operates under the supervision of a steering committee. indian Pharmacopeia commission, Ghaziabad is an autonomous organization under mohfW, having primary mandate for preparation of standards for all drugs including bulk antigens and vaccine products, publish of indian Pharmacopoeia (iP) with monographs for all drugs including vaccines, publish of national formulary (nfi), preservation of reference standards for drugs, but not the antigens of vaccine which is maintained at niB (noida) and cdl (kasauli). this organization has also been mandated by mohfW to act as ncc for all adr centers across the country to collect, collate adr for all drugs including aefi cases of human vaccines, line listing of these adrs (aefis), conduct the meeting of signal review Panel (srP) approved by mohfW, which in turn place their recommendation to the nra (cdsco) for appropriate regulatory action on vaccines licensed in the country for marketing by mahs. in case of vaccine related aefi, the signal review Panel place their observations to the national aefi causality analysis committee at lhmc (new delhi). after due deliberation, the committee proposes its recommendation on the further course of action, including regulatory action to be undertaken by nra (cdsco). these recommendations are finally approved by the national aefi committee (currently chaired by dr. n.k. arora, retd. Prof. hod of Paediatrics, aiims, new delhi) for appropriate regulatory action by the o/o dcG(i) on the functioning of mah and/or the vaccine product, which was lincesed in the country by mah. Role of PvPi at iPC: • To monitor Adverse Drug Reactions (ADRs) in Indian population. • To create awareness amongst health care professionals about the importance of adr reporting in india. • To monitor benefit-risk profile of medicines and vaccines • Generate independent, evidence based recommendations on the safety of medicines. • Support the CDSCO for formulating safety related regulatory decisions for medicine. • Communicate findings with all key stakeholders. • Create a national centre of excellence at par with global drug safety monitoring standards. • Collaborating with the other international health agencies. • to share the adverse reaction reported for vaccines to (i) district immunization officer (dio), (ii) state aefi committee and (iii) the national aefi committee for examination and recommendation. the results of the cases discussed in the signal review Panel of the Pharmacovigilance Programme of india (PvPi) will be shared with aefi secretariat and cdsco. these results will be used as additional evidence during causality assessment by the ca sub- committee and finalised by the national aefi committee. 10major roles and responsibilities of PvPi at iPc includes development and implementation of pharmacovigilance system in india, enrolment of all mci approved medical colleges in the program covering north, south, east and west of india, encouraging healthcare professionals in reporting of adverse reaction to drugs, vaccines, medical devices and biological products and collection of case reports and data in the suspected adverse drug reaction reporting form. the long term goal of PvPi at iPc includes developing and implementing electronic reporting system (e-reporting), to develop reporting culture amongst healthcare professionals and to make adr reporting mandatory for healthcare professionals. the “Guidance document for reporting individual case safety report” drafted by PvPi at iPc to be referred for vaccine adverse reaction reporting in suspected adverse drug reaction form. 2.3 AEFi sECREtARiAt, immunizAtiOn DivisiOn OF ministRy OF hEAlth AnD FAmily WElFARE: immunization is one of the most cost effective public health interventions resulting in reduction of morbidity and mortality of children. under the universal immunization Programme (uiP), Govt. of india is providing vaccination to prevent 7 vaccine preventable diseases (vPds) namely, diphtheria, Pertussis, tetanus, Polio, measles, hepatitis B and tuberculosis and targets 2.6 crore births and 3.0 crores pregnant women annually. immunizAtiOn sChEDulE in univERsAl immunizAtiOn PROgRAm s. no vaccine Protection number vaccination schedule of Doses 1 BcG (Bacillus tuberculosis 1 at birth (up to 1 year if not calmette given earlier) Guerin) 2. oPv (oral Polio 5 Birth dose for institutional deliveries, Polio three primary doses at 6, 10 & 14 vaccine) week and one booster dose at 16- 24 month of age. Given orally 3. hepatitis B hepatitis 4 Birth dose for institutional deliveries with 24 hour, three primary doses at 6, 10 14 week 4. dPt (diphtheria, diphtheria, 5 three primary doses at 6, 10 & 14 Pertussis and Pertussis and weeks and two booster dose at 16- tetanus toxoid) tetanus 24 month and 5 years of age 5. measles measles 2 1 st dose at 9-12 months of age and 2nd dose at 16-24 months 11Guidance for industry on PharmacoviGilance requirements for BioloGical Products 6. tt (tetanus tetanus 2 - 10 years and 16 years of age, toxoid) -for pregnant woman, two doses (one dose if previously vaccinated within 3 year) 7 Je vaccination Japanese 2 2 doses of Je vaccine are given at (in selected 112 encephalitis 9-12 months and 16-24 month of high disease (Brain age in endemic districts burden districts) disease) in 15 states + 62 new districts i.e. total 174 districts in 19 states. 8 hib (given as haemophilus 3 6, 10 & 14 week of age currently pentavalent influenza type used in 8 states i.e. kerala, containing B vaccine hib tamil nadu, haryana, karanataka, hib+dPt+hep B) Pneumonia Gujarat, Goa, Puducherry and hib and Jammu and kashmir meningitis (brain disease) immunizAtiOn DivisiOn bRiEF FROm mOhFW in 2012, aefi secretariat was established at immunization technical supportive unit (itsu) of Public health foundation of india (Phfi) with due approval of mohfW with mandate of collection, collation, line listing, reporting, sharing with partner organizations (e.g. cdsco), investigation and causality analysis of aefi cases. aefi surveillance monitors immunization safety, detects and responds adverse events following immunization. adverse events after immunization can be serious or non serious. serious aefis such as death, hospitalization, disability, and cluster or community concern need to be reported immediately on standard format crf and investigated timely in the Pcif and fcif. aefi surveillance system in the country is currently passive system with immediate direct reporting of serious aefis (death, hospitalization, prolongation of hospitalization, persistent or significant disability/ incapacity, or is life threatening, community concern) while the non-serious aefis are reported routinely in the health management information system (hmis). serious aefis are investigated by the district immunization officer (dio) with support of district aefi committee and reviewed by the state aefi committee of which the state ePi officer (sePio) is the member secretary. the state aefi committee conducts a causality assessment to the report and sends to the national level in specified formats (crf, Pcif and fcif) within pre- defined timelines. these are then collated and are put up to the national aefi committee for review and assessment. the role of the aefi committees at different administrative