[NAME OF NATIONAL REGULATORY AUTHORITY] PROCEDURE FOR SUBMISSION CLINICAL TRIAL APPLICATIONS VACCINES AND BIOLOGICALS [COUNTRY]

Transcription

1 [TEMPLATE] [NAME OF NATIONAL REGULATORY AUTHORITY] PROCEDURE FOR SUBMISSION OF CLINICAL TRIAL APPLICATIONS OF VACCINES AND BIOLOGICALS IN [COUNTRY] 1of 19

2 General Procedures for clinical trial applications for vaccines and Biologicals Guidelines for the Review & Evaluation Process of Applications for Clinical Trials of Vaccines & Biological medicines [National Regulatory Authority of Country] CONTENTS 1 Introduction 1 2 Definition of Terms and Abbreviations 2 Check-list for documents in an Application 2 3 Procedures for Application submission and review 3 4 Institutional Review Board and/or Independent Ethics Committee 3 5 Amendments to Trial Protocol 4 6 Regulatory Authority Inspections 5 7 Reports and Final Review 5 Attachment 1: Time line for Review of Applications 6 Attachment 2: Clinical Trial Application Form Attachment 3: Format for declaration by Investigators Attachment 4: Explanation of information required to confirm GMP 1 Introduction: 1.1 It is required that all medicines used in [country] are registered (licensed) with the National Regulatory Authority 1 (NRA), and any clinical study using registered or unregistered medicine must receive written approval from the NRA for that purpose [Insert applicable Law title] The importation of unregistered medicines is subject to [applicable law] and written approval is required prior to importation (see Document 3). 3 Where such medicines are intended for use in clinical trials, they will be subject to the NRA review and control procedures detailed in these documents. 1.3 This guideline sets out the procedures that should be followed by applicants who wish to conduct clinical studies in [country], and the steps that the regulatory authority will take to review, evaluate and permit the conduct of such studies. 1.4 The review and approval process in [country] is expected to take [?10] weeks from the time the completed application is received by the Clinical Trials Review focal point of the NRA. Incomplete applications or those where additional information is required will take longer to review. Where applications are especially complex, additional review may be necessary that may extend the review period. 1.5 For further information refer to the WHO Guidelines for Clinical Evaluation of Vaccines TRS-924 (2004) ICH Guidelines for clinical Trials E6(R1) CPMP/ICH/135/95, updated in EU Directive 2005/28/EC. 1.6 Approval by the NRA for conduct of the clinical trial does not absolve the applicant from compliance with all laws and regulations in [COUNTRY] In particular, other laws may apply to import or use of Infectious or genetically modified organisms. 1 The specific name of the NRA in each country can replace the term NRA if desired 2 Establishes the legal framework for these guidelines. These will be country specific. 3 Required in some countries where the law is vague on NRA control of clinical studies. 2of 19

3 2 DEFINITION OF TERMS The Glossary of terms set out in the WHO TRS 924 is accepted in these documents. 3of 19

4 2.1 ABBREVIATIONS ABPI Association of British Pharmaceutical Insurers CTA Clinical Trial Application form CTG Clinical Trial Group within the NRA responsible for approval of a trial application CV Curriculum vitae DSMB Data Safety Monitoring Board EU European Union IB Investigators Brochure ICON Informed Consent Form ICH International Committee on Harmonization IEC Independent Ethics Committee IRB Institutional Review Board (Institutional Ethics Committee) GCP Good Clinical Practice GLP Good Laboratory Practice GMP Good Manufacturing Practice GPS Global Positioning System MS-word MicroSoft Word v7 NRA National Regulatory Authority (Agency) PDF Acrobat reader file format PIL Participant Information Leaflet WHO World Health Organization 2.2 Documents required for Clinical Trial Applications CHECKLIST Fees Proof of payment Application for import of unregistered medicine/s, if necessary Application for export of biological specimens (clinical samples) if necessary. CTA Clinical Trial Application Form - signed & dated APPENDIX 1: Trial Protocol - In the ICH E6(R1) format APPENDIX 2: Investigators Brochure - in the ICH E6(R1) Format APPENDIX 3: Report Summaries of prior clinical trials with this medicine. These may be part of the IB. APPENDIX 4: Participant Information Leaflet (PIL) and Informed Consent (ICON). Specific for use in this country. APPENDIX 5: Acceptable Certificate of GMP manufacture of the trial medicine. Or other evidence of manufacture quality, safety and consistency. APPENDIX 6: Package Insert/s for other trial medicines. APPENDIX 7: Certificate of GMP manufacture of the placebo - if appropriate. APPENDIX 8: Evidence of accreditation of the designated Laboratories. Or other evidence of GLP and assay validation APPENDIX 9: Insurance Certificate specific for this trial, APPENDIX 10: Signed and completed Declarations by all Investigators Malpractice Insurance, GCP training & CV attached. APPENDIX 11: Approval of Ethics Committees In the case of a parallel submission to the Ethics Committee/s, the letter of application should be appended. APPENDIX 12 Full, legible copies of key, peer-reviewed published articles supporting the application. APPENDIX 13 Other Appended documents 4of 19

