WHO GLOBAL BENCHMARKING TOOL (GBT) FOR EVALUATION OF NATIONAL REGULATORY SYSTEM OF MEDICAL PRODUCTS

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1 0 WHO GLOBAL BENCHMARKING TOOL (GBT) FOR EVALUATION OF NATIONAL REGULATORY SYSTEM OF MEDICAL PRODUCTS FACT SHEETS FOR REGISTRATION AND MARKETING AUTHORIZATION (DRAFT REVISION VI VERSION ) (DECEMBER ) DRAFT FOR COMMENTS Should you have any comments on the attached text, please send these to: Country Regulatory Support (CRS) Group, Regulatory Systems Strengthening (RSS), World Health Organization, Geneva,Switzerland; Alireza Khadem (khadembroojerdia@who.int); fax: (+ ) ; and to Laura Brown (brownl@who.int) by February. Working documents are sent out electronically and they will also be placed on the Medicines website for comment. World Health Organization All rights reserved. This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any form or by any means outside these individuals and organizations (including the organizations' concerned staff and member organizations) without the permission of the World Health Organization. The draft should not be displayed on any website. Please send any request for permission to: Dr Alireza Khadem Broojerdi, Scientist, Country Regulatory Support, Regulatory Systems Strengthening, Department of Essential Medicines and Health Products, World Health Organization, CH- Geneva, Switzerland. Fax: (+ ) ; khadembroojerdia@who.int. The designations employed and the presentation of the material in this draft do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. This draft does not necessarily represent the decisions or the stated policy of the World Health Organization.

2 0 0 WHO global benchmarking tool rev. VI ver., MA Page 0- REGISTRATION AND MARKETING AUTHORIZATION (MA) The issuance of marketing authorization (also referred as product licensing or registration) is critical to any National Regulatory Authority (NRA). It is a procedure of release a medical product for marketing after it has undergone a process of evaluation in order to determine its safety, efficacy and quality and the appropriateness of the product information. The objective of this regulatory function is to provide a system which ensures that only medical products which have been duly authorized by the NRA are allowed to be manufactured, imported, distributed or sold/supplied to end-users. The process of assessment for marketing authorization includes the review of data on quality, safety and efficacy submitted by the applicant, applying the same standards to imported and locally manufactured medical products. Nevertheless, evaluation of the complex toxicological and clinical data from new chemical entities requires resources and experience not always available in the NRA; therefore countries with limited resources may wish to give priority to well-established products. In relation to the evaluation of well-established products the NRA may prepare its own report, rely on revaluation reports prepared by other national authorities or rely on decisions made by other NRA or use a combination of these approaches. GMP inspection or certification should be part of the marketing authorization requirements. A legal provision should exist to mandate the NRA to grant marketing authorization with limited validity and also request that marketing authorization should be renewed. Mechanisms should exist to ensure that information on marketing authorization applications, including authorized, suspended, rejected and completed applications are published to promote transparency and information sharing amongst stakeholders. Regular publication of marketing authorization decisions is helpful to procurement and distribution networks and to other NRAs. Mechanisms and /or procedures should be in place to monitor and ensure that all activities within the marketing authorization function are checked to reduce errors and to reasonably ensure that the processes are consistent in order to generate an assured output. This would lead to consistency in the regulatory performance of the marketing authorization function as well as reliable outputs. Indicator: MA0 Legal provisions, regulations and guidelines required to define regulatory framework of registration and/or marketing authorization. The objective of this indicator is to assure that legal provisions, regulations and guidelines, which form the backbone of the regulatory framework, ensure that medical products for human use in a particular jurisdiction have been assessed by a NRA, and found of adequate quality, safety and efficacy/effectiveness before registered or granted marketing authorization. The legal provisions empower the NRA with the legal mandate to register and/ or grant marketing authorization but also to punish those who market medical products without the proper health registration or marketing authorization. Category: Legal provisions, regulations and guidelines Sub-Indicator: MA0.0: There are legal provisions to hold a registration and/or marketing authorization (MA) before placing the product on the market. Maturity:

