WHO GLOBAL BENCHMARKING TOOL (GBT) FOR EVALUATION OF NATIONAL REGULATORY SYSTEM OF MEDICAL PRODUCTS FACT SHEETS FOR CLINICAL TRIALS OVERSIGHT

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1 0 0 0 WHO GLOBAL BENCHMARKING TOOL (GBT) FOR EVALUATION OF NATIONAL REGULATORY SYSTEM OF MEDICAL PRODUCTS FACT SHEETS FOR CLINICAL TRIALS OVERSIGHT (DRAFT REVISION VI VERSION ) (DECEMBER 0) 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 0. Working documents are sent out electronically and they will also be placed on the Medicines website for comment. World Health Organization 0 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 WHO global benchmarking tool rev. VI ver., CT Page CLINICAL TRIALS OVERSIGHT (CT) National Regulatory Authorities (NRAs) should have the legal mandate to authorize and regulate clinical trials, including terminate clinical trials if necessary. They should develop the necessary requirements, guidelines, procedures and forms in line with major international guidelines on clinical trials including the Declaration of Helsinki and WHO Good Clinical Practices guidelines. Clinical trials oversight is aimed to: protect the safety and rights of human subjects participating in clinical trials, ensure that trials are adequately designed to meet scientifically sound objectives and prevent any potential fraud and falsification of data. NRAs are responsible at two stages for the critical evaluation of the documentation supporting clinical studies: when clinical trials are being proposed for authorization and when the results are submitted in an application for marketing authorization. Clinical trials protocols should be reviewed and approved by Independent Ethics Committees before they are submitted to the NRA for authorization. A clinical trial review committee composed of members with the appropriate medical and scientific knowledge, experience and skills, who are also free of conflicts of interest, should review the protocols and may require where necessary, protocol revisions. They will be also responsible for the review of the trials results. In order to ensure the quality and safety of investigational products they should be manufactured in compliance with Good Manufacturing Practices (GMP) for investigational medical products; the supporting preclinical studies should be in compliance with Good Laboratory Practices (GLP) and the importation, storage, use, and/or destruction of investigational products should follow the national requirements. Qualified and experienced inspectors should carry out on-site inspections of the clinical trial sites to verify compliance with Good Clinical Practices (GCP), ethical principles and regulatory requirements, including the quality and reliability of the data obtained, with due concern for the confidentiality. The legal provisions should allow the NRA to recognize and/or rely on relevant clinical trials decisions, reports or information from other NRAs, or regional and international bodies. They should also allow in special circumstances (e.g. for public-health interest) that the NRA does not follow the routine clinical trials procedures. Transparency in the process is fundamental to ensure the safety of patients and to ensure that no product that has failed clinical trials will be made available to the public. 0 0 Indicator: CT0 LEGAL PROVISIONS, REGULATIONS AND GUIDELINES REQUIRED TO DEFINE REGULATORY FRAMEWORK OF CLINICAL TRIALS OVERSIGHT. The objective of this indicator is to assure that the NRA has the legal mandate to both authorize and suspend the implementation of Clinical Trials (CTs). The mandate will ensure, amongst others, that regulations and guidelines are in place to protect the safety and rights of the subjects participating in a trial, and to ensure that trials are adequately designed to meet scientifically sound objectives. Category: Legal provisions, regulations and guidelines Sub-Indicator: CT0.0: LEGAL PROVISIONS AND/OR REGULATIONS FOR CLINICAL TRIALS (CT) OVERSIGHT EXIST.

3 WHO global benchmarking tool rev. VI ver., CT Page Maturity: Legislation on CT oversight The objective of this sub-indicator is to assure the legal provisions and /or regulations that require authorization from NRA for conducting clinical study prior to study exist. The NRA should review the protocol and other relevant documentation to be sure that all required aspects such as safety of participants are considered and it is according Good clinical practices. The assessor should verify that the legal provisions and/or regulations for clinical trials oversight exist, are enacted and implemented. The legal provisions should clearly specify the entity (ies) with the mandate for clinical trial oversight and the extent of their mandate (s), as well as shared responsibilities among/between the entity (ies). The assessor should verify the legal provisions and/or regulations that require authorization from NRA for conducting clinical study prior to study exist, are enacted and implemented. The assessor should review all provided documentation such as importation licensing/control of investigational medical products (IMPs) with GMP certificate, on-site inspections mandate for ensuring the location is acceptable and the product quality is maintained during storage, as well as review informed consent forms and investigator brochure. The assessor should verify that provided information and documentation are following GCP. The assessor should be guided by the existing law and regulation before applying the scoring.. Legal provisions and/or regulations that grants the NRA the legal mandate for CT oversight.. The sections in the law that define the extent/scope of the CT mandate allocated to the NRA and other entity (ies) involved in CT related activities.. Relevant sections of the law on CT that require authorization from NRA for conducting clinical study prior to study.. The guidelines on the format and content of protocol, as well as the submission procedure as well as timeframe for review of application. Structure/Foundation/Input N: There is no legal provisions and/or regulations for clinical trials (CT) oversight. OI: The NRA has recently drafted and adopted legal provisions for clinical trials (CT) oversight but it has not yet been followed.

