Notice-27.09.2018_Draft Pharmacovigilance System Inspection Guideline

Central Drugs Standard ControlOrganization Directorate General of Health Services Ministry of Health and Family Welfare Government of India Risk based programme for pharmaco-vigilance inspections of market authorisation holders (MAHs) for human medicinal products Applies to Inspectorate staff deputed by CDSCO This document provides harmonized standards on the planning, preparation, conduct and reporting of risk-based Summary of Scope pharmacovigilance inspections of market authorization holder (MAHs) for medicinal products, approved for marketing in India. Planning, Preparation, Conduct, Reporting, Pharmacovigilance Keywords Inspection, PVOI, MAH, Licence, Import, Manufacture. Procedure No: CDSCO/INS/PV/001/2018 Supersedes Prepared by Reviewed by Approved by 1ABBREVIATIONS & DEFINITIONS ADR Adverse Drugs Reaction AE Adverse event AEFI Adverse Events following Immunization ASP Active Surveillance Plan CCDS Company Core Data Sheet CDSCO Central Drugs Standard Control Organisation DCA Drugs & Cosmetics Act DCG(I) Drugs Controller General (India) DCR Drugs & Cosmetics Rules DGHS Directorate General of Health Services DCC Drugs Consultative Committee DTAB Drugs Technical Advisory Board EC Ethics Committee EIP Extended Immunization Programme FDC Fixed Dose Combination ICMR Indian Council of Medical Research ICSR Individual Case Safety Reports ICMR Indian Council for medical Research IPC Indian Pharmacopeia Commission ITSU Immunization Technical Support Unit MAH Marketing Authorisation Holder (Manufacturers/Importer) MoH&FW Ministry of Health & Family Welfare, Govt. of India NACO National AIDS Control Organization NCC-PvPI National Coordination Centre for Pharmacovigilance Programme of India NHSRC National Health Systems Resource Centre 2NVBDCP National Vector Born Disease Control Programme NRA National Regulatory Authority PI Package Inserts PMS Post Marketing Surveillance PSUR Periodic Safety Update Report Pv Pharmacovigilance RNTCP Revised National TB Control Programme RMP Risk Management Plan SAE Serious Adverse Events SDLA State Drugs Licensing Authority SEC Subject Expert Committee SEC Subject Expert Committee. SUSAR Serious Unexpected Suspected adverse reaction UIP Universal Immunization Programme 3TABLE OF CONTENT Sl No Content Page Number 1 Introduction 3 2 Purpose 4 3 Scope 6 4 Procedure 6 5 Gathering of Information 6 6 Preparation & revision of the program 7 7 Adoption of the program 7 8 Implementation of the program 8 9 Re-inspections 8 10 Procedure 9 11 Annexure-1 10 12 Annexure-2 10 13 Annexure-3 11 14 Context of Drugs 11 4Introduction CDSCO, under DGHS of MoH&FW is the NRA for medicinal products, Cosmetics and Medical devices in India. This organization as nodal agency, discharges the regulatory functions to ensure safety, efficacy and quality of “Drugs” as defined under Section 3 (b) (i-iv) of Drugs & Cosmetics Act and Rules. CDSCO is headed by the DCG(I) as Licensing Authority defined under Rule 21 in respect of grant of permission for manufacture / import of “New drugs”, which is also defined under Rule-122E of DCR. A. As per Schedule –Y of DCR, Point no (3) for studies in special populations, Para (4) specifies Post Marketing Surveillance; as given below; 1. The applicant shall have a pharmacovigilance system in place for collecting, processing and forwarding the report to the licensing authority for information on ADR emerging from the use of the drugs manufactured or marketed by the applicant in the country, vide GSR Notification no. 287(E), dated 08.03.16 (effective:08-03-2016). 2. The system shall be managed by qualified, trained personnel & the officer in- charge for collection and processing of data shall be a medical officer or a pharmacist trained in collection and analysis of ADR reports, vide GSR Notification no. 287(E), dated 08.03.16 (effective:08-03-2016). 53. Subsequent to approval of the product, “New drug” shall be closely monitored for its clinical safety once it is marketed and the MAH shall have to submit PSUR every 6 monthly for first 2 years and every year for the next two years. B. Also, under Schedule M of DCR according to section 28.2, every MAH (the Licencee for manufacture Drugs) shall report serious adverse drug reactions resulting from the use of a drug along with comments and documents to the concerned Licensing Authority (s). C. Similarly, in Schedule-D (II) of DCR, an MAH (the Licencee for Import of Drugs), it is mandatory in section 2.18 that they should submit the detailed PMS study Report for marketing period not exceeding five years to the Licensing Authority (s) for their