3 WHO global benchmarking tool rev. VI ver., MA Page 0 Legal provisions for medical product registration /marketing authorization The objective of this sub-indicator is to assure legal provisions require that before a medical product is marketed /or placed on the market, the product should have been registered /or granted marketing authorization by the NRA. The assessor should verify that legal provisions requiring registration and /or marketing authorization before placing a medical product on the market should be in existence, enacted and implemented. The legal provisions should clearly mandate that all medical products require registration /marketing authorization before they are placed on the market. It should provide the list of medical products classes (e.g. drugs, vaccines, medical devices, among others) that require registration / marketing authorization before they are marketed/ sold. The legal provisions should present the applicable fines/ charges/penalty/ sanctions in the event of non-compliance. The assessor should note that some medical products may be imported and marketed before registration and /or marketing authorization in special circumstances such as during an emergency or public health concern. The NRA should have systems in place to do active monitoring of such medical products. The assessor may refer to the legal provisions on emergency situations before applying the scoring.. Legal provisions that mandate that all medical products require registration /marketing authorization before they are placed on the market, as well as the applicable fines/ charges/penalty/sanctions in the event of non-compliance.. Whether the legal provisions have been published and implemented, and are applicable to all medical products.. Evidence of registration or marketing authorization, this may be the registration or marketing authorization number or the registration or marketing authorization certificate. Structure/Foundation/Input N: There is no evidence of legal provisions to hold a registration and/or marketing authorization (MA) before placing the product on the market. OI: The NRA has recently drafted legal provisions to hold a registration and/or marketing authorization (MA) but it has not yet been followed. PI: The NRA has legal provisions to hold a registration and/or marketing authorization (MA) and has been applying it for less than two years. I: The NRA has legal provisions to hold a registration and/or marketing authorization (MA) before placing the product on the market and can demonstrate a proven track record of applying them.

4 WHO global benchmarking tool rev. VI ver., MA Page 0 Limitations and remarks:. - WHO TRS 0, Annex, 0.Chapter. and. (b). - WHO TRS, Annex, Sub-Indicator: MA0.0: There are legal provisions to withhold, suspend, and/or withdraw or cancel a MA in case there is/are concerns on quality, safety or efficacy issues. Maturity: Legal provisions on withholding, suspension and /or withdrawal or cancellation in MA The objective of this sub-indicator is to assure that legal provisions exist mandating the NRA to withhold, suspend and /or withdraw or cancel registration /marketing authorization in the event of adverse findings related to the quality, safety and efficacy of medical products. The NRA is empowered by legal provisions to withhold, suspend and /or withdraw or cancel a registration /marketing authorization if it becomes convinced that any requirement that allowed the products to be registered is no longer being met. This legal provision should also sanction those who market medical products without the proper registration / marketing authorization. The assessor should verify that legal provisions with respect to withholding, suspending and /or withdrawing or cancelling a registration and /or marketing authorization in the event of uncovering quality, safety or efficacy issues should be in existence, enacted and implemented. The legal provisions should provide requirements on when and how to withhold, suspend and /or withdraw or cancel registration /marketing authorization.. Legal provisions that mandate the NRA to withhold, suspend and/or withdraw or cancel a registration / marketing authorization in the event of adverse findings related to the quality, safety and efficacy of the medical products.. Regulations and /or guidelines presenting details on when and how to withhold, suspend and /or withdraw or cancel registration /marketing authorization,. Whether the legal provisions have been implemented, and if possible evidence of implementation.. Whether stakeholders including applicants, wholesalers, and retailers among others, are aware of the legal provisions.

5 WHO global benchmarking tool rev. VI ver., MA Page 0 Structure/Foundation/Input NI: There is no evidence of legal provisions to withhold, suspend, and/or withdraw or cancel a MA in case there is/are concerns on quality, safety or efficacy issues. OI: The NRA has recently drafted the legal provisions but they have not yet been followed. PI: The NRA has legal provisions and has been applying them for less than two years. I: The NRA has legal provisions to withhold, suspend, and/or withdraw or cancel a MA in case there is/are concerns on quality, safety or efficacy issues and can demonstrate proven track record of applying them. Limitations and remarks:. - WHO TRS, Annex,. - WHO TRS 0, Annex, 0. Chapter. and. (b) Sub-Indicator: MA0.0: There are legal provisions that require demonstration of the product quality, safety and efficacy prior to registration and/or marketing authorization Maturity: Quality, safety and efficacy prerequisites for registration and/or marketing authorization The objective of this sub-indicator is to assure that legal provisions exist mandating the NRA to request for a demonstration - technically and scientifically - that the medical product meets all quality, safety and efficacy regulatory requirements prior to registration /marketing authorization. The NRA should require that applicants comply fully with the legal requirements for product registration / marketing authorization. The assessor should verify that legal provisions on demonstration of acceptable quality, safety and efficacy profiles being a pre-requisite to registration / marketing authorization should be in existence, enacted and implemented. The legal provisions should empower the NRA to request satisfactory information on the quality, safety and efficacy of medical products seeking registration and /or marketing authorization. The submission should be as per CTD format or other international acceptable format. It should be supported by regulations and guidelines that provide guidance to applicants on the required quality, safety and efficacy documentation. All the necessary legal documentation should be published and easily accessible, as well as enforceable.

