National Drug Policy and Authority (Conduct of Clinical Trials) Regulations, 2014 (S.I. No. 32 of 2014)

STATUTORY INSTRUMENTS SUPPLEMENT No. 8 28th March, 2014 STATUTORY INSTRUMENTS SUPPLEMENT to The Uganda Gazette No. 18 Volume CVII dated 28th March, 2014 Printed by UPPC, Entebbe, by Order of the Government. S T A T U T O R Y I N S T R U M E N T S 2014 No. 32. THE NATIONAL DRUG POLICY AND AUTHORITY (CONDUCT OF CLINICAL TRIALS) REGULATIONS, 2014 ARRANGEMENT OF REGULATIONS Regulation PART I—PRELIMINARY. 1. Title. 2. Interpretation. PART II—AUTHORISATION OF CLINICAL TRIALS. 3. Requirement for authorisation of clinical trials. 4. Application for authorisation to conduct a clinical trial. 5. Approval of clinical trial by the Uganda National Council of Science and Technology. 6. Consideration of application by the Authority. 7. Authorisation of clinical trials. 8. Clinical trial certificate. 9. Importation and manufacture of drugs for clinical trials. 10. Authorisation to deviate from conditions of clinical trial. 11. Amendments to conditions of clinical trial by the Authority. 12. Conclusion of a clinical trial. 13. Suspension or termination of clinical trial. 1133 Regulation PART III—CONDUCT OF CLINICAL TRIALS. 14. Protection of subjects. 15. Responsibilities of a sponsor. 16. Responsibilities of the principal investigator. 17. Labeling. 18. Records to be maintained. 19. Urgent safety measures. 20. Insurance and indemnity. PART IV—ADVERSE EVENT MONITORING 21. Notification of adverse events 22. Notification of suspected unexpected serious adverse reactions. PART V—INSPECTION OF CLINICAL TRIALS AND ENFORCEMENT 23. Requirements for inspection of clinical trials. 24. Offences. SCHEDULE 1 - FORMS SCHEDULE 2 - FORMATS 1134 S T A T U T O R Y I N S T R U M E N T S 2014 No. 32. The National Drug Policy And Authority (Conduct Of Clinical Trials) Regulations, 2014. (Made under section 40 and 64 of the National Drug Policy and Authority Act, Cap 206) IN EXERCISE of the powers conferred on the Minister responsible for health by section 40 of the National Drug Policy and Authority Act, Cap 206 and on the advice of the National Drug Authority, these Regulations are made this 24th day of March, 2014. PART I—PRELIMINARY 1. Title. These Regulations may be cited as the National Drug Policy and Authority (Conduct of Clinical Trials) Regulations, 2014. 2. Interpretation. In these Regulations, unless the context otherwise requires— “Act” means the National Drug Policy and Authority Act; “adverse drug reaction” means a response to an investigational drug product which is noxious and unintended and which occurs at doses normally used in humans for prophylaxis, diagnosis, or therapy of disease or for the modification of physiologic function; “adverse event” means any undesirable medical occurrence in a subject to whom a investigational drug product is administered, including occurrences which are not necessarily caused by or related to that product; “Authority” means the National Drug Authority; 1135 “clinical trial” means an investigation in a human subject which is intended to discover or verify the clinical, pharmacological or other pharmacodynamic effects of an investigational drug product or to identify any adverse reactions to an investigational drug product; “consent” means a written, signed and dated voluntary confirmation by a subject about his or her willingness to participate in a clinical trial, after being informed of all the aspects of the clinical trial that are relevant to the decision to be made by the subject regarding his or her participation in the clinical trial; “investigational drug product” means a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial and includes a registered product when used or assembled or formulated or packaged in a way different from the approved form, or when used for an unapproved indication or when used to gain further information about an approved use; “investigator’s brochure” means a document containing a summary of the clinical and non-clinical data relating to an investigational medicinal product which are relevant to the study of the investigational drug product in a subject; “licensed person” means a person licensed under section 14 of the Act; “serious adverse event” means any undesirable medical occurrence that at any dose— (a) results in death; (b) requires insubject hospitalization or prolongation of existing hospitalization; (c) is life threatening; (d) results in persistent or significant disability or incapacity; or 1136 (e) results in a congenital anomaly or birth defect; “sponsor” means a person who is responsible for the management and financing of a clinical trial; “subject” means a human participant in a clinical trial. PART II—AUTHORISATION OF CLINICAL TRIALS 3. Requirement for authorisation of clinical trials. (1) A person shall not start or cause to be started a clinical trial or conduct a clinical trial without the authorisation of the Authority. (2) Authorisation for clinical trial shall be granted for drugs registered under the Act and for drugs that are not registered under the Act. (3) Where a clinical trial is for a drug that is registered under the Act, the clinical trial shall be for aspects of the drug for which an amendment of the registration is necessary or for aspects of the drug that are not included in the registration, such as— (a) the drug indications and clinical use; (b) the target subject population; (c) routes of administration; (d) the dosage; and (e) the dosage form. 4. Application for authorisation to conduct a clinical trial. (1) A person who wishes to conduct a clinical trial shall make an application to the Authority using Form 29 in Schedule 1 to these Regulations. (2) An application for authorisation to conduct a clinical trial shall be made by a sponsor who shall be— 1137 (a) the holder of the patent of the drug; (b) a licensed person; (c) the manufacturer of the drug; or (d) an agent of the holder of the patent or the manufacturer, of the drug. (3) Where an application for authorisation to conduct a clinical trial is made by an agent, the agent shall submit a power of attorney attesting to the appointment as an agent or a letter of authorisation written in the format in Form 30 in Schedule 1 to these Regulations. (4) The application shall be accompanied by the following— (a) the clinical trial protocol in the format in Schedule 2 to these Regulations; (b) evidence of approval of the clinical trial by the Uganda National Council of Science and Technology or an institution approved by the Uganda National Council for Science and Technology; (c) the investigator’s brochure or prescribing information data sheet in the format in Schedule 2 to these Regulations; (d) a declaration by the principal investigator made using Form 31 in Schedule 1 to these Regulations; (e) a declaration by the monitor made using Form 32 in Schedule 1 to these Regulations; (f) the financial declaration by the sponsor and the principal investigator made using Form 33 in Schedule 1 to these Regulations; 1138 (g) the information to be provided to the subjects and the written consent forms of the subjects; (h) valid evidence of the insurance of the subjects; (i) pharmaceutical data on the dosage form of the investigational medicinal product made using Form 34 in Schedule 1 to these Regulations; (j) capacity building plans for the training of the staff to be involved in the clinical trial; (k) the prescribed fees; and (l) any other requirement as may be determined by the Authority. 