Clinical research in Tanzania is regulated and overseen by the Tanzania Medicines and Medical Devices Authority (TMDA) and the Tanzania Commission for Science and Technology (COSTECH).

Tanzania Medicines and Medical Devices Authority

As per the TMMDAct, the TMDA is the regulatory authority responsible for clinical trial approvals, oversight, and inspections in Tanzania. (Note: while the TMMDAct is formatted as a “Revised Draft,” it incorporates the final changes from 2019 that are codified in the FinanceAct.) The TMDA grants permission for clinical trials to be conducted in the country in accordance with the TMMDAct and the CT-Regs.

Per TZA-29, the TMDA is an executive agency under the Ministry of Health, Community Development, Gender, Elderly and Children (MoHCDGEC). The TMDA is responsible for regulating the safety, quality, and effectiveness of medicines, medical devices, and diagnostics.

Per the TMMDAct, the agency has a Ministerial Advisory Board (MAB), which consists of:

• The MoHCDGEC Permanent Secretary who serves as Chairman

• Up to 12 Minister-appointed members

• The Director General who serves as Secretary to the board

In accordance with TZA-29, TMDA is responsible for the following regulatory processes:

• Regulating the manufacture, importation, distribution, and sale of medicines, medical devices, and diagnostics
• Prescribing standards of quality, safety, and effectiveness for medicines, medical devices, and diagnostics
• Inspecting manufacturing industries and business premises dealing with regulated products and ensuring the standards required are attained
• Evaluating and registering medicines, medical devices, and diagnostics so as to reach the required standards before marketing authorization
• Issuing business permits for premises dealing with regulated products
• Assessing the quality, safety, and efficacy of controlled drugs
• Conducting laboratory investigations for regulated products to ascertain their quality specifications
• Conducting pharmacovigilance of medical products and vigilance of medical devices and diagnostics circulating on the market
• Promoting rational use of medicines, medical devices, and diagnostics
• Educating and sharing accurate and reliable information to stakeholders and the general public on regulatory matters

The established the Pharmacovigilance Technical Committee, under the National Pharmacovigilance Centre of TMDA, to provide recommendations to the Director General on pharmacovigilance-related safety issues, including causality assessment of adverse drug reactions and adverse events. In addition, as stated in TZA-37, there is a TMDA Clinical Trials Technical Committee (CTTC), pursuant to the TMMDAct, that provides independent technical advice to the Director General. Members of the CTTC provide technical advice to assure that clinical trials are designed, conducted, analyzed, and reported in accordance with TMDA and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (TZA-13) guidelines. Members of the CTTC are required to be prudent, transparent, independent, and committed to their professional ethics while discussing all matters pertaining to clinical trials. The CTTC, which meets at least once quarterly, is composed of experts with knowledge and experience in at least the following fields:

• Clinical Trials
• Medical Research
• Clinical Pharmacology
• Clinical Epidemiology
• Medicine
• Dental Surgery
• Pharmacy
• Medical Statistics
• Public Health
• Toxicology
• Microbiology
• Pathology
• Regulatory Affairs

Tanzania Commission for Science and Technology

According to TZA-45, COSTECH is under the Ministry of Education, Science and Technology and is responsible for coordinating and promoting research and technology as the chief advisor to the government. Its principal roles and responsibilities include:

• Preparing and reviewing national science, technology, and innovation programs, including dissemination and transfer of technology
• Monitoring and coordinating the activities relating to scientific research, technology development, and innovation of all persons or body concerned with such activities
• Acquiring, storing, and disseminating scientific and technical information
• Registering scientific research institutions operating in Tanzania
• Advising the government on matters such as priority areas for scientific research; the allocation and use of research and innovation funds; regional and international cooperation in scientific research, innovation, and technology development and transfer; and matters relating to the training and recruitment of research personnel

Per the G-ResearchClearance and TZA-47, the COSTECH must review, approve, and issue permits for all research in Tanzania. The G-ResearchClearance specifies that COSTECH, through its National Research Clearance Committee (NRCC), receives and reviews research proposals for their scientific merit, safety, and ethics. Upon approval, NRCC issues research permits. (Note that TZA-47 refers to it as the National Research Registration Committee.)

Contact Information

Tanzania Medicines and Medical Devices Authority

Tanzania Commission for Science and Technology

According to TZA-46, COSTECH’s contact information is as follows:

Director General
Tanzania Commission for Science and Technology
P.O. Box 4302
Ali Hassan Mwinyi Road, Kijitonyama (Sayansi) COSTECH Building
Dar es Salaam, Tanzania

Phone, general: 255 22 2771358
Phone, Director General’s Office: 255 22 277 4023
Phone, Research Registry Office: 255 22 2700749
Email, Director General: dg@costech.or.tz
Email, Research Clearance: rclearance@costech.or.tz

Overview

As indicated in the TMMDAct and the CT-Regs, the Tanzania Medicines and Medical Devices Authority (TMDA) is responsible for reviewing, evaluating, and approving clinical trial applications in Tanzania. The scope of the TMDA’s assessment includes all clinical trials (Phases I-IV). As delineated in the TMMDAct, the CT-Regs, and the G-AppConductCT, the TMDA’s approval of a clinical trial application is dependent upon obtaining proof of national ethics committee (EC) approval from the National Health Research Ethics Committee (NatHREC). According to the G-AppConductCT, the TMDA and national EC reviews may be conducted in parallel. However, the TMDA application must include a copy of the national EC's acknowledgement of receipt for the study protocol. In addition, the TMDA's approval will only be finalized once national EC approval is obtained.

Per the G-ResearchClearance, the Tanzania Commission for Science and Technology (COSTECH) must review and approve all research in Tanzania to:

• Ensure research conduct complies with national laws and regulations
• Document and register research
• Secure research results and promote its use in policy and practice
• Safeguard the dignity, rights, safety, and well-being of research participants
• Reduce systemic risks imposed through the research
• Provide research permits

Clinical Trial Review Process

Tanzania Medicines and Medical Devices Authority

As set forth in the TMMDAct, the CT-Regs, and G-AppConductCT, the TMDA coordinates the clinical trial application process. Upon receipt of a clinical trial application, the TMDA initially screens the application for completeness. If complete, the TMDA officer acknowledges receipt of the application by returning a signed copy of the cover sheet to the applicant (see Annex 1 of the G-AppConductCT). The TMMDAct states that the TMDA Director General must issue a Clinical Trial Certificate to authorize the trial to be conducted. (See the Submission Content section for submission requirements.)

Per the G-AppConductCT, the clinical trials certification will be valid up to the proposed duration of the study indicated in the application. However, the validity will not extend beyond five (5) years. If the trial will last more than five (5) years, the applicant must request an extension. Further, TMDA must approve amendments to a previously authorized protocol for changes that affect participant selection and monitoring; changes that affect clinical efficacy and safety requirements; changes that affect participant discontinuation; addition/deletion of an investigational site(s); changes that result in the extension of duration of a trial; and/or changes that relate to the chemistry and manufacturing information that may affect drug safety and quality. An application for amendment(s) must be accompanied by clearance or authorization from NatHREC.

(See the Submission Process section for additional details on the clinical trial application and amendments submissions.)

Tanzania Commission for Science and Technology

As for COSTECH review, the G-ResearchClearance indicates that once COSTECH receives a new application, the Secretariat screens the application for completeness; registers the applications; sends an acknowledgement to the applicant; submits the application for the appropriate expert, local, and National Research Clearance Committee (NRCC) review; records NRCC’s final decision; and informs the applicant of the decision. COSTECH’s NRCC must reach a decision through a consensus of members forming a quorum at their meeting. The decision may be approval without amendments, approval subject to minor or major amendments, a denial, or a postponement pending further information. If approved, researchers should collect their permit within 90 days after the decision is communicated, and failure to do so requires a new application.

Per the G-ResearchClearance, permits are valid for one (1) year, and can be renewed, provided that COSTECH receives satisfactory progress reports for the previous periods. COSTECH must review the research to ensure compliance with the approved permit and see if any material changes have occurred in the research or if there are findings that may cause termination. The PI must write to COSTECH two (2) months before the expiration date to request a renewal of the permit. For renewals, COSTECH will submit the registered application to an internal reviewer for evaluation, and otherwise, follow the same review and notification procedures as outlined above for a new permit.

Regarding applications for amendments, if there is a change in PI, the affiliate institution must notify COSTECH within one (1) month of the departure of the outgoing PI in writing with an accompanying progress report. If a new researcher joins an ongoing project, the PI must submit a request for a research permit for the new member to COSTECH at least two (2) months prior to joining the team, accompanied with a detailed CV and rationale. Changes to the study site, objectives, and methodologies to an ongoing research project must be submitted in writing to COSTECH at least two (2) months prior to implementing the change.

See TZA-47 for additional information about national research registration.

Tanzania Medicines and Medical Devices Authority

As per the G-AppConductCT and the TMMDAFees, applicants are responsible for paying a processing fee to submit a clinical trial application. The TMMDAFees indicates that the Tanzania Medicines and Medical Devices Authority (TMDA) levies the following processing fees:

• $3,000 USD for submitting a clinical trial application

• Double the cost of registration and analysis fee for fast-track clinical trial applications

• $500 USD for amendments for major changes in clinical trials

• $300 USD for amendments for minor changes in clinical trials

See the TMMDAFees for a complete list of TMDA fees and charges.

Payment Instructions

The G-AppConductCT states that the fee must be paid to the order of TMDA directly to the bank by draft electronic transfer through the following accounts:

Foreign applicants: Account Numbers 100380013 Citibank (T) and 02J1021399100 CRDB
Local applicants: Account Number 2041100069 NMB

Applicants are responsible for all bank charges when payment is made by bank transfer. In addition, applicants must include a note with payment details, including the applicant’s name, the product(s) paid for, and the amount of fees paid.

Tanzania Commission for Science and Technology

As delineated in the G-ResearchClearance, the Tanzania Commission for Science and Technology (COSTECH) charges an application fee of $50 USD to review and register a research proposal. The principal investigator (PI) should pay the nonrefundable research application fee, which is paid per project. Before the permit is issued, COSTECH requires foreign researchers to pay a research permit fee of $300 USD.

Payment Instructions

Per the G-ResearchClearance and TZA-47, foreign researchers can pay the research permit fee via the following bank account:

National Bank of Commerce Ltd
Samora Avenue Branch
P.O. Box 9002
Dar es Salaam, Tanzania

Account Number: 012105018998
Swift Number/Code: NLCBTZTX

According TZA-47 for in-country applicants, the fee can be paid with a control number (payment bill) which will be used for a deposit. A control number for payment can be obtained through a request to COSTECH via email rclearance@costech.or.tz.