marketed drug products at the time of submission of renewal application. In accordance to the above mentioned requirements; every MAHs (Licencees) in the country shall have an established Pv-system in place for collecting, processing and forwarding the report to the Licensing Authority (s). In compliance with the “Pharmacovigilance guidance document for marketing authorization holder” published by NCC-PvPI IPC in collaboration with CDSCO, the regulatory authorities should determine a program for inspection in relation to marketed pharmaceutical products. These inspections will be prioritized based on the potential risk to public health, the nature of the products, the extent of use, number of products that the MAH marketed. The Licensing Authority(s) under the legislative provisions (DCA & DCR) shall ensure by means of repeated inspections, and if necessary unannounced inspections, that the legal 6requirements governing medicinal products are complied with. The Licensing Authority(s) may inspect the premises, enquire the records and documents of MAH or any firms employed by the MAH to perform such other activities. The Licensing Authority(s) of National & State level shall establish written procedure for preparation and revision of guidance documents to impose implementation and supervision of systematic risk-based inspections. The programme shall ensure the extent and frequency of inspections that can be adhered and also sufficient resources must be determined and made available to ensure that the designated program of inspection can be carried out in an appropriate manner. The national level pharmacovigilance inspection programs will fulfil the need for the routine inspections. However, based on recommendations from SEC and other statutory bodies (e.g DTAB, DCC), various Government bodies e.g. ICMR, NACO, RNTCP, NVBDCP etc. if necessitate the targeted / triggered inspections will also be reflected in this programme as they may replace the need for a routine inspection. Purpose This guidance document provides the procedure for a risk-based planning of routine pharmacovigilance inspections schedule which shall present the list of companies and list of products which are prioritised based on criteria, as per Annexure-1, although considerations should be given to inspection early post authorisation and to introduce a random element to the inspection programme at an early stage. The programme will be separated from any targeted / triggered inspection, but if a targeted inspection has been or will be conducted in a similar timeframe it may replace the planned routine inspection and for this reason it will remain reflected in the programme with a new scheduled year for that inspection. Specific triggers for targeted inspection are listed in Annexure-2. 7Scope  This procedure shall cover the PV-inspection (Routine) of MAHs who are placing human medicinal products in Indian market based on approval from the LA (CDSCO and / or SDLA) as defined in Section-21 of DCA for manufacture and import. National PV-inspection programmes (NPVIP) is expected to fulfil the need for regulatory compliances by routine inspections and if required targeted /triggered Inspections.  Therefore, when a Competent Authority has carried out, or intends to carry out an inspection covering the scope of that requested within the required timeframe, the inspection results will be made available to the DCG(I) for further reviewing by a committee constituted by the DCG(I) at CDSCO (HQ).  If such situations arise that PV-inspections would be specifically requested by any committee appointed by Govt. of India e.g. SEC, DTAB, DCC, the focus of such inspections would be to determine whether the MAH has the personnel, systems and facilities in place to meet their regulatory PV- obligations for “Drugs” placed by them in the Domestic & overseas market.  These inspections will be requested as system inspections with one or more specific products selected as examples, for which specific information can be traced and verified through various processes. This shall provide a practical evidence for the functioning of the MAH’s PV-system and their compliance with the regulatory requirements.  The timing of the first inspection and any further inspection will be determined on the basis of prioritisation criteria described in this procedure but as a principle, re-inspections will take place based on risk assessment criteria. A four-year inspection cycle will be used but may be shortened or lengthened based on the risk assessment. This process and the methodology should be revised as appropriate. 