5. Approval of clinical trial by the Uganda National Council of Science and Technology. An applicant shall prior to making an application to the Authority for authorisation to conduct a clinical trial, get approval to carry out the clinical trial, from the Uganda National Council of Science and Technology or from an institution authorised by the Uganda National Council of Science and Technology. 6. Consideration of application by the Authority. (1) Upon receipt of an application for authorisation of a clinical trial, the Authority shall verify whether the application conforms to the requirement of these Regulations. (2) Where the Authority is not satisfied with the information provided in the application, the Authority shall direct the applicant to provide further information as may be necessary to complete the application. (3) Where the Authority does not accept an application, the Authority shall, in writing, inform the applicant of this and the reasons for the decision. 1139 (4) Where the Authority is satisfied with an application, the Authority shall approve the application and issue a clinical trial certificate to the sponsor. (5) The Authority may issue a clinical trial certificate with conditions. (6) A clinical trial certificate shall be in Form 35 in Schedule 1 to these Regulations. 7. Authorisation of clinical trials. (1) In considering an application for a clinical trial, the Authority shall take into account— (a) the relevance of the clinical trial; (b) the suitability of the principal investigator; (c) the quality of the facilities to be used for the clinical trial; (d) the adequacy and completeness of the information to be given and the procedure to be followed, to obtain the consent of the owners of the animal to be used in the clinical trial; (e) the provision for indemnity for the principal investigator and insurance for the animals to be used in the clinical trial; and (f) the terms of the agreement between the sponsor and the principal investigator. (2) The Authority shall in addition to subregulation (1), in considering an application for a clinical trial, confirm that the principal investigator— (a) holds a university degree in medicine, pharmacy, pharmacology, toxicology, biochemistry, veterinary medicine or any other related profession; (b) has practical experience within the relevant profession; 1140 (c) has previous experience as an investigator, in at least two clinical trials in the relevant field; and (d) has good professional conduct. (3) The Authority shall not authorize a clinical trial where— (a) the requirements of these Regulations are not complied with; (b) the application contains false or misleading information; (c) the information provided is insufficient and does not enable the Authority to assess the safety or the risks of the investigational medicinal product or of the clinical trial; (d) the queries raised by the Authority, if any, in relation to the application are not adequately responded to; (e) the applicant does not submit evidence of ethical approval of the clinical trial protocol; (f) the use of the drug, in a clinical trial may endanger the health of the subjects or any other person; (g) the objectives of the clinical trial will not be achieved; or (h) it is not in the public interest to authorise the clinical trial. 8. Clinical trial certificate. A clinical trial certificate shall— (a) authorise the sponsor to conduct the clinical trial; (b) authorise the sponsor to import the investigational drug product to be used in the clinical trial; (c) provide that the clinical trial is to be conducted in accordance with the clinical trial protocol approved by the Authority; 1141 (d) indicate the duration of the clinical trial; (e) where necessary, indicate the conditions for authorisation of clinical trials; and (e) contain any other information as may be necessary. 9. Importation and manufacture of drugs for clinical trials. (1) A sponsor who is granted a clinical trial certificate under these Regulations shall apply to the Authority for a permit to import the investigational drug product approved for the clinical trial. (2) The Authority shall grant a permit for the importation of the investigational drug product which shall be limited to only the investigational drug products approved for the clinical trial. (3) Where the investigational drug product is to be manufactured in Uganda, the sponsor who is granted a clinical trial certificate under these Regulations shall apply to the Authority for a licence to manufacture the investigational drug product approved for the clinical trial. (4) The licence granted under subsection (3) shall be for the manufacture of only the investigational drug products approved for the clinical trial. (5) For the avoidance of doubt, where an investigational drug product to be imported or manufactured under this regulation is not registered by the Authority under the Act, the investigational drug product shall not be registered before the clinical trial report is approved by the Authority. 10. Authorisation to deviate from conditions of clinical trial. (1) A sponsor who intends to deviate from any condition of the clinical trial specified in the clinical trial certificate or who intends to engage additional investigators, additional clinical trial sites or to change investigators shall make an application to the Authority for authorisation of the deviation or the change. 1142 (2) An application for deviation from a condition of a clinical trial shall be made using Form 36 in Schedule 1 to these Regulations and shall be accompanied by evidence of ethical approval of the amendment to the clinical trial protocol, where applicable and the prescribed fees. (3) An application for additional investigators, additional clinical trial sites or for change of the investigators shall be made using Form 37 in Schedule 1 to these Regulations and shall be accompanied by evidence of ethical approval of the amendment to the clinical trial protocol, where applicable and the prescribed fees. (4) An application under this regulation shall be considered using the procedure and requirements for an application for authorisation to conduct a clinical trial. 