Overview

As indicated in the G-AppConductCT, all clinical trials require national ethics committee (EC) approval for each trial site. Per the G-TMRCC and TZA-50, the national EC in Tanzania is the National Health Research Ethics Committee (NatHREC), which focuses on the ethical issues surrounding submitted research proposals. As delineated in the G-TMRCC and TZA-18, NatHREC is a subcommittee of the Medical Research Coordination Committee (MRCC), which serves as the national health research coordinating body, and is responsible for supervising health research in Tanzania. The MRCC, which is part of the National Institute for Medical Research (NIMR), delegates the registration, review, approval, and monitoring of clinical research to NatHREC.

Per the G-AppConductCT, TZA-18, TZA-5, and TZA-1, proposed health research in Tanzania must also get institutional EC approval at the host institution where the research will be based. If there is no institutional EC, the approval must still be obtained from NatHREC. For all health research involving foreign collaborators, the applicant must get both the institutional EC and NatHREC’s ethical approval.

Ethics Committee Composition

National Health Research Ethics Committee

As per the G-TMRCC and TZA-5, NatHREC is composed of 15 members—scientists and non-scientists with varying backgrounds—to promote a complete and adequate review of health research proposals commonly received by NIMR. NatHREC members are appointed by their respective institutions based on knowledge, qualifications, and experience in reviewing and evaluating the scientific, medical, and ethical aspects of research protocols. The chairperson is to be non-affiliated with the NIMR, and the Secretary is to be affiliated with the NIMR. According to TZA-5, committee members must include medical scientists; biomedical scientists; social scientists; a legal representative; unaffiliated community representatives (e.g., teacher or nurse); and representatives of religious/faith-based organizations. As per the G-TMRCC, NatHREC is represented by the following organizations:

• NIMR

• Tanzania Commission for Science and Technology (COSTECH)

• Muhimbili University of Health and Allied Sciences (MUHAS)) (formerly known as Muhimbili University College of Health Science (MUCHS))

• Christian Social Services Commission (CSSC)

• The National Muslim Council of Tanzania (BAKWATA)

• Economic and Social Research Foundation (ESRF)

• Tanzania Gender Networking Programme (TGNP)

• Legal and Human Rights Centre (LHRC)

• University of Dar es Salaam (UDSM)

• Ministry of Health, Community Development, Gender, Elderly and Children (MoHCDGEC)

• Ministry of Education (MoE)

Institutional Ethics Committees

As per the G-EthicsHR-TZA, the composition and qualification requirements for the institutionally based ECs vary by host institution. A committee consisting of up to 12 members is considered to be appropriate. See section 1.2.1 for detailed information on composition requirements, and TZA-23 for links to specific institutions.

Terms of Reference, Review Procedures, and Meeting Schedule

The G-TMRCC and TZA-5 state that NatHREC must operate within written standard operating procedures (SOPs), including a process to be followed for conducting reviews. The SOPs should include information on NatHREC composition, meeting schedules, frequency of reviews, requirements for initial and ongoing evaluation of the research study, and requirements for notifying the investigator and the institution of results related to the study’s initial and ongoing evaluation.

Committee members should agree to disclose their names, occupations, and affiliations, and to sign the confidentiality and conflict of interest agreements. The appointment of committee members is valid for four (4) years. The majority of committee members must be involved in the review and approval process.

According to TZA-5, the Secretary and Secretariat of NatHREC are responsible for providing training and educational programs to new and continuing committee members, and the scientific community in Tanzania on issues related to health research ethics. The training must include programs about the basic principles of human subject protection, current literature, and regulations and guidelines affecting NatHREC and NIMR. Additional functions of the Secretariat are as follows:

• Organizing an effective and efficient tracking procedure for each proposal received
• Prepare, maintain, and distribute proposals and meeting materials for review
• Organize committee meetings, including preparation and maintenance of meeting agenda and minutes
• Maintain the committee’s documentation and archive, including designing and maintaining a system for collecting and filing all committee documents, including meeting minutes, member qualifications, proposal submission versions, deviations from approved proposals, and periodic and final reports
• Communicate with the committee members and applicants
• Organize the preparation, review, revision, and distribution of SOPs and guidelines
• Provide the necessary administrative support for the committee-related activities to the chairperson of the committee, such as communicating a decision to the applicant
• Provide updates on relevant and contemporary issues related to ethics in health research, as well as relevant contemporary literature to committee members
• Perform a pre-review of each submission of the committee to ensure adherence to administrative submission requirements
• Design and disseminate templates for committee submission documents, including research proposals, informed consent materials, agreements, and periodic and final reports
• Communicate with all submitting researchers at all times throughout the submission and review process, while remaining independent of the researcher’s proposal operations; advise submitting investigators on preparing and submitting proposals for review
• Assist the Chairperson with the conduct of committee meetings
• Nominate consultant reviewers

The committee must meet once a month unless stated otherwise and in such a case, an alternate meeting time, date, and venue must be provided by the Secretary. A quorum of at least half the number of committee members, including at least one (1) member whose primary concern is in non-scientific areas and one (1) medical scientist is required for NatHREC to conduct business. The Secretariat will keep a record of attendance, indicating which members were present for the discussion of each proposal application review. The Secretary must notify all committee members of an upcoming meeting at least two (2) weeks in advance and include a meeting agenda. The agenda must outline all proposal and related research submissions for consideration in the meeting, and must include all related materials, including copies of proposals, informed consent materials, continuing and final reviews, safety reports, etc.

TZA-5 also states that, for all active study files, NatHREC must send the closed or completed study files to an off-site storage facility and store them for at least 15 years after the study's conclusion. For all prematurely terminated studies, the relevant records must be stored and “inactivated.” The principal investigator must keep the original versions of NatHREC’s termination memorandum and the Continuing Review Application Form in the proposal file. The proposal file should be stored and archived indefinitely.

For detailed NatHREC procedures and information on other administrative processes, see TZA-5.

Note that because each institutional EC has its own terms and procedures, sponsors check with their relevant institutional EC.

Overview

According to the G-TMRCC, the G-EthicsHR-TZA, and TZA-5, the primary scope of information assessed by the National Health Research Ethics Committee (NatHREC) and the institutional ethics committees (ECs) relate to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in health research studies. NatHREC and the institutional ECs must also pay special attention to reviewing informed consent and to protecting the welfare of certain classes of participants deemed to be vulnerable. (See the Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired sections for additional information about these populations).

NatHREC is responsible for ensuring an independent, timely, and competent review of all ethical aspects of the clinical trial protocol. Per the G-EthicsHR-TZA, institutional ECs provide a peer review from the institution’s perspective and ascertain the quality of the research outputs. The ECs must act in the interests of the potential research participants and the communities involved, evaluating the possible risks and expected benefits to participants, confirming the suitability of the investigator(s), facilities, and methods, and verifying the adequacy of confidentiality and privacy safeguards. See the G-EthicsHR-TZA and TZA-5 for detailed ethical review guidelines.

Role in Clinical Trial Approval Process

As per the G-AppConductCT, the TMMDAct, the CT-Regs, and TZA-5, the Tanzania Medicines and Medical Devices Authority (TMDA) and NatHREC must approve a clinical trial application prior to the sponsor, the contract research organization (CRO), or the principal investigator (PI) initiating the clinical trial. As described in TZA-31, NatHREC’s ethics review is managed through its Research Ethics Information Management System (REIMS) (TZA-32), which is an online web application for the submission of research protocols for NatHREC’s review, validation of protocols per NatHREC checklist (TZA-1), online review of proposals, and application status tracking.

As delineated in TZA-5, investigators must submit all documents for NatHREC review and approval at least three (3) months prior to the study’s commencement. In addition, NatHREC must review and approve any protocol amendments prior to those changes being implemented. After screening for application completeness, a letter/e-mail acknowledging receipt of the application will be sent to the PI by NatHREC within five (5) working days from the date of receipt. Following receipt of a valid application, three (3) primary, expert reviewers will review the protocol prior to full review by NatHREC. The committee must summarize its decision and include the proposal title and date of review, checklist of documents reviewed, and decision reached (e.g., approved, approved with stipulation, recommended for resubmission after revision, or rejected). Recommendations and/or suggestions, if any, including reasons for disapproving a study must be summarized. The summary must also include a list of members participating in a review meeting. A PI may appeal a decision in writing to NatHREC within 30 days of receipt of the decision, stating the precise issues upon which the appeal is based. NatHREC must respond to PIs in writing within 30 days or may invite the PI to present in person to the full committee within 30 days on receiving the written complaints.

As indicated in TZA-5, the study duration must be stated in the application form. The EC is required to conduct a continuing review of the approved research study. However, if NatHREC has not conducted a follow-up review and approval of the study by the expiration date provided in the initial TMDA approval letter, EC approval is deemed to have expired and all research activities should stop.

Expedited Review

TZA-5 delineates the categories of research that qualify for an expedited review:

• Research activities that present no more than minimal risk to human participants
• Minor changes (modification or amendment) to a previously approved research proposal
• Studies that involve interviews of a non-confidential nature and not likely to harm the status or interest of study participants
• Studies that involve collection of small amounts of biological specimens by non-invasive means (e.g., body fluids, excreta, hair or nail in non-disfiguring or threatening manner) for local analysis and no transfer of specimens outside of Tanzania
• Collection of data for research purposes through non-invasive procedures (not involving general anesthesia or sedation), routinely employed in clinical practices and using medical devices which have been already approved for use
• Research involving data, documents, or specimens that have been already collected or will be collected for on-going medical treatment or diagnosis
• Continuing review of certain research previously approved by NatHREC
• Final study reports/close-outs

Expedited review must be conducted by the NatHREC Chairperson or by one (1) or more experienced reviewers designated by the Chairperson from among members of the committee in accordance with the requirements. The expedited review must include a review of the complete study proposal with all required attachments including an application form. Results of the review process may be communicated to the PI before being reported to the committee. Expedited reviewers may exercise all the authorities of the committee except that the reviewers may not disapprove the research. A research activity may be disapproved only after review in accordance with the non-expedited procedure. Once expedited approval has been granted, the proposal may be implemented as approved. The approval need not be ratified or otherwise approved by the convened NatHREC. The Secretariat must notify NatHREC of all completed expedited reviews at the next scheduled meeting via a listing in the meeting agenda.

National Health Research Ethics Committee

According to the G-TMRCC, the National Health Research Ethics Committee (NatHREC) requires the sponsor, the contract research organization, or the principal investigator (PI) to pay a nonrefundable fee to submit a clinical trial research protocol for ethical review and approval.

The latest fees are presented in TZA-33:

• Tanzanian researchers, expedited review – 3,100,000 Tanzanian Shillings
• Tanzanian researchers, ordinary review – 2,100,000 Tanzanian Shillings
• Tanzanian students, expedited review – Not applicable
• Tanzanian students, ordinary review – 1,100,000 Tanzanian Shillings
• International researchers, expedited review – $4,100 USD
• International researchers, ordinary review – $2,100 USD
• International students, expedited review – Not applicable
• International students, ordinary review – $750 USD

Payment Instructions

To inquire about how to submit payment with the application form (TZA-33), contact NatHREC at 255 22 2121400 or 255 758 587885 (mobile), as per at TZA-18.

Institutional Ethics Committees

Institutionally based ethics committees (ECs) may independently decide whether to charge fees for a protocol review.