4 WHO global benchmarking tool rev. VI ver., CT Page PI: The NRA has legal provisions for conducting clinical trials (CT) oversight and has been applying it for less than two years. Y: The NRA has legal provisions for conducting clinical trials (CT) oversight supported with enough documented evidences. Limitations and remarks:. - WHO TRS, Annex,. 0- WHO TRS 0, Annex, (Chapter.,,.,.,) Sub-Indicator: CT0.0: LEGAL PROVISIONS AND/OR REGULATIONS REQUIRE AUTHORIZATION FROM NRA AND NOTIFICATION TO THE NRA ON CHANGES/VARIATIONS (AMENDMENTS) IN THE ORIGINAL PROTOCOL AND RELEVANT DOCUMENTS OF THE CT. Maturity: Changes/variations to already approved (original protocol) CT protocols The objective of this sub-indicator is to assure that legal provisions and /or regulations require that the NRA should be notified of changes/variations (amendments) to the original protocol, and should authorize changes /variations to the original protocol before they are implemented. The assessor should verify that legal provisions and/or regulations on changes/variations to the original (approved) CT protocols exist, are enacted and implemented. It should clearly state that the NRA should be notified of any changes/variations to the original protocol, and authorization from the NRA is required before the changes /variations (amendments) are implemented. The assessor should note that some amendments to protocol may not require authorization from the NRA prior to implementation. Some may require either a notification prior to implementation or implementation before notification. The assessor should be guided by the existing law, regulation and regulation before applying the scoring.. Relevant sections of the legal provisions (laws, decrees, regulations or any legal binding document) on CT with emphasis on the requirement for either notification or authorization prior to implementation of changes/variations to original protocol and relevant documents.

5 WHO global benchmarking tool rev. VI ver., CT Page The guidelines on the format and content preparation on changes /variations to original protocol, including the submission procedure as well as timeframe for review of variations. Structure/Foundation/Input NI: There are no legal provisions and/or regulations requiring authorization from and notification to the NRA on changes/variations (amendments) in the original protocol of the CT. OI: The NRA has recently drafted or adopted this legal provision but it has not yet been followed. PI: The NRA has legal provision and has been applying it for less than two years. I: The NRA has legal provisions and/or regulations requiring authorization from NRA and notification to the NRA on changes/variations (amendments) in the original protocol of the CT supported with documented evidences. Limitations and remarks:. - WHO TRS, Annex, WHO TRS 0, Annex, (Chapter.,,.,.,). -WHO TRS 00, Annex, 0. - WHO TRS, Annex, 0 Sub-Indicator: CT0.0: LEGAL PROVISIONS AND/OR REGULATIONS REQUIRING RESEARCH CENTRES, RESEARCHERS, SPONSORS, CLINICAL RESEARCH ORGANIZATIONS (CROs) AND ALL RELEVANT INSTITUTIONS IN THE CLINICAL TRIAL TO COMPLY WITH GOOD CLINICAL PRACTICE (GCP) Maturity: Stakeholder acting in compliance with GCP The objective of this sub-indicator is to assure the legal provisions and /or regulations that mandates stakeholders, including research centers, researchers, sponsors, Clinical Research Organizations (CROs) and everyone involved in clinical trials to comply with Good Clinical Practice (GCP) exist. It will ensure all stakeholder, including research centers, researchers, sponsors, Clinical Research Organizations (CROs) and everyone involved CTs operate within set globally acceptable standards for the conduct of biomedical research on human subjects.

6 WHO global benchmarking tool rev. VI ver., CT Page The assessor should verify the legal provisions and /or regulations that request stakeholders, including research centers, researchers, sponsors, Clinical Research Organizations (CROs) and everyone involved in clinical trials to comply with the principle of Good Clinical Practice (GCP) exist, are enacted and implemented. Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides assurance that the rights, safety and well-being of trial subjects are protected consistent with the principles established in the Declaration of Helsinki, and that clinical trial data are credible. The legal provisions should be supported by detailed and published regulatory requirements for GCP. The published GCP principles should be current and up to date with information on inspections, suspension and/or stoppage of trials among others. In the event of adoption or reference of GCP, there should be documentation to demonstrate recognition. The assessor should verify that Ethics Committees and NRA conduct evaluation according to GCP.. The legal provisions(laws, decrees, regulations or any legal binding document) that require stakeholders involved in CT comply with GCP principles.. The current GCP requirements for all CTs. The requirement should be published and easily accessible.. Guidelines and/ or similar documents (e.g., checklist, SOPs, etc.) used for guidance in the application of the legal provision and/or regulation. Structure/Foundation/Input NI: There are no legal provisions and/or regulations requiring research centers, researchers, sponsors, clinical research organizations (CROS) and everyone involved in the clinical trials to comply with good clinical practice (GCP) OI: The NRA has recently drafted or adopted this legal provision and/ or regulation but it has not yet been followed. PI: The NRA has developed this legal provision and has been applying it for less than two years, or not all involved organizations have fully followed this regulation. I: The NRA has legal provisions and/or regulations requiring research centers, researchers, sponsors, clinical research organizations (CROS) and everyone involved in clinical trials to comply with good clinical practice (GCP) supported with documented evidence. Limitations and remarks: The assessor should consider legal binding of existent written documents.. 0- WHO TRS 0, Annex, (Chapter.,,.'.,)