5 PROCEDURES FOR APPLICATION, REVIEW & APPROVAL 3 APPLICATION 3.1 Format of Applications Applications must be submitted to the NRA Focal Point for Clinical Trials Office number & location: Postal Address: Telephone & Fax: The Application Form (CTA) The application should be submitted in writing, in the format and numbering set out in the Clinical Trial Application Form [Attachment 2]. The text and diagrams must be clear and legible (e.g.12 pt Arial font). If information is supplied in a less legible format it could lead to misunderstandings and delay. The detail requested in the application form should be completed briefly, but in full, to enable quick review of studies. However each section should be cross-referenced to the detail in the Trial Protocol, Investigators Brochure, and other appended documentation Application integrity The application should be bound in a single volume (or series of volumes) and the pages of the CTA numbered sequentially. The appended documents should be bound together with the application, with tabbed sections identifying each appended document Supporting publications Complete, legible copies of key (peer reviewed) publications supporting the information in the application should be attached (Appendix 12). They should be cross-referenced from within the CTA text. Requests for additional publications will delay the application Electronic format Some regulatory authorities may require that the Protocol, Investigators Brochure, and Reference publications, are also supplied on a Compact Disk. MS-word v7 is usually an acceptable format, although Acrobat PDF files are also acceptable Fees Proof of payment of the required fee must be appended. The Fee for a New Application is: The Fee for a Protocol Amendment is: 3.2 Confidentiality The NRA commits to maintain the confidentiality of any information submitted as part of a clinical trial application, supporting documents or associated correspondence. A separate, trial-specific, confidentiality agreement with the applicant can be entered into prior to an application, if this is desired by the applicant 3.3 Screening On receipt the NRA will screen the application for completeness All documents and Appendices (see check list below) Proof of payment of the required fees Application for import of unregistered medicine/s, if necessary Application for export of biological specimens (clinical samples), if necessary. 5of 19

6 3.3 Expert review - See Document 2 for details of NRA expectations. The application will be reviewed by experts appointed by the NRA. There is a confidentiality agreement with the reviewers, and committee members to ensure that the content of the application remains confidential. The initial review may result in queries that need to be answered by the applicant. It is required that the reviewers do not have direct contact with the applicant and that all correspondence is directed through the NRA. The reviewers will generate a report that will be circulated to a committee (Clinical Trials Group -CTG) appointed by the NRA where a recommendation for approval will be made. 3.4 APPROVAL The NRA will consider the recommendation of the CTG, the approval of the Ethics Committee/s and other relevant information. The NRA may approve the trial application or may reject the application and specify the reasons for rejection. Approval will be dependent on receipt of approval of the protocol by the local Independent Ethics Committee. The Approval for importation of trial related medicines will be dependent on the approval of the clinical trial. This decision will be communicated to the applicant in writing. In the case of rejection, the applicant may appeal and provide additional information to satisfy the NRA expectations. This may need to be referred to the Expert reviewers for a recommendation. 3.5 Post trial review The Final Report from each study conducted in [COUNTRY] should be submitted to the NRA and referred to the CTG that reviewed the initial application. The format should follow the ICH E3 137/95 The review should include scrutiny of Interim Reports, Monitor Reports and any NRA Inspection Reports. If all the requirements of GCP and local requirements are met, the CTG will provide a recommendation for approval. The NRA may then issue a statement certifying that the Clinical Study has been conducted within the legal, ethical and regulatory requirements of [COUNTRY]. 4 The Institutional Review Board (IRB) or Independent Ethics Committee (IEC) An independent body, constituted by medical professionals and non-medical members, whose responsibility is to verify that the safety, integrity and human rights of the subjects participating in a particular trial are protected, thereby providing public reassurance. Ethics committees should be constituted and operated so that the suitability of the investigators, facilities, protocols, the eligibility of trial subject groups, and the adequacy of confidentiality safeguards may be objectively and impartially reviewed independently of the investigator, sponsor, and relevant authorities. 4.1 For NRA approval of each clinical trial application, approval is also required from an IRB, where the study is conducted in an approved educational institution and/or from a local IEC where the trial site is located within the community. To expedite the review of the application by both the NRA and the IEC, the applicant may submit an additional 2 copies of the complete application to the NRA for redirection to an IEC by the NRA. It may be acceptable to the NRA that parallel submissions are made to the NRA and the IEC by the applicant. Approval of each would then be dependent on approval by the other body. It is important that queries and amendments required by either body are conveyed, for information, to the other. 6of 19