6 WHO global benchmarking tool rev. VI ver., MA Page 0. Legal provisions that empower the NRA to request for satisfactory information on the quality, safety and efficacy of medical products seeking registration /marketing authorization.. Whether legal provisions are published and easily accessible to applicants and other stakeholders, as well as the systems and structures in place to enforce implementation of the legal provision.. Whether legal provisions have been implemented. The assessor should verify whether MA applications guidance documents provide direction on the quality, safety and efficacy aspects of the legal provisions. Structure/Foundation/Input NI: There is no evidence of existence of legal provisions that require demonstration of the product quality, safety and efficacy prior to registration and/or marketing authorization. OI: The NRA has recently established these legal provisions, but have not yet been implemented. PI: The NRA has legal provisions and has been applying it for minimum two years. I: The NRA has legal provisions that require demonstration of the product quality, safety and efficacy prior to registration and/or marketing authorization and can demonstrate a proven track record of applying them. Limitations and remarks:. - WHO TRS, Annex,. - WHO TRS 0, Annex, 0. Chapter. and. (b) Sub-Indicator: MA0.0: There are legal provisions and/or regulations regarding the limited duration of the validity of the ma and for periodic reviews to MAs (i.e. renewals) Maturity: Registration /marketing authorization validity period and registration /marketing authorization renewal The objective of this sub-indicator is to assure that legal provisions and/or regulations exist to mandate the NRA to register /grant marketing authorization with limited validity and also request that the

7 WHO global benchmarking tool rev. VI ver., MA Page 0 registration /marketing authorization is renewed before the medical product is re-introduced onto the market The assessor should verify that the legal provisions and /or regulations with respect to the validity period for registrations and /or marketing authorizations and their renewals should be in existence, enacted and implemented. The legal provisions and / or regulations should mandate the NRA to register /grant marketing authorization with limited validity and also request that the registration /marketing authorization is renewed before the medical product is re-introduced onto the market. The legal provision and /or regulation should specify the validity periods of the initial registration / marketing authorization and subsequent registration / market authorization (renewals), as well as provide information on the requirements for renewing registration / marketing authorization.. Legal provisions and/or regulations that mandate the NRA to register /grant marketing authorization with limited validity and also request that the registration /marketing authorization is renewed before the medical product is re-introduced onto the market. Legal provisions and/or regulations on the validity periods of the initial registration / marketing authorization and subsequent registration / market authorization renewals.. Regulations and/or guidelines on the requirements for renewing registration / marketing authorization. Structure/Foundation/Input NI: There is no legal provisions and/or regulations regarding the limited duration of the validity of the MA and for periodic reviews to MAs OI: The NRA has recently drafted these legal provisions, but they have not yet been implemented. PI: The NRA has legal provisions and has been applying them for less than two years. I: The NRA has legal provisions and/or regulations regarding the limited duration of the validity of the MA and for periodic reviews to Mas and can demonstrate a proven track record of applying them. Limitations and remarks: The assessor should note that some NRAs will have regulations that mandate them to grant a One Time registration to a medical product due to active post-market surveillance (PMS) (market surveillance and vigilance)activities. The assessor may review the PMS portfolio of the NRA for more information, and the scoring should be Not Applicable.. - WHO TRS 0, Annex, 0. Chapter. and. (b)

8 0 WHO global benchmarking tool rev. VI ver., MA Page Sub-Indicator: MA0.0: There are regulations and/or guidelines for the definition, types and the scope of variations along with the required documentation Maturity: Regulations/ guidelines on variations The objective of this sub-indicator is to assure that regulations / guidelines exist to provide definitions, types and the scope of variations as well as the documentation requirement for each variation. Due to scientific and technological advancement, new developments/approaches that may affect the requirements that permitted the registration of the product or the granting of marketing authorization should be made known to the NRA. The assessor should verify that the regulations and / or guidelines with respect to the definition, types and the scope of variation as well as the documentation requirements should be in existence, enacted and implemented. The regulations and / or guidelines should provide details of the corresponding documentation requirements for each type/class of variation as well as guidance on the scope of evaluation required.. Regulations and / or guidelines that document the definition, types and scope of variations, as well as the corresponding documentation requirements.. Whether the regulations and / or guidelines are published, easily accessible, implemented and known to the applicant, as well as what is required of them.. Types of variations documented, the scope of evaluation required and the corresponding fees (if any) for appropriateness.. Processes and procedures for submitting variations to the NRA for review, and receiving feedbacks, as well as timelines. Structure/Foundation/Input NI: There is no regulations and/or guidelines for the definition, types and the scope of variations along with the required documentation. OI: The NRA has recently drafted these regulations and/or guidelines but they have not yet been implemented. PI: The NRA has regulations and/or guidelines and has been applying them for less than two years.