7 WHO global benchmarking tool rev. VI ver., CT Page WHO TRS, Annex,. -WHO TRS 00, Annex, 0. - WHO TRS, Annex, 0 Sub-Indicator: CT0.0: LEGAL PROVISIONS, REGULATIONS AND/OR GUIDELINES REQUIRING THAT INVESTIGATIONAL MEDICAL PRODUCTS (IMPs) COMPLY WITH GOOD MANUFACTURING PRACTICE (GMP) FOR IMPs Maturity: Investigational medical products (IMPs) good manufacturing practice (GMP) requirements The objective of this sub-indicator is to assure that legal provisions, regulations and guidelines that mandate IMPs to be used in CTs comply with GMP requirements exist. The assessor should verify that legal provisions, regulations and/or guidelines on IMPs GMP compliance exist, are enacted and implemented. It should clearly state that only IMPs produced in compliance with current GMP standards for IMPs will be used in CTs, and that trial s applicant or sponsor is responsible for supplying IMPs produced in accordance with GMP principles. The legal provision should be supported with regulation and or guidelines that clearly present the applicable GMP standards/requirements and the type of evidence to present (e.g., certificate, summary product release documents, others). The assessor should note that some NRAs may not require a GMP certificate when the IMP is already licensed or registered in the country of origin. However, per good regulatory practices, a current GMP certificate from the national regulatory authority of the country of origin should be required when the IMP has a marketing authorization in the country of origin or has a marketing authorization but the original indication is modified for the purpose of the trial.. The legal provisions(laws, decrees, regulations or any legal binding document) and /or guidelines requiring that IMPs used in CTs are produced in compliance with the principles of GMP for IMPs.. The legal provisions/ regulations and /or guidelines that states that it is the responsibility of the sponsors / applicants to supply IMPs produced in compliance with the principles of GMP for IMPs.. Format of IMPs GMP certificate requirement prior to CT authorization. The GMP certificate should be issued by the national competent authority of the country of origin of the IMP. Structure/Foundation/Input

8 WHO global benchmarking tool rev. VI ver., CT Page NI: There is no evidence of existence of legal provisions, regulations and/or guidelines requiring that investigational medical products (IMPS) comply with good manufacturing practice (GMP) for IMPs. OI: The NRA has recently drafted or adopted this legal provisions, regulations and or guidelines but they have not yet been implemented. PI: The NRA has legal provisions, regulations and or guidelines and has been applying them for at minimum two years. I: The NRA has legal provisions, regulations and or guidelines requiring that investigational medical products (IMPs) comply with good manufacturing practice (GMP) for IMPs. Limitations and remarks:. - WHO TRS, Annex, WHO TRS 0, Annex, (Chapter.,,.,.,). 0- WHO TRS, Annex, Sub-Indicator: CT0.0: THERE ARE LEGAL PROVISIONS OR REGULATIONS COVERING CIRCUMSTANCES IN WHICH THE ROUTINE CT EVALUATION AND PROCEDURE MAY NOT BE FOLLOWED (E.G. FOR PUBLIC-HEALTH INTERESTS) Maturity: Exemptions from routine CT application evaluation and procedures The objective of this sub-indicator is to assure legal provisions and/or regulations are established to allow the NRA/ responsible regulatory authority (ies) apply non-routine CT procedures such as fast-track or expedite receipt, evaluation, and authorization of a CT application in certain situations/circumstances (e.g. Public health emergencies). This sub-indicator will establish whether there is an abridge route other than the normal CT application route for CT authorization. The assessor should verify that legal provisions and/or regulations that allows the NRA to apply non routine CT procedures such as fast-track or expedite receipt, screening, evaluation/review, and authorization (taking a decision on) of a CT application in certain situations/circumstances (e.g. public health emergencies) exist, are enacted and implemented. The legal provisions and / or regulations should provide clear statements /directives on the circumstances/instances where the fast-track CT authorization should apply. It should provide guidance on the relationship between the fast-track CT authorization and the mandate of the IEC. It should be supported with guidelines that would provide guidance on the