7 4.2 The IRB/IEC should be established and function as set out in the ICH Guideline for Good Clinical Practice Section The IRB/IEC approval of the study protocol should be submitted to the NRA with the Clinical Trial Application, and should include Details of IRB/IEC membership; Statement of compliance with the requirements in the ICH Guide; A summary of the deliberations; Any amendments to the trial protocol required by the IRB/IEC; Any conditions included in the approval; The final decision. 5 Amendments to the Trial Protocol. 5.1 Amendments to the protocol, during the NRA evaluation process, can lead to confusion and undue delay. If amendment is essential, it is recommended that the application should be withdrawn and the complete amended version re-submitted. If the NRA requires amendments, a revised CTA and supporting documents should be submitted or only the revised section may be replaced if the NRA approves. 5.2 Amendments, post approval by the NRA can be submitted for review If the amendment is judged (by the DSMB and/or Principal Investigator) as urgently necessary to protect life or well-being of trial participants or the community, the change may be effected immediately, and the investigator must inform the IRB/IEC and the NRA as soon as possible - by telephone followed by a written full explanation and the information in 5.3 below, If the amendment may affect the safety of the trial participants (e.g. changes to dose, regimen, concomitant medication, monitoring, etc.) the amendment must be submitted in full and approval from the NRA and IRB/IEC obtained prior to implementation If the amendment is unlikely to impact on participant safety (e.g. change of investigator (except Principle Investigator), end point assay, laboratory, statistical analysis, etc.) the full detail of the change must be submitted to the NRA in writing, and the change may be implemented [14] days after receipt of the amendment by the NRA, if no notification to the contrary is received by the applicant. 5.3 Information to be supplied when submitting a protocol amendment An amended CTA Application form should be completed. A Bold Heading should note that this is an Amendment and the date. Each amendment should be BOLD and in a BOX at the relevant position in the text. A Table in a covering letter should detail all amended parts of the Application Form. The reasons for the amendments must be provided. The possible consequences for participants already enrolled must be described. An amended PIL & ICON may be required. Any additional risks or safety issues should be highlighted. The amended supporting documents should be appended, including any new relevant publications. 5.4 The NRA will review the application together with supporting approval from the IEC, and possibly refer it to expert reviewers before making a decision to approve the amendment. 7of 19