levels is to strengthen aefi reporting, conduct thorough investigation, reduce program error and timely detection of signals. an aefi report can be sent to the email address aefi.cdsco@gmail.com the reporting can occur from any level of government or private sector including the private practitioner in the crf form. to obtain detail about completing crf, 12Pcif & fcif, aefi- surveillance and response operational Guidelines of ministry of health & family Welfare, Govt. of india has to be referred. each serious event (s) should be followed up to determine the cause for its occurrence (causality assessment). the causality assessment is done by the state aefi committee/ national aefi committee depending on the urgency of the situation. AEFi ORgAnizAtiOnAl stRuCtuRE aefi secretariat at itsu immunization serious national division, aefi aefi mohfW committee the dio sends fir within next 24 state ePi state aefi hours and Pir in office committee 7 days, the dir is submitted within next 90 days notify aefi within district 24 hours of district aefi immunizaton information committee office Pvt Practitioner health facilities and outreach sessions the aefi secretariat will share limited linelist in excel format with cdsco for deaths and clusters on a weekly basis and all serious and severe cases on a monthly basis. limited linelist will be in excel format and will have state, age, sex, dov, antigens administered, manufacturing details (name, batch number and expiry date) and reason for reporting. Based on the causality assessment report detailed inspection related to GmP, product etc. and further regulatory action are initiated by cdsco in case the quality of the implicated vaccines are indicated to be responsible for the adverse events in the causality assessment report. also as mentioned in the aefi operational guidelines, in case of urgent situation, the state aefi committee along with the state drug control authorities should 13Guidance for industry on PharmacoviGilance requirements for BioloGical Products immediately inform to cdsco/national aefi committee, Govt. of india to take the following steps together. • Report the findings of the investigation of the state government & Govt. of India. • The details of the implicated vaccine or product should be submitted to Govt. of india immediately so that a decision could be made on the temporary suspension of its use & await further instruction from Govt. of india. • CDSCO along with CDL & Immunization division will co-ordinate a re-evaluation of the quality of the vaccine & communicate to the manufacturer (by cdsco), if necessary. 2.4 PhARmACOvigilAnCE DivisiOn (humAn vACCinE) At CDsCO Pharmacovigilance division (human vaccine) is a part of Biological division and monitors all post licensure activities of vaccine related aefi, Psur and any other data on adverse reactions. Pharmacovigilance division (human vaccine) shall be responsible for (i) the coordination with ncc-PvPi (iPc-Gzb.) and immunization division, ministry of health and family Welfare for the various aefi reported in the field (ii) to attend various meeting with the stake holders for coordination purpose or whenever situation arises (iii) collecting all the adverse events/ sae reported by the immunization division and iPc, which shall be reviewed by the expert committee constituted for this purpose for taking further regulatory action. Pms/Psur being conditions for market authorization and licensing and therefore in order to ensure the regulatory conformance and proper design of post marketing studies, this division shall work within the licensing division. this division is responsible for collecting, compiling and collating the data received from the mah as per the requirements of schedule y. the compiled Pms/ Psur data will then be reviewed by the advisory committee constituted by the drugs controller General of india in consultation with ministry of health and family Welfare. Based on the analysis of the advisory expert committee, regulatory decision will be taken by cdsco for further generation of safety and efficacy data not limiting to the initial pre licensure study, if necessary. the design of the study will be suggested by the advisory expert committee and the committee may also review the need for further submission of Pms/Psur data beyond 4 years as per drugs and cosmetics act and rules. further, all cases involving serious unexpected adverse reactions must be reported to the licensing authority within 15 days of initial receipt of the information by the industry. the same will be reviewed by advisory committee and a regulatory decision for marketing shall be taken. if marketing of the new drug is delayed by the applicant after obtaining approval to market, such data will have to be provided on the deferred basis beginning from the time the new drug is marketed. sharing of AEFi with marketing Authorization holder: the aefi secretariat will share limited linelist in excel format with cdsco for deaths and clusters on a weekly basis and all serious and severe cases on a monthly basis. limited linelist will be in excel format and will have state, age, sex, dov, antigens administered, manufacturing details (name, batch number and expiry date) and reason for reporting. cdsco will share linelist details for vaccines relevant to the particular manufacturer with instructions that these are being shared with the mah for internal review and not for investigations in the field. 143. PhARmACOvigilAnCE PlAn the mah will develop a comprehensive pharmacovigilance plan as outlined below. 3.1 PhARmACOvigilAnCE mEthODs the best method to address a specific situation can vary depending on the product, the indication, the population being treated and the issue to be addressed. the method chosen can also depend on whether an identified risk, potential risk or missing information is the issue and whether signal detection, evaluation or safety demonstration is the main objective of further study. When choosing a method to address a safety concern, the mah should employ the most appropriate design. following are the key methods used in pharmacovigilance. 3.1.1 individual Case safety Report: after obtaining either manufacturing licence and/or import registration and /or import licence from the office of dcG (i) at cdsco (hq), all mahs shall place the vaccine products in the market and simultaneously initiate collection, collation and monitoring of all major and minor aefi cases across the country by choosing an appropriate method of vigilance activities as follows:: A) Passive surveillance • Spontaneous Reports a spontaneous report is an unsolicited communication by healthcare professionals or consumers to a mah, regulatory authority that describes one or more adverse drug reactions in a patient who was given one or more biological products and that does not derive from a study or any organized data collection scheme. spontaneous reports play a major role in the identification of safety signals once a drug is marketed. in many instances, a mah can be alerted to rare adverse events that were not detected in earlier clinical trials or other pre-marketing studies. spontaneous reports can also provide important information on at-risk groups, risk factors, and clinical features of known serious