9 WHO global benchmarking tool rev. VI ver., MA Page 0 I: The NRA has regulations and/or guidelines for the definition, types and the scope of variations along with the required documentation and required evidence of implementation. Limitations and remarks: MA WHO TRS, Annex,. - WHO TRS, Annex,. 0- WHO TRS, Annex,. - WHO TRS 0, Annex, Sub-Indicator: MA0.0: There are legal provisions to cover circumstances in which the routine MA procedures may not be followed (e.g. for public- health interests) Maturity: Exemptions to routine MA procedures The objective of this sub-indicator is to assure that legal provisions exist to mandate the NRA to use a non-routine approach/procedure in exceptional cases in the interest of public health (e.g. emergencies, epidemics, among others) for registration/marketing authorization of medical products. The assessor should verify that legal provisions, with respect to circumstances in which the routine medical product registration or marketing authorization procedures may not be followed, should be in existence, enacted and implemented. The legal provisions should clearly indicate instances or situations when the normal or routine procedure should not be applied. It should also provide guidance on the scope of evaluation, as well as the documentation required in the event of use of the non- routine approach for registration/marketing authorization. In addition, if the conditional authorization is time limited, the assessor should verify duration of validity in this regulation.. Legal provisions that cover circumstances / instances in which the routine marketing authorization procedures may not be followed.. Regulations and /or guidelines that give clarity on the regulatory requirements for granting marketing authorization to medical products through the non-routine route other than the routine marketing authorization procedure.

10 WHO global benchmarking tool rev. VI ver., MA Page 0. Records of medical products that have been authorized by this route. Structure/Foundation/Input NI: There is no evidence of existence of legal provisions to cover circumstances in which the routine MA procedures may not be followed. OI: The NRA has recently drafted these legal provisions but they have not yet been followed. PI: The NRA has legal provisions and has been applying them less than two years. I: The NRA has legal provisions to cover circumstances in which the routine MA procedures may not be followed and has applied them for all medical products that are used under this condition. Limitations and remarks: It is proposed that the NRA should establish a provision to clarify the role and responsibilities of all involved stakeholders who are involved in the emergency. The establishment of an advisory committee under emergency, to make decisions and share the responsibilities, is suggested. Non-routine MA procedures are those applicable only under specific circumstances e.g. emergencies with public health impact and aimed to reduce the time for registration/granting MA. Names may vary according the national legislation. The collaborative procedure is a procedure for collaboration between the World Health Organization (WHO) Prequalification Team (WHO/PQT) and interested national regulatory authorities in the assessment and accelerated national registration of WHO-prequalified pharmaceutical products and vaccines. The collaborative procedure can be of particular relevance when implemented for pharmaceutical products and vaccines in emergency situation. (WHO TRS, Annex, ). - WHO TRS, Annex, Sub-Indicator: MA0.0: There are legal provisions and/or regulations that define regulatory requirements to approve donation medical products. Maturity: MA procedures for donation medical products approval The objective of this sub-indicator is to assure that legal provisions and/or regulations exist and are implemented to mandate the NRA to have adequate regulatory oversight on received medical products through donation.

11 WHO global benchmarking tool rev. VI ver., MA Page 0 The assessor should verify that legal provisions and/or regulations with respect to circumstances in which the medical products are received through donation exist and are implemented. The legal provision should provide guidance regarding required information and documentation that should be reviewed before approval of donation medical products. It should also provide guidance on the scope of evaluation as well as the documentation required to show quality, safety and efficacy of medical products.. Legal provisions that mandate the NRA to have adequate regulatory oversight on received medical products through donation.. Regulations and /or guidelines giving clarity on the regulatory requirements for using medical products that are received through donation.. Records. Structure/Foundation/Input NI: There is no evidence of existence of legal provisions and/or regulations to define regulatory requirements to use donation medical products OI: The NRA has recently drafted this legal provisions and or regulations but it has not yet been followed. PI: The NRA has legal provisions and has been applying it less than two years. I: The NRA has legal provisions and/ or regulations defining regulatory requirements to use donation medical products and has been applied for all received medical products through donation. Limitations and remarks: Use a non-routine approach/procedure in exceptional cases in the interest of public health (e.g. emergencies, epidemics, etc.) to use donation medical product or grant marketing authorization to a medical product should be considered. If the NRA use the same regulatory approach established for review other medical products for review of donation medical products, this sub indicator can score as not applicable.. - GPV Policy statement. Vaccine donations. (WHO/VSQ/.0) Sub-Indicator: MA0.0: Legal provisions and/or regulations allow the NRA to recognize and/or use MA-relevant decisions, reports or information from other NRAs or regional and international bodies Maturity:

12 WHO global benchmarking tool rev. VI ver., MA Page 0 Recognition/reliance of MA application decision /information The objective of this sub-indicator is to establish whether legal provisions and/ or regulations exist to allow the NRA to establish a systematic framework to recognize and/or use relevant MA decisions, reports or information from other NRAs, or regional and international bodies. The assessor should verify that the legal provisions and/or regulations allowing the NRAs to recognize and/or use relevant MA decisions, reports or information from other NRAs or regional and international bodies should be in existence, enacted and implemented. The legal provisions and /or regulations should provide clarity on the modalities/processes and procedures to recognize and/or use relevant MA decisions, reports or information from other NRAs or regional and international bodies, as well as clarity on the conditions (when/how) to recognize and/or use relevant MA decisions, reports or information from other NRAs, or regional and international bodies. The legal provisions and/ or regulations should also provide clear directives on the scope or extent of recognition and/or use of MA decisions, reports or information from other NRAs, or regional and international bodies.. Legal provisions including guidelines that permits the NRA to recognize and/or use relevant MA decisions, reports or information from other NRAs or regional and international bodies. The scope /extent of recognition and /or use of relevant MA decisions, reports or information from other NRAs, or regional and international bodies.. Instances or situations that permit recognition and/or use relevant MA decisions, reports or information from other NRAs or regional and international bodies. List of NRAs or regional and international bodies whose relevant decisions, reports or information may be used to influence a MA application decision, and whether those NRAs, or regional and international bodies are aware that their relevant MA decisions, reports or information on certain MAs may be used (aware of the legal provision). Structure/Foundation/Input NI: There is no evidence of existence of legal provisions and/or regulations that allow the NRA to recognize and/or use MA-relevant decisions, reports or information from other NRAs or regional and international bodies OI: The NRA has recently drafted this legal provisions and/or regulations or other documented producers but it has not yet been followed. PI: The NRA has legal provisions and/or regulations for that and has been applying it for less than two years with some supported resources.

13 WHO global benchmarking tool rev. VI ver., MA Page 0 I: The NRA has legal provisions and/or regulations allowing the NRA to recognize and/or use MArelevant decisions, reports or information from other NRAs or regional and international bodies including other supporting evidence of implementation like the list of NRAs or regional and international bodies. Limitations and remarks: If the NRA has adequate resources this sub indicator can be considered not applicable, but if any reliance exist, the NRA should have the legal bases.. - Good regulatory practices: guidelines for national regulatory authorities for medical products. Working document QAS. Sub-Indicator: MA0.0: Specific guidelines on the quality, nonclinical/safety and clinical aspects are established and implemented Maturity: Requirement on quality, nonclinical/safety and clinical aspects The objective of this sub-indicator is to establish whether specific guidelines exist on the quality, nonclinical/ safety and clinical requirements for registering and/or granting marketing authorization, and to verify whether they have been implemented. The assessor should verify that specific guidelines on quality, nonclinical/safety and clinical requirements for registering and/or granting marketing authorization should be established and implemented. The guidelines should be detailed and should provide the specific regulatory requirements for each section in the quality, nonclinical/safety and clinical dossier. They should be specific on the type of application and the medical product. These specific guidelines may be documents not prepared by the NRA but adopted in accordance with proper process.. Guidelines detailing the specific regulatory requirements for the quality, nonclinical/ safety and clinical aspects of the MA dossier. The requirements, including the content and format should comply with updated international best practices such as WHO or ICH.. Whether the guidelines are specific to the quality, nonclinical/safety and clinical aspect of the MA application dossier and to the type of application and pharmaceutical product, and whether they are published and implemented.. Sample of MA application submissions that is complying with the published guidelines.

14 WHO global benchmarking tool rev. VI ver., MA Page 0. Whether the document submitted was appropriate for the type of product and type of application (new drug application, multisource drug, and product of biological origin or chemical synthesis among others).. Specific guidelines on product labelling and packaging, package insert and the summary of product characteristics information pamphlet for professionals or equivalent, as well as information pamphlet for patients.. All quality and safety/efficacy reports for recently approved MA applications to determine whether reviews are done thoroughly and based on guidelines requirements. Structure/Foundation/Input NI: There is no evidence of existence of specific guidelines on the quality, nonclinical/safety and clinical aspects. OI: The NRA has recently drafted these guidelines but they have not yet been followed. PI: The NRA has these guidelines and has been applying them for less than two years. I: The NRA has established and implemented specific guidelines on the quality, nonclinical/safety and clinical aspects. Limitations and remarks:. - Quality Assurance of pharmaceuticals. WHO guidelines, good practices, related regulatory guidance and GXP training materials. WHO (CD-ROM). - WHO TRS, Annex,. - WHO TRS, Annex,. - WHO TRS 0, Annex, Sub-Indicator: MA0.: There are guidelines on the format and content for submission of marketing authorization applications consistent with the WHO or other internationally accepted standards Maturity: Format and content for MA application

