Clinical research in Malawi is regulated and overseen by the Pharmacy and Medicines Regulatory Authority (PMRA) and the National Commission for Science and Technology (NCST).

Pharmacy and Medicines Regulatory Authority

As per the PMRAAct, the PMRA is the regulatory authority responsible for clinical trial approvals, oversight, and inspections in Malawi. MWI-47 indicates that in accordance with the PMRAAct, the PMRA replaced the Pharmacy, Medicines and Poisons Board (PMPB) in 2019. (Note: ClinRegs will continue to reference PMPB documents when this name is still used in website and regulatory material. New PMRA regulations will be incorporated into the Malawi profile as they become available.)

According to the PMRAAct, the Ministry of Health (MOH) established and manages the PMRA, which is overseen by the Minister of Health. The MOH grants authority to PMRA to monitor the registration and quality of drugs in Malawi. Further, per MWI-45, the PMRA’s registration department registers clinical trials; issues import permits; conducts pharmacovigilance; and registers medicinal products and pharmacy personnel and businesses. The PMRAAct indicates that the PMRA is composed of part-time members appointed by the Minister. See MWI-49 for a list of the current PMRA Board of Directors.

The G-CTARevVacBiol and the G-CTAProcsVacBiol specify that the PMRA must appoint a Clinical Trial Review Committee (CTRC) to review clinical trial applications and make recommendations. Per MWI-34, the guidance in the G-CTARevVacBiol and the G-CTAProcsVacBiol also apply to clinical trials of drugs.

Please note: Malawi is party to the Nagoya Protocol on Access and Benefit-sharing (MWI-3), which may have implications for studies of investigational products developed using certain non-human genetic resources (e.g., plants, animals, and microbes). For more information, see MWI-35.

National Commission for Science and Technology

The SciTechAct and MWI-24 indicate that the NCST appraises, reviews, monitors, and evaluates priority research and development programs, plans, and projects of research and development institutions. The NCST also encourages the use of local expertise in science and technology matters via a set of professional standards, ethics, and guidelines.

Per MWI-26, research conducted in Malawi is approved through the NCST’s established and recognized research ethics committees (ECs), which include the National Health Sciences Research Committee (NHSRC) and the College of Medicine Research and Ethics Committee (COMREC).

For detailed information on the NCST composition and responsibilities, see the SciTechAct, MWI-24, MWI-26, MWI-37, and MWI-38.

Contact Information

Pharmacy and Medicines Regulatory Authority

As per MWI-46, the PMRA contact information is as follows:

Postal Address:
Pharmacy and Medicines Regulatory Authority
P.O Box 30241
Lilongwe, Area 5, Malawi

Physical Address:
Off Paul Kagame Road
Next to MRA Offices
Area 5, Lilongwe

Phone: +265 212 755 165 or +265 212 750 108
Email: info@pmra.mw

National Commission for Science and Technology

Per MWI-57, the NCST contact information is as follows:

Mailing Address:
National Commission for Science and Technology
1st Floor Lingadzi House, Robert Mugabe Crescent
Private Bag B303
Lilongwe 3, Malawi

Phone: +265 1 771 550
Email: infor@ncst.mw

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 and TZA-4, 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

As described in TZA-2, TMDA’s Clinical Trials Control and Pharmacovigilance (CTPV) section is under the Directorate of Human and Veterinary Medicines, and is responsible for the regulation of clinical trials, pharmacovigilance, and post-marketing surveillance. The regulation of clinical trials mainly includes authorization of clinical trials and good clinical practice (GCP) inspection of investigator sites. See the Scope of Assessment section for additional details.

The PV-Regs 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

Other Considerations

Per TZA-9, Tanzania has adopted several clinical trial related guidelines of the International Council for Harmonisation (ICH) of Technical Requirements for Pharmaceuticals for Human Use including the ICH Guideline for Good Clinical Practice E6(R2) (TZA-13). See TZA-9 for a listing of the adopted guidelines.