adverse drug reactions. caution should be exercised in evaluating spontaneous reports, especially when comparing drugs. the data accompanying spontaneous reports are often incomplete, and the rate at which cases are reported is dependent on many factors including the time since launch, pharmacovigilance-related regulatory activity, media attention, and the indication for use of the drug. b) stimulated Reporting several methods have been used to encourage and facilitate reporting by health professionals in specific situations (e.g., in-hospital settings) for new products or for limited time periods. such methods include on-line reporting of adverse events and systematic stimulation of reporting of adverse events based on a pre-designed method. although these methods have been shown to improve reporting, they are not devoid of the limitations of passive surveillance, especially selective reporting and incomplete information. during the early post-marketing phase, mah might actively provide health professionals with safety information and at the same time encourage cautious use 15Guidance for industry on PharmacoviGilance requirements for BioloGical Products of new products and the submission of spontaneous reports when an adverse event is identified. a plan can be developed before the product is launched (e.g., through site visits by mah representatives, by direct mailings or faxes, etc.). stimulated adverse event reporting in the early post-marketing phase can lead mah to notify healthcare professionals of new therapies and provide safety information early in use by the general population. this should be regarded as a form of spontaneous event reporting, and thus data obtained from stimulated reporting cannot be used to generate accurate incidence rates, but reporting rates can be estimated. C) Active surveillance active surveillance, in contrast to passive surveillance, seeks to ascertain completely the number of adverse events via a continuous pre-organized process. an example of active surveillance is the follow-up of patients treated with a particular drug through a risk management program. Patients who fill a prescription for this drug may be asked to complete a brief survey form and give permission for later contact in general; it is more feasible to get comprehensive data on individual adverse event reports through an active surveillance system than through a passive reporting system. all the sae during the period of Pms/Psur shall be reported within 15 days to the licensing authority in the prescribed format (vaers) vaccine adverse events reporting system. 3.1.2 Periodic safety update Report: Psur are important pharmacovigilance documents. they provide an opportunity for mahs to review the safety profile of their products and ensure that the smPc and Package leaflet within reasonable tme frame. Periodic safety update reports (Psur) present the world-wide safety experience of a medicinal product/vaccines at defined times post-authorization, in order to report all the relevant new safety information from appropriate sources; relate these data to patient exposure; summarize the market authorization status in different countries and any significant variations related to safety; create periodically the opportunity for an overall safety re-evaluation; indicate whether changes should be made to product information in order to optimize the use of the product as per the drugs and cosmetics rules, the applicants shall furnish Periodic safety update reports (Psurs) in order to- (a) report all the relevant new information from appropriate sources; (b) relate these data to patient exposure; (c) summarize the market authorization status in different countries and any significant variations related to safety; and (d) indicate whether changes should be made to product information in order to optimize the use of the product. (i) ordinarily all dosage forms and formulations as well as indications for new drugs should be covered in one Psur. Within the single Psur separate presentations of data for different dosage forms, indications or separate population need to be given. (ii) all relevant clinical and non-clinical safety data should cover only the 16period of the report (interval data). the Psurs shall be submitted every six months for the first two years after approval of the drug is granted to the applicant. for subsequent two years – the Psurs need to be submitted annually. licensing authority may extend the total duration of submission of Psurs if it is considered necessary in the interest of public health. Psurs due for a period must be submitted within 30 calendar days of the last day of the reporting period. however, all cases involving serious unexpected adverse reactions must be reported to the licensing authority within 15 days of initial receipt of the information by the applicant. if marketing of the new drug is delayed by the applicant after obtaining approval to market, such data will have to be provided on the deferred basis beginning from the time the new drug is marketed. new studies specifically planned or conducted to examine a safety issue should be described in the Psurs. a Psur should be structured as follows: (a) title Page: the title page of Psur should capture the name of medicinal product(s); reporting interval; approved indication of medicinal Products; date of approval of new drug; date of marketing of new drug; mah(s) name(s) and address(es). (b) introduction: this section of Psur should capture the reporting interval; medicinal product(s) – mode(s) of action, therapeutic class(es), dose(s), route(s) of administration, formulation(s); a brief description of the approved indication(s) and population(s). (c) current Worldwide marketing authorization status: this section of Psur should capture the brief narrative overview including details of country where the product is currently approved along with date of first approval, date of marketing and if product was withdrawn in any of the countries with reasons thereof. (d) actions taken in reporting interval for safety reasons: this section of Psur should include a description of significant actions related to safety that have been taken during the reporting interval, related to either investigational uses or marketing experience by the mah, sponsor of a clinical trial(s), regulatory authorities, data monitoring committees, or ethics committees. (e) changes to reference safety information: this section of Psur should capture any significant changes to the reference safety information within the reporting interval. such changes might include information relating to contraindications, warnings, precautions, adverse drug reactions (adrs), overdose, and interactions; important findings from ongoing and completed clinical trials and significant non-clinical findings (e.g., carcinogenicity studies). 