11. Amendments to conditions of clinical trial by the Authority. (1) The Authority may, on its own initiative, make amendments to the conditions for conducting a clinical trial where it is necessary for the safety or scientific validity of the clinical trial. (2) Where the Authority proposes to make an amendment to the conditions for conducting a clinical trial, the Authority shall before making the amendments, give fifteen days notice of the intended amendment to the sponsor and the principal investigator with reasons for the amendment. (3) The Authority shall request the sponsor or the principal investigator to give a written response to the proposed amendments prior to effecting the amendments. (4) The Authority shall, in making amendments to the conditions of conducting a clinical trial, take into consideration the response of the sponsor or principal investigator. 12. Conclusion of a clinical trial. (1) A sponsor shall within ninety days after the conclusion of a clinical trial, in writing, inform the Authority of the conclusion of the clinical trial, using the format for the clinical trial report in Schedule 2 to these Regulations. 1143 (2) The Authority may during the course of a clinical trial, request the sponsor to submit an interim report of the clinical trial. (3) Where a sponsor is requested to submit an interim report, the sponsor shall make the report using the format for a clinical trial report in Schedule 2 to these Regulations. (4) A sponsor may, before the date indicated in the clinical trial certificate or before the occurrence of the event specified in the clinical trial protocol as the event which indicates the end of the clinical trial, terminate a clinical trial. (5) Where a sponsor terminates a clinical trial, the sponsor shall, within fifteen days of the termination, notify the Authority in the format specified in Schedule 2 to these Regulations. (6) A notification made under subregulation (5) shall give reasons for the termination, indicate how the investigational product that is not used is to be disposed of and the effective date of the termination. 13. Suspension or termination of clinical trial. (1) The Authority may by notice, suspend or terminate a clinical trial, where— (a) the conditions of a clinical trial certificate are not complied with; or (b) the Authority has information regarding the safety or scientific validity of the clinical trial or the conduct of the clinical trial. (2) The notice by the Authority shall be served on the sponsor or the principal investigator. (3) A notice shall apply to the clinical trial generally, or to one or more of the clinical trial sites. (4) Where a notice is for the suspension of the clinical trial, the suspension shall be for the period specified in the notice. 1144 (5) A notice shall indicate, where applicable, the conditions to be fulfilled before the clinical trial or, as the case may be, the conduct of the clinical trial at a particular site, may resume. (6) The Authority shall before issuing a notice, inform the sponsor or the principal investigator of the notice and the reasons for the notice and advise the sponsor or the principal investigator to make a written representation on the intended suspension or termination within five days. (7) The Authority shall consider the written representation of the sponsor or principal investigator made under subregulation (6) and inform the sponsor or principal investigator of its decision within seven working days. (8) Subregulation (6) shall not apply where it appears to the Authority that there is an imminent risk to the health or safety of any of the animals used in a clinical trial or any person involved in a clinical trial. PART III—CONDUCT OF CLINICAL TRIALS 14. Protection of subjects A sponsor or a principal investigator shall conduct a clinical trial in accordance with the following principles— (a) the anticipated benefits of the clinical trial shall justify the risks; (b) the rights, safety, and well being of the subjects shall prevail over the interests of science and society; (c) prior to the clinical trial, there shall be adequate information on an investigational medicinal product to be used, which shall support the clinical trial; (d) a clinical trial shall be scientifically sound; 1145 (e) a qualified medical doctor or dentist shall be available to provide medical care and to make medical related decisions, on behalf of the subjects; (f) a monitor shall be qualified and with experience to conduct the clinical trial; (g) a subject shall prior to participation in a clinical trial, give written consent to participate in the clinical trial; (h) the records of the clinical trial that identify the subjects shall be confidential; and (i) the investigational medicinal product shall be used in accordance with the clinical trial protocol. 15. Responsibilities of a sponsor. (1) A sponsor shall— (a) maintain quality assurance and quality control systems for the conduct of the clinical trials and for the generation, documentation, recording and reporting of data; (b) allow the Authority access, for purposes of inspection, to the clinical trial site, data, documents and reports; (c) provide insurance for the subjects against any clinical trial related injuries or harm, and indemnity for the investigator, against claims arising from the clinical trial, except for claims that arise from malpractice or negligence; (d) have sufficient safety and efficacy data from pre-clinical studies or other clinical trials, that support human exposure by the route, at the dosages, for the duration, and in the trial population to be studied; (e) update the investigator’s brochure, where new information becomes available; 1146 (f) avail, without cost, to the subjects, the investigational medicinal products to be used in the clinical trial and any devices to be used for the administration of the products; and (g) do anything the Authority may lawfully determine. (2) A sponsor shall appoint monitors who shall be appropriately trained, and have the scientific and clinical knowledge needed to monitor the clinical trial. (3) A monitor appointed under this section shall declare his or her scientific or clinical knowledge using the Form 32 in Schedule 1 to these Regulations. 16. Responsibilities of the principal investigator. A principal investigator shall— (a) be responsible for the clinical trial site; (b) inform the persons involved in the clinical trial about the clinical trial protocol, the investigational medicinal product and of their functions and responsibilities in the clinical trial; (c) for any adverse events, including clinically significant laboratory values related to the clinical trial, provide adequate medical care to the subjects; (d) follow the randomization procedures, if any, and ensure that the code is broken only in accordance with the protocol; and (e) be responsible for, and accountable for, the investigational medicinal product. 