Tanzania Commission for Science and Technology

According to TZA-45 and TZA-16, 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 (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• 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
• Defining national resource priorities and research guidelines
• Communicating research results
• Providing technical support to institutions related to ethics and monitoring implementation of research and innovative activities

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 and TZA-47, COSTECH’s contact information is as follows:

Tanzania Commission for Science and Technology
Ali Hassan Mwinyi Road, Kijitonyama (Sayansi) COSTECH Building
Dar es Salaam, Tanzania

Email: info@costech.or.tz
Research Clearance Email: rclearance@costech.or.tz

Overview

In accordance with the PMRAAct, the Pharmacy and Medicines Regulatory Authority (PMRA) is responsible for reviewing and approving clinical trial applications for new drugs, generic drugs, and imported drugs to be registered in Malawi. The PMRA has replaced the Pharmacy, Medicines and Poisons Board (PMPB). (Note: ClinRegs will continue to reference PMPB documents when this name is still used in website and regulatory material. New PMRA regulations will be incorporated into the Malawi profile as they become available.)

The R-HlthResCoord indicates that before submitting a clinical trial application to the PMRA, the sponsor or principal investigator (PI) must obtain full ethical approval from either of the two (2) National Commission for Science and Technology (NCST)-approved ethics committees (ECs)—the National Health Sciences Research Committee (NHSRC) or the College of Medicine Research and Ethics Committee (COMREC). Parallel submissions of a clinical trial application to an EC and the PMRA are prohibited.

Clinical Trial Review Process

According to MWI-50, the PMRA receives clinical trial applications through the office of the Director General, and the applicant must submit evidence of ethical clearance from either the NHSRC or COMREC.

Per MWI-34, the guidance in the G-CTARevVacBiol and the G-CTAProcsVacBiol also apply to clinical trials of drugs. The G-CTARevVacBiol and the G-CTAProcsVacBiol indicate that upon receipt of a clinical trial application, the PMRA initially screens the application for completeness and assigns a PMRA reference number to the application. According to the G-CTARevVacBiol, the result of the screening will be communicated, and the screening form will be forwarded by fax, to the applicant. The applicant will forward any outstanding documents to the PMRA. The PMRA’s technical staff then reviews the application or may forward it to an expert, or to an evaluator for scientific review.

The G-CTAProcsVacBiol specifies that the application is evaluated by three (3) PMRA-appointed expert clinical trial reviewers who will provide a written report to the designated registration office, also known as the “Focal Point” division. The Focal Point will then collate and present the expert reviews to the PMRA Clinical Trial Review Committee (CTRC). The CTRC then reviews all the available documentation and provides a recommendation for approval or rejection. The PMRA considers the CTRC’s recommendation and issues a written approval or rejection.

MWI-50 further specifies that the PMRA may grant full or conditional approval depending on the nature of the CTRC’s findings. Depending on the study’s risk profile, the PMRA may conduct post-authorization good clinical practice (GCP) inspections for select clinical trials. Per the G-CTARevVacBiol, if the application is neither approved nor rejected, the PMRA’s technical staff will communicate its recommendation to the applicant. The response from the applicant will be considered at the PMRA’s subsequent scheduled meeting, and the subsequent decision will be communicated to the applicant. If changes must be made to the protocol, investigator’s brochure, or any other document, the amended document should be submitted with the applicant’s response.

The G-CTAProcsVacBiol states that the applicant may appeal a rejection decision, providing additional information, or amending the application to meet the PMRA’s requirements. The appeal will be referred to the CTRC for a final recommendation to the PMRA.

(See the Submission Process and Timeline of Review sections for details on the administrative and technical processing and review timelines. See also the G-CTARevVacBiol and the G-CTAProcsVacBiol for more information on the PMRA’s review procedures.)

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 and TZA-4, 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.