8 6 INSPECTIONS - PRE-TRIAL AND DURING THE TRIAL 6.1 The NRA may inspect the trial site, the sponsor or the manufacturer of the medicine, and will typically provide [24] hours notice of such inspections. - Notice will be addressed to the Contact provided in the application. - Such inspections may be before commencement of the trial, or at predetermined intervals, or may be at the request of the Expert Committee, responsible for clinical trial review. - However, in the case of complaints or reports of unexpected adverse reactions, inspections may take place at short notice and may be unannounced. 6.2 The Inspections will include - but not be limited to: The facilities and staff used for the trial: as approved by the NRA Compliance with the approved Protocol All amendments to the Protocol have been approved Accurate, complete and current records according to the Protocol Serious Adverse Events are reported as required by the Protocol Monitor and Audit inspections are conducted as required by the Protocol and the reports are available for inspection. 7 REPORTS AND FINAL REVIEW 7.1 Reports of Serious Adverse Events These must be reported to the NRA within [7 days] of the Principal Investigator becoming aware of them. A follow-up report of causality and a recommendation from the Safety Monitoring Board for the study must be submitted to the NRA when available. 7.2 Interim Reports The NRA will expect to receive interim reports at six monthly intervals. For trials of less that one year duration, an interim report at about half way through the trial should be provided. The interim Report should include: - Numbers of participants enrolled to date; - Numbers of participants who have completed the study; - Number of enrolled participants that have left the study; - Number of doses of each trial medicine used to date; - List of Serious Adverse Reactions - report with causality; - List of all adverse reactions; - List of any changes to trial personnel - including full CV and Declaration. - List of Monitor and Audit reports to date. 7.2 The Final report - general considerations The Final Report should follow international expectations for Clinical trial Reports - see ICH Part 3 and Part 6. This must be a complete and comprehensive description of the trial and its outcomes after completion. The protocol, statistical and clinical aspects should be integrated in order to obtain a final study report that is entirely consistent with the study data generated. The essential elements in the review of a Vaccine/Biological clinical study are: assessment at baseline and at pre-specified post vaccination times; the number of participants actually randomized into the study by treatment group and the number of participants excluded from any of the analysis, by reason and by treatment group; major efficacy and safety results by treatment group in the form of tables, graphs, test variables and statistical parameters (e.g. p-values) as appropriate; an assessment of between-group differences with confidence intervals; and in multicenter studies, an evaluation of center effect may be a valuable addition and should always be conducted where significant inter-center variation is suspected; an account must be made of missing, unused or spurious data during statistical analysis. All omissions of this type must be documented to enable review to be performed. Reports must be made available via paper submission and an electronic version, see above. 8of 19

9 ATTACHMENT 1 Table of expected time periods for the review procedure (To be completed by the NRA of each COUNTRY) Date of Submission Screening period Response from Applicant Evaluation by Experts Distribution of Report Review by NRA Committee NRA Approval day 0 * 7 days not counted 21 days? days 14 days 7 days *: suggested time periods - but the reality will depend on the NRA capacity and the completeness of the application 9of 19

10 The Clinical Trial Application form (CTA) ATTACHMENT 2 [COUNTRY] CTA Section 1 Identification of the Clinical Trial 1.1 Title of the Study 1.2 Protocol#: 1.3 Contact Person and contact details 1.4 [Space for NRA Reference Number] 1.5 Declaration of Intent, Signed by Contact Person & National Principal Investigator We, the undersigned have submitted all the required documentation and have disclosed all the information required for approval of this application. We have read the Protocol and the Investigators brochure, appended. We have the authority and responsibility to oversee this clinical trial, and agree to ensure that the trial will be conducted according to the Protocol and all legal, ethical and regulatory requirements in this country. Applicant (Local Contact): NAME Date: Signature: Designation National Principle Investigator: NAME Signature: Designation Date: CHECKLIST of REQUIRED DOCUMENTS Fees Proof of payment Applications for import and/or export of materials (if required) CTA Clinical Trial Application Form APPENDIX 1: Trial Protocol APPENDIX 2: Investigators Brochure APPENDIX 3: Report Summaries of prior clinical trials with this medicine APPENDIX 4: Participant Information Leaflet (PIL) and Informed Consent (ICON) APPENDIX 5: Certificate of GMP manufacture of the trial medicine APPENDIX 6: Package Insert/s for other trial medicines. APPENDIX 7: Certificate of GMP manufacture of the placebo - if appropriate. APPENDIX 8: Evidence of accreditation of the designated Laboratories APPENDIX 9: Insurance Certificate specific for this trial, APPENDIX 10: Signed and completed Declarations by Investigators APPENDIX 11: Ethics Committee/s approval of the Protocol APPENDIX 12: Full, legible copies of key, peer-reviewed published articles supporting the application. APPENDIX 13: Other supporting documents