9 WHO global benchmarking tool rev. VI ver., CT Page content (e.g. critical requirements) and format of the CT application for fast-track authorization, as well as the scope of the evaluation/review process (screening, verification, etc.). It should also provide guidance on how CTs authorized through the fast-track procedure should be managed (e.g. the number of GCP inspections (random, announced/scheduled, responsive, etc.), reports. The supporting guidelines may provide clarity on whether a CT application rejected through the fast-track procedure could be resubmitted through the routine procedure. In addition, there should be a guidance document to provide direction to the NRA on how to justify application of the non-routine procedure to the CT. The assessor should verify that the proposed procedure meet targeted timeframe for public health emergency or any other unmet medical need. There is need for clarification when and how the CT conducted faster manner, for example authorization procedures. Guidelines or similar document that provides the list of situation where the routine CT procedures should not be followed.. Legal provisions(laws, decrees, regulations or any legal binding document) that cover circumstances /instances where non-routine CT procedures such fast-track CT authorization is required/applied. The legal provisions should be published and implemented.. The supporting guidelines and /or regulations.. The content and format of CT application requiring non- routine CT procedures such as fasttrack.. The scope of the evaluation process (screening or verification, etc.).. Regulatory actions post-authorization. The assessor should verify and discriminate between the routine procedure and the fast-track procedure. Structure/Foundation/Input NI: There are no legal provisions and/or regulations to cover circumstances in which the routine CT application evaluation may not be followed (e.g. for public-health interests) OI: The NRA has drafted or adopted this legal provision and/ or regulation, but it has not yet been followed. PI: The NRA has legal provision and/ or regulation and has been applying it for less than two years. I: The NRA has legal provisions and/or regulations covering circumstances in which the routine CT application evaluation may not be followed (e.g. for public-health interests). Limitations and remarks: Thea assessor should consider any kind of legal document that address this requirement.

10 WHO global benchmarking tool rev. VI ver., CT Page WHO TRS 0, Annex, (Chapter.,,.,.,). - EUAL for candidate medicines for use in the context of a public health emergency. WHO; 0. - EUAL for candidate vaccines for use in the context of a public health emergency. WHO; 0 Sub-Indicator: CT0.0: LEGAL PROVISIONS, REGULATIONS AND/OR GUIDELINES EXIST FOR NRA TO INSPECT, SUSPEND AND/OR STOP CT Maturity: Legal provisions, regulations and /or guidelines to inspect, suspend and/or stop CTs The objective of this sub-indicator is to assure legal provisions and/or regulations are established to give the NRA enforcement powers to inspect, suspend and /or stop CTs. The assessor should verify that legal provisions and/or regulations regarding the NRA enforcement powers to inspect, suspend and /or stop CTs should exist, are enacted and implemented. It should be supported with clear regulation and/or guidance on when (i.e., routine, randomly and/or for specific reasons) and how to inspect, suspend and/or stop CT. Clear guidance on what to inspect e.g., quality and reliability of data obtained or reported results, subjects, equipment, protocols, environment, among others should also be included.. The legal provisions (laws, decrees, regulations or any legal binding document) that give the NRA the enforcement power to inspect, suspend and/or stop CTs.. When, how and whom to inspect, suspend and/or stop CTs.. List of CTs inspected, suspended and/or stopped. Structure/Foundation/Input Rating scale: NI: There are no legal provisions, regulations and/or guidelines for NRA to inspect, suspend and/or stop CT

11 WHO global benchmarking tool rev. VI ver., CT Page OI: The NRA has recently drafted or developed the regulations and/or guidelines, but these have not yet been followed. PI: The NRA has legal provisions, regulations and/or guidelines and has been applying it for less than two years or the guideline or regulation is not fully implemented for all CTs applications. I: The NRA has legal provisions, regulations and/or guidelines to inspect, suspend and/or stop CT and these are implemented and followed for all approved CTs applications. Limitations and remarks: The assessor should consider if there is no clinical trial ongoing, the assessor can score as implemented by reviewing guidelines or other required documentation.. -WHO TRS 00, Annex, 0. - WHO TRS, Annex, 0. 0-WHO TRS 0, Annex,. (Chapter.,,.,.,). - WHO TRS, Annex, 0 Sub-Indicator: CT0.0: THERE ARE LEGAL PROVISIONS AND /OR A REGULATIONS THAT REQUIRE THE ESTABLISHMENT OF AN INDEPENDENT ETHICS COMMITTEE (IEC) Maturity: Establishment of independent ethic committee (IEC) The objective of this sub-indicator is to assure regulations are in place requiring the establishment of an IEC to review the CTs. The IEC should verify that safety, integrity, and human rights of participating subjects in a particular CT are protected, and should consider the general ethics of the trial, thereby providing public reassurance. The assessor should verify that regulations requesting the establishment of an IEC exist, are issued and implemented. The regulation should be clear on the authority that should host and assist the IEC to successfully discharge its duties/mandate. It should also provide guidance on what it is meant by independent, and provide supporting regulations and /guidelines to sustain the IEC s independence. The objectives, functions and composition of the IEC should be clearly presented and documented, as well as the general policy on potential conflicts of interest for IEC members. The assessor should note that there may be more than one legally established IEC in a country. The assessor should therefore be particular about the legal mandate of the IEC in question and the scope of their activity (ies).