As described in TZA-2, TMDA’s Clinical Trials Control and Pharmacovigilance (CTPV) section is responsible for the regulation of clinical trials, pharmacovigilance, and post-marketing surveillance. Its functions include the following:

• Review and assess applications to conduct clinical trials in Tanzania, including evaluating clinical trial protocols, including preclinical studies, clinical data, and quality of investigational products (IPs)
• Approve clinical trial applications with minimum requirements
• Inspect clinical trial sites to ensure compliance with good clinical practices (GCPs), good clinical laboratory practices (GCLPs), clinical trials regulations, guidelines, standard operating procedures (SOPs), and internationally accepted standards
• Update and maintain the Tanzania Clinical Trials Registry, which is accessed via the Regulatory Information Management System (RIMS) Customer Self Service Portal (TZA-34)
• Review and evaluate all safety information (adverse events) from clinical trials
• Review and evaluate progress reports of all approved clinical trials
• Serve as Secretariat to Tanzania’s Clinical Trials Technical Committee
• Monitor and respond to all inquiries regarding conduct of clinical trials in Tanzania

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.) TZA-4 indicates that the TMDA may request a clarification or additional documents through the online submission system (TZA-34). The assessment will resume once the applicant has provided clarification and responded to the queries.

Per the G-AppConductCT, the TMDA reviews clinical trial applications and amendments to assess the quality of the products and determine that the use of the IP for the purposes of the clinical trial does not endanger the health of participants or other persons, the clinical trial is not contrary to the best interests of a participant, and the objectives of the clinical trial may be achieved. Evaluation of applications is conducted on a first-in, first-out basis unless the IP meets the fast-track criteria. The application assessment must involve the TMDA and external evaluators. If the TMDA requests additional information from the applicant, the evaluation process will stop until the TMDA receives a written response to the query. The response should be submitted within six (6) months after being issued with a query letter. All queries issued in the same letter must be submitted together in one (1) transaction. Non-compliance to these requirements in content and format will lead to rejection of the clinical trial. Evaluation of applications will be completed within 60 working days of receiving the application. A new clinical trial application may be fast tracked and assessed within 30 working days of its submission if the applicant has requested this and paid twice the prescribed clinical trials application fees.

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, the 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 trial duration; 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.

The G-AppConductCT indicates that the TMDA must not authorize a clinical trial where it finds that:

• The information and documents as set out in the guidelines have not been provided
• The application contains false or misleading information
• The information provided is insufficient to enable the TMDA to assess the safety and risks of the IP or clinical trial
• Queries raised by the TMDA in relation to the application were not adequately responded to
• The applicant has not submitted an ethical clearance from any approved medical research institute
• The use of the IP for the purposes of the clinical trial endangers the health of a clinical trial participant or any other person
• The objectives of the clinical trial will not be achieved
• It is not in the public interest to authorize the clinical trial
• Any other reasonable grounds as may be determined by the TMDA

Next, the G-AppConductCT states that following the TMDA’s authorization of a new clinical trial or amendment, information regarding refusals by other regulatory authorities or ECs should be submitted as a notification. Further, the TMDA may suspend, terminate, or withdraw authorization of a clinical trial if it finds that the conditions of authorization of a trial have been violated; or there is information raising doubts about the safety or scientific validity of the trial or the conduct of the trial at a particular trial site. For additional information, see TZA-4.

(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 application; 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 for 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.

Pharmacy and Medicines Regulatory Authority

According to the PMRAAct, a person who intends to conduct a clinical trial must apply to the Pharmacy and Medicines Regulatory Authority (PMRA) for a clinical trial certificate upon payment of the prescribed fee.

Per the PMRAFeesRegs, the following fees apply to clinical trials:

• Application, review, and registration: 5% of total budget
• Annual renewal: $2,200 USD
• Amendments: $300 USD

As delineated in the PMRAFeesRegs, a fee equaling 6% of the total invoice value must also be paid for the importation of unregistered medicines or allied substances from authorized sources.

Payment Instructions

As stated in MWI-29, either of the below accounts may be used to pay for any service at the PMRA:

Bank Name: National Bank of Malawi
Account Number: 1007551955
Account Name: Pharmacy and Medicines Regulatory Authority
Branch: Capital City

Bank Name: Standard Bank
Account Number: 9100002325559
Account Name: Pharmacy and Medicines Regulatory Authority
Branch: Capital City

National Commission for Science and Technology

No information is available regarding fees for the National Commission for Science and Technology (NCST).

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 the 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.