17Guidance for industry on PharmacoviGilance requirements for BioloGical Products (f) estimated Patient exposure: this section of Psur should provide the estimates of the size and nature of the population exposed to the medicinal product. Brief descriptions of the method(s) used to estimate the subject/patient exposure should be provided. (i) cumulative and interval subject exposure in clinical trials (ii) cumulative and interval patient exposure from marketing experience from india (iii) cumulative and interval patient exposure from marketing experience from rest of the world (g) Presentation of individual case histories: this section of Psur should provide the individual case information potentially available to a mah provide brief case narrative, concomitant medications, medical history indication treated with suspect drug(s), re-challenge & de-challenge, causality assessment. Provide following information: (i) reference Prescribing information for causality assessment (ii) individual cases received from india (iii) individual cases received from rest of the world (iv) cumulative and interval summary tabulations of serious adverse events from clinical trials (v) cumulative and interval summary tabulations from Post-marketing data sources (h) studies: this section of Psur should capture the brief summary of clinically important emerging efficacy/effectiveness and safety findings obtained from the mah’s sponsored clinical trials and published safety studies that became available during the reporting interval of the report which has potential impact on product safety information. (i) summaries of significant safety findings from clinical trials during the reporting period (ii) findings from non-interventional studies (iii) findings from non-clinical studies (iv) findings from literature (i) other information: this section of Psur should include the details about signals and risk management Plan in place by mah (if any). • Signal and risk evaluation: In this section MAH will provide the details of signal and risk identified during the reporting period and evaluation of signals identified during the reporting period. • Risk Management Plan: In this section MAH will provide the brief details of safety concern(s) and necessary action taken by him to mitigate these safety concerns. (j) overall safety evaluation: this section of Psur should capture the overall safety evaluation of the medicinal product based upon its risk benefit evaluation for approved indication. 18(i) summary of safety concerns (ii) Benefit evaluation (iii) Benefit risk analysis evaluation (k) conclusion: this section of Psur should provide the details on the safety profile of medicinal product and necessary action taken by the mah in this regards. (l) appendix: the appendix includes the copy of marketing authorization in india, copy of prescribing information, line listings of individual case safety reports (icsr), soP’s for data collections & review etc. it is recommended that the mah can submit the Psur data either in schedule y format or in conformity with Periodic Benefit-risk evaluation report (PBrer) as per ich e2c (r2) according to the current practices of the developed countries and developing countries and continue to monitor the safety of the vaccines throughout the lifecycle of the product and produce the report as and when required by the licensing authority. 3.1.3 Post marketing trials (Phase-iv): Post marketing trials are studies (other than routine surveillance) performed after drug approval and related to the approved indication(s). these trials go beyond the prior demonstration of the drug’s safety, efficacy and dose definition. these trials may not be considered necessary at the time of new drug approval but may be required by the licensing authority for optimizing the new drug’s (vaccine’s) use. they may be of any type but should have valid scientific objectives. Phase iv trials include additional drug-drug interaction(s), dose-response or safety studies and trials designed to support use under the approved indication(s), e.g. mortality/morbidity studies, epidemiological studies etc. 19Guidance for industry on PharmacoviGilance requirements for BioloGical Products (4) ROlEs AnD REsPOnsibilitiEs OF thE DEsignAtED PERsOn (a) within the company of mAh: in accordance with the Govt. Gazettenotification no. Gsr 287 (e) dated march, 2016, for the purpose of Post market surveillance, the mah shall have a pharmacovigilance system in place for collecting, processing and forwarding the reports to the licensing authorities for information on adverse event following immunization (aefi) emerging from the use of the vaccine manufactured and marketed by the mah in the country. the system shall be managed by qualified and trained personnel and officer-in-charge of collection and processing of data shall be a medical officer or a pharmacist trained in collection and analysis of adr. hence, the marketing authorization holder (mah) should establish an appropriate pharmacovigilance system by assuming the responsibilities and liabilities for its vaccine product(s) circulating in the market and should ensure that appropriate action may be taken whenever safety concerns arise after due investigation and scientific evaluation. the marketing authorization holder (mah) should appoint as per the norms laid down in schedule-y under drugs & cosmetics act 1940 and rules 1945, a qualified and trained personnel with duly given responsibilities for continuously monitoring of the vaccine products at his disposal (b) Adverse Drug Reaction Reporting: 4.1. Procedures and Processes 4.1.1 the mah shall have a pharmacovigilance system in place for collecting, processing and forwarding the report to the licensing authority for information on adverse drug reactions emerging from the use of the drug manufactured or marketed by the applicant in the country. the system shall be managed by qualified and trained personnel and the officer in-charge of collection and processing of data shall be a medical officer or a pharmacist trained in collection and analysis of adverse drug reaction reports. the procedure should include but not be limited to the following: 4.1.1.1 Provisions for timely and thorough review to determine whether the complaint represents an adr; 4.1.1.2 Personnel responsible to receive the incoming correspondence (phone calls, letter, email, etc.) relating to potential adrs through product complaints; 4.1.1.3 how an unique identifier is assigned to each case; and 4.1.1.4 clear and defined processes on adr/complaint, evaluation and follow-up. 4.2 manufacturers and importers should have in place systems and procedures for the receipt, handling, evaluation and reporting of adrs that are adequate to effectively sustain adr reporting within 15 days of receipt to cdsco of domestic serious expected and unexpected adrs, foreign serious unexpected adrs, as well as any follow-up information for initial case reports. this should be read in conformity 20with para 4, under heading Post marketing surveillance sub para (iii) of schedule y of drugs and cosmetics rules. for importer, india specific Psur should be compiled and submitted in a separate section within the Psur data. all the sae shall be reported within 15 days. in case of manufacturer, distributing countries specific Psur should be compiled and submitted in a separate section within the Psur data. all the sae reported in the distributing countries shall be reported within 15 days. 4.3 mahs should have in place adequate procedures for adr receipt, handling, evaluation and reporting and should include but not be limited to the following. 