17. Labeling. An investigational medicinal product shall be labelled as specified in Form 38 in Schedule 1 to these Regulations. 1147 18. Records to be maintained. (1) The sponsor shall keep the records, documents and information of a clinical trial specified in regulation 4 (4) at the clinical trial site for a period of twenty years, after completion of the clinical trial. (2) Notwithstanding subregulation (1), where the investigational medicinal product is to be registered, the records, documents and information of a clinical trial shall be kept for two years after the registration of the investigational medicinal product. (3) For the purposes of this regulation, a sponsor shall maintain, for the investigational medicinal product used in a clinical trial— (a) the investigator’s brochure for the investigational medicinal product and a record of the changes made to the investigator’s brochure, if any, including the rationale for each change; (b) a record of the adverse events of the investigational medicinal product, that occurred inside or outside Uganda, indicating the indication for use and the dosage form of the investigational medicinal product at the time of the adverse event; (c) a record of the subjects with their identifications and contacts; (d) a record of the shipment and receipt of the investigational medicinal product and where applicable, a record of the return and destruction of the investigational medicinal product; and (e) a copy of the protocol and consent forms, at the clinical trial site. 19. Urgent safety measures. (1) A sponsor and a principal investigator shall take the appropriate safety measures to protect the subjects against any immediate hazard to their health or safety. (2) Where safety measures are taken, the sponsor shall within three working days from the date the safety measures are taken, give written notice to the Authority of the measures taken and the circumstances that give rise to the measures. 1148 20. Insurance and indemnity. (1) The sponsor shall provide insurance, against any clinical trial related injuries that may arise during the clinical trial, for the subjects involved in the clinical trial. (2) The sponsor shall indemnify the principal investigator against claims that may arise during or from the clinical trial, except claims that are as a result of malpractice or negligence of the sponsor. PART IV—ADVERSE EVENT MONITORING 21. Notification of adverse events. (1) A principal investigator shall within 48 hours of becoming aware, report to the sponsor, any serious adverse event which occurs in a subject during a clinical trial. (2) The report shall identify each subject referred to in the report by a number assigned to that subject. (3) Where the serious adverse event reported results in the death of a subject, the investigator shall supply the sponsor with any additional information requested by the sponsor. (4) The sponsor shall keep detailed records of the adverse events relating to a clinical trial which are reported by the principal investigator. (5) The Authority may, by written notice, request for the reports of the adverse effects from the sponsor. 22. Notification of suspected unexpected serious adverse reactions. (1) The principal investigator shall record and report to the sponsor any suspected unexpected serious adverse reaction which occurs during the course of a clinical trial. (2) The sponsor shall, within seven days of becoming aware, report to the Authority and the Uganda National Council of Science and Technology or an institution authorised to receive the report by the Uganda National Council of Science and Technology, any suspected unexpected serious adverse reactions. 1149 (3) The sponsor shall inform the principal investigator of any suspected unexpected serious adverse reaction which occurs during the course of another clinical trial for which the sponsor is responsible, where the reaction is in relation to an investigational medicinal product used in the clinical trial. (4) The Authority shall keep a record of all suspected unexpected serious adverse reactions relating to an investigational medicinal product which are reported to the Authority. PART V—INSPECTION OF CLINICAL TRIALS AND ENFORCEMENT 23. Requirements for inspection of clinical trials. The Authority may at any reasonable time, inspect the staff and the facilities used for the clinical trial for compliance with the conditions of the clinical trial certificate. 24. Offences. (1) A person commits an offence, who— (a) in an application for authorisation to conduct a clinical trial or in the course of conducting a clinical trial, provides to the Authority, information which is false or misleading in a material particular; (b) has in his or her possession an investigational medicinal product, in contravention of these Regulations; (c) fails to comply with a notice of suspension or termination; (d) sells or supplies, or procures the sale or supply, of an investigational medicinal product, for a clinical trial, where the labeling of the investigational medicinal product is contrary to the requirements of these Regulations; or (e) contravenes any of other provision of these Regulations. (2) A person who commits an offence is on conviction liable to a penalty specified in the Act. 1150 SCHEDULES SCHEDULE 1 FORM 29 Regulation 4(1) THE CLINICAL TRIAL APPLICATION FORM (The application form shall be completed in full, each part is to be cross referenced to the detail in the clinical trial protocol, the investigator’s brochure, and the other documents attached the application) Part 1: Identification of the clinical trial 1. Title of the clinical trial 2. Number of the clinical trial protocol, its number, date and version 3. Contact person and contact details 4. [NDA reference number] 5. Declaration of intent signed by the 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 clinical trial protocol and the investigator’s brochure which are submitted with this application. We have the authority and responsibility to oversee this clinical trial, and agree to ensure that the trial will be conducted according to the clinical trial protocol and the laws of Uganda. Applicant (Local contact): Name: Date: Signature: Designation Principal investigator: Name: Date: Signature: Designation 1151 Part 2: Basic administrative data on the application Name and address of the registered office of the applicant Part 3: Drugs to be used in the clinical trial 1. Investigational drug 1. Identifier or name of investigational drug (code if applicable) 2. Registration number 3. Manufacturer(s) (include all sites) 4. Active ingredient, complete composition, potency and presentation 5. See Attachment 4 for details of the required information. 