Overview

As mandated by the MedRsrchAct, the National Institute for Medical Research (NIMR) is the central body responsible for oversight, and for the promotion and coordination of research in Tanzania. The NIMR is a semi-autonomous organization under the Ministry of Health, Community Development, Gender, Elderly and Children (MoHCDGEC). The G-TMRCC and TZA-5 state that the NIMR’s Medical Research Coordination Committee (MRCC) serves as the national health research coordinating body, and is responsible for supervising health research in Tanzania. The MRCC, as the NIMR’s clearance body, delegates the registration, review, approval, and monitoring of research to National Health Research Ethics Committee (NatHREC), which is a subcommittee of MRCC. The NatHREC focuses on the ethical issues surrounding submitted research proposals. All clinical trial protocols to be conducted in Tanzania are also reviewed by a specialized nine (9)-member Clinical Trials Sub-Committee, which meets monthly and reports to NatHREC. For detailed information on NatHREC responsibilities, see the G-TMRCC, the G-EthicsHR-TZA, and TZA-5.

Registration, Auditing, and Accreditation

TZA-5 indicates that accrediting and monitoring ethics committees (ECs) is a function of NatHREC. It is the responsibility of the NatHREC Secretariat, members, Chairperson, and administrative staff to perform his/her task according to the standard operating procedures (SOPs) and to be prepared and available to answer questions during evaluation, audit, or inspection visits by regulatory authorities. See SOP #26 of TZA-5 for detailed inspection requirements.

No additional information is available on registration and accreditation responsibilities by NatHREC.

Overview

According to the G-AppConductCT, the TMMDAct, and the CT-Regs, the Tanzania Medicines and Medical Devices Authority (TMDA) requires the sponsor, his/her designated contract research organization (CRO), or the investigator to obtain TMDA approval. Per TZA-5, an application for ethical review of a research study to the national ethics committee (EC), the National Health Research Ethics Committee (NatHREC) is also required and should be made by the PI for that study. According to the G-AppConductCT, the TMDA and NatHREC reviews may be conducted in parallel. However, the TMDA application must include a copy of the national EC's acknowledgement of receipt for the study protocol. In addition, the TMDA's approval will only be finalized once national EC approval is obtained. Per the G-AppConductCT, TZA-18, TZA-5, and TZA-1, proposed health research in Tanzania must also get institutional EC approval at the host institution where the research will be based. If there is no institutional EC, the approval must still be obtained from NatHREC. For all health research involving foreign collaborators, the applicant must get both the institutional EC and NatHREC’s ethical approval.

Per the G-ResearchClearance, the Tanzania Commission for Science and Technology (COSTECH) must review and approve all research in Tanzania.

Regulatory Submission

Tanzania Medicines and Medical Devices Authority

Per the G-AppConductCT, applicants must submit both paper and electronic copies of the clinical trial application (CTA). Per the TZA-36, electronic CTA(s) must be completed online via the Regulatory Information Management System (RIMS) Customer Self Service Portal (TZA-34). Applicants must fill out CTAs as per the Modules and the Common Technical Document (CTD) highlighted in the G-AppConductCT. Applications for amendment(s) to a previously authorized clinical trial must be submitted on the applicable form in RIMS. The clinical trial application form is available at TZA-38, and the application forms for protocol amendments are at TZA-43 and TZA-44. Note that a list of clinical trial forms is posted to TZA-35.

Per the G-AppConductCT, the hard copy of the application may be delivered in person or by courier to TMDA. TZA-36 lists the current TMDA address and contact information as follows:

In addition, the TMDA Regulatory Information Management System (RIMS) Customer Self Service Portal (TZA-34) provides applicants with various online regulatory services.

As per the G-AppConductCT and the TZA-36, applicants must submit paper (A4) and electronic copies. The paper documents should be arranged in spring file folders. The G-AppConductCT specifies that the electronic documents should be in Word format, Bookman Old Style, font size 11 and submitted on CD-ROM. TZA-36 requires electronic format on Compact Discs (CDs).The number of copies to be submitted is not specified in the G-AppConductCT. Annex 1 of the G-AppConductCT provides the Clinical Trial Application Form template. Applicants should submit their applications as per the Modules in the G-AppConductCT and the Common Technical Document (CTD) highlighted in the G-AppConductCT. The overall organization of the CTD format should not be modified.

Per the G-AppConductCT, all applications and supporting documents must be in English. The informed consent documents must be in both Kiswahili and English.

Tanzania Commission for Science and Technology

Per the G-ResearchClearance, the principal investigator (PI) should submit an application for a research permit. It must be submitted to the Director General of COSTECH through the online system (TZA-48) at least three (3) months before the intended commencement of research in Tanzania. According to TZA-47, when the online COSTECH system is not working, applicants should email COSTECH at either rclearance@costech.or.tz or dg@costech.or.tz. After a foreign researcher obtains his/her research permit, he/she is required to apply for a class C residence permit from the Tanzanian Immigration Services Department. See the G-ResearchClearance and TZA-47 for additional information about applying for a research permit through the National Research Clearance Committee (NRCC).

Ethics Review Submission

National Health Research Ethics Committee

The TZA-5 specifies that NatHREC requires all applicants to complete the Application Form for Ethics Approval (see Form 03 in TZA-5) with the research protocol to obtain ethics approval. An application for ethical review of a research study should be made by the PI for that study. Applications may not be submitted by the sponsor(s) on behalf of the PI. Applications must be accompanied by a completed checklist (TZA-1). As described in TZA-31, applicants should submit the form to the online Research Ethics Information Management System (REIMS) (TZA-32). While TZA-49 only provides instructions for online submittal, TZA-5 also includes instructions for submittal of hard copies.

The G-TMRCC indicates that four (4) copies of the research proposal with a cover letter should be submitted to NatHREC.

Regulatory Authority Requirements

Tanzania Medicines and Medical Devices Authority

As per the G-AppConductCT and the CT-Regs, the following documentation must be submitted to the Tanzania Medicines and Medical Devices Authority (TMDA):

• Comprehensive table of contents
• Cover letter
• Application form (See the Regulatory Information Management System (RIMS) Customer Self Service Portal (TZA-34) or Annex 1 of the G-AppConductCT and First Schedule of the CT-Regs)
• General investigational plan
• Capacity building plans (including plans for staff training and updates)
• Overall summary of the protocol (See Annex 2 of the G-AppConductCT)
• Protocol, signed and approved with data compiled as prescribed in Annex 3 of G-AppConductCT and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (TZA-13), including case report form (CRF) copies or descriptions; See TZA-42 for a clinical trial protocol template
• Participant Information Leaflet, informed consent forms (ICFs), and any other information to be given to participants (See Annex 4 of the G-AppConductCT)
• Declarations by the principal investigator (PI) (TZA-39), co/sub investigators (TZA-41), and monitors (TZA-40) (Also see Annexes 5-7 of the G-AppConductCT)
• Joint declaration by sponsor and national PI in format prescribed in Annex 8 of the G-AppConductCT
• Investigator’s Brochure (IB), nonclinical overall summary (See Annex 10 of the G-AppConductCT), and prescribing information data sheet, if applicable
• Certified copy of insurance of research participants
• Ethics clearance certificate or a copy of protocol submission acknowledgement from the National Institute for Medical Research (NIMR)’s National Health Research Ethics Committee (NatHREC) or any approved medical research institute
• Investigator(s) Curriculum Vitae(s) (CVs) (See Annex 9 of the G-AppConductCT)
• Blank CRFs and serious adverse events reporting form to be used in the study
• Certificate of good manufacturing practice (GMP) for manufacture of the trial medicine or other evidence of manufacturing quality, safety, and consistency
• GMP certificate for manufacture of the placebo, if applicable
• Investigational product (IP) labels and packages insert(s)
• Mock-up labels for IPs
• Evidence of accreditation/certifications of the designated laboratories or other evidence of good laboratory practice
• Letters of access (if applicable) authorizing TMDA to access related files
• Copies of key, peer-reviewed published articles supporting the application
• Filled-in, quality overall summary – Chemical Entities Template (See Annex 11 of the G-AppConductCT)
• Investigational medicinal product dossier
• Application fees
• Summaries of nonclinical, clinical, and quality data (See Module 2 of the G-AppConductCT)
• Quality of the IP (See Module 3 of the G-AppConductCT)
• Nonclinical study reports (See Module 4 of the G-AppConductCT)
• Clinical study reports (See Module 5 of the G-AppConductCT)

As delineated in G-AppConductCT, an application must not cross reference the details or documentation between one (1) clinical trial and another. The applicant must include a statement indicating that all information in the application is complete and accurate. In the case of multi-center trials, a coordinating investigator must also sign the application form. If the trial is part of an international study, information must be provided regarding the other participating countries and the part of the trial that will be conducted locally.

In addition, per the G-AppConductCT, applicants can submit an application for amendment to a previously authorized clinical trial, using the required forms (Annexes 12 and 13). The following must be submitted to the TMDA by the sponsor or sponsor’s agent:

• Amendment fees
• Description and reasons for the proposed amendment
• Original wording, revised wording, and the rationale for the change, including a complete protocol incorporating all amendments
• Supporting data for the amendment: updated overall risk-benefit assessment, possible consequences for participants already in the trial and for assessment of trial results, and summaries of data

For details on when TMDA approval must be obtained for amendments, see G-AppConductCT.

Tanzania Commission for Science and Technology

According to the G-ResearchClearance and TZA-47, to obtain a research permit for a clinical trial, the following must be submitted to the Tanzania Commission for Science and Technology (COSTECH) (Note: the regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source.):

• A full research proposal, including a summary, abstract, introduction, objectives of research, problem statement, hypotheses or questions framework, methodologies, and timeframe
• Literature review
• Beneficiaries of the research
• Bibliography
• Detailed CV(s) of all researchers
• Sponsor’s cover letter
• For foreign applicants, scientific and ethics committee approval from an institution in the PI’s country of residence
• Clearance from TMDA
• A supporting letter from a Tanzanian affiliate institution
• A Tanzanian applicant should submit either a copy of their national ID, passport details, driving license, or voters ID
• A foreign applicant should submit a copy of their passport details page and a current passport size photo with a blue background
• A scanned copy of a receipt as proof of payment of the non-refundable research application fee to COSTECH (See Regulatory Fees section for details)

The G-ResearchClearance indicates that an application to renew a permit must contain a renewal application form, an annual progress report, a supporting letter of recommendation from the affiliate institution, passport information, updated CVs, and an extension table form.