4.3.1 requirement to report to cdsco within 15 days of receipt by the mah, reports of serious adrs occurring within india, and serious unexpected adrs occurring outside of india and any unusual failure in efficacy for new drugs occurring within india, if applicable; 4.3.2 address all the specific indian regulatory requirements, such as when notification is required, definition of serious and non-serious adverse reactions, definition of unusual failure in efficacy of new drugs, if applicable, retention of all records associated with adr, etc.; 4.3.3 requirement to have a qualified health care professional to evaluate and assess adr reports, including the process to review adrs. 4.3.4 identifying the 4 minimum criteria (an identifiable reporter (source), an identifiable patient, a suspect product and an adverse reaction) for submitting a case; 4.3.5 identifying key personnel who are responsible for forwarding the adr reports to the licensing authority; 4.3.6 Procedure on how complaints and adrs are tracked/logged in; 4.3.7 Procedure on how the mah is to be notified of foreign serious unexpected drug reactions; 4.3.8 the decision-making process to assess report ability of adrs; 4.3.9 the responsibilities for the final approval of adr evaluation and appropriate follow-up; 4.3.10 requirement to conduct a critical analysis of adr reports received and preparation of a summary report on an annual basis, or at the request of the licensing authority (cdsco). as per drugs and cosmetics rules, schedule m para 28 under heading “complaints and adverse reaction”, sub-para 28.2 reports of serious adverse drug reaction resulting from the use of a drug along with comments and documents shall be forthwith reported to concerned licensing authority. the licensing authority in this case shall be both cdsco and state licensing authorities. 4.4 importers should have in place adequate procedures for adrs receipt, handling, evaluation (for determination of complaints or adr) and forwarding adrs to the mah and should include but not be limited to the following 4.4.1 Procedure on how complaints and adrs are tracked/logged in; 4.4.2 Procedure on how complaints are assessed in order to determine if it is an adr; 4.4.3 identifying key personnel who are responsible for forwarding the adrs reports to the mah; 4.4.4 requirement to report adrs to the mah within an appropriate timeframe to allow for expedited reporting (if required); and all saes to be reported within15 days of receipt of information to cdsco this should be read in conformity with para 4, 21Guidance for industry on PharmacoviGilance requirements for BioloGical Products under heading Post marketing surveillance sub para iii of schedule y of drugs and cosmetics rules. 4.4.5 requirement to follow up with the mah to ensure that adrs have been assessed and sent to drugs controller General (india), if required; 4.4.6 requirement to maintain records of all adrs received and adrs sent to the mahs and subsequent correspondence; and ensure that as per drugs and cosmetics rules, schedule m para 28 under heading complaints and adverse reaction, sub- para 28.2 reports of serious adverse drug reaction resulting from the use of a drug along with comments and documents are forthwith reported to concerned licensing authority (cdsco). 4.5 Procedures should be written, reviewed and approved by qualified personnel. 4.6 Procedures should be made available to all relevant personnel involved in pharmacovigilance activities before the procedures are effective. 4.7 Procedures should be reviewed on a periodic basis to ensure that they accurately reflect current practice. 4.8 changes to procedures should be tracked and documented. 4.9 deviations from procedures relating to pharmacovigilance activities should be documented 4.10 When part or all pharmacovigilance activities are performed by a third party, mah and importers should review procedures to ensure that procedures are adequate and compliant with applicable requirements stated in the drugs and cosmetics act and rules. copies of the procedures should be readily available to the inspector/ regulator. 4.11 mahs 4.11.1 the adr evaluation, including but not limited to, seriousness and expectedness assessment should be completed in a manner which would ensure expedited reporting timelines are met. for both domestic and foreign reports, the expectedness should be determined from the relevant labeling such as the product monograph, labeling standards, information approved for market authorization, or the product label. 4.11.2 mechanisms should be in place to determine whether an adr qualifies for 15 day expedited reporting. When a case is found not reportable, justification is provided and documented. 4.11.3 for adr reports that qualify for expedited reporting, the 4 minimum criteria (an identifiable reporter (source), an identifiable patient, a suspect product and an adverse reaction) for submitting a case are met. 4.11.4 Process should be in place for determining if a solicited report is to be submitted to licensing authority in an expedited fashion (within 15 days). 4.11.5 a qualified health care professional evaluates and assesses adrs to determine whether the adr qualifies for expedited 15-day reporting. 4.12 Reports of ADR cases from 2 or more sources 4.12.1 a mechanism should be in place to identify adr data that were reported to the mah more than once. 4.12.2 When similar reports are found, verifications should take place to determine if they are duplicate reports. 4.12.3 multiple copies of the same adr reports should be nullified within the 22pharmacovigilance system and the record of nullification should be maintained, allowing for auditing of the nullified record in the future. 4.12.4 documented procedure and process should be in place describing when adr reports may be nullified. 4.12.5 documentation related to nullified cases should be retained. 4.12.6 additional information received for previously submitted adr reports 4.12.7 upon receipt of follow-up information, adr reports should be re-evaluated. 4.12.8 follow-up information received for previously submitted adr reports must be sent to licensing authority within the prescribed timelines. reference should be made to the initial report by including the mah number specific to the report either in the follow-up report or on the fax cover sheet. 4.12.9 all reportable adrs that have been upgraded to serious upon receipt of follow- up information are to be sent to licensing authority within the prescribed timelines 4.12.10 rationale for changing the seriousness of an adr report should be documented. 4.12.11 Process for seeking follow-up information and submitting it to licensing authority should be in place. all attempts to obtain follow-up information should be documented. 4.13 Reporting of ADR data 4.13.1 mahs 4.13.2 all adrs shall be reported to licensing authority (cdsco) in accordance with drugs and cosmetics rule. 4.14 importers 4.14.1 all suspected adrs received should be sent to the mah within an appropriate time frame to allow for expedited reporting (if required), and should therefore be reported to licensing authority by the mah in accordance with the requirements of the drugs and cosmetics rule, if required. 4.14.2 importers should follow-up with the mah to ensure that adrs have been assessed and submitted, if required. 