6. Release specifications and tests. (include certificate of analysis). 7. Current approved package insert if available. 2. Comparator, concomitant and rescue medications (and placebo) 1. Proprietary name and INN 2. Active ingredient(s), composition, and presentation 3. Registration number(s) (country) 4. Approved package inserts to be appended to application [Appendix 6] 3. Details of handling clinical trial drugs 1. Shipping, delivery and distribution of trial drugs 2. Details of storage requirements and arrangements for cold-chain maintenance where necessary and monitoring during distribution. 3. Details of dispensing trial drugs and waste disposal procedures. 4. Packaging and labelling of the medical products 5. Estimates of quantities of each medication (presentation) to be used for the trial, and for which an import permit is needed. 1152 Name: Telephone number(s): Fax E-mail address Physical address Postal address Applicant Sponsor (if any) Manufacturer Part 4: Sites and investigators 1. Principal investigator 2. For each clinical trial site indicate the following 1. Site identifier (Name) 2. Physical address: (for rural sites include GPS coordinates) 3. Telephone and fax numbers 4. E-mail address 3. Description of the site facilities and staff 1. Clinic and counselling rooms 2. Emergency facilities 3. Facilities for special examinations (if required) 4. Capacity to collect, prepare, store and transport clinical samples 5. Storage and handling facilities for drugs 6. Name and qualifications of person with responsibility for dispensing drugs 4. Site principal investigator 5. Site investigators and trial-specific support staff 1153 Name: Qualifications Contact details Physical address Declaration of capacity and interests [Appendix 10] Name: Qualifications Contact details Physical address Declaration of capacity and interests [Appendix 10] Name: Qualification Contact details Physical address Declaration of capacity and interests [Appendix 10] 6. For a clinical site that is a hospital or public health clinic indicate 1. The responsible administrator 2. The Contact details 3. Append signed letter of agreement for clinical trial to take place. 7. Append signed agreement between the principal investigator and the sponsor. (Appendix 13) Part 5: Subjects 1. Numbers of subjects as stipulated in the table below 2. Duration of the clinical trial 3. Estimated duration of the clinical trial: From first enrolment to final report 4. Duration for individual subject (a) Screening period (b) Intervention period (c) Follow-up period 5. What is the intended compensation for time and other inconvenience per subject? (This is not compensation in terms of damage). Part 6: History of previous clinical trials and clinical trials in progress 1. List the titles of previous trials with this (or similar) drugs in Uganda 2. List the titles of previous trials with this (or similar) drugs in other countries 3. Append interim or final report of the clinical trials. (This may be in the investigator’s brochure or APPENDIX 3) 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 satisfactory. 1154 (a) Total number to be enrolled worldwide (b) Total number to be enrolled in Uganda (c) Number of trial sites in Uganda (d) Intended numbers of participants at each site - evidence of availability Part 7: Ethics review 1. Provide approval for clinical trial protocol for each site [Appendix 11] 2. What GCP Guidelines have been followed in compiling this protocol? 3. Will GCP training be provided for local staff and investigators? Part 8: Monitoring and reporting of clinical trials 1. Describe the safety and monitoring plan for each site. 2. Describe the system to be used to detect, record, assign causality and the actions for adverse events. 3. Describe the actions to be taken following reports of serious adverse events. 4. Describe the composition and remit of the data safety monitoring board or similar body. Include conditions for pause- or stop- rules. 5. When are interim reports to be submitted? 6. Estimated due date of final report Part 9: Insurance 1. Provide a copy of the current insurance certificate. (Schedule 9) 2. Provide evidence that each member of the clinical trial team is covered for the relevant malpractice insurance for this trial. Part 10: Description of the clinical trial 1. Is the title of the clinical trial fully descriptive? 2. Summarized rationale for the clinical trial, including relevance to Uganda 3. Brief background information should include: (a) The disease or condition and local epidemiology (b) Properties of the drug - hypothesis for action (c) Description of risks of the protocol and the potential harms of the drug. (d) Pre-clinical animal toxicology test results in-animals and in-vitro that establishes probable safety and efficacy in humans (this should be cross referenced to the details in the Investigator’s brochure) (e) Prior clinical trial report summaries that establishes probable safety and efficacy in humans (this should be cross referenced to the details in the Investigator’s brochure) 1155 (f) 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. (this should be cross referenced to the details in the Investigator’s brochure) (g) Published reviews or reports relevant to this disease and this type of drug. 4. Objectives of this clinical trial (List as primary and secondary objectives and provide justification) 5.1 Trial design: describe and justify each component by 1. Phase 2. Placebo or comparator 3. Randomization and blinding 4. Other detail 5.2 Time sequence – (Insert a table of screening, intervention and follow-up visits). 5.3 Participants 1. Eligibility 2. Inclusion criteria - list and justify each 3. Exclusion criteria - list and justify each 5.4 Treatment regimens for each group. (The table in 5(2) may be used to set this out) 5.5 Follow-up, sampling collection and monitoring plans: (1) Immediate monitoring - intermediate monitoring - long term monitoring (2) Diary cards (3) Telephone access to investigators 6. Outcomes measurements and analysis 1. Describe each outcome or variable (including safety) and explain or justify. 2. Describe the samples that will be collected and the analyses to be conducted on each sample. 3. 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 8) 1156 4. Describe the intended statistical analysis to be conducted. Provide evidence that the clinical trial is powered to provide the intended outcome. 7. Are any sub-studies intended? Provide full details. 