11 CTA Section 2 Basic Administrative Data on the Application 2.1 Name and address of the registered office of the Applicant Name: Telephone Number/s: Fax Number/s: address/es: Physical Address: Postal address: 2.2 Name and address of the registered office of the Sponsor/s Telephone Number/s: Fax Number/s: address/es: Physical Address: Postal address: If there is no sponsor as in Investigator initiated trials - a statement to this effect. 2.3 Name and address of the site of the Manufacturer/s Telephone Number/s: Fax Number/s: address/es: Physical Address: Postal address: CTA Section 3 Medicines to be used in the trial 3.1 Investigational Vaccine or Biological medicine Identifier or name of investigational medicine (code if applicable) Registration number in (country) Manufacturer/s (Include all sites) 3,1.4 Active ingredient, complete composition, potency and presentation Evidence of manufacture under conditions compliant with current codes of Good Manufacturing Practice [APPENDIX 5] See Attachment 4 for details of the required information Release Specifications and tests. Include Certificate of Analysis Current approved Package Insert if available. 3,2 Comparator, Concomitant and Rescue medications (and Placebo) Proprietary name and IN Active ingredient/s, composition, and presentation Registration number/s (country) Approved Package inserts to be appended to application [Appendix 6] Evidence that Placebo is manufactured under GMP. [Appendix 7] 3.3 Details of handling Trial medicines Shipping, delivery and distribution of trial medicines Details of storage requirements, and arrangements for cold-chain maintenance and monitoring during distribution Details of dispensing trial medicines and Waste disposal procedures Packaging and Labelling 3.4 Estimates of quantities of each medication (presentation) to be used for the trial, and for which an import permit is needed. See document 3.

12 CTA Section 4 Sites & Investigators 4.1 National Principal Investigator or co-ordinator (Responsible person) Name: Qualifications Contact Details Physical address Declaration of Capacity & Interests [Appendix 10] For each Site list the following: 4.2 Site Identifier (Name) Physical Address: (for rural sites include GPS coordinates) Telephone & Fax numbers address Description of the site facilities & Staff Clinic and counselling rooms Emergency facilities Facilities for special examinations (if required) Capacity to collect, prepare, store and transport clinical samples Storage and handling facilities for medicines Name and qualifications of person with responsibility for dispensing medicines 4.3 Site Principal Investigator Name: Qualifications Contact Details Physical address Declaration of Capacity & Interests [Appendix 10] 4.4 Site Sub-investigators and trial-specific support staff Name: Qualifications Contact Details Physical address Declaration of Capacity &Interests [Appendix 10] 4.5 For Hospital or Public Health Clinic Sites Responsible Administrator Contact Details Append Signed Letter of Agreement for Trial to take place. 4.6 Append Signed Agreement/s between the Investigators and the Sponsor/s and/or Clinical Research Organization. Appendix 13. CTA Section 5 PARTICIPANTS 5.1 Numbers of Participants Total number to be enrolled, world wide Total number to be enrolled in this country Number of trial sites in this country Intended numbers of participants at each site - evidence of availability. 5.2 Duration Estimated trial duration: First enrolment to Final Report Duration for individual Participant Screening period Intervention period Follow-up period 5.3 What is the intended remuneration/compensation per participant.