Ethics Committee Requirements

National Health Research Ethics Committee

As per the G-TMRCC and the NatHREC’s Checklist for Ethical Clearance Application Submission (see TZA-1), the NatHREC requires applicants to submit the following documentation for ethics approval (Note: the regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source.):

• Application Form for Ethics Approval (see Form 03 in TZA-5 and the Research Ethics Information Management System (REIMS) (TZA-32))

• Cover letter signed by PI or co-PI
• Summary, introduction, and literature review
• Statement of the problem, the rationale, and study objectives
• Budget and budget justification
• Ethical consideration (e.g., written information to be provided to participants in English and Kiswahili, obtaining verbal/ written informed consent, obligations of investigators and sponsors, benefits and risks of study participation, recruitment, cultural values, and confidentiality measures)
• Limitations of the study

• Dissemination of research results
• Commitment letter from affiliated institution and/or local government officials

• ICFs/Assent Forms in English and Kiswahili

• EC approval certificate from affiliating institution(s), where applicable

• Methodology, including data collection tools in English and Kiswahili

• Elaborated recruitment procedure

• Research team CVs

• Evidence of payment of application and registration fees (Bank slip)

• Completed Data Transfer Agreement (see TZA-8) and/or Material Transfer Agreement (see TZA-10), where applicable

• IBs and CRFs

• Proof of insurance coverage

• List of Data and Safety Monitoring Board members (with at least one (1) Tanzanian)

Institutional Ethics Committee

Each institutional EC has its own requirements.

Clinical Protocol

The G-AppConductCT requires the following protocol contents in the format prescribed in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (TZA-13):

• General information (protocol title, identifying number, and date; contact information for the sponsor, medical expert, investigator(s), trial site(s), qualified physician(s), and laboratory and/or institutions involved in the study)
• Background information
• Objectives and purpose
• Trial design
• Selection, withdrawal, and treatment of participants
• Assessment of efficacy
• Assessment of safety
• A description of the statistical methods to be used in the trial
• Direct access to source data and documents
• Quality control and quality assurance
• Ethical considerations
• Data handling and recordkeeping
• Publication policy

Overview

Based on the G-AppConductCT, the TMMDAct, and the CT-Regs, the Tanzania Medicines and Medical Devices Authority (TMDA)'s approval of a clinical trial application is dependent upon obtaining proof of ethical approval from the national ethics committee (EC), the National Health Research Ethics Committee (NatHREC). According to the G-AppConductCT, the TMDA and NatHREC reviews may be conducted in parallel. However, the TMDA application must include a copy of NatHREC's acknowledgement of receipt for the study protocol. In addition, the TMDA's approval will only be finalized once NatHREC approval is obtained. As per the G-ResearchClearance, after receiving TMDA and NatHREC’s approvals, the researcher must submit an application for research clearance to the Tanzania Commission for Science and Technology (COSTECH).

Regulatory Authority Approval

Tanzania Medicines and Medical Devices Authority

According to the G-AppConductCT, the TMDA review process is conducted on a first-in, first out basis. TMDA will evaluate complete applications within 60 working days of receiving the application. The fast-track evaluation provides that a new clinical trial application may be fast tracked and assessed within 30 working days of its submission if the applicant has requested and paid twice the prescribed clinical trial application fee.

As set forth in the G-AppConductCT, the TMMDAct, and the CT-Regs, the TMDA coordinates the clinical trial application process. Upon receipt of a clinical trial application, the TMDA initially screens the application for completeness. If complete, the TMDA officer acknowledges receipt of the application by returning a signed copy of the cover sheet to the applicant (see Annex 1 of the G-AppConductCT or First Schedule of the CT-Regs). Per the G-AppConductCT, the TMDA may request clarification, certificates, and/or samples through a query letter. Once a query has been raised and sent to the applicant, the evaluation process stops until the TMDA receives a written response to the query. The response should be submitted within six (6) months after the query letter was issued. In addition, TMDA reserves the right to request information or set conditions not specifically described in the G-AppConductCT to allow it to adequately assess the safety, efficacy, or quality of an investigational product (IP).

The TMMDAct states that the TMDA Director General must issue a Clinical Trial Certificate to authorize the trial to be conducted. Per the G-AppConductCT, the TMDA’s clinical trial authorization will be valid up to the proposed duration of the study indicated in the application. However, the validity will not extend beyond five (5) years. If the trial needs more than five (5) years, the applicant must request an extension. If granted, TMDA will issue an updated certificate.

Tanzania Commission for Science and Technology

The G-ResearchClearance indicates that once COSTECH receives a new application, the Secretariat screens the application for completeness; registers the application; sends an acknowledgement to the applicant within five (5) business days. If approved after COSTECH’s review, the principal investigator (PI) is then required to collect the research permit certificate from COSTECH. Per TZA-47, COSTECH’s review committee meets every two (2) months, and applicants are advised to apply two (2) months before commencement date of research.

Ethics Committee Approval

National Health Research Ethics Committee

As set forth in the G-TMRCC and TZA-5, NatHREC meets once a month to evaluate application submissions. TZA-5 indicates that NatHREC will send a letter or email to the PI acknowledging receipt of the application within five (5) business days from the date of receipt. Registered proposals are returned to the Secretariat office again within one (1) day of receiving the documents from the National Institute for Medical Research (NIMR) Registry section. The proposal is then registered into NatHREC's Register and Electronic database and a step-by-step review process is begun. Applicants will receive acknowledgement of proposal acceptance for review within three (3) working days following NatHREC's receipt of the proposal documents from the NIMR Registry section.

Per TZA-5, the proposal is sent to three (3) primary reviewers for evaluation, prior to full review by NatHREC. The committee must summarize its decision and include a list of members who participated in the review meeting. NatHREC’s decision summary must include the date of review. A PI may appeal that decision in writing to NatHREC within 30 days of receipt of the decision, stating the precise issues upon which the appeal is based. NatHREC will respond to PIs in writing within 30 days, or upon scrutiny of the complaints, NatHREC may invite the PI to present in person to the full committee within 30 days of receiving the written complaints.

Institutional Ethics Committees

According to TZA-5, the institutional EC review may occur prior to the proposal review by NatHREC as the application to NatHREC requires an EC approval certificate from an affiliated institution(s), where applicable (i.e., for foreign sponsors and when an institution has an EC). The ethical review and approval timeline varies by institution.

Overview

In accordance with the G-AppConductCT, the TMMDAct, and the CT-Regs, a clinical trial can only commence after an applicant receives permission from the Tanzania Medicines and Medical Devices Authority (TMDA) and approval from the national ethics committee (EC), the National Institute for Medical Research (NIMR)’s National Health Research Ethics Committee (NatHREC). Per the G-ResearchClearance, following the TMDA and NatHREC approvals, the applicant must also apply to the Tanzania Commission for Science and Technology (COSTECH) for review, registration, and to obtain a research permit prior to initiating a study. No waiting period is required following the applicant’s receipt of these approvals.

In addition, as per the G-AppConductCT, the TMMDAct, the CT-Regs, and the TFDCA-ImptExpt, the sponsor or the principal investigator (PI) is required to obtain an import license for the shipment of an investigational product to be used in the trial. (See the Manufacturing & Import section for additional information).

Clinical Trial Agreement

Prior to the trial’s commencement, the G-AppConductCT specifies that the protocol must be dated and signed by the investigator, the host institution, and the sponsor, and can function as a contract. In addition, as per the G-CTInsurance-TZA, a clinical trial agreement must be signed by the Chief Executive of the host institution, the sponsor, and the PI.

Per the G-AppConductCT, the sponsor and researchers are required to conduct the clinical trial in compliance with applicable Tanzanian laws and regulations and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (TZA-13). TZA-13 states that the sponsor is responsible for obtaining agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, reports for monitoring and auditing purposes, and inspection by domestic and foreign regulatory authorities. Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been correctly processed. A written agreement must be signed by both the sponsor and the investigator or any other parties involved with the clinical trial, verifying that both parties agree to the trial protocol, the monitoring and auditing practices, the standard operating procedures (SOPs), and their respective duties.

The sponsor must also obtain the investigator(s)’ and the institution(s)’ agreement to:

• Conduct the trial in compliance with TZA-13, applicable regulatory requirement(s), and the protocol agreed to by the sponsor and approved by the EC
• Comply with data recording and reporting procedures
• Permit monitoring, auditing, and inspection
• Retain essential documents until the sponsor informs them that they are no longer needed

Also, per the CT-Regs, the sponsor must ensure that all agreements made with the PI and any other parties involved in a clinical trial are in writing, as part of the protocol or in a separate agreement.

Clinical Trial Registration

As per the CT-Regs, all clinical trials taking place in Tanzania must be registered with the Tanzania Clinical Trials Registry (TzCTR) which is accessed via the Regulatory Information Management System (RIMS) Customer Self Service Portal (TZA-34). An applicant must submit detailed clinical trial information to the TzCTR not later than 21 days after the first participant is enrolled in the trial. See the CT-Regs for complete registry submission requirements. The G-AppConductCT further stipulates that applicants have the option to register their clinical trials in the Pan African Clinical Trials Registry (PACTR) (TZA-51) or any other publicly accessible registries accepting international clinical trial information and recognized by the World Health Organization (WHO). The registration number should be made available to TMDA.

Safety Reporting Definitions

In accordance with the G-ReptSafetyData, the G-AppConductCT, and the CT-Regs, the following definitions provide a basis for a common understanding of Tanzania’s safety reporting requirements:

• Adverse Event (AE) – Any adverse medical occurrence in a research participant to whom a drug product was administered, and which does not necessarily bear a causal relationship to the treatment

• Adverse Drug Reaction (ADR) – All noxious and unintended responses to a medicinal product related to any dose

• Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (SADR) – Any untoward medical occurrence that at any dose: results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect

• Suspected Unexpected Serious Adverse Reaction (SUSAR) (also referred to as Unexpected ADR) – A serious adverse reaction where the nature and severity of the event is not consistent with the medicinal product

The PV-Regs reaffirms that the reporting of SAEs and SUSARs occurring during clinical trials should comply with the requirements in the CT-Regs.

Safety Reporting Requirements

Investigator Responsibilities

As stated in the G-ReptSafetyData and the G-AppConductCT, the investigator is responsible for documenting and reporting all AEs/ADRs, SAEs/SADRs, and SUSARs to the sponsor using the case report form (CRF)/reporting form and the SAE/SADR Reporting Form approved in the protocol, or the CIOMS Form I (TZA-7). See section 3.0 of the G-ReptSafetyData for key data elements to include on the form.

The CT-Regs states that the principal investigator (PI) must immediately report to the Tanzania Medicines and Medical Devices Authority (TMDA) any SAE/SADR that occurs to a participant at a trial site where he/she is responsible for the conduct of the trial. The report may be made orally or in writing and must be followed up with a written report in 14 days. Also, the PI must report AEs that the protocol identifies as critical to safety evaluations. The reports must identify each participant by a number assigned to that participant in accordance with the protocol.

The CT-Regs further states the PI or sponsor must record and report SUSARs that are fatal or life-threatening to the TMDA within seven (7) days and other SUSARs within 15 days.

Sponsor Responsibilities

The G-ReptSafetyData states that the sponsor is responsible for the assessment and timely reporting of SAEs/SADRs and SUSARs to the TMDA. The sponsor must retain detailed records of safety information reported by the investigator(s) and ensure that all reports required by the TMDA are submitted on time. In addition, the sponsor must report all SAEs and SUSARs occurring from trial sites outside the country to the TMDA.