8Flow Diagram of systematic risk based pharmacovigilance program Pharmacovigilance Inspection Routine or Periodic Inspection Cause or Triggered Inspection System Inspection Products specific inspection:  The inspection aims to address specific Feed Back questions related to a product  This does not include a systems review. Because the PV- system has recently “New Drugs” used as been examined. Products used as examples: examples:  Specific Questions for a product may 1. Companies who are placing arise from intelligence output, media  When significant changes to PV- “New Drugs” will be (electronic/ print) report. system have occurred since the prioritized for routine  Report from procurement agencies / previous inspection systemic Pv-Inspection, customer / foreign party.  Critical findings were identified depending upon number,  Frequent Complaints related to NSQ during the previous systems categories and frequencies and / or ADRs on medicinal products review (eg. Delays in expedited of market launch of the from the market. or PSUR submission or poor same  Significant number of Adverse Reports quality or incomplete PSURs 2. Rest of the companies will on medicinal products from electronic etc.) be inspected based on and print media from multiple places.  Frequent Complaints related to number, categories and  Recommendations / comments from NSQ and / or ADRs on medicinal frequencies of market various Govt. bodies ICMR, RNTCP, products from the market. launch. NVBDCP, UIP etc. or any Organized 3. Re-inspection frequency  Significant number of Adverse procurement agencies e.g. ESIC will depend on any Reports on medicinal products  High rate & extent of Cluster ADRs significant changes to the from electronic and print media  Frequent and too many changes in system since the previous from multiple places. CCDS, PI and labels of medicinal inspection or on any critical products. findings identified during the previous systems review etc. 9Procedure  Based on the dynamic List of “New Drugs” approved by the DCG(I), the pharmacovigilance section in CDSCO (HQ) will prepare a 4-yearly program for routine PV-inspections.  This 4-yearly program will be revised on year-to-year basis.  The preparation and revision of this program will be initiated 12 months in advance of the implementation of the first year of such program and allow for having always a consecutive four-yearly program  For example, considering a 2018-21 program, during the implementation of the 2018 program, the new 2019 program should be prepared in order to have the consecutive 2019-2022 four-yearly program).  The periodicity of re-inspections will be determined by various risk factors associated with the Medicinal products, functioning of the MAH. Gathering Information  At least twice per year, CDSCO will gather information from the MAH e.g. changes in the location of the PVOI, changes in data base system, too many changes proposing in product label & package inserts, too many & frequent Post-approval Changes and also information on any new MAHs add on the market force with New drug to be included in the program.  In addition, previous information available on inspections or inspections conducted / planned at national level will also be taken into 10consideration (e.g. the re-inspection dates proposed by the inspectors and / or review committee, if any, after conduct of the inspections proposed in this program).  Other necessary tools will be identified and implemented to facilitate the collection and exchange of information on risk factors / triggers for inspections like the “Template for collecting information on PV issues for the attention of the inspectors/assessors”. Preparation and revision of the program This document envisages a programme covering composite PV- inspections plan for rolling out a 4-year cycle with revision by 12 months in advance. Thus the first year of such programme will replace that year and allow for a consecutive 4-yearly programme to be in place and further revisions in order to introduce any necessary changes to the programme. Thus a dynamic, rolling on 4-year cycle programme shall be revised each year to reflect the inspections already performed, the revised priorities, new MAHs, New drugs joining the system, new signals of ADR, Cluster ADRs. The PV section in CDSCO (HQ) will prepare first 4yearly programme based on the information gathered from the official website of CDSCO and prioritising “MAHs” and “specific Drugs” to be inspected, as per “primary prioritisation factors” (Annexure-1). The priority list in this first programme will be in principle established based on the number of prioritisation factors 11that concur at the same time for a particular MAH. Once a preliminary selection has been made, the “secondary prioritisation factors” (see annex 1),may be used in order to refine this selection. The preparation / revision of further 4-yearly programmes will be made as per the following rules:  For new MAH to be included in the program, the feedback from the inspectorates on when they plan to inspect these MAHs will be considered. This proposal may need to change based on the prioritising factors in Annex-1.  