13 CTA Section 6 History of Previous and in-progress trials 6.1 List the titles of previous trials with this (or similar) medicines in this country 6.2 List the titles of previous trials with this (or similar) medicines in other countries 6.3 Append Interim or Final report-summaries of these trials to this application. (This may be in the Investigators Brochure or APPENDIX 3) 6.4 Include a letter or certificate from the regulatory authorities in countries where previous trials have been undertaken (including those in-progress) that these trials have been GCP compliant. CTA Section 7 Ethics review 7.1 Provide the local IRB/IEC approval of the Protocol for each site - [Appendix 11] 7.2 What GCP Guidelines have been followed in compiling this protocol? 7.3 Will GCP training be provided for local staff and investigators? CTA Section 8 Trial conduct monitoring and reports 8.1 Describe the Safety and Monitoring Plan for each site. 8.2 Describe the system to be used to detect, record, assign causality and the actions for Adverse events. 8.3 Describe the actions to be taken following reports of Serious Adverse Events. 8.4 Describe the composition and remit of the Data Safety Monitoring Board or similar body. Include conditions for Pause- or Stop- rules. 8.5 When will Interim Reports be submitted? 8.6 Final Report - Estimated due-date? CTA Section 9 INSURANCE 9.1 Provide a copy of the current insurance certificate. APPENDIX Provide evidence that each member of the Investigator team is covered by relevant Malpractice insurance for this trial. APPENDIX 10. CTA Section 10 Description of the Trial 10.1 Is the Title of the Trial fully descriptive? 10.2 Summarized Rationale for this Clinical Trial, including relevance to this country BRIEF Background information should include The disease or condition and local epidemiology Properties of the medicine - hypothesis for action Description of risks of the protocol and the potential harms of the medicine. Pre-clinical animal toxicology test results in-animals and in-vitro that establishes probable safety and efficacy in humans * Prior Clinical trial report summaries that establishes probable safety and efficacy in humans * Include evidence that the formulations used in the pre-clinical and previous studies are identical to that in this application. Any variations should be highlighted and justified. * Published reviews or reports relevant to this disease and this type of medicine * : Cross-reference to detail in the IB Objectives of this trial (List as Primary and Secondary objectives and provide justification)

14 10.5 Trial Design: Describe and justify each component Phase Placebo or comparator Randomization and blinding Other detail Time sequence - A Table of screening, intervention and follow-up visits will be of assistance Participants Eligibility Inclusion criteria - list and justify each Exclusion criteria - list and justify each Treatment regimens for each group. The table in above can be used to set this out Follow-up, sampling collection and monitoring plans Immediate monitoring - intermediate monitoring - long term Diary cards, Telephone access to investigators Outcomes Measurements and Analysis Describe each outcome/variable (including safety) and explain or justify Describe the samples that will be collected and the analyses to be conducted on each sample Provide evidence that the Laboratories that will conduct the Safety screening, and the End-point assays are accredited and competent to do the assays. APPENDIX Describe the intended statistical analysis to be conducted. Provide evidence that the study is powered to provide the intended outcome Are any Sub-studies intended. Provide full details Are any genetic studies (HLA-typing or gene marker analysis) intended? Provide full details, and justify this. Is there a separate Informed Consent Form for this Will clinical samples be stored for any period beyond the duration of this trial? What is the purpose of such archiving? What controls are to be placed on their confidentiality and possible future use? 10.9 Participant Information Leaflet (PIL) and Informed Consent (ICON) Append a copy of the PIL & ICON [Appendix 4] In what languages will this be available? Append the Parent / guardian consent form, in the case where minor participants will be included Separate ICON for sub-studies or Genetic studies. 11 Publication Policy Provide details of the Investigators and Sponsors intentions and freedom to publish the outcomes of this study. (Required by some countries).

15 Appended to CTA: FEES Proof of payment Application for the Import Permit medicines for this study if required Application for the export of biological materials (clinical samples) if required APPENDIX 1: Trial Protocol APPENDIX 2: Investigators Brochure APPENDIX 3: Report Summaries of prior clinical trials with this medicine APPENDIX 4: Participant Information Leaflet (PIL) and Informed Consent (ICON) as intended for use in this study. Separate consent for Sub-studies or Genetic Analysis. Guardian/parental consent for minor age participants APPENDIX 5: Certificate of GMP manufacture of the trial medicine or sufficient information on the manufacture and control that enables the reviewer to assess that trial medicine is well characterised, and that cgmp has been assured See Attachment 4 for details of the required information. Include Certificate of Analysis - Release test results. APPENDIX 6: Package insert leaflets from concomitant and comparator medicines. APPENDIX 7: Certificate of GMP manufacture of the placebo. Certificate of Analysis APPENDIX 8: Evidence of accreditation of the designated Laboratories to conduct the safety-screening tests and the end-point assays. APPENDIX 9: Insurance Certificate specific for this trial, including reference to compensation according to ABPI guidelines. APPENDIX 10: Signed and completed Declarations by Investigators Example format - see below - Include current CV Evidence of Malpractice Insurance Evidence of recent GCP training Declaration of Capacity & Interests APPENDIX 11: Approval of Local Ethics Committee/s. Include REC composition and Process. In case of parallel submission provide the NRA with a copy the application letter APPENDIX 12: Full, legible copies of key, peer-reviewed published articles supporting the application. APPENDIX 13 Other supporting documents