8. Are any genetic studies (HLA-typing or gene marker analysis) intended? Provide full details, and justify this. Is there a separate consent form for this? 9. Will clinical samples be stored for any period beyond the duration of this trial? (a) What is the purpose of such archiving? (b) What controls are to be placed on their confidentiality and possible future use? 10. Participant information leaflet and consent form (a) Append a copy of the participant information leaflet and consent form [Appendix 4] (b) In what languages will this be available? (c) For the subjects who are minors, append the consent form of the parents or guardians of the minors. (d) Are there separate consent form for sub-studies or genetic studies? Part 11: Publication Policy Provide details of the investigators and sponsors intentions and freedom to publish the outcomes of this clinical trial. 1157 FORM 30 Regulation 4 (3) LETTER OF AUTHORIZATION FROM HOLDER OF PATENT OF DRUG, LICENCED PERSON OR MANUFACTURER OF DRUG Date: ………………………………………. Company name …a company operating under the laws of ………. located at: Physical address ……………………………………………………………….. Tel No: …………………………………………………………………………. Fax No: ………………………………………………………………………… E-mail address:…………………………………………………………………. Company in Uganda Name ………………………………………………………………………….. Physical address ……………………………………………………………….. Tel No: …………………………………………………………………………. Fax No: ………………………………………………………………………… E-mail address:…………………………………………………………………. To represent us in Uganda for the application authorization to conduct a clinical trial for Protocol No: Release date: …………………………………………………... (name and address of local company) is authorized to be the agent of the holder of the patent of the drug or licensed person or manufacturer of the drug in the clinical trial and is to be responsible for all matters pertaining to the clinical Trial certificate. ……………………………………… Authorised name and signature 1158 FORM 31 Regulation 4 (4) (d) DECLARATION BY PRINCIPAL INVESTIGATOR Clinical trial protocol number..............……………………............................... Name: Role in clinical trial Title of clinical trial:...................……………......... Clinical trial site:......................………………........ (Please attach Curriculum vitae). 1. I am aware of the responsibilities of my role as……………….in clinical trial, number……………as required by the Laws of Uganda. 2. I have read and understand the attached clinical trial protocol, investigator’s 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 Authority and confirm that the information is complete, true and accurate, and conform to the clinical trial protocol and supporting documentation. 4. I will not commence with this clinical trial before a clinical trial certificate is issued by the Authority. I will provide the Authority and any other relevant authority, with reports as may be required. 5. I will obtain the consent of the subjects, or if they are not legally competent, from their legal representatives, parents or guardians. 6. I will ensure that every subject (and other person involved in the clinical trial including the relatives of the subjects) is treated in a dignified manner and with respect. 7. I DECLARE: I have or have (delete as applicable) no conflict of interest in terms of financial interests or personal relationships that may inappropriately influence my responsibilities and conduct of this trial. Initials: ……………………………………………………………… 1159 8. I DECLARE: I have not previously been associated with any clinical trial that has been terminated, or a clinical trial site that was closed, due to failure to comply with internationally accepted Good Clinical Practice Guidelines adopted by the Authority. Initials: ………………………………………………………………… 9. I have received suitable, recent training in internationally accepted Good Clinical Practice Guidelines adopted by the Authority. Signed …………………………… Date ………………………… Witness …………………Name…………………………Date ……………… 1160 FORM 32 Regulations 4 (4) (e)and 15 (3) DECLARATION BY MONITOR Name:…………………………………………………………………………... Title of the clinical trial: Number of the clinical trial protocol: Clinical trial site: I, the undersigned, declare that: 1. I am familiar with the internationally recognized and national guidelines of internationally accepted Good Clinical Practices Guidelines adopted by the Authority and understand the responsibilities and obligations of the clinical trial monitor within the context of this trial. 2. I have notified the Authority of any aspects of the above with which I do not or which I am unable to, comply. (If applicable, this may be attached to this declaration.) 3. I will carry out my responsibilities as specified in the trial protocol and in accordance with requirements by the Authority on internationally accepted Good Clinical Practices Guidelines adopted by the Authority. 4. I declare that I have no financial or personal relationship(s) which may inappropriately influence me in monitoring this clinical trial. 5. I have* or have not (delete as applicable) previously been the monitor at a site which has been closed due to failure to comply with internationally accepted Good Clinical Practices Guidelines adopted by the Authority. (*Attach details.). 6. I have*or have not (delete as applicable) previously been involved in a clinical trial which has been closed as a result of unethical practices. (*Attach details). 7. I will submit all required reports when needed. Signed …………………………………… Date ………………………… Witness ………………………………………Date………………………… 1161 FORM 33 Regulation 4 (4) (f) DECLARATION BY SPONSOR AND PRINCIPAL INVESTIGATOR OF FUNDS OF THE CLINICAL TRIAL Title of the clinical trial: Number of the clinical trial protocol: I, …………………………………………………………………….. (Sponsor) and I, ………………………………………………………, (principal investigator) hereby declare that the funds available for the clinical trial are sufficient for the clinical trial. Signed Date SPONSOR Name Address Contact details Signed Date PRINCIPAL INVESTIGATOR Name Address Contact details 1162 FORM 34 Regulation 4 (4) (i) PHAMACEUTICAL DATA ON DOSAGE FORM. PRODUCT: REF: (Supporting documents should be appropriately numbered and referenced). 1. FINISHED PRODUCT 1. Description (physical characteristics): 2. Composition (complete formula) 3. Active ingredient 4. Other ingredients (adjuncts, exicipents, preservative, colour, flavour, etc): 5. Packing or pack size (brief): 2. MANUFACTURE OF PRODUCT (Enclose the product in an envelope marked ‘CONFIDENTIAL’, if desired. If so indicate here, with appropriate reference). 1. Complete batch manufacturing master formula: 2. Manufacturing process: (Provide a brief description and the principles of the process). 1163 Name of ingredients (active and otherwise) Quantities used per batch Name of other ingredients Content Active ingredient: Content 3. QUALITY CONTROL 1. State whether quality control is done in part or solely by the quality control department of the manufacturer or in an external laboratory. 2. If quality control tests are done by an external laboratory, indicate : (a) The name and address of the laboratory; (b) The tests done by the external laboratory; (c) Why the tests are not done by the manufacturer. 