The conduct of an inspection early post authorisation and/or the introduction of a random element to the inspection program may be used as well to refine the selection.  For the MAHs already included in the program, the inspectorates will be asked to confirm whether or not a change is needed, ensuring that these CAP inspections fit in with CDSCO’s national PV-Inspection programs.  CDSCO may trigger inspection of a particular “MAH” and “Drug” based on feedback from the assessors (e.g. SEC)/PVPI/Immunization division (MOHFW) /SDLA/ Institutional procurement agencies.  Re-inspections will be determined by risk factors and will be focused on addressing critical findings observed in previous inspections, changes in the system or any product specific issues of concern for the assessors. 12 The preparation & revision of further 4-yearly programs will take place at least twice per year i.e. 1Q and 3Q of 2018.  The program should at least include the below details: (i) Full name of The MAH (ii) Registered / corporate Office address of MAH (iii) Contact person, e-mail and telephone (Land & Mobile) No. (iv) PVOI and his organogram (v) Work Station of the PVOI and his team. (vi) Name Contact Phone No. & addresses of the hired Service providors (vii) List of all “New Drugs” approved in previous 4-year (viii) Licences / permission granted for manufacture and / or Import of such “New drugs” (ix) Brand name and INN of such “New drugs” (x) Routine or triggered Inspection (xi) If triggered, the entity of requestor (xii) Inspected sites, dates of inspection will be tracked in other working documents e.g Inspection Trackers, Inspection Reports, Ad-memoir etc. 13Adoption of Program This four-yearly programme should be concurred and duly approved by the DCG(I) before its implementation. As this programme will be a live document requiring periodic revision through the year, it is expected to be circulated to the appropriate persons for review at least twice, in the 2Q and 4Q of the year. Implementation of the program The nominated inspectorate should ensure that these inspections take place as agreed and approved by the DCG(I). The inspectors should submit a summary report along with the critical and major findings on the concluding day of Inspection to DCG(I) by official e-mail. The final elaborated inspection report including how these substantial issues are to be addressed may be submitted within 15-calender days of the concluding day of inspection. For those inspections requested by the SEC the specific recommendation should be followed. A flow diagram on the circulation of the inspection reports related to this programme is available in Annexure-3. 14Re-inspection The calculation of the next inspection date should result from the last inspection date and the risk assessment process. In principle a 4-year inspection cycle will be used but may be shortened or lengthened based on this risk assessment. Summary of Procedure Steps for the preparation of the 2018-2021; CDSCO routine pharmacovigilance program Sl Time Steps Sources Responsibility No Line i. CDSCO website ii. PvPI At least 1Q & Gathering iii. Immunization Division 3Q 200(X-1) information for Pharmacovigilance iv. Market complaints. e.g For 2019, 1 making PV- division in CDSCO v. Print/ Electronic Media do it in 1st& Inspection plan (HQ) vi. Peer review journals / Periodicals 3rd quarter of / calendar vii. State drugs Control Deptt 2018 viii. PSUR i. CDSCO website ii. PvPI Preparation iii. Immunization Division Pharmacovigilance At least 1Q & and revision of iv. Market complaints. division in CDSCO 3Q 200(X-1) 2 the Programme ix. Print/ Electronic Media HQRS, Inspectors To be done in 200X-200(X+3) x. Peer review journals / Periodicals deputed by DCG(I) 2018 e.g. 2019-2022 v. State drugs Control Deptt. vi. PSUR i. CDSCO website ii. PvPI iii. Immunization Division Pharmacovigilance Adoption of the iv. Market complaints. division in CDSCO At least 3Q 3 program x i . P r i n t / E lectronic Media HQRS, Inspectors &4Q 200(X-1) 200X-200(X+3) xii. Peer review journals/ Periodicals deputed by DCG(I) v. State drugs Control Deptt. vi. PSUR 15i. Pharmacovigilancework station of the MAH, ii. SOPs and