15 WHO global benchmarking tool rev. VI ver., MA Page 0 The objective of this sub-indicator is to establish whether guidelines exist on the format and content for submitting a marketing authorization application to the NRA, by considering the nature of products and different medical product streams. The presented content and format should be consistent with that recommended by the WHO or other internationally accepted agencies. The assessor should verify that guidelines on the format and content of a marketing authorization submission should exist and should be consistent with international best practices, such as those proposed or recommended by WHO or other internationally established agencies such as ICH. It should provide clarity on the format and content on all sections of the MA application submission by considering specifically each medical product streams, as well as, the processes and procedures for submitting the application to the NRA. The guidelines should be established and implemented.. Guidelines providing clarity on the format and content of the MA application submission, as well as the processes and procedures for submitting the application to the NRA.. Guidelines should be consistent with international best practices, such as those proposed by the WHO or other internationally accepted agencies.. The checklist used to ensure that MA submissions actually comply with the content of the guidelines before a MA application is acknowledged by the NRA. Structure/Foundation/Input NI: There are no guidelines on the format and content for submission of marketing authorization applications. OI: The NRA has recently developed or drafted these guidelines, but it has not yet been followed. PI: The NRA has developed or adopted these guidelines and has been applying them for less than two years, or these guidelines have not been applied for all marketed medical products. I: The NRA has guidelines on the format and content for submission of marketing authorization applications consistent with WHO or other internationally accepted standards including other required documentation. This process is implemented and followed for all marketed medical products. Limitations and remarks: In case of benchmarking of more than one medical products stream, the assessor should consider and review different guidelines, as applicable. In some cases, instructions for dossier compilation may be part of the main (technical) guideline. There is need to add more guidance in this regard such as other international references.

16 WHO global benchmarking tool rev. VI ver., MA Page 0. - WHO TRS 0, Annex,. - WHO TRS, Annex,. - WHO TRS, Annex,. -WHO TRS, Annex,. - WHO TRS, Annex,. - ICH. The Common Technical document for registration of pharmaceuticals for human use: quality. MQ, September 0 Sub-Indicator: MA0.: There are guidelines for marketing authorization holders defining the types and scopes of variations, the format and the documentation required as well as specifications of the variations that are subjected to prior approval or notification. Maturity: Variation documents for MA holders The objective of this sub-indicator is to assure that guidelines exist for marketing authorization holders (MAHs) providing guidance on the types and scopes of variations, the format and the documentation required, as well as specifications of the variations that are subjected to prior approval or notification. The assessor should verify that the guidelines for MAHs providing guidance on the types and scopes of variations, the format and the documentation required, as well as specifications of the variations that are subjected to prior approval or notification should be in existence and implemented. It should include directives on changes made to leaflets, package inserts, labelling (container and package), and summaries of product characteristics. It should also clearly specify to the MAH, variations that would require their approval before the change(s) is /are implemented, those that require just notifying the NRA before or during implementation and those that do not need notifying the NRA.. Guidelines for MAHs providing guidance on the types and scopes of variations, the format and the documentation required, as well as specifications of the variations that are subjected to prior approval or notification. The assessor should note that the guidelines should include changes to information contained in leaflets, package inserts, labelling (package and containers), and summaries of product characteristics that have been previously approved.. The guidelines that specify to the MAH, variations that would require their approval before the change(s) is /are implemented, those that require just notifying the NRA before or during implementation

17 WHO global benchmarking tool rev. VI ver., MA Page 0 and those that do not need notifying the NRA. The assessor should request for a sample of submitted and processed variation application and relate it to the guidelines for the purpose of conformance. Structure/Foundation/Input NI: There is no evidence of existence and implementation of guidelines for marketing authorization holders defining the types and scopes of variations, the format and the documentation required as well as specifications of the variations that are subjected to prior approval OI: The NRA has recently developed or drafted these guidelines, but it has not yet been followed. PI: The NRA has developed or adopted these guidelines and it is applying for less than two years or it has not been applied for all marketed medical products. I: The NRA has guidelines for marketing authorization holders defining the types and scopes of variations, the format and the documentation required as well as specifications of the variations that are subjected to prior approval and they are implemented and documented for all marketed medical products. Limitations and remarks: In case of benchmarking of more than one medical products stream, the assessor should consider and review different guidelines as applicable. MA WHO TRS 0, Annex, 0. Chapter. and. (b). - WHO TRS, Annex, Sub-Indicator: MA0.: There are established guidelines to cover circumstances in which the routine MA procedures may not be followed (e.g. for public- health interests) Maturity: Guidance on non-routine MA procedures The objective of this sub-indicator is to assure that guidelines exist to provide guidance to the NRA on how to process MA applications using the non-routine MA approach/procedure in exceptional cases and in the interest of public health (e.g. emergencies, epidemics, others). The assessor should verify that guidelines providing guidance to the NRA on how to manage MA applications through the non-routine MA application procedures due to emergencies and /or in the interest