The G-ReptSafetyData requires that fatal or life-threatening SAEs/SADRs or SUSARs must be immediately reported to the TMDA by telephone, fax, or email followed by a complete report within seven (7) additional calendar days. The G-AppConductCT specifies that the immediate reporting period is within 24 hours. Further, the report should include an assessment of the importance and implication of the findings, including relevant previous experience with the same or similar products. All deaths during the study, including the post treatment follow-up period, and deaths that resulted from a process that began during the study, should be reported.

Per the G-ReptSafetyData and the G-AppConductCT, all other SAEs and SUSARs that are not fatal or life-threatening must be filed as soon as possible but no later than 14 calendar days after first knowledge by the sponsor. Please note that the CT-Regs states that non-life-threatening SUSARs should be reported in 15 days.

See the G-ReptSafetyData and the CT-Regs for detailed reporting requirements.

Form Completion & Delivery Requirements

As per the G-ReptSafetyData and the G-AppConductCT, all SAEs/SADRs and SUSARs must be reported on the protocol approved case report form (CRF)/reporting form, or the CIOMS Form I (TZA-7), and should include trial specific details such as participants’ ID numbers and/or protocol number. The form must be submitted to the TMDA office by courier, mail, email (as an attachment), or by fax.

According to TZA-26, current TMDA address and contact information is as follows:

See Annex 15 of the G-AppConductCT and Appendix 1 of the G-ReptSafetyData for the reporting forms.

Interim and Annual Progress Reports

As delineated in the G-AppConductCT, the sponsor or the principal investigator (PI) must submit progress reports to the Tanzania Medicines and Medical Devices Authority (TMDA) on a six (6)-month basis from the date of the clinical trial’s commencement. The content should be as prescribed in TZA-11. The CT-Regs states that progress reports should be submitted annually, or more frequently, as required by the TMDA.

According to TZA-5, the investigator must submit written progress reports every six (6) months to the National Health Research Ethics Committee (NatHREC) for all ongoing approved health research activities in Tanzania.

In addition, per the G-ResearchClearance, the PI is required to submit annual progress reports (as part of the annual permit-renewal process) to the Tanzania Commission for Science and Technology (COSTECH) that include the title of the study, COSTECH registration reference number, study site, brief background and objective of the study, progress in the reporting period, any problems encountered, and implementation plan for the next period.

Final Report

The G-AppConductCT requires the sponsor or the PI to submit a closing report to the TMDA within 60 days of the trial’s completion. This report should be followed by a final study report within six (6) months after trial closure unless otherwise justified. The structure and content of the final report should comply with TZA-11.

In addition, per TZA-5, the PI is required to submit a final report to NatHREC once the last participant has completed all visits and all adverse experiences have been brought to appropriate resolution. Final reports must be submitted to NatHREC on a Close-out Form (Form 08) and processed as an expedited review. The Secretariat will review the Close-out Form. The expedited reviewer will request additional information from the researcher, as needed. Written documentation acknowledging the close-out will be provided to the investigator and a copy retained in the proposal file.

The G-ResearchClearance requires the researcher to submit a soft and hardcopy of the final report to COSTECH. The report should be accompanied with any relevant publications, electronic raw data, and proof of dissemination if applicable. The final report should include:

• COSTECH registration reference number
• Title of study
• Summary of report in English and Swahili
• Brief background and objective of the study
• Methodology, including study sites
• Key findings
• Constraints or problems encountered
• Conclusions and recommendations

As per the G-AppConductCT and the CT-Regs, a sponsor is defined as an individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial.

In accordance with the G-AppConductCT and the CT-Regs, the Tanzanian government also permits a sponsor to authorize a contract research organization (CRO) to perform one (1) or more of a sponsor’s trial-related duties and functions.

Overview

The Tanzanian government complies with the requirements delineated in the G-AppConductCT and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (TZA-13) for conducting clinical trials. As set forth in TZA-13, the sponsor is responsible for selecting the investigator(s) and the institution(s) for the clinical trial, and for ensuring that the investigator(s) are qualified by training and experience. Additionally, the sponsor must define and allocate all study related duties and responsibilities to the relevant parties participating in the study. As delineated in TZA-13 and the G-AppConductCT, prior to entering into an agreement with the investigator(s) and the institution(s) to conduct a study, the sponsor should provide the investigator(s) with the protocol and an investigator’s brochure. Furthermore, the sponsor must sign an agreement or contract with the participating institution(s).

The G-AppConductCT delineates that the principal investigator (PI) must have the following minimum qualifications and experience:

• University degree in medicine, pharmacy, pharmacology, toxicology, or biochemistry and related fields
• Practical experience within the relevant professional area
• Previous experience as a co-investigator in at least two (2) trials in the relevant professional area
• Must be responsible for the conduct of the clinical trial at a clinical trial site
• Tanzanian resident
• In good standing with a professional organization
• For multicenter studies where the PI is not a resident of Tanzania, the appointed national PI must be a resident and should assume full responsibilities for all local clinical trial sites
• Ensure that he or she has sufficient time to conduct and complete the trial, and that other commitments or trials do not divert essential subjects, resources, or facilities away from the trial in hand
• The maximum number of clinical trials that a PI is allowed to supervise at the same time is five (5)

All investigators in a clinical trial, as well as the trial monitor, must have had formal training in Good Clinical Practices (GCP) within the last three (3) years. Evidence of attending the GCP course should be submitted.

Per the G-AppConductCT, clinical trials must be carried out under conditions that ensure adequate safety for the participants. The site selected should be appropriate to the stage of development of the product and the potential risks involved. The trial site must have adequate facilities, including laboratories, equipment, and sufficient medical, paramedical, and clerical staff to support the trial and to deal with all reasonably foreseeable emergencies. All laboratory assays must be validated, and principles of Good Laboratory Practice (GLP) should be observed.

Foreign Sponsor Responsibilities

The G-ResearchClearance requires all foreign researchers to identify and affiliate to a local institution that has the appropriate capacity in the relevant type of research and obtain a local collaborator. Minimum qualifications of the local collaborator should be a person with a master’s degree and an expert in the relevant field of study. There should be a memorandum of agreement between the local institution/collaborator and the foreign researcher that includes methods for sharing data, material transfer agreements, access benefit sharing agreements, managing intellectual property, and dissemination of research results.

Data and Safety Monitoring Board

As delineated in TZA-5, the National Health Research Ethics Committee (NatHREC) may require a Data and Safety Monitoring Board (DSMB) for studies intended to save lives, prevent serious disease progression, or reduce the risk of a major adverse health outcome. DSMBs are particularly important where interim data analysis is required to ensure the safety of research participants. The primary responsibility of a DSMB is to safeguard participants by analyzing accumulating data relevant to the risks and benefits on a regular basis, especially in long-term trials. The DSMB also decides whether adverse events are serious enough to warrant termination of the study. See TZA-5 for examples of the kinds of studies that may require a DSMB.

The CT-Regs states that the DSMB requirement may depend on trial design and scientific background, risk and benefit assessment, or any other reasons determined by NatHREC.

TZA-5 states that for clinical trials conducted only in Tanzania, the DSMB must include representation from Tanzania. For multi-country clinical trials, the DSMB should include regional representation, preferably Tanzanian, on its roster. DSMBs should submit reports to NatHREC. In contrast, per TZA-1, for clinical trials that require a DSMB, the PI must submit a list of DSMB members, including at least one (1) Tanzanian, to the National Institute for Medical Research (NIMR). Additionally, the CT-Regs requires the following information:

• Trial objectives and terms of reference
• Member composition, qualifications, specific roles, and relationship to the investigators and study
• How meetings will be organized

The G-AppConductCT also specifies that a DSMB/Data Monitoring Committee (DMC) is required in situations where safety concerns may be unusually high. A DMC is recommended for any controlled trial of any size that will compare rates of mortality of major morbidity. It also indicates that a DSMB or DMC must be considered in the following situations:

• The study endpoint is such that a highly favorable or unfavorable result, or even a finding of futility, at an interim analysis might ethically require termination of the study before its planned completion
• There are a priori reasons for a particular safety concern (e.g., if the procedure for administering the treatment is particularly invasive)
• There is prior information suggesting the possibility of serious toxicity with the study treatment
• The study is being performed in a potentially fragile population such as children, pregnant women, the very elderly, other vulnerable populations, or those who are terminally ill or of diminished mental capacity
• The study is being performed in a population at elevated risk of death or other serious outcomes, even when the study objective addresses a lesser endpoint
• The study is large, of long duration, and multi-center

Additional details on the procedures and composition of the DSMB or DMC are provided in the G-AppConductCT and Part VIII of the CT-Regs. In addition, per the G-ReptSafetyData, the sponsor must also ensure that the DSMB’s interim safety data analyses are submitted to the Tanzania Medicines and Medical Devices Authority (TMDA).

Multicenter Studies

As delineated in TZA-13, in the event of a multicenter clinical trial, the sponsor must ensure that:

• All investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor, and, if required, by the TMDA, and given ethics committee (EC) approval
• The case report forms (CRFs) are designed to capture the required data at all multicenter trial sites
• Investigator responsibilities are documented prior to the start of the trial
• All investigators are given instructions on following the protocol, complying with a uniform set of standards to assess clinical and laboratory findings, and completing the CRFs
• Communication between investigators is facilitated

The CT-Regs and the G-AppConductCT also state that in the case of multicenter studies where the PI is foreign, the appointed national PI must be a resident and assume full responsibilities for all local clinical trial sites.

Insurance

As set forth in the G-AppConductCT, the G-CTInsurance-TZA, and the CT-Regs, the sponsor or his/her designated contract research organization (CRO) is responsible for providing insurance coverage for any unforeseen injury to research participants. Before a clinical trial begins, the sponsor should also provide insurance and indemnify the investigator and the institution against claims arising from malpractice or negligence, and provide a copy of a valid insurance certificate from a recognized insurer in the clinical trial application submission. Additionally, per the CT-Regs, the insurance policy should be obtained from an insurance company registered in Tanzania. The G-CTInsurance-TZA and the G-AppConductCT states that details and proof of insurance must be provided in the ethics review submission. Furthermore, per the CT-Regs, for investigator-initiated trials, proof of current malpractice insurance that covers clinical trials must be provided to the Tanzania Medicines and Medical Devices Authority (TMDA). (See the Submission Content section for additional submission requirements.)

As per G-CTInsurance-TZA and the CT-Regs, the sponsor or his/her designated CRO must sign an indemnity agreement with the host institution and the investigator(s) to cover any risks related to a research participant being injured by an investigational product, or from any procedure necessary as part of the protocol. The indemnity must be signed by the sponsor and the institution’s chief executive officer. See Appendix 1 of the G-CTInsurance-TZA for a sample agreement. Per the CT-Regs, the sponsor must also indemnify the investigator against claims arising from the trial, except for claims that arise from malpractice or negligence.