3. Specifications for the active and other ingredients 4. In- process quality control: Tests performed during manufacturing process and sampling protocols: 5. Finished product quality control: Tests and specification limits (check and release specifications): The certificate of analysis to be certified by quality assurance manager. Certificate of analysis of recent batch of product (minimum 1 batch) enclosed: [ ] 4. STABILITY OF PRODUCT: 1. Storage condition must be included on the label. 2. Proposed shelf life of product: (Where the extension of the shelf life for a clinical trial material is required, the manufacturer shall provide data to support the extension and data in the form of retest results shall be considered). 1164 Test Acceptance limits Release for test method and Limits (B.P. or U.S. Pormanufacturers) Tests Stage at which test is done Frequency of sampling Quality of sample taken each time Name of ingredient Specifications Source (state whether B.P or U.S.P or manufacturer’s) Manufacturer and country of origin 5. STABILITY STUDIES 1. Completed stability studies or accelerated stability studies. (provide a summary of the stability studies, characteristics and degradation products monitoring results and conclusions of completed stability studies). Results of studies of at least one batch are required. 2. On-going or proposed stability studies. (Outline of on-going or proposed stability studies). 6. CONTAINERS AND PACKAGING 1. Description of the immediate (primary) containers or packaging: (a) Type (b) Material (c) Capacity, where applicable (d) Closure and liner (type and material), where applicable. 2. Description of outer container or packaging 3. Dose-measuring device, applicators and administration set, if any: (a) Descriptionortype (b) Material (c) Capacity, where applicable 4. Packaging inclusions (such as desiccant and fillers) if any: Description and compositions 5. Is there any known interaction between the product and packaging material? (Yes or No); if yes, specify. 7. LABELLING (Refer to Attachment 3). Enclose samples or proposed drafts of the following: 1. Label for immediate package or container of product 2. Label for outer package or container of product 3. Original package insert for comparator drug 1165 FORM 35 Regulation 6 (6) CLINICAL TRIAL CERTIFICATE Clinical trial certificate number ……………………………….. issued under section 40 of the Act by the Authority. Name of sponsor..……………………………………………………………… Physical address………….Telephone number …………Fax number………… E-mail address ……………….……….……………………………………….. Title of clinical trial protocol:………………………………………………… Number of clinical trial protocol:……………………………………………… Date of approval:……………………………Date of expiry:………………… Name and address of principal investigator…………………………………… Investigational drug product…………………………………………………. Clinical trial site ……………………………………………………………. The conditions of this clinical trial certificate ………………………………… ……..………………………… EXECUTIVE SECRETARY DATE 1166 FORM 36 Regulation 10 (2) APPLICATION FOR DEVIATION FROM CLINICAL TRIAL CERTIFICATE Title of the clinical trial: Number of the clinical trial protocol: Date: 1. APPLICANT 1. Name 2. Address 3. Telephone 4. Fax number 2. PARTICULARS OF CLINICAL TRIAL (original application) 1. Clinical trial number: 2. Date of approval of original protocol: 3. Principal investigator approved for the clinical trial: 4. Number of sites approved for the clinical trial: 5. Number of subjects approved for the clinical trial: 3. AMENDMENT PARTICULARS 1. Does the applicant wish to increase the number of subjects participating in the clinical trial? Yes r No r 2. Does the applicant wish to change the dose or regimen of the investigational medicinal product? Yes r No r 1167 3. Does this amendment request require a new consent form to be signed by the participant? Yes r No r If “Yes” please submit new PIL together with this application. 3. Does this amendment request require a new consent form to be signed by the participant? Yes r No r If “Yes” please submit new PIL together with this application. 1. Clinical trial protocol amendment number: 2. Number and date of amendment (for each document submitted): 3. General motivation for the proposed amendment: [List all of the issues included in the amendment and provide the rationale for each amendment] 4. Details of the proposed amendment: [For each amendment, provide reasons for amendment and clearly highlight changes to the original protocol; this can be done either as “old text” replaced with “new text” or with the old text deleted with a line through it and the new text in bold and underlined] 4. Will this amendment apply to all approved site(s)? Yes r No r If No: Specify the sites for which the amendment will apply: 4. APPROVAL BY THE UGANDA NATIONAL COUNCIL OF SCIENCE AND TECHNOLOGY 1. Date of application to the Uganda National Council of Science and Technology: 1168 2. Date of approval by the Uganda National Council of Science and Technology: I or we, the undersigned, agree to conduct the clinical trial under any conditions that may be granted by the Authority. Applicant (Sponsor or principal investigator) Date 1169 Regulation 10 (3) FORM 37 APPLICATION FOR ADDITIONAL INVESTIGATORS, CHANGE OF INVESTIGATOR OR ADDITIONAL CLINICAL TRIAL SITES APPLICATION FOR APPROVAL OF: r CHANGES IN INVESTIGATOR(S) AT APPROVED SITE (includes additional investigators) r ADDITIONAL SITE(S) 1. Title of the clinical trial: 2. Number of the clinical trial protocol: 3. Date: 1. APPLICANT 1. Name 2. Address 3. Telephone 4. Fax number 2. TRIAL PARTICULARS (original application) 1. Trial approval number: 2. Date of approval of original protocol: 3. Principal investigator approved for this clinical trial: 4. Number of sites approved for this clinical trial: 5. Number of subjects approved for this clinical trial: 1170 3. DETAILS OF INVESTIGATOR 1. Name and address of additional investigator or change to investigators: [Proof of ICH - GCP training must be provided for investigators who have not previously participated in clinical trials] 2. Summaries other ongoing or planned studies at the site involving the investigator: [Provide details of studies, including numbers of participants of the clinical trial, whether the investigator is involved in research in a full time or part-time capacity, and any other details that may affect the capacity of the site at any one time] 3. Date of application to Uganda National Council for Science and Technology 4. Date of approval by Uganda National Council of Science and Technology 5. Is CV for additional investigator(s) attached? Yes r No r 6. Is the declaration of intent attached? Yes r No r (If yes, attach declaration) 4. CAPACITY OF THE SITE Describe how the site is structured so as to be able to take on the work for which this application is being made: [Give details of support staff, facilities, back up and any other relevant infrastructure]. 