4.15 literature search 4.15.1 mahs 4.15.1 the process, including but not limited to how the search is done, the database(s) used, and the periodicity of those searches describing the search in the literature should be written in a procedure. 4.15.2 adrs found during literature searches should be classified according to their seriousness and expectedness. these assessments should be retained and be well documented. 4.15.1.3 adr reports from the scientific and medical literature must be reported to licensing authority in accordance with the drugs and cosmetics rule. 4.15.1.4 results of the literature searches should be documented. 4.15.1.5 When literature search is performed by a third party, contractual agreements describing each party’s responsibilities should exist. Periodic self-inspections 4.16 mahs and importers 4.16.1 a self-inspection program that covers all departments that may receive adr reports or that are involved in pharmacovigilance activities may help to ensure 23Guidance for industry on PharmacoviGilance requirements for BioloGical Products compliance with the appropriate sections of the drugs and cosmetics rule applicable to adverse drug reaction reporting. self-inspection programs should be in place and should include but not be limited to the following; 4.16.1.1 a comprehensive written procedure that describes the functions of the self- inspection program. 4.16.1.2 Periodic self-inspections that are carried out at defined frequencies, which are documented. if no adrs have been received, the periodic self-inspections should include a simulation exercise. 4.16.1.3 reports on the findings of the self-inspections and on corrective actions. these reports should be reviewed by appropriate senior mah management. corrective actions should be implemented in a timely manner. 4.17 Periodic self-inspections should be conducted by personnel independent from the pharmacovigilance department and that are suitably qualified to perform and evaluate the inspections. Personnel and training 4.18 mahs and importers 4.18.1 the individual in charge of the pharmacovigilance department should be qualified by pertinent training and experience relevant to their assigned responsibilities 4.18.2 the qualified health care professional; 4.18.2.1 should have knowledge of all applicable sections of the food and drug regulations related to the adr reporting requirements, and of key pharmacovigilance activities performed as part of the mah’s pharmacovigilance system. 4.18.2.2 should be responsible for establishing and managing/maintaining a system which ensures that information concerning all suspected adrs that are reported to the personnel of the mah and to medical representatives is collected and evaluated. 4.18.2.3 all personnel involved in pharmacovigilance activities, which may include customer service, sales representatives and receptionists, should have their specific duties recorded in a written description and have adequate authority to carry out their responsibilities. 4.18.2.4 all personnel involved in pharmacovigilance activities should be aware of the principles of pharmacovigilance that affect them, and all personnel should receive relevant training. 4.18.2.5 When responsible personnel are absent, qualified personnel should be appointed to carry out their duties and functions. 4.18.2.6 a qualified health care professional with adequate experience and training, should be available to evaluate information in respect of a potential adrs, assesses the seriousness, expectedness, and report ability of adrs, and determine if the adr report qualifies for expedited reporting (within 15 days) and if the report is to be included in the annual summary 4.18.2.7 training should be provided prior to implementation of new or revised procedures. records of training should be maintained. 4.18.2.8 consultants and contractors should have the necessary qualifications, training, and experience to fulfill their responsibilities. Contractual Agreements 4.19 mahs and importer 4.19.1 contractual agreement should exist with every party that conducts pharmacovigilance activities, including third- party private label or other mah whose name is included in the product information or appears on the label and should 24include; 4.19.1.1 who is responsible for determining if a complaint is a potential adr, 4.19.1.2 Who is responsible to report adr, 4.19.1.3 Who is responsible for preparing the asr, including the critical analysis of the annual summary reports, and what process is utilized to conduct the critical analysis, 4.19.1.4 Who is responsible for conducting literature searches? 4.19.1.5 Processes by which an exchange of safety information, including timelines and regulatory reporting responsibilities, are taking place between the mah and its partners (including, but not limited to, consultants and contractors). 4.19.1.6 to notify other party if changes to procedures are made. 4.19.2 in the case of foreign mahs, the contractual agreement should specify to send known adrs to the local mah in a timely manner so as to promote compliance with regulatory reporting obligations. 4.19.3 in the case where the importer is responsible for the pharmacovigilance activities, the contractual agreement should specify that the foreign mah is to send the adr data to the importer in a timely manner. 4.19.4 all records (including, but not limited to, contractual agreements and safety data/adr data) should be available on the premises of the mah and the importer for auditing purposes 4.19.5 When there is a transfer of market authorization/mergers, contractual agreement should exist between the previous mah and the new one outlining each party responsibility. 4.19.6 contractual agreement should be shared and signed off by each party. 4.19.7 contractual agreement should be reviewed periodically in order to reflect current regulations and practices. validation of Computerized systems 4.20. mahs, importer, and all parties involved in pharmacovigilance activities who use an electronic system. 4.20.1 data of the validation of system(s) used for recording, evaluating, and tracking complaints and adrs should be available. 4.20.2 computerized systems should be validated and systems are periodically and suitably backed up at predefined intervals. 