The G-CTInsurance-TZA states that the insurance policy must meet the following requirements:

• Cover the conduct of the relevant clinical trial in Tanzania

• Provide a policy registered by the Tanzania Insurance Regulatory Authority (TIRA)

• Contain insurance coverage for an amount sufficient to meet the indemnification requirements applicable to the ethics committee-specified level of risk

• Cover claims made by research participants during the trial as well as those made after the trial is completed

Compensation

Injury or Death

As specified in the G-CTInsurance-TZA, the sponsor or his/her designated contract research organization (CRO) is responsible for providing compensation to research participants and/or their legal heirs in the event of trial-related injuries or death. The sponsor must also ensure that participants who suffer any trial-related injuries are provided with free medical treatment for such injuries.

The G-CTInsurance-TZA indicates that the sponsor should provide financial compensation and medical treatment as per the recommendations of the ethics committee (EC) and ultimately the Tanzania Medicines and Medical Devices Authority (TMDA).

As per the G-CTInsurance-TZA, the amount of compensation paid should be appropriate to the nature, severity, and persistence of the injury. Compensation should be abated, or in certain circumstances excluded, in light of the following factors (which will depend on the risk level the participant can reasonably be expected to accept):

• The seriousness of the disease being treated

• The degree of probability that adverse reactions will occur and any warning given
• The risks and benefits of the established treatments relative to those known or suspected of the trial medicines

Trial Participation

As per the CT-Regs and the G-AppConductCT, participants may also be compensated for travel and incidental expenses incurred while participating in the trial. Per the G-AppConductCT, the clinical trial application must indicate the compensation to be received by participants, including a breakdown of costs.

Quality Assurance/Quality Control

As stated in the G-AppConductCT and the CT-Regs, the Tanzanian government complies with the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (TZA-13) requirement that the sponsor implement and maintain quality assurance (QA) and quality control (QC) systems with written standard operating procedures (SOPs) to ensure that trials are conducted and data are generated, recorded, and reported in compliance with the protocol.

Per TZA-13, the sponsor should implement a system to manage quality throughout all stages of the trial process, focusing on trial activities essential to ensuring participant protection and the reliability of trial results. The quality management system should use a risk-based approach that includes:

• Identifying processes and data that are critical to ensure participant protection and the reliability of trial results during protocol development
• Identifying risks to critical trial processes and data
• Evaluating the identified risks, against existing risk controls
• Deciding which risks to reduce and/or which risks to accept
• Documenting quality management activities and communicate to those involved in or affected by these activities
• Periodically reviewing risk control measures to ascertain whether the implemented quality management activities are effective and relevant
• Describing the quality management approach implemented in the trial and summarize important deviations from the predefined quality tolerance limits and remedial actions taken in the clinical study report

The sponsor is responsible for obtaining agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, reports for monitoring and auditing purposes, and inspection by domestic and foreign regulatory authorities. QC should be applied to each stage of data handling to ensure that all data are reliable and have been correctly processed.

As described in the G-AppConductCT, study design, statistical considerations, choice of control groups, reporting of data, and conduct of the trial should also comply with the International Council for Harmonisation’s Efficacy Guidelines (E3-E16), provided in TZA-24.

Monitoring Requirements

As part of its QA system, the G-AppConductCT and TZA-13 note that the sponsor should ensure the trial is monitored and audited. The purpose of the audit should be to evaluate trial conduct and compliance with the protocol, SOPs, TZA-13, and other applicable regulatory requirements. The sponsor should appoint auditors to review the clinical trial, ensure that the auditors are qualified by training and experience, and document their qualifications. The sponsor must also ensure that the audit is conducted in accordance with his/her own SOPs, the auditor observations are documented, and data are available as needed for the Tanzania Medicines and Medical Devices Authority (TMDA).

No specific timeframe is provided for the audit process. The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. The extent and nature of monitoring is flexible and permits varied approaches that improve effectiveness and efficiency. The sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or where justified, centralized monitoring. The sponsor should document the rationale for the chosen monitoring strategy (e.g., in the monitoring plan).

The G-GCPInspections provides guidance on clinical trial inspections to ensure the trial is conducted in accordance with the study protocol, procedures, TZA-13, and regulatory requirements, and that the data is accurate and valid. Inspectees (i.e., sponsor, investigator site, and contract research organization) should follow the G-GCPInspections requirements to ensure consistent conduct of trial inspections, including uniform reporting.

Premature Study Termination/Suspension

The CT-Regs and the G-AppConductCT state that if a trial is prematurely terminated or suspended, the principal investigator (PI) or the sponsor must inform the TMDA no later than 15 days after the date of the termination, and explain the reason(s) for the termination and its impact on the proposed or ongoing clinical trials. The sponsor or PI must also inform all co-investigators of the termination, the reasons for the termination, and advise them in writing of potential health risks to research participants. For each discontinued clinical trial site, the sponsor must stop the use or importation of the investigational product (IP) from the date of the trial’s discontinuation and take all reasonable measures to ensure the recovery of all unused quantities of the IP.

According to TZA-13, if it is discovered that noncompliance significantly affects or has the potential to significantly affect participant protection or reliability of trial results, the sponsor should perform a root cause analysis and implement appropriate corrective and preventive actions. Further, the ethics committee (EC) should also be informed promptly and provided the reason(s) for the termination or suspension by the sponsor.

Electronic Data Processing System

As stated in the G-AppConductCT and the CT-Regs, the Tanzanian government complies with the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (TZA-13). As per TZA-13, when using electronic trial data processing systems, the sponsor must ensure that the electronic data processing system conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistency of intended performance. Per TZA-13, the sponsor should base their approach to validate such systems on a risk assessment that takes into consideration the intended use and the potential of the system to affect participant protection and reliability of trial results. In addition, the sponsor should maintain SOPs for the systems that cover system setup, installation, and use. The responsibilities of the sponsor, investigator, and other parties should be clear, and the system users should be provided with training. Refer to TZA-13 for additional information.

Records Management

As set forth in the CT-Regs and TZA-13, all sponsor-specific essential documents used in the trial should be retained for at least two (2) years after formal discontinuation of the trial or the last approval of a marketing application. The CT-Regs states that the investigator and the sponsor must retain all trial-related records, documents, and information at the trial site for a period not less than 20 years following the trial’s completion. See the CT-Regs for detailed record retention requirements. The sponsor should inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed.

In addition, TZA-13 states that the sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents including source documents. The storage system used during the trial and for archiving (irrespective of the type of media used) should allow for document identification, version history, search, and retrieval. The sponsor should ensure that the investigator has control of and continuous access to the data reported to the sponsor. The investigator/institution should have control of all essential documents and records generated by the investigator/institution before, during, and after the trial.

Responsible Parties

No information is currently available.

Data Protection

No information is currently available.

Consent for Processing Personal Data

No information is currently available.

Obtaining Consent

In all Tanzanian clinical trials, a freely given informed consent must be obtained from each participant in accordance with the requirements set forth in the G-AppConductCT, the G-EthicsHR-TZA, and the CT-Regs. As per the G-AppConductCT and the G-EthicsHR-TZA, the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by the national ethics committee (EC), the National Health Research Ethics Committee (NatHREC), and provided to the Tanzania Medicines and Medical Devices Authority (TMDA) for approval with the clinical trial application. (See the Required Elements section for details on what should be included in the form.)

The G-AppConductCT and the G-EthicsHR-TZA state that the investigator, or his/her designated representative, must provide detailed research study information to the participant and/or his/her legal representative(s) or guardian(s). The G-AppConductCT and the G-EthicsHR-TZA also specify that the oral and written information concerning the trial, including the ICF, should be easy to understand and presented without coercion or unduly influencing a potential participant to enroll in the clinical trial. The participant, and his/her legal representative(s) or guardian(s), should also be given adequate time to consider whether to participate.

As per the G-AppConductCT, none of the oral and written information concerning the research study, including the written ICF, should contain any language that causes the participant and/or his/her legal representative(s) and/or guardian(s) to waive or to appear to waive his/her legal rights, or that releases or appears to release the investigator(s), the institution, the sponsor, or their representatives from their liabilities for any negligence.

Research Involving the Community

The G-EthicsHR-TZA specifies that in circumstances where it is unfeasible to obtain individual participant informed consent, a community may choose to have a representative who will provide consent where a study is planned to take place. The representative should be selected in a manner that conforms to the community’s traditions and culture. The authenticity of the community approval may also need to be established. An individual’s refusal to participate in a trial must be respected regardless of the community’s consent.

Re-Consent

According to G-AppConductCT, any change in the ICF due to a protocol modification or an alteration in treatment modality, procedures, or site visits, should be approved by NatHREC and the TMDA prior to implementing any changes. The participant and/or his/her legal representative(s) or guardian(s) should also be informed in a timely manner if new information becomes available that may be relevant to the participant’s willingness to continue participation in the trial. The communication of this information should be documented.

Language Requirements

As stated in the G-AppConductCT, the ICF content should be presented in both English and Kiswahili, and all information to be given to participants, both oral and written, must be in both English Kiswahili.

Documenting Consent

The G-AppConductCT states that the participant and/or the participant’s legal representative(s) or guardian(s), and the person who conducted the informed consent discussion must sign and date the ICF. Where the participant is illiterate, and/or his/her legal representative(s) or guardian(s) is illiterate, verbal consent should be obtained in the presence of and countersigned by an impartial witness.

Before participating in the study, the participant should receive a copy of the signed and dated ICF, and any other written information provided during the informed consent process. The participant and/or his legal representative(s) or guardian(s) should also receive a copy of any updates to the signed and dated ICF, and copies of any amendments to the written information originally provided.

Waiver of Consent

Per the G-EthicsHR-TZA, in rare cases, exception from informed consent requirements may be considered by an institutional EC. Among the allowable situations, the institutional EC may approve a trial if it could not be reasonably carried out without a waiver of consent. See Special Circumstances/Emergencies section for additional information.

Based on the G-AppConductCT and the G-EthicsHR-TZA, the informed consent form (ICF) should include the following statements or descriptions, as applicable. (Note: The regulatory sources provide overlapping and unique elements so each of the items listed below will not necessarily be in each source.):

• The study purpose, procedures, and duration

• Approximate number of participants involved in the trial

• Experimental aspects of the study

• The participant’s responsibilities in participating in the trial

• Expected risks or discomforts to the participant, and when applicable, to an embryo, fetus, or nursing infant

• Disclosure of alternate procedures or treatments available to participants

• Clinical trial treatment schedule(s) and the probability for random assignment to each treatment

• Benefits or prorated payment to the participant or others reasonably expected from the research; if no benefit is expected, the participant should be made aware of this

• Compensation and/or treatment available for the participant in the case of trial-related injury

• Participation is voluntary, and that the participant can withdraw from the study at any time without penalty or loss of benefits, including medical treatment, to which the participant is otherwise entitled

• Extent to which confidentiality of records identifying the participant will be maintained, and the possibility of record access by the Tanzania Medicines and Medical Devices Authority (TMDA)

• The participant and/or his/her legal representative(s) or guardian(s) will be notified in a timely manner if significant new findings develop during the course of the study which may affect the participant's willingness to continue

• Individuals to contact for further information regarding the trial, the rights of trial participants, and whom to contact in the event of trial-related injury

• Foreseeable circumstances under which the investigator(s) may remove the participant without his/her consent

• Consequences of a participant’s decision to withdraw from the research, and procedures for orderly withdrawal by the participant

• The participant and/or his/her legal representative(s) or guardian(s) will be notified in a timely manner if significant new findings develop during the course of the study which may affect the participant's willingness to continue

• Additional costs to the participant that may result from participation in the research

See the Vulnerable Populations and Consent for Specimen sections for further information.