5. RATIONALE FOR APPLICATION 1. Briefly explain the reason for the new investigator or site: I or we, the undersigned, agree to conduct or manage the above-mentioned trial under the conditions as stated in this application. (The person(s) undertaking legal responsibility should sign this form). Applicant (Sponsor or principal investigator) Date 1171 Form 38 Regulation 17 LABELLING INVESTIGATIONAL DRUG PRODUCTS FOR CLINICAL TRIAL The following information shall be labelled on the carton, inner label and the blisters or strips of the investigational drug product for a clinical trial: NA Not Applicable * Exempted for small label such as ampoule and vial. ** Where applicable *** With letter of authorisation If the product is supplied without an outer carton, the information that is required on the outer carton should be stated on the inner carton. 1172 Parameters Unit carton or subject kit Inner Labels Blister or Strips Clinical trial protocol number √ √ √ Visit √** √** √** No. of the subjects or initial of the subject √ √* √ Investigational drug product name or code √ √ NA Dosage form √** √** √** Name of active substance √** √** √** Strength of active substance √** √** √** Instructions for use √ √* √ Batch number √** √** √** Manufacturing date or retest date √ √ √ Expiry date √ √ √ For clinical trial use only √ √* √ Name and address of manufacturer, final release, product owner (corporate address) or sponsor √*** √*** √*** Route of administration √ √ NA Storage condition √ √* NA Pack sizes (unit or volume) √ √* NA SCHEDULE 2 Regulation 4 (4) (a) FORMAT FOR CLINICAL TRIAL PROTOCOL A clinical trial protocol should contain the following particulars, as may be appropriate— 1. The name and dosage form of the investigational drug product. (a) State the name or code number under which the investigational drug product is to be imported and known during the clinical trial. A separate application is required for each clinical trial. (b) State clearly the pharmaceutical dosage form of the investigational drug product, e.g. tablet, capsule, injection, etc. 2. Identification of the clinical trial (a) Title of the trial (b) The clinical trial registration number or code 3. Aim of the clinical trial (a) State the specific objective (b) Rationale of the clinical trial. 4. Description of the clinical trial design. (a) Clinical trial design (randomised controlled trial, open-label parallel group, cross-over technique) (b) Blinding technique (double blind, single blind) (c) Describe procedure of randomisation (d) Total number required to achieve the trial objective based on statistical consideration (should be sufficient to allow dropout, variability of effect etc). 5. Description of clinical trial subjects. (a) Criteria for inclusion and exclusion of potential clinical trial subjects (b) Process of screening, recruitment and follow up. 6. Treatment profile (a) Dose – including justification for route of administration, dosage, dosage interval and treatment period for the investigational drug product being tested and the product being used as a control. 1173 (b) Previous, any other treatment that may be given or permitted concomitantly or subsequent therapy, if any. (c) Washout period, where applicable. 7. Parameters of the clinical trial (a) Indices, variables etc that were selected for measuring parameter under the clinical trial (effect, reaction etc). (b) Methods of measurements and assessment of observations including details of measuring techniques, assessment, qualification of response, clinical and laboratory tests, pharmacokinetic analysis, etc. (c) The rationale for choice of indices, variables and their methods of determination, specificity, sensitivity and the precision of the method selected. 8. Operational aspects (a) Information on the establishment of the trial code where it will be kept and when, how, by whom it can be broken in the event of an emergency. (b) Measures to be implemented to ensure the safe handling and storage of pharmaceutical products. 9. Adverse event (a) Methods of recording and reporting adverse events or reactions (b) Provisions for dealing with complications. 10. Evaluation of results. (a) Data management procedures (b) Statistical methods and considerations (c) Subjects withdrawn from the trial. 11. Name and designations of the principle investigator and investigators. 1174 Regulation 4 (4) (c) FORMAT FOR INVESTIGATOR’S BROCHURE TITLE PAGE NAME OF SPONSOR Product Name Chemical and generic (if approved) Trade name (if legally permissible and desired by the sponsor) INVESTIGATOR’S BROCHURE Edition number Release date Previous edition and its numbers Dates of previous editions TABLE OF CONTENTS OF INVESTIGATOR’S BROCHURE Confidentiality Statement (optional) Signature page (optional) (1) Table of contents (2) Summary (3) Introduction (4) Physical, chemical and pharmaceutical properties formulation (5) Non clinical studies (a) Non clinical pharmacology (b) Pharmacokinetics and product metabolism in animals (c) Toxicology (6) Effects in humans 1175 (a) Pharmacokinetics and product metabolism in humans (b) Safety and efficacy (c) Marketing experience (7) Summary of data and guidance for the investigator. (8) Reference on publications and reports (to be provided at the end of each chapter) (9) Appendices (if any) 1176 Regulation 12 (1)and (3) FORMAT OF CLINICAL TRIAL REPORT 1. Title page 2. Synopsis 3. Table of contents for the individual clinical trial report 4. List of abbreviations and definition of terms used in the report 5. Ethics 6. Investigators and the clinical trial administrative structure 7. Introduction 8. Objectives of the clinical trial 9. Investigation plans 10. Subjects 11. Efficacy evaluation 12. Safety evaluation 13. Discussion and overall conclusion 14. Tables, figures and graphs referred to but not included in the text 15. Reference list 16. Appendices 1177 Regulation 12 (5) FORMAT OF REPORT FOR TERMINATED CLINICAL TRIAL Date………………………………….. The Executive Secretary National Drug Authority REPORT OF TERMINATED CLINICAL TRIAL Title and number of clinical trial protocol ……………………………………. Reference or registration number of Authority ………………………………… The following is a summary of the (title of clinical trial)……………..trial conducted in …………………………………….. (insert name of institution): First subject in: …………………………………………………. (insert date) Last subject in: ……………………………………………………. (insert date) Last subject out: …………………………………………………. (insert date) Number of subject screened: …………………………………………………. Number of subjects randomized: ……………………………………………… Number of subjects discontinued: …………………………………………….. RUHAKANA RUGUNDA Minister of Health. 1178