16 ATTACHMENT 3 APPENDIX 10: FORMAT for Declarations by Investigators Trial Protocol Number NAME: Role in Trial Trial Title: Site: A current Curriculum Vitae is attached. 1 I am aware of the responsibilities of my role as in clinical trial number as required by the legal, ethical and regulatory requirements of [Country] 2 I have read and understand the attached Protocol, Investigators Brochure and supporting documentation and I will comply with the procedures and requirements included in them. 3 I have read the attached Clinical Trial Application form as submitted to the regulatory authority in [COUNTRY] and confirm that the information is complete, true and accurate, and conforms to the Protocol and supporting documentation. 4 I will not commence with this trial before written authorization has been received from the National Regulatory Authority of [COUNTRY] and the relevant Ethics Committee/s. I will provide the IEC and NRA with reports as required. 5 I will obtain Informed consent from all participants, or if they are not legally competent, from their legal representatives, parents or guardian. I will ensure that every participant (and other involved person, such as relatives) will be treated in a dignified manner and with respect. 6 I DECLARE: I have no conflict of interest in terms of financial interests or personal relationships that may inappropriately influence my responsibilities and conduct of this trial. Initials: I DECLARE: I have not previously been associated with any clinical study that has been terminated, or study-site that was closed, due to failure to comply with Good Clinical Practice. Initials: I have the malpractice insurance, that will provide cover for my activities in this clinical trial, as required in [COUNTRY] Malpractice Insurance Number I have received suitable, recent training in Good Clinical Practice in [COUNTRY] context. 10 SIGNED DATE WITNESS: NAME DATE

17 ATTACHMENT 4 Guide to Applicants and NRA reviewers: Requirements for Information on Manufacture of Medicines for Clinical Trials Introduction Applications for clinical trials may be for registered medicines, but for Phase 1, II & III trials, with novel products, many gaps in the knowledge exist regarding the disease process and the recovery from, (or suppression) of infection. Thus trial materials may not be in the form of products in their final form, dosage, packaging or even mode of delivery. Such trials may be considered as proof of concept, where the new types of product are under evaluation and where the end points are novel and there is little prior knowledge in the field. For example: several of the HIV vaccines, methods of manufacture, delivery, and end points are radically different from other pharmaceuticals or vaccines for which experience and knowledge has accumulated. However, for these conceptual materials to be accepted for use in humans, it is important that they adhere as far as possible to the expectations for quality and safety of any medicinal product. Generally, trials of vaccines are intended to investigate and demonstrate, sequentially, the SAFETY, DOSAGE, IMMUNO-GENICITY and EFFICACY of the product. It is expected that the medicine used in humans has been: manufactured in a facility under the control, (inspected by) of a competent national regulatory authority and certified as GMP compliant. manufactured under a Quality Assurance program that ensures consistency of product quality. made in suitable facilities with equipment which is qualified, using processes that are validated by staff that are suitably qualified and trained is manufactured to meet defined specifications for raw materials, intermediate and final product shown to meet the specifications using meaningful tests is documented with regard to materials, equipment, methods and tests. shown to be stable for key parameters, in the defined packaging and storage conditions for at least the duration of the trial. and that product, manufactured and formulated identically, and meeting the same specifications has been subjected to adequate, comprehensive pre-clinical and toxicological testing. The Applicant must satisfy the reviewers that Good Manufacturing Practices are in place, and employed, at all stages of manufacture of the trial vaccine, and must expect that inspectors from the regulatory authority will inspect the sites involved. It is possible that a current certificate from a suitable competent authority will be acceptable evidence of GMP. Proof of concept materials may not have the completeness in this regard as expected for normal medicines or trial materials. But it would be unethical to proceed with a trial where substantial and significant parts of the information were not available and satisfactory. During review, the following issues should be considered. Product Consistency during development As the product passes through the different phases of pre-clinical testing, clinical trials, use and post marketing surveillance, it is important that product with identical specifications has been used throughout. Variations or uncertainty regarding product quality or specifications will invalidate any previous results and may necessitate restarting the process. Any changes must be high-lighted and the applicability of extrapolating results clearly justified.