Guidelines; iii. Work Instructions, iv. Computerized Data base System v. Contract agreements with hired Lead Inspector, his services parties team, concerned Implementation vi. ICSR and ADR Formats DDC(I) of At least 1Q & 4 of the program vii. QMS- manual DCSO(Zone Office), 3Q 200(X+3) 200X-200(X+3) viii. Line Listing of SAE/AE, Concerned SLA ix. Minutes of Pv-deptt of MAH. DCG(I) x. PSUR, if any xi. Follow-up Letters, mail communications with Doctors,/ HCPs/ Customers / regulators etc. xii. Archeivals , Library for Journals Lead Inspector, his Four year team, concerned i. Previous Inspection Reports, cycle unless DDC(I) of 5 Re-inspections ii. Meeting Minutes within time lag considered to CDSCO(Zone Office), iii. CAPA adopted be performed Concerned SLA later/earlier DCG(I) 16Annexure-1 Factors to be considered on deciding a routine pharmacovigilance inspection Primary Prioritisation Factors  When and how many times MAH was inspected (PV-inspection)  What were the critical findings in such inspections;  Whether MAH has any product with additional Risk Minimization /Management Activities;  The MAH has never been inspected;  Number and categories of New Drugs placed by the MAH in the market.  Whether MAH is out sourcing entire or partial PV activities with one or multiple licensing partners;  Sale Volume and Patient exposure  Quantum and frequency of CCDS & Package insert update  Whether re-inspection recommended in previous inspection report.  If CDSCO receives too many and frequent post-approval changes on marketed medicinal products.  If CDSCO receives feed-back, recommendation, specific alert/ information about product related complaints, ADRs from various Govt. bodies, organizational procurement agencies. Secondary Prioritisation Factors (the following situations / issues may be considered) 17 If CDSCO has information that MAH has recently been or is involved in a merger or takeover process;  If CDSCO has information that MAH has changed their system significantly (e.g. new data base system, contracting out of reporting activities);  If CDSCO has information that MAH has changed the sub contracted PV activities partner.  Critical results of previous inspections (GCP, GMP, GLP);  If CDSCO has information that Adverse comments / safety concerns from agencies/bodies outside India.  If CDSCO has information that MAH has established PV system only to address third country regulations;  If MAH has changed the PVOI since the last inspection;  Whether MAH has many products in the market, covering many active ingredients;  If MAH has only one New drug in the market;  Size of the MAH (Large/ medium/ small);  Non-availability of Detailed Description of the PV System (DDPS) in respect of any New drug  Whether the MAH has many products with large sales volume; 18Annexure-2 Triggers to be considered when deciding on a targeted pharmacovigilance inspection  Delays in carrying out or failure to carry out specific obligations or follow-up measures relating to the monitoring of product safety, identified at the time of the marketing authorisation;  Delays in expedited or periodic reporting;  Incomplete reporting;  Submission of poor quality or incomplete PSURs;  Inconsistencies between reports and other information sources;  Change in risk-benefit balance;  Failure to communicate change in risk-benefit balance;  Previous inspection experience;  Information received from other authorities;  Poor follow-up to requests for information from the Competent Authorities;  Communication of information on PV concerns to the general public without giving prior or simultaneous notification to the Competent Authorities or Agency as applicable;  Product withdrawal in other foreign market with little or no advance notice to CDSCO 19Annexure-3 Procedures to be adopted by CDSCO  The Inspectorate Team will prepare the Preliminary Report (PIR) of PV inspection with salient observations on the concluding day of Inspection.  In case of routine PV-Inspection, this PIR will be forwarded to the DCG(I) through e-mail with copy to company  In case of for-cause / triggered inspection, the PIR will be directly sent to the DCG(I) through e-mail on the same day.  In both cases the detailed reports shall be prepared within 5- working days from the concluding day of Inspection and submitted to the DCG(I).  The concerned division in CDSCO (HQ) will follow-up the matter for further regulatory action  Such regulatory actions arranged in chronological manner will be incorporated as major contributing factor in planning for the 4-year cycle of PV-Inspection program. ************************* END OF INSPECTION GUIDELINE******************* 20