Overview

As stated in the G-AppConductCT and the G-EthicsHR-TZA, the Tanzanian government complies with the ethical principles set forth in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (TZA-13) and the Declaration of Helsinki (TZA-30) which promote respect for all human beings and safeguard the rights of research participants. A participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process. (See the Required Elements and Vulnerable Populations sections for additional information regarding requirements for participant rights.)

The Right to Participate, Abstain, or Withdraw

As set forth in the G-AppConductCT and the G-EthicsHR-TZA, the participant or his/her legal representative(s) or guardian(s) should be informed that participation is voluntary, that he/she may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.

The Right to Information

As delineated in the G-AppConductCT and the G-EthicsHR-TZA, a potential research participant and/or his/her legal representative(s) or guardian(s) has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation for participation or injury/treatment, and any significant new information regarding the research study. (See the Required Elements section for more detailed information regarding participant rights.)

The Right to Privacy and Confidentiality

As per the G-AppConductCT and the G-EthicsHR-TZA, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right.

The Right of Inquiry/Appeal

The G-AppConductCT states that the research participant and/or his/her legal representative(s) or guardian(s) should be provided with contact information for the sponsor and the investigator(s) to address trial-related inquiries. (See the Required Elements section for more detailed information regarding participant rights.)

The Right to Safety and Welfare

As specified in the G-AppConductCT and the CT-Regs, the Tanzanian government complies with TZA-13 principles that state a research participant’s right to safety and the protection of his/her health and welfare must take precedence over the interests of science and society.

As per the G-AppConductCT, in an emergency, if the signed informed consent form (ICF) cannot be obtained from the research participant, the consent of his/her legal representative(s) or guardian(s) should be obtained. If prior consent from the participant or his/her legal representative(s) or guardian(s) cannot be obtained, participant enrollment should require measures described in the protocol and/or elsewhere. Tanzania Medicines and Medical Devices Authority (TMDA) approval should also be obtained in order to protect the participant’s rights, safety, and well-being and to ensure compliance with the National Health Research Ethics Committee (NatHREC) and TMDA requirements. The participant or his/her legal representative(s) or guardian(s) should provide consent as soon as possible.

In addition, per the G-EthicsHR-TZA, in rare cases, such as an emergency, exception from informed consent requirements may be considered by an institutional ethics committee (EC). In this case, the institutional EC may approve a trial without requiring informed consent from participants provided that:

• The participant(s) are in a life-threatening situation, available treatments are unproven or unsatisfactory, and collecting valid scientific evidence is necessary to determine the safety and effectiveness of the particular intervention

• The participant will not be able to give informed consent as a result of a medical condition, the intervention under investigation must be administered before consent from the legal representative(s) or guardian(s) is feasible and there is no reasonable way to identify prospectively the participant likely to become eligible to participate in the trial

• Participation in the trial holds direct benefits for the participant

• The trial could not be reasonably carried out without the waiver

• The proposed trial activity plan defines the length of the potential therapeutic window based on scientific evidence, and the investigator is committed to attempting to contact a legal representative(s) or guardian(s) for consent within this prescribed window rather than proceeding without consent

• The institutional EC has reviewed and approved the informed consent procedures and approved the use of these procedures/documents for use with participant(s) or their legal representative(s) or guardian(s) where feasible, and, for use when providing an opportunity for a family member to object to the participant’s involvement in the trial

Please refer to the G-EthicsHR-TZA for detailed requirements to be complied with during emergency situations.

As delineated by the G-EthicsHR-TZA, informed consent can be waived by NatHREC and an institutional EC in circumstances where before the use of the investigational product (IP), both the investigator and the practicing physician, who is not otherwise participating in the trial, certify in writing the following:

• The participant is facing a life-threatening situation necessitating the use of the IP

• Informed consent cannot be obtained from the participant due to an inability to communicate with or obtain legally effective consent from the participant

• Time is insufficient to obtain consent from the legal representative(s) or guardian(s)

• No available approved alternative or generally recognized therapy exists that provides an equal or greater likelihood of saving the participant’s life

If the investigator determines that immediate use of the IP is required to preserve the participant’s life, and he/she does not have the time to obtain an independent determination by NatHREC or the institutional EC, the investigator must submit written documentation within five (5) working days to both an independent physician, who is not participating in the trial for review and evaluation, and to the institutional EC for review.

Overview

As per the G-AppConductCT and the G-EthicsHR-TZA, in all Tanzanian clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process. The G-AppConductCT characterizes vulnerable populations as those who are incapable of protecting their own interests due to a lack of autonomy, intelligence, education, resources, strength, or other necessary attributes, and have an increased likelihood of being wronged or of incurring additional harm during clinical trials. For example, this includes persons who are illiterate, marginalized by their social status or behavior, or living in an authoritarian environment. Vulnerable groups include individuals in hierarchical relationships, institutionalized persons, poor people and the unemployed, some ethnic and racial minorities, homeless persons, nomads, refugees or displaced persons, people living with disabilities, people with incurable or stigmatized conditions or diseases, and people faced with physical frailty.

As per the G-EthicsHR-TZA, trials involving vulnerable persons must meet the following requirements:

• Critical review by an ethics committee

• Expose the participants to no or minimal risk

• Is not contradictory to the participant’s interests

• Must be impossible to carry out research in participants with the capacity to consent

• Must be designed to have maximum benefit to others in this category of participants

See the Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired sections for additional information about these vulnerable populations.

Information on the other vulnerable populations specified in the G-EthicsHR-TZA is provided below.

Elderly Persons

As per the G-EthicsHR-TZA, it is important to exercise special care when involving the elderly who have been in the hospital or in a residential home for a long time because they may be more dependent on others for their care. Independent but caring observer(s) for the elderly must be fully informed about the study, and must ensure that the elderly participant understands the intended research activities prior to consent.

As per the G-AppConductCT, TZA-14 should be followed for clinical trials that involve:

• New investigational products that are likely to have significant use in the elderly
• New formulations and new combinations of established medicinal products when there is specific reason to expect that conditions common in the elderly are likely to be encountered and are not already dealt with in current labeling
• New formulation or new combination is likely to alter the geriatric patient’s response in a way different from previous formulations
• New uses that have significant potential applicability to the elderly

Students

The G-EthicsHR-TZA states that students involved with research studies are a vulnerable group, especially when the institution where they attend is conducting the research. Students should be permitted to withdraw from the study at any time without undue consequences. Students should also not be subject to any form of coercion, pressure, or financial inducement other than that proposed as a fee for participation.

The ChildAct states that a person less than 18 years of age should be known as a child. As per the G-AppConductCT and the G-EthicsHR-TZA, when the research participant is a child, the informed consent form (ICF) must be signed by the child’s legal representative(s) and/or guardian(s). However, according to the G-EthicsHR-TZA, all pediatric participants should be informed to the fullest extent possible about the study in language and terms that they are able to understand easily. In addition, when appropriate, the pediatric participants will be provided with additional information after participating in the trial.

The G-AppConductCT delineates that data on the appropriate use of investigational products (IPs) in the pediatric population should be generated unless its use in pediatric patients is clearly inappropriate. The pediatric development program should not delay completion of adult studies and availability of IPs for adults. The decision to proceed with a pediatric development program for an IP and the nature of that program should follow the requirements in TZA-12.

The G-EthicsHR-TZA state that a study may only be conducted on children with a legal representative and/or guardian if the following conditions are fulfilled:

• The approval/favorable opinion is obtained from the National Institute for Medical Research (NIMR)’s National Health Research Ethics Committee (NatHREC)

• The trial objectives cannot be met by selecting other participants who can give informed consent personally

• The foreseeable risks to the participants are low, or if the risk is greater than minimal, the trial presents the prospect of direct benefit to pediatric participants, or will yield generalizable knowledge about a pediatric disorder or condition

• The negative impact on the participants’ well-being is minimal

• The procedures should be first tested on consenting adults prior to being carried out in children

• The trial is not prohibited by law

Assent Requirements

Per the G-EthicsHR-TZA, when NatHREC determines that the child is capable of providing assent, the committee must verify that adequate provisions are made for soliciting the assent of the child based on his/her age, maturity, and psychological state.

NatHREC may determine that a child’s assent is unnecessary based on the following:

• His/her limited capacity to comprehend is so limited that he/she cannot be reasonably consulted

• The procedure will have a direct benefit to his/her health and well-being, and is available only by participating in the trial

Even if NatHREC determines that a child is capable of assent, the committee may still waive the assent requirement if:

• The trial involves no more than minimal risk

• The waiver will not adversely affect the research participant’s rights and welfare

• The trial could not be conducted without the waiver

The G-AppConductCT recommends that women of child-bearing potential be included at the earliest possible stages of clinical trial research so that potential sex-related differences are identified and taken into consideration when planning Phase III trials. The timing of including women of childbearing potential or pregnant women in clinical trials should comply with guidance in TZA-15. Any research involving pregnant women should be individualized and based on a careful risk/benefit assessment, considering:

• The nature and severity of the disease
• The availability and results of previous nonclinical and clinical data
• The availability of alternative therapy and knowledge about their risks
• The stage of pregnancy in relation to the overall development of the fetus, especially regarding fetal brain development
• The potential for harm to the woman, the fetus, or child
• The long-term follow up of the pregnancy, fetus, and child, when possible

Additional considerations for including pregnant women in clinical trials are provided in the G-AppConductCT.