18 WHO global benchmarking tool rev. VI ver., MA Page 0 of public health are established and implemented. The guidelines should provide guidance on the critical requirements that need to be reviewed by the NRA (e.g. label indication, mode of usage or application, storage, GMP certificate and /or report, among others), on what has to be documented and monitored (e.g. location of deployment, quantities to be deployed, identity of persons to receive and manage deployment and others) by the NRA before registration of the medical products. It should be supported with SOPs that provide guidance on the assessment /evaluation process as well as the scope of evaluation needed. The assessor should verify if NRA will have access to experts (advisory committee) to support NRA during the decision making process. The application processing flow and corresponding timelines should be available.. Guidelines that provide guidance to the NRA on the application of a non-routine MA procedure in emergency situation, as well as the corresponding SOPs or similar documents.. A sample application that was processed using the guidelines. The assessor should verify whether the requirements in the guidelines were submitted and duly evaluated, and whether the evaluation process flow and timelines were respected.. Evidence of access to experts or advisory committee in case of emergency Structure/Foundation/Input NI: There are no guidelines to cover circumstances in which the routine MA procedures may not be followed. OI: The NRA has recently developed or drafted these guidelines but it has not yet been followed. PI: The NRA has developed or adopted officially this guideline but has not been applied for all medical products that were approved by non-routine regulatory procedures. I: The NRA has guidelines to cover circumstances in which the routine MA procedures may not followed and has applied them for all medical products that have been approved under this condition. Limitations and remarks: There is need to verify if these guidelines have been applied in emergency situation and all relevant records are available. If there was not any emergency situation after the guidelines development, the assessor should verify that at least all required resources are available. MA0 0 MA0 0 MA0 0 MA0 0

19 WHO global benchmarking tool rev. VI ver., MA Page 0. - Guidance on development and implementation of a national deployment and vaccination plan for pandemic influenza vaccines. WHO. - Emergency response framework. WHO, Sub-Indicator: MA0.: There are guidelines on the content of product information leaflets, summary of product characteristics (SPC) like information, packaging and labelling Maturity: Guidance on content of product information leaflets, summary product characteristics (SPC), packaging and labelling The objective of this sub-indicator is to assure that guidelines exist to provide guidance on the MA application requirements on the content of the product information leaflets, summary product characteristics (SPC), packaging and labelling. The assessor should verify that guidelines providing guidance on the MA application requirements on the content of the product information leaflets, summary product characteristics (SPC) like information, packaging and labelling should be in existence and should be implemented. These should also provide clarity on the information to be included in the package inserts (inserts, patient information leaflets), summary of product characteristics (information leaflet for professionals or equivalent) and labelling of container-packaging.. Guidelines that provide guidance on the MA application requirements on the content of the product information leaflets, summary product characteristics (SPC), packaging and labelling.. Relevant documentation including forms and records Structure/Foundation/Input NI: There is no guidelines on the content of product information leaflets, summary of product characteristics (SPC), packaging and labelling OI: The NRA has recently drafted this guideline but it has not yet been followed PI: The NRA has developed or adopted this guideline and has been applying it for less than two years or not fully followed for all marketed medical products.

20 WHO global benchmarking tool rev. VI ver., MA Page 0 I: The NRA has a guidelines on the content of product information leaflets, summary of product characteristics (SPC), packaging and labelling and are followed for all marketed medical products. Limitations and remarks: MA0.0 MA WHO TRS 0, Annex, 0 Indicator: MA0 Arrangement for effective organization and good governance. The objective of this indicator is to assure that there is a legal basis and relevant administrative process and documentation for the organizational structure and governance that allows for the smooth coordination, collaboration and exchange of information within and without the entity that is responsible for registration and/or granting marketing authorization (MA). The arrangement should establish and define the role and responsibilities within and without the NRA for registration/ma activities. It should ensure that the NRA responsible for registration and /or MA has complete control or access to all information related to produced, procured or received medical products, relevant information such as GMP inspection reports, lab analysis data, collected vigilance data, registration and /or MA applications, the number and identity of medical products registered and/or granted MA, on-going registration and /or MA activities, new directives, newly registered products, withdrawn/suspended registration and/or MA, rejected applications, etc. The objective of this indicator is to establish that structures are in place at the organizational and governance levels to promote effective intra- and inter NRA relationships where information traffic is efficiently managed. Category: Organization and governance Sub-Indicator: MA0.0: There is a defined structure with clear responsibilities to conduct registration and/or marketing authorization activities Maturity: Structure and responsibilities The objective of this sub-indicator is to assure whether there are structures in place, with clearly defined roles and responsibilities for each structural and governance level for registration and/ or marketing authorization activities to ensure effectiveness, efficiency and consistency.