TZA-4 indicates that the banks accounts are linked to Government Electronic Payment Gateway (GEPG) payments as follows:

• Name: GEPG TMDA Collection Account (USD), Bank: NMB Revenue Bank, Account No: 20810015291, Branch University
• Name: GEPG TMDA Collection Account (USD), Bank: NBC USD, Account No: 040105002468, Branch: UDSM
• Name: GEPG TMDA Collection Account (USD), Bank: CRDB Bank US, Account No: 0250021399100, Branch: Holland House

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:

Account name or beneficiary: Tanzania Commission for Science and Technology

Bank Name: National Bank of Commerce Ltd
Branch: Samora Avenue, P.O. Box 9002, Dar es Salaam, Tanzania
Account Number: 012105018998
Account Currency: US Dollars
Swift Number/Code: NLCBTZTX

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

Overview

Malawi has a centralized registration process for ethics committees (ECs) and EC review. As mandated by the SciTechAct, the National Commission for Science and Technology (NCST) is the governmental body responsible for EC oversight, and for the promotion and coordination of research in Malawi.

As per the G-NHSRC, the G-COMREC, MWI-5, and MWI-50, the National Health Sciences Research Committee (NHSRC) and the College of Medicine Research and Ethics Committee (COMREC) are the two (2) NCST-approved ECs responsible for monitoring and evaluating health research studies involving humans. The G-HlthResConduct and the R-HlthResCoord indicate that COMREC, as a subsidiary of the NHSRC, only reviews and approves studies involving or originating from College of Medicine (COM) or Kamuzu College of Nursing (KCN) (now known collectively as the Kamuzu University of Health Sciences (KUHeS), per MWI-62) faculty members and students, and their collaborators/coinvestigators/affiliates. The NHSRC has the sole jurisdiction to review studies with a national interest and multicenter studies, including those from COM and KCN, as well as studies from all other researchers and institutions. Per the R-HlthResCoord, each EC has members representing the other committee in order to facilitate the transfer of information between the ECs. The NHSRC and COMREC report to and are centrally monitored by the NCST.

MWI-25 indicates that as of July 2023, COMREC is operating under KUHeS and will be changing its name to Kamuzu University of Health Sciences Research Committee (KUREC), following approval from the NCST. The COMREC guidance and forms provided in the Malawi profile are still being used.

Ethics Committee Composition

National Health Sciences Research Committee

As per the G-NHSRC, NHSRC must consist of members with varying backgrounds, including the social sciences, to promote complete and adequate research proposal review. The committee should include one (1) lay person, as well as members from the following organizations:

• National Research Council of Malawi (one (1) member)
• Ministry of Health (MOH) headquarters (two (2) members)
• COMREC (two (2) members)
• Community Health Sciences Unit (one (1) member)
• National AIDS Commission (one (1) member)
• Center for Social Research (one (1) member)
• Queen Elizabeth Central Hospital (one (1) member)
• Zomba Central Hospital (one (1) member)
• Lilongwe Central Hospital (one (1) member)
• Christian Health Association of Malawi (one (1) member)
• Mzuzu University (one (1) member)
• Mzuzu Central Hospital (one (1) member)
• Nurses and Midwives Council of Malawi (one (1) member)
• Ministry of Justice (one (1) member)

The members elect the chairperson and the vice-chairperson.

College of Medicine Research and Ethics Committee

The G-COMREC specifies that COMREC should be multidisciplinary, and its members must have the basic qualifications, experience, and expertise to conduct fair scientific and ethical proposal reviews. The committee must have a maximum membership of 15, and include representatives from the biomedical sciences, research methods, behavioral science, and research ethics areas. Additionally, there must also be representatives from the NCST, the NHSRC, the KCN, and the lay community.

Furthermore, the committee must be diverse, have balanced gender representation, and embody community interests and concerns. Members are also required to sign a confidentiality agreement and refuse projects in which they have a conflict of interest. Members from the COM staff serving on the committee must be a minimum grade of senior lecturer, and preferably have peer reviewed publications.

See the G-NHSRC and the G-COMREC for additional EC membership criteria and qualification requirements.

Terms