25Guidance for industry on PharmacoviGilance requirements for BioloGical Products 5. DEvElOPmEnt AnD usE OF Risk minimizAtiOn ACtiOn PlAns the mah shall develop, implement and evaluate risk minimization action plan which shall include (1) initiating and designing plans called risk minimization action plans or risk maPs to minimize identified product risks, (2) selecting and developing tools to minimize those risks, (3) evaluating risk maPs and monitoring tools. the goal of risk minimization is to minimize a product’s risks while preserving its benefits. the statutory standard for nra approval of a product is that the product is safe and effective for its labeled indications under its labeled conditions of use. rather, a product is considered to be safe if the clinical significance and probability of its beneficial effects outweigh the likelihood and medical importance of its harmful or undesirable effects. in other words, a product is considered safe if it has an appropriate benefit-risk balance for the intended population and use. Benefit and risk information emerges continually throughout a product’s lifecycle (i.e., during the investigational and marketing phases) and can reflect the results of both labeled and off-label uses. assessment and comparison of a product’s benefits and risks is a complicated process that is influenced by a wide range of societal, healthcare, and individualized patient factors. to help ensure safe and effective use of their products, sponsors have always sought to maximize benefits and minimize risks. routine risk minimization measures such as labeling practices describing the conditions in which the drug can be used safely and effectively, updated from time to time to incorporate information from post marketing surveillance or studies revealing new benefits (e.g., new indications or formulations) or risk concerns. communication of risks and benefits through product labeling is the corner stone of risk management efforts for prescription drugs. risk maps should be used judiciously to minimize risks without encumbering drug availability or other wise interfering with the delivery of product benefits to patients. to help ensure safe and effective use of their products, mah has always sought to maximize benefits and minimize risks. routine risk minimization measures such as labeling practices describing the conditions in which the drug can be used safely and effectively, updated from time to time to incorporate information from post marketing surveillance or studies revealing new benefits (e.g., new indications or formulations) or risk concerns. risk maP is a strategic safety program designed to meet specific goals and objectives in minimizing known risks of a product while preserving its benefits. a risk maP targets one or more safety zrelated health outcomes or goals and uses one or more tools to achieve those goals. a risk maP could also be considered as a selectively used type of safety action Plan. a risk warranting the consideration of a risk maP could emerge during premarketing or post marketing risk assessment. the appropriate information for consideration in making such a determination should include, as applicable, (1) data from the clinical development program, post marketing surveillance, and phase 4 studies, and (2) the product’s intended population and use. although it is expected and hoped that ma holders will determine when a risk maP would be appropriate, it may be recommended for a risk maP based on the authority’s own interpretation of risk information. decisions to develop, submit, or implement a risk maP are always made on a case-by-case basis, but several considerations are common to most determinations of whether development of a risk maP may be desirable: 265.1. nAtuRE AnD RAtE OF knOWn Risks vERsus bEnEFits: comparing the characteristics of the product’s adverse effects and benefits may help clarify whether a risk maP could improve the product’s benefit-risk balance. the characteristics to be weighed might include the 1. types, magnitude, and frequency of risks and benefits; 2. populations at greatest risk and/or those likely to derive the most benefit; 3. existence of treatment alternatives and their risks and benefits; and 4. reversibility of adverse events observed. Preventability of adverse effects: serious adverse effects that can be minimized or avoided by preventive measures around drug prescribing are the preferred candidates for risk maPs. Probability of benefit: if factors are identified that can predict effectiveness, a risk maP could help encourage appropriate use to increase benefits relative to known risks. a risk minimization tool is a process or system intended to minimize known risks. tools can communicate particular information regarding optimal product use and can also provide guidance on prescribing, dispensing, and/or using a product in the most appropriate situations or patient populations. a number of tools are available and may be used as required. a variety of tools are currently used in risk minimization plans. these fall within three categories: (1) targeted education and outreach, (2) reminder systems, and (3) performance linked access systems. 5.2. tARgEtED EDuCAtiOn AnD OutREACh it is recommended that ma holders consider tools in the targeted education and outreach category. (i) When routine risk minimization is known or likely to be insufficient to minimize product risks or (ii) as a component of risk maPs using reminder or performance-linked access systems. sponsors are encouraged to continue using tools, such as education and outreach, as an extension of their routine risk minimization efforts even without a risk maP. tools which may be used as routine risk minimization efforts even without a risk maP may be: • Training programs for healthcare practitioners or patients • Continuing education for healthcare practitioners such as product-focused programs developed by sponsors and/or sponsor-supported accredited ce programs • Prominent professional or public notifications • Patient labeling such as Medication Guides and patient package inserts Promotional techniques such as direct-to-consumer advertising highlighting appropriate patient use or product risks • Patient-sponsor interaction and education systems such as disease management and Patient access programs • Healthcare practitioner letters 27Guidance for industry on PharmacoviGilance requirements for BioloGical Products in addition to informing healthcare practitioners and patients about conditions of use contributing to product risk, educational tools can inform them of conditions of use that are important to achieve the product’s benefits. on the other hand, deviations from the labeled dose, frequency of dosing, storage conditions, or other labeled conditions of use might compromise the benefit achieved, yet still expose the patient to product related risks. risks and benefits can have different dose-response relationships. risks can persist and even exceed benefits when products are used in ways that minimize effectiveness. therefore, educational tools can be used to explain how to use products in ways that both maximize benefits and minimize risks. it is recommended that tools in the reminder systems category be used in addition to tools in the targeted education and outreach category when targeted education and outreach tools are known or likely to be insufficient to minimize identified risks. tools in the reminder system include systems that prompt, remind, double- check or otherwise guide healthcare practitioners and/or patients in prescribing, dispensing, receiving, or using a product in ways that minimize risk. examples of tools in this category are as follows: • Patient education that includes acknowledgment of having read the material and an agreement to follow instructions. these agreements are sometimes called consent forms. • Healthcare provider training programs that include testing or some other documentation of physicians’ knowledge and understanding. • Enrolment of physicians, pharmacies, and/or patients in special data collection systems that also reinforce appropriate product use. • Limited number of doses in any single prescription or limitations on refills of the product. • Specialized product packaging to enhance safe use of the product. • Specialized systems or records that are used to attest that safety measures have been satisfied (e.g. Prescription stickers, physician attestation of capabilities). 