18 Product Characterisation Biological products cannot be characterised to the same extent as other pharmaceuticals and product consistency is assured by a combination of standardised starting materials, consistent production methods and final testing to meet defined specifications. Standardisation of packaging, distribution, storage and waste disposal are also important. Evaluation of documentation Evaluation of the information provided regarding manufacture enables confidence in application of GMP. Submissions for clinical trials must be accompanied by complete documentation and the NRA must be satisfied that the process is fully controlled. The actual release protocols and test results for the batches to be used for the trial, will assist in the review. Future modifications During product development it is probable that changes to methods or specifications will be proposed, as better information on the product becomes available, or scale-up is necessary. These changes can be evaluated only if full information on the initial submission is available. Completeness of submission It is unreasonable for the NRA to expect that products in early stages of development will have the same level of available information as those which approach the marketing stage. None-the-less the need for the most complete information possible at the earliest stages of the trials will reduce any later uncertainties. As more information becomes available it should be submitted to the NRA for review. Qualification of equipment and validation of processes and assays is not expected to be complete during early phases of clinical trials, but there must be evidence that they are fit for the task and there must be suitable controls and standards in use. GMP Information for Clinical Trial Evaluation: The following items of information will provide assurance that the quality concerns have been met. The reviewer may request additional information where the applicant has given insufficient or inconsistent information. The detail must relate directly to the medicine to be used in this trial application 1 Names, qualifications & experience of personnel responsible for manufacture, quality assurance, quality control and Final product release 2 Manufacturing site: Addresses and location of each site of manufacture, processing, packaging, storage, test laboratories and Animal facilities used for this product. Some information regarding: layout, finishes, HVAC, product flow, containment, other activities in the same facility and arrangements to prevent contamination of the product. Information on the implementation of documentation: Standard Operating Procedures, Change Control procedures etc. 3 Raw materials: Derivation, maintenance and testing of organisms & constructs [Master Seed Characterisation) Derivation, maintenance and testing of production substrates cells, tissues or eggs. Key raw materials and animal or human derived materials used in the process (prion safety) Specifications and tests of materials used during subsequent processing; e.g. inactivation, or chromatography media and reagents, including materials for regeneration and storage (an indication of the potential toxicity of these materials) - include water quality. Specifications of containers and closures. Specifications and tests of all materials which are included in the final formulation. Where the tests are not pharmacopoeia or similar, then evidence of suitability, consistency and accuracy is required.

19 4 Manufacturing methods: Explanation in words. If there are deviations from the methods used for product for pre-clinical tests or earlier clinical trial phases, these must be described and explained. Description and/or specifications of equipment used Flow chart showing steps in the process and sample points with the in-process tests at each step. A description of the in-process tests and limits at each stage. Methods for removal of materials used during preparation, and tests to confirm this. Filling, freeze-drying and packaging methods. Evidence of consistency of manufacture or validation of the processes. 5 Final product Quantities of all constituents in the final product formulation (including limits for residues) Specifications for the final product including upper & lower limits of acceptance The measure of potency must be defined and justified Preservative/s, stabilizer/s and adjuvant/s must be defined and justified. Testing methods for demonstrating that the specifications are met. (Reference materials) Where the tests are not pharmacopoeia or similar, then validation information is expected. Specifications for the final container and closure. Evidence for suitability. Packaging processes, Labelling, transport and storage Batch Manufacturing Records for three consecutive recent production lots, made according to the submitted protocol, and including the records for the lot to be used in this trial 6 Stability There must be data that demonstrate the stability of the product in the final container and closure, over the proposed time of the trial, and/or a documented program that collects and tests field samples, at all trial sites, to demonstrate that this stability has been achieved during the trial. 7 Safety I. Measures to ensure cold-chain maintenance and storage II. Evidence that the product to be used for the trial is identical in specifications and manufacture to material that has been used in preclinical testing and earlier phases of clinical trials. Where there is uncertainty, this should be described, and the reasons for the changes explained. III. Measures of waste disposal and disposal of unused product.