The G-AppConductCT identifies the following considerations for deciding whether to include breastfeeding women in clinical trials:

• A new indication is being sought for an approved therapeutic product and there is evidence of use or anticipated use by breastfeeding women
• After market authorization, use of a therapeutic product in breastfeeding women becomes evident
• There is concern that the consequences of uninformed dosages for use while breastfeeding are potentially serious and/or severe
• A therapeutic product is under review for market authorization and is expected to be used by women of reproductive age
• The trial involves marketed medications that are commonly used by women of reproductive age
• The risk to the infant or mother is not greater than that from established procedures routinely used during breastfeeding, is comparable to those being studied, and the purpose of the research is the development of biomedical knowledge which cannot be obtained by any other means

As per the G-EthicsHR-TZA, any research studies involving pregnant women, women who may become pregnant, or fetuses, requires additional safeguards to ensure the research conforms to appropriate ethical standards and upholds societal values. The following conditions are required for the research to take place:

• Should only be carried out if the pregnancy plays an essential role in the proposed research

• Appropriate studies on animals and non-pregnant women have been completed

• The risk to the fetus is primarily due to interventions or procedures that have the greatest potential to directly benefit the woman or the fetus; or, if there is no such prospect of benefit, the risk to the fetus is not greater than minimal, and the purpose of the research is to develop important biomedical knowledge which cannot be obtained by any other means

• Any risk is the least possible for achieving the research objectives

• Each individual providing consent is fully informed about the reasonably foreseeable impact of the research on the fetus or neonate

• No inducements, monetary or otherwise, should be offered to terminate a pregnancy

• Individuals engaged in the research will have no part in any decisions as to the timing, method, or procedures used to terminate a pregnancy

• Individuals engaged in the research will have part in determining the viability of a neonate

For all studies involving pregnant women, fetuses in utero, and fetuses ex utero, the mother and father must be both legally competent and have been fully informed of the possible impact on the fetus, and have given their informed consent to proceed. However, the father’s consent will not be required if the purpose of the study is primarily to meet the mother’s health needs, the father’s identity or whereabouts are unknown, the father is not reasonably available, or the pregnancy resulted from rape or incest.

See section 3.11 of the G-EthicsHR-TZA for additional details on pregnant women and fetuses.

According to the G-EthicsHR-TZA, prisoners are considered vulnerable because incarceration could affect their ability to make a voluntary decision regarding participation in research. A research study involving prisoners should ensure that:

• The research results will benefit the study population in the same category

• The prisoners must be assured that they will not be subject to undue pressure or coercion in their decision to participate, and that their willingness or refusal to participate will not impact any decisions regarding their release or further detention

The G-EthicsHR-TZA defines “mentally disordered persons” as including the mentally ill, mentally handicapped, demented, and the unconscious. The ethics committee must approve the participation of research participants who are incompetent or mentally incapable of giving consent, and sufficient justification must be provided for involving this population in a study.

A research study may involve mentally impaired persons or those with learning disabilities under the following conditions:

• The study carries no or minimal risk

• The research may potentially benefit this category of participants and is in their best interests

• The research may potentially benefit others in the same category

For research on mentally ill persons, apart from patients suffering from severe conditions such as dementia, most patients will be able to give consent to therapeutic trials. Non-therapeutic trial should not be carried out on mentally ill persons.

As delineated in the G-AppConductCT, an investigational medicinal product is defined as a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial. This includes:

• A product with a marketing authorization when it is used or assembled (formulated or packaged) in a different way from the approved form
• When used for an unapproved indication
• When used to gain further information about an approved use

Manufacturing

According to the G-AppConductCT, the TMMDAct, and the CT-Regs, the Tanzania Medicines and Medical Devices Authority (TMDA) is responsible for authorizing the manufacture of investigational products (IPs) in Tanzania. The TMDA will approve the manufacture of an IP after the clinical trial application has been approved.

Import

Per the G-AppConductCT, the TMMDAct, the CT-Regs, and the TFDCA-ImptExpt, the TMDA is also responsible for authorizing the import of IPs. As per the TMMDAct and the TFDCA-ImptExpt, the sponsor or the principal investigator (PI) may apply for an import license once the clinical trial application has been approved by the TMDA. Importation of raw or packaging materials is restricted to pharmaceutical manufacturers.

The TFDCA-ImptExpt specifies that in order to be granted an import license, the applicant must:

• Have a pharmacist registered by the Pharmacy Council who must be a Superintendent of the business
• Have premises registered by the TMDA
• Hold a valid business permit

The import license application should be accompanied by the clinical trial approval letter issued by the TMDA. The applicant must fill out the Application for Importation of Pharmaceutical Products provided in the First Schedule of the TFDCA-ImptExpt and pay the fee pursuant to the TMMDAFees. In addition, the application should be accompanied by the three (3) copies of the proforma invoice numbered and dated, and signed by the superintendent of the business. (A proforma invoice is an abridged or estimated invoice sent in advance of a shipment or delivery of goods.) The proforma invoice should include the following:

• Name and address of the supplier
• Name and address of the manufacturer of each product
• Trade or proprietary name of each product
• The international nonproprietary name (generic name) of the drug and its strength
• In the case of the product containing more than one (1) active ingredient, the name and strength of each product
• The pharmacopoeia specification of the ingredient of each product
• Product registration number issued by the authority for each product
• The quantity, pack size, unit value, and total value in convertible currency
• Batch or lot number where applicable for each product
• Manufacturing and expiration date, where applicable, for each product
• Mode of shipment (sea, air, or road)
• Authorized port of entry
• Signature and stamp of the supplier

Per TZA-34, the import license application can be submitted to the TMDA via the Regulatory Information Management System (RIMS) Customer Self Service Portal (TZA-34), which can be accessed by first creating a trader account. A registration form is also available in TZA-6 and can be sent to TMDA at P.O Box 77150, Dar es Salaam, Tanzania or emailed to info@tfda.go.tz.

As delineated in the TFDCA-ImptExpt, the import permit is valid for six (6) months, not transferable, and issued to cover only one (1) shipment. In the case of partial shipments, three (3) shipments may be allowed based on the initial import permit. See the TFDCA-ImptExpt for detailed import application requirements.

The TFDCA-ImptExpt identifies the authorized ports of entry for pharmaceutical products imported into Tanzania. An importer must provide all necessary documents as may, from time to time, be requested by the inspector. When it is deemed necessary to collect samples or where the inspector suspects that any product may contravene any regulation or law, he/she may take samples for further investigation.

Investigator’s Brochure

In accordance with the G-AppConductCT and the CT-Regs, the Tanzanian government follows the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (TZA-13), and requires the sponsor or his/her designated contract research organization (CRO) to provide investigators with an Investigator’s Brochure (IB). The G-AppConductCT and TZA-13 specify that the IB must contain all of the relevant information on the investigational product(s) (IPs) obtained through the earlier research phases, including preclinical, toxicological, safety, efficacy, and adverse event data. Per the CT-Regs, the sponsor should also update the IB as significant new information becomes available and maintain records of each change.

TZA-13 requires the IB to provide coverage of the following areas:

• Physical, chemical, and pharmaceutical properties and formulation parameters
• Non-clinical studies (pharmacology, pharmacokinetics, toxicology, and metabolism profiles)
• Effects of IP in humans (pharmacology, pharmacokinetics, metabolism, and pharmacodynamics; safety and efficacy; regulatory and post marketing experiences)
• Summary of data and guidance for the investigator(s)
• Bibliography

See Section 7.3 of TZA-13 for detailed content guidelines.

The sponsor is also accountable for supplying the IP, including the comparator(s) and placebo, if applicable. As specified in the CT-Regs, the sponsor must ensure that the products are manufactured in accordance with the current codes of Good Manufacturing Practice (GMP). (See the Product Management section for additional information on IP supply, storage, and handling requirements).

Quality Documentation

As stated in the Manufacturing & Import section, the Tanzania Medicines and Medical Devices Authority (TMDA) requires the importer to provide documentation and/or samples as requested by the customs inspector.

Investigational product (IP) labeling in Tanzania must comply with the requirements set forth in the TFDCA-ImptExpt and the CT-Regs. The TFDCA-ImptExpt and the CT-Regs state that for an IP to be used in a clinical trial, it must be properly labeled in English or Kiswahili (also known as Swahili) language or both, and the information printed on the labels must be indelible, engraved, or embossed on a primary and secondary container.

As set forth in the TFDCA-ImptExpt and the CT-Regs, the following information must be included on the label:

• Statement indicating that the product is for “clinical trial purpose only”

• Name, number, or identifying mark

• Recommended storage conditions

• Sponsor name and address

• Protocol code or identification

• Trade or brand name where appropriate

• International Non-Proprietary Name (INN, Generic name)

• Active ingredient quantities listed in the formulation

• Manufacture and expiration dates

• Batch or lot number

• Storage conditions

• Manufacturer name and address

• Product registration number issued by the Tanzania Medicines and Medical Devices Authority (TMDA) included in the outer and inner packaging, where applicable

• Immediate outer packaging and the enclosed and accompanying literature must be in English or Kiswahili

• Active pharmaceutical ingredient specification (BP, USP, etc.)

According to the CT-Regs, where applicable, investigational medicinal products must be labeled in the manner that protects the blinding. Also, re-labelling of any remaining investigational medicinal product from previously manufactured batches must be performed in accordance with established written procedures and Good Manufacturing Practice principles.

Supply, Storage, and Handling Requirements

As defined in the G-AppConductCT, the sponsor, his/her designated contract research organization (CRO), or the principal investigator (PI) must also supply the investigator(s)/institution(s) with the investigational product(s) (IPs), including the comparator(s) and placebo, if applicable. The sponsor, his/her designated CRO, or the PI should not supply either party with the IP(s) until he/she obtains approval from the Tanzania Medicines and Medical Devices Authority (TMDA) and the National Institute for Medical Research (NIMR)’s National Health Research Ethics Committee (NatHREC).

The G-AppConductCT and the CT-Regs, specify that the sponsor, his/her designated CRO, or the PI must ensure the following:

• IP product quality and stability over the period of use
• IP manufactured according to any applicable Good Manufacturing Practices (GMPs)
• Proper coding, packaging, and labeling of the IP(s)
• Records maintained for document shipment of the IP(s)
• Acceptable IP handling and storage conditions and shelf-life

The TFDCA-ImptExpt requires that every importer or exporter of a pharmaceutical product must, in respect to his premises, make available the following information to the TMDA: an appropriate inventory control system; inspection reports file; complaints handling procedures; and unfit medicines, controlled drugs, recall, and customer registers. Further, an importer should maintain the following documents on the premises for a period of not less than one (1) year after the expiration date of the pharmaceutical product: final invoices with corresponding import permits; copies of delivery notes; and sales invoices.

Refer to the G-AppConductCT, the TFDCA-ImptExpt, and the CT-Regs, for detailed sponsor-related IP requirements.

Record Requirements

As set forth in the G-AppConductCT, which complies with the IP recordkeeping requirements delineated in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (TZA-13), the sponsor must ensure maintenance of the following:

• Records documenting IP(s) handling, storage, shipment, receipt, disposition, return, and destruction
• A system for retrieving IPs and documenting this retrieval
• A system to dispose of unused IP(s) and corresponding documentation
• Sufficient quantities of the IP(s) used in the trial to reconfirm specifications, should this become necessary, and maintenance of records of batch samples analyses and characteristics

As per the CT-Regs and TZA-13, the sponsor should inform the investigator(s) and institution(s) in writing of the need for record retention and should notify the investigator(s) and institution(s) in writing when the trial related records are no longer needed. All sponsor-specific essential documents used in the trial should be retained for at least two (2) years after formal discontinuation of the trial, or the last approval of a marketing application. The CT-Regs states that the investigator and the sponsor must retain all trial-related records, documents and information at the trial site for a period not less than 20 years following the trial’s completion. See the CT-Regs for detailed record retention requirements.