21 WHO global benchmarking tool rev. VI ver., MA Page 0 The assessor should verify that the defined structures with clear responsibilities to conduct registration or MA activities should be established and implemented. The structure should show identity (ies) of entity (ies) within the NRA that has/have the mandate for registration /marketing authorization activities. The structure should be supported with regulations and/or guidelines mandating such entity (ies) to conduct registration /marketing authorization activities, as well as defining the scope/extent of their role/responsibilities within the NRA in relation to registration /marketing authorization activities, as well as their reporting lines. The structure of the entity (ies) relative to relationships and ranks, as well as information exchange / flow within and without (e.g. officers at the port of entry, officers in the post market surveillance unit) the entity (ies) should be defined.. Roles and responsibility (ies) of the entity (ies) responsible for registration /marketing authorization activities and their placement on the organizational chart in relation to other entities involved in registration /marketing authorization related activities. Regulation and/or guidelines mandating such entity (ies) or authority (ies) with the responsibility to conduct registration /marketing authorization activities.. The document with the organizational structure or organogram. Structure/Foundation/Input NI: There is no evidence of the defined structure with clear responsibilities to conduct registration and/or marketing authorization activities. OI: The NRA has recently drafted a defined structure with clear responsibilities to conduct registration and/or marketing authorization activities, but it has not yet been placed. PI: The NRA has a defined structure with clear responsibilities to conduct registration and/or marketing authorization activities and has been established, however there is the need to improve this function by providing adequate resources or more support for effective implementation and coordination with other entities. I: The NRA has a defined structure with clear responsibilities to conduct registration and/or marketing authorization activities that is fully supported with the required resources. Limitations and remarks:. - WHO TRS, Annex,. - WHO TRS 0, Annex,

22 0 WHO global benchmarking tool rev. VI ver., MA Page Sub-Indicator: MA0.0: Documented and implemented procedures exist to ensure involvement and communication with all relevant regulatory entities (assessors, quality control (QC) laboratory and inspectorate) as necessary Maturity: Procedures for effective communication The objective of this sub-indicator is to assure there are documented procedures and /or structures/mechanisms in place to ensure proper inter- and intra-relationships between and within entities involved in dossier assessment, quality control laboratory and inspectorate in order to ensure effective and efficient exchange of information amongst stakeholders. The assessor should verify the documented procedures promoting involvement and communication between all relevant entities inside the NRA should be in existence and implemented, and supported with adequate documentation. The procedure should provide clear directives on the regulatory divisions and guidance on how to implement the operational procedures to ensure the involvement and communication between relevant entities within the NRA such as dossier assessment, quality control laboratory and inspectorate. It should be clear on the scope/extent of role/ responsibilities of each relevant entity (ies). In addition, the procedure should be supported by information and/or documentation transfer policy to ensure that directives/ information and/or documentation reach the intended recipients and feedback is received. The procedures should be captured in the form of SOPs and guidelines which are approved and authorized to be implemented, and with appropriate disclosure.. The registration /marketing application guidelines capturing duties/roles and responsibilities of the relevant entities inside the NRA involved in registration /marketing activities and whether documents are known to the relevant organizations, divisions, institutions, and/or departments.. Whether documented procedures have been implemented, and the impact of the implementation has been evaluated.. Standard operating procedures (SOPs) that guide and/or inform effective communication and collaboration between relevant entities inside the NRA such as the quality control laboratory, vigilance, inspectorate, among others.. The feedback mechanism in the information and /or documentation transfer policy (ies) among all relevant regulatory divisions. Process

23 WHO global benchmarking tool rev. VI ver., MA Page 0 NI: There is no evidence of documented procedures to ensure involvement and communication with all relevant regulatory entities (assessors, quality control (QC) laboratory and inspectorate) as necessary. OI: The NRA has recently drafted procedures to ensure involvement and communication, but it has not yet been followed. PI: The relevant entities inside the NRA established the procedures to ensure involvement and communication, but these have not been fully incorporated neither is consistent with relevant SOPs. I: The NRA has procedures to ensure involvement and communication with all relevant regulatory entities (assessors, quality control (QC) laboratory and inspectorate) as necessary, including required documentation and records. Limitations and remarks:. - WHO TRS 0, Annex, 0. Chapter. (d). - WHO TRS, Annex, Indicator: MA0 Human resources to perform registration and marketing authorization activities. The objective of this indicator is to assure all entity (ies) within an NRA is/are adequately resourced with trained, experienced and skilled workforce, as well as empowered to fully perform their functions of registering and/or granting marketing authorization to medical products. This will ensure that medical products registration and/or marketing authorization processes or activities are performed in accordance with international best practices. The objective of this indicator is to evaluate the human resource capacity of the entity (ies) with respect to the number of personnel, their composition, their skill set and experience, as well as their specific areas of expertise to perform the registration and/or marketing authorization function. Category: Resources (HR, FR, infrastructure and equipment) Sub-Indicator: MA0.0: Enough competent staff (education, training, skills and experience) are assigned to perform marketing authorization and/or registration activities Maturity: Enough number of competent human resources in charge of MA activities.