5.3. PERFORmAnCE-linkED ACCEss systEms Performance-linked access systems include systems that link product access to laboratory testing results or other documentation. tools in this category, because they are very burdensome and can disrupt usual patient care, should be considered only when (1) Products have significant or otherwise unique benefits in a particular patient group or condition, but unusual risks also exist, such as irreversible disability or death, and (2) routine risk minimization measures, targeted education and outreach tools, and reminder systems are known or likely to be insufficient to minimize those risks. in choosing tools for a risk maP, it is recommended that sponsors: • Maintain the widest possible access to the product with the least burden to the healthcare system that is compatible with adequate risk minimization (e.g., a reminder system tool should not be used if targeted education and outreach would likely be sufficient). 28• Identify the key stakeholders who have the capacity to minimize the product’s risks (such as physicians, pharmacists, pharmacies, nurses, patients, and third party payers) and define the anticipated role of each group. • Seek input from the key stakeholders on the feasibility of implementing and accepting the tool in usual healthcare practices, disease conditions, or lifestyles, if possible. examples of considerations could include (but would not be limited to) patient and healthcare practitioner autonomy, time effectiveness, economic issues, and technological feasibility. • Acknowledge the importance of using tools with the least burdensome effect on healthcare practitioner- patient, pharmacist-patient, and/or other healthcare relationships. it is recommended that ma holders periodically evaluate each risk maP tool to ensure it is materially contributing to the achievement of risk maP objectives or goals. 6. DEFinitiOns A. Adverse Event (AE): any untoward medical occurrence (including a symptom / disease or an abnormal laboratory finding) during treatment with a pharmaceutical product in a patient or a human volunteer that does not necessarily have a relationship with the treatment being given. also see serious adverse event. b. Adverse Event Following immunization (AEFi): this is defined as any untoward medical occurrence which follows immunization and which does not necessarily have a causal relationship with the use of the vaccine. the adverse event may be any unfavourable or unintended sign, an abnormal laboratory finding, a symptom or a disease. C. Adverse Drug Reaction (ADR): (a) in case of approved pharmaceutical products: a noxious and unintended response at doses normally used or tested in humans (b) in case of new unregistered pharmaceutical products (or those products which are not yet approved for the medical condition where they are being tested): a noxious and unintended response at any dose(s). the phrase adr differs from ae, in case of an adr there appears to be a reasonable possibility that the adverse event is related with the medicinal product being studied. adverse drug reactions are type a (pharmacological) or type B (idiosyncratic). type a reactions represent an augmentation of the pharmacological actions of a drug. they are dose-dependent and are, therefore, readily reversible on reducing the dose or withdrawing the drug. in contrast, type B adverse reactions are bizarre and cannot be predicted from the known pharmacology of the drug. D. serious Adverse Event (sAE) or serious Adverse Drug Reaction (sADR) an ae or adr that is associated with death, inpatient hospitalization, prolongation of 29Guidance for industry on PharmacoviGilance requirements for BioloGical Products hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or is otherwise life threatening. this is to be read along with the definition as mentioned in drugs & cosmetics act 1940 and rules 1945 there under as- a serious adverse event is an untoward medical occurrence during clinical trial that is associated with death, in patient hospitalization, prolongation of hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or is otherwise life threatening. E. suspected serious Adverse Reaction (ssAR): an adverse reaction that is classed in nature as serious and which is consistent with the information about the medicinal product in question set out. • In the case of a licensed product, in the summary of product characteristics (smPc) for that product. • In the case of any other investigational medicinal product, in the investigator’s Brochure (iB) relating to the trial in question. F. suspected unexpected serious Adverse Reaction (susAR): an adverse reaction that is classed in nature as serious and which is not consistent with the information about the medicinal product in question set out. • In the case of a licensed product, in the summary of product characteristics (smPc) for that product. • In the case of any other investigational medicinal product, in the IB relating to the trial in question. g. third Party: for the purpose of this guidance documents means that the entity who is nor the manufacturer neither the importer. h. market Authorization holder (mAh): for the purpose of this guidance document means the manufacturer or the importer of the drug, who has valid manufacturing or import license. i. Cluster: two or more cases of the same event or similar events related in time, geography, and/or the vaccine administered. 7. REFEREnCEs • ICH Guideline. E2E: Pharmacovigilance Planning • Drugs and Cosmetics Act 1940 & Rules 1945– Schedule Y • Guidance for Industry – Development and Use of Risk Minimization Action Plans – us fda 30Page 50 of 71 31Guidance for industry on PharmacoviGilance requirements for BioloGical Products Page 51 of 71 32Page 52 of 71 33Guidance for industry on PharmacoviGilance requirements for BioloGical Products Page 53 of 71 34Page 54 of 71 35Guidance for industry on PharmacoviGilance requirements for BioloGical Products Page 55 of 71 36Page 56 of 71 37Guidance for industry on PharmacoviGilance requirements for BioloGical Products Page 57 of 71 38Page 58 of 71 39Guidance for industry on PharmacoviGilance requirements for BioloGical Products Page 59 of 71 40Page 60 of 71 41Guidance for industry on PharmacoviGilance requirements for BioloGical Products Page 61 of 71 42Page 62 of 71 43Guidance for industry on PharmacoviGilance requirements for BioloGical Products Page 63 of 71 44Page 64 of 71 45Guidance for industry on PharmacoviGilance requirements for BioloGical Products Page 65 of 71 46Page 66 of 71 47Guidance for industry on PharmacoviGilance requirements for BioloGical Products Page 67 of 71 48Page 68 of 71 49Guidance for industry on PharmacoviGilance requirements for BioloGical Products Page 69 of 71 50Page 70 of 71 51Guidance for industry on PharmacoviGilance requirements for BioloGical Products Page 71 of 71 52Central DrugS StanDarD Control organiSation Directorate General of Health Services Ministry of Health and Family Welfare, Government of India FDA Bhawan, Kotla Road, New Delhi -110002