12 WHO global benchmarking tool rev. VI ver., CT Page Legal provisions (laws, decrees, regulations or any legal binding document) requesting the establishment of the independent EC.. The identity of the designated authority mandated to host and assist the IEC in discharging its duties.. The selection criteria for the members of the IEC and the number of members, as well as their term of office.. The mechanisms and structures to ensure the independence of the IEC, as well as the code of conduct for its members.. The general policy on potential conflicts of interest for members of the IEC. Structure/Foundation/Input NI: There are no legal provisions and /or regulations requiring the establishment of an independent ethics committee (IEC). OI: The legal provisions and /or regulations that require the establishment of an independent ethics committee (IEC) have recently defined or drafted, but these have not yet been implemented. PI: The legal provisions and /or regulations requiring the establishment of an independent ethics committee (IEC) have been developed and the IEC has been established for less than two years. I: The NRA has legal provisions and /or regulations requiring the establishment of an independent ethics committee (IEC)and the IEC is established. Limitations and remarks: CT0.0 CT0.0 CT Handbook for good clinical research practice (GCP): guidance for implementation. WHO; 00 (Principle : GLP; Principle ). 0- WHO TRS 0, Annex,. (Chapter.,,.,.,) Sub-Indicator: CT0.0: Legal provisions, regulations and /or guidelines that require authorization for the import, export and destruction of investigational medical products

13 WHO global benchmarking tool rev. VI ver., CT Page Maturity: Legal provisions, regulation and /or guidelines to import, export and destroy IMPs The objective of this sub-indicator is to assure legal provisions, regulations and /or guidelines exist requiring the NRAs / responsible regulatory authority (ies) to authorize import, export or destruct of IMPs. The assessor should verify that the legal provisions, regulations and/or guidelines requiring the NRA authorize import, export and destruction of IMP sexist. The assessor should verify this regulation is enacted and implemented as well. It should be supported with regulation and /or guidelines that provide guidance on the permitted quantities to export or import. The assessor should note that the quantities to import, export or destroy should be justified in relation to the timelines and /or use of the IMPs discussed in the protocol. It should provide guidance on the import, export or destruction process, including the roles and responsibilities of the various stakeholders, including the sponsor, principal investigator (PI), others. The guidelines should discuss procedures to follow for NRA assistance, the acceptable /allowable quantities of IMPs to import or export and the appropriate destruction methods (by the NRA or supervised by the NRA), and the feedback mechanism to inform the NRA on quantities left over after CT. The guideline and application forms should be developed and easily available to the sponsor and other stakeholders. The processes and procedures to seek authorization for import, export or destruction should be published and easily available.. Legal provisions(laws, decrees, regulations or any legal binding document) and / or guidelines on the import, export and destruction of IMPs. The assessor should verify whether IMPs imported and/or exported for the purposes of CT application submissions require authorization.. The guidance documents and application forms for requesting assistance from the NRA to import export or destroy IMPs, as well as the processes executed upon receipt of an application.. Records of IMPs imported, exported or destroyed since the last NRA inspection.. Guidelines or similar documents providing guidance on the justifiable quantities of IMPs that should be imported and /or exported relative to the timelines in the CT protocol, as well as the stage in the CT application process where IMPs may be imported or exported. Structure/Foundation/Input NI: There are no legal provisions, regulations and /or guidelines that require authorization for the import, export and destruction of investigational medical products.

14 WHO global benchmarking tool rev. VI ver., CT Page OI: The legal provisions and /or regulations or guidelines that require authorization for the import, export and destruction of investigational medical products exist, but these have not yet been implemented. PI: The legal provisions and /or regulations or guidelines that require authorization for the import, export and destruction of investigational medical products have been established for less than two years. I: The NRA has legal provisions, regulations and /or guidelines that require authorization for the import, export and destruction of investigational medical products and applies for all IMPs. Limitations and remarks:. 0- WHO TRS 0, Annex, (Chapter.,,.,.,). -WHO TRS 00, Annex, 0. - WHO TRS, Annex, 0. - WHO TRS, Annex, 0 Sub-Indicator: CT0.0: THERE ARE REQUIREMENTSON MONITORING ADVERSE EVENTS/ REACTIONSAND REPORTINGDURING CONDUCTING CT. Maturity: Monitoring and reporting adverse reactions/events The objective of this sub-indicator is to assure requirements that mandate investigators and /or sponsors to monitor all subjects involved in CTs exist including obligation to report to the NRA/ responsible regulatory authority (ies) all adverse and /or serious adverse reactions and /or events within the approved time frame for reporting. The assessor should verify that the requirements on monitoring and reporting adverse and/reactions should be in existence and implemented. It should clearly provide guidance on monitoring adverse reactions and follow up. It should provide clarity on the roles/responsibility/duties of all stakeholders, including the NRA, as well as the exact requirement for monitoring, such as data collection and evaluation, and reporting adverse reactions/ events during the period of the CT. It should provide the type/nature/form of adverse reaction and/or event to report. The sequence of report in the event of reporting to more than one NRA or authority and other stakeholders, e.g. sponsor, should be indicated. The guideline should be supported by a form for monitoring and reporting adverse reaction/events.

15 WHO global benchmarking tool rev. VI ver., CT Page The guidelines and / or regulations on monitoring adverse events/ reactions and reporting, as well as follow up. The assessor should verify if the guidelines have been implemented.. The exact roles/responsibilities/duties of each stakeholder, and compare with the WHO recommendations or other international standards.. The NRA recommendations to the sponsor /investigator on the procedures for monitoring adverse events/ reactions and reporting. The assessor should verify if the recommendations are in line with WHO or other international standards.. Committee responsible for reviewing adverse reactions/events reports, the composition of the committee and specialties of committee members.. The timelines allocated for investigating adverse reactions/events on the part of the investigator/sponsor and generating a report on the adverse reaction and /or event to the NRA.. Records of the completed form sent to the NRA. The assessor should verify the format and content to assure compliance with the guidelines. Structure/Foundation/Input NI: There are no requirements and guidance on monitoring adverse event/reactions and reporting. OI: The requirements on monitoring adverse event/ reactions and reporting are drafted or defined, but these have not yet been followed. PI: The requirements and guidance on monitoring adverse event/reactions and reporting have been developed less than two years or there are no reports from all CTs. I: The requirements and guidance on monitoring adverse event/reactions and reporting exist and all sponsors are following them. Limitations and remarks: The assessor should score this sub-indicator as implemented if there is no record due no ongoing CT study.. - Handbook for good clinical research practice (GCP): guidance for implementation. WHO; 00(Principle : GLP; Principle ). 0- WHO TRS 0, Annex, (Chapter.,,.,.,) Sub-Indicator: CT0.0: THERE ARE GUIDELINES ON THE FORMAT AND CONTENT OF CLINICAL TRIAL APPLICATIONS Maturity:

16 WHO global benchmarking tool rev. VI ver., CT Page Format and content of CT applications The objective of this sub-indicator is to assure the existence of a clear guidance document that guides the applicant/sponsor on the information to be included in the application pack (content and format) and the procedure for submitting the application to the NRA for evaluation. Its content should be sufficient to facilitate CT activities. The assessor should verify that the guidelines on the format and content of CT applications should be in existence, issued and implemented. It should clearly provide guidance on the format and content (list of requirements/documents) of the CT application dossier to be submitted to the NRA. The content may include but not limited to ;CT registration with a registry that is approved/recognized by the NRA, covering letter addressed to head of the NRA, completed CT application forms that should be signed by an authorized person(s) and dated, CT Protocol, investigator s brochure (IB), investigational product dossier, good manufacturing practice (GMP) certificate, ethics committee / evidence of institutional review board approval,, evidence of insurance cover (from a recognized insurance company), statement/evidence of financial support/declaration, data safety monitoring board membership (DSMB) and signed charter, evidence of sponsor-pi contractual agreement, sample of informed consent form, assent forms (if applicable), statistical analysis plan (SAP), professional profile of potential PI, study pharmacist and local monitor (i.e. qualification, experience/ expertise, evidence of excellent knowledge of local CTs regulatory requirements, past CTs managed), others. The guidelines should also provide guidance on the sequence of events to be complied with before the actual submission (e.g. meetings, workshops, seminars, IEC, etc.). The guidelines may provide guidance on choosing a CT site and selection of subjects.. The guidelines on the format and content of the CT application are available, implemented and published on the NRA s website.. Accessory documents such as CT application forms and other CT related forms exist, are issued and used.. The form/nature of CT application pack submission (i.e. electronic or face-to-face, hard or soft copies and the number of copies.. List of critical documents that should be included in the application pack. Structure/Foundation/Input NI: There is no guidelines on the format and content of clinical trial applications. OI: The guidelines on the format and content of clinical trial applications drafted or adopted, but it has not yet been implemented.

17 WHO global benchmarking tool rev. VI ver., CT Page PI: The format and content of clinical trial applications has been established and it has been applying for less than two years. I: The NRA has guidelines on the format and content of clinical trial applications and it is followed for all received CTs application. Limitations and remarks:. -WHO TRS 00, Annex, WHO TRS 0, Annex, (Chapter.,,.,.,). - Handbook for good clinical research practice (GCP): guidance for implementation. WHO; 00 (Principle : GLP; Principle ). - WHO TRS, Annex, 0. - WHO TRS, Annex, 0 Sub-Indicator: CT0.: LEGAL PROVISIONS AND/OR REGULATIONS ALLOW THE NRA TO RECOGNIZE AND/OR USE RELEVANT CLINICAL TRIAL DECISIONS, REPORTS OR INFORMATION FROM OTHER NRAS, OR REGIONAL AND INTERNATIONAL BODIES. Maturity: Recognition and/ reliance on CT application decision/information The objective of this sub-indicator is to assure legal provisions and/ or regulations exist to allow the NRA to recognize and/or use relevant CT decisions, reports or information from other NRAs, or regional and international bodies. The assessor should verify that the legal provisions and/or regulations that allow the NRAs to recognize and/or use relevant CT decisions, reports or information from other NRAs or regional and international bodies should be in existence, enacted and implemented. The legal provision and /or regulation should provide guidance on the modalities/processes and procedure to recognize and/or use relevant CT decisions, reports or information from other NRAs or regional and international bodies, as well as guidance on the conditions (when/how) to recognize and/or use relevant CT decisions, reports or information from other NRAs, or regional and international bodies. The legal provision and/ or regulation should also provide clear directives on the scope or extent of recognition and/or use of the CT decisions, reports or information from other NRAs, or regional and international bodies.

18 WHO global benchmarking tool rev. VI ver., CT Page The legal provisions(laws, decrees, regulations or any legal binding document) that permits the NRA to recognize and/or use relevant CT decisions, reports or information from other NRAs or regional and international bodies.. The scope /extent of recognition and /or use of relevant CT decisions, reports or information from other NRAs, or regional and international bodies.. Instances or situations that permit recognition and/or use relevant CT 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 CT application decision, and whether those NRAs, or regional and international bodies are aware that their relevant CT decisions, reports or information on certain CTs may be used (aware of the legal provision). Structure/Foundation/Input NI: There are no legal provisions and/or regulations that allow the NRA to recognize and/or use relevant clinical trial decisions, reports or information from other NRAs, or regional and international bodies. OI: The legal provisions and/or regulations that allow the NRA to recognize and/or use relevant clinical trial decisions, reports or information from other NRAs, or regional and international bodies are drafted or pending for adoption. PI: Legal provisions and/or regulations allowing the NRA to recognize and/or use relevant clinical trial decisions, reports or information from other NRAs, or regional and international bodies have been established and the NRA has been applying them for less than two years. I: There are legal provisions and/or regulations allowing the NRA to recognize and/or use relevant clinical trial decisions, reports or information from other NRAs, or regional and international bodies, supported with adequate documentation such as criteria for selection or list of other NRAs. Limitations and remarks:. -Good regulatory practices: guidelines for national regulatory authorities for medical products. Working document QAS. Indicator: CT0 ARRANGEMENT FOR EFFECTIVE ORGANIZATION AND GOOD GOVERNANCE The objective of this indicator is to assure that there is a legal basis for the organizational structure and governance that allows for the smooth exchange of information within and outside the entity responsibly

19 WHO global benchmarking tool rev. VI ver., CT Page for CT (NRA, ECs, CROs, others) as appropriate. The arrangement should establish the responsible roles and persons within the entity responsible for the various sectors within the CT, and how their roles relate to the governance structure of the organization, as well as other CT related NRAs/ competent regulatory authority(ies) without the entity for CT. It will ensure that the NRA responsible for CT has complete control of all the information related to CT, including, on-going CTs, new directives, new authorizations, suspensions and rejections 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: CT0.0: THERE IS A DEFINED STRUCTURE WITH CLEAR RESPONSIBILITIES TO CONDUCT CLINICAL TRIAL OVERSIGHT ACTIVITIES Maturity: Structure and Responsibilities The objective of this sub-indicator is to assure there are structures in place, with clearly defined roles and responsibilities for each structural and governance level for CT activities. The assessor should verify that the defined structure with clear responsibilities to conduct CT activities exist and are implemented. It should be supported by legal provisions, regulations and guidelines, and clearly delineating roles, responsibilities and duties of all stakeholders within the NRA and outside of the NRA. The scope/extent of their role/responsibilities within the NRA in relation to CT activities, as well as their reporting lines should be clearly established. The structure of the entity (ies) or authority relative to relationships and ranks, as well as information exchange / flow within and outside (e.g. IEC) the entity (ies) or authority (ies) should be established and implemented. Guidelines for the establishment of advisory committees, such as technical experts committees, external experts among others, with clear objective/functions, composition, terms of reference, others should be established and implemented.. The roles/responsibility (ies) /duties of the entity (ies) responsible for CT within the NRA and their placement on the organizational chart in relation to other entities involved in CT.. The regulation and/or guidelines mandating such entity (ies) or authority (ies) with the responsibility to conduct CT activities within the NRA.. A clearly defined policy on conflict of interest.

20 WHO global benchmarking tool rev. VI ver., CT Page The operational manual or similar document of the entity (ies). The manual should contain all the authorized /approved guidelines (published or not), application form (published or not), and SOPs or similar documents.. Published CT application processing flow diagrams and corresponding timelines, as well as the fees and charges schedule. Structure/Foundation/Input NI: There is no defined structure with clear responsibilities to conduct clinical trial oversight activities. OI: The NRA has recently drafted a defined structure with clear responsibilities to conduct clinical trial oversight activities. PI: The NRA has established a defined structure with clear responsibilities to conduct clinical trial oversight activities, however there is the need to improve this function by providing required support for effective implementation and coordination. I: The NRA has established a defined structure with clear responsibilities to conduct clinical trial oversight activities that is fully supported with required resources. Limitations and remarks: Sub-Indicator: CT0.0: DOCUMENTED PROCEDURES ARE IMPLEMENTED TO ENSURE THE INVOLVEMENT AND COMMUNICATION BETWEEN ALL STAKEHOLDERS RELEVANT TO CT Maturity: CT stakeholders interactions 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 CT in order to ensure effective and efficient exchange of information amongst stakeholders. The assessor should verify the documented procedures that promote involvement and communication between all stakeholders should be in existence and are implemented. 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 all stakeholders within and outside the NRA such as

21 WHO global benchmarking tool rev. VI ver., CT Page the CT entity, IEC, GCP inspectorate, sponsors/ip, etc. It should be clear on the scope/extent of the role/ responsibilities of each stakeholder. 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 feedbacks are received. SOPs or similar documents and guidelines should be approved, authorized and implemented.. Whether procedures are documented and implemented, and the impact of the implementation is periodically assessed.. Standard Operating Procedures (SOPs) or similar documents that guide and/or inform effective communication and collaboration between stakeholders.. The CT application guidelines that captures the duties/roles and responsibilities of the various stakeholders involved in CT activities and whether the document is known to the relevant organizations, institutions, and/or departments.. The CT application processing flow that captures the roles/duties and responsibilities of the various stakeholders and the corresponding timelines allocated to the various levels. The feedback mechanism in the information and /or documentation transfer policy (ies) among the various stakeholders. Process NI: There are no procedures to ensure involvement and communication with all stakeholders relevant to CT. OI: The NRA has recently drafted procedures to ensure involvement and communication between all stakeholders relevant to CT. PI: The NRA established the procedures to ensure involvement and communication between all stakeholders relevant to CT but these have not been fully incorporated and are not consistent with relevant guidance. I: The NRA has implemented procedures to ensure involvement and communication with all relevant stakeholders including required documentation and records of communication, as well as feedback. Limitations and remarks:

22 WHO global benchmarking tool rev. VI ver., CT Page Indicator: CT0 HUMAN RESOURCES TO PERFORM CLINICAL TRIALS OVERSIGHT ACTIVITIES. The objective of this indicator is to assure to that all entity (ies) within an NRA that is/are adequately resourced with trained, experienced and skilled workforce, as well as empowered to fully perform clinical trials oversight activities. This will ensure that clinical trials oversight 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 clinical trials oversight activities. The assessor should consider that some NRAs may outsource CT activities. Category: Resources (HR,FR, infrastructure and equipment) Sub-Indicator: CT0.0: ENOUGH COMPETENT STAFF (EDUCATION, TRAINING, SKILLS AND EXPERIENCE) ARE ASSIGNED TO PERFORM CLINICAL TRIALS OVERSIGHT ACTIVITIES. Maturity: Enough number of competent human resources in charge of clinical trials oversight activities. The objective of this sub-indicator is to assure the existing human resources for clinical trials oversight activities is adequate in terms of numbers, their experience and their specific competences to perform all the activities along the entire clinical trials oversight activities The assessor should verify that the human resources assigned to perform clinical trials oversight activities should be enough in terms of numbers and are competent with the requisite skills, education, experience and training. There should be technical documents and /or SOPs that provide guidance on the required background for CT activities taking into account the educational background, competencies/skills, and experience and training requirements. The assessor should verify that the NRA estimated the adequate number of staff required to effectively and efficiently perform CT function and such number is actually recruited. In addition, the assessor should verify that these competency requirements are well set and maintained by the NRA Metrics and statistics on the different activities performed as well as performance indicators can be used for estimating the adequacy of the number of the assigned staff. The assessor should also verify that the competency of the assigned staff is built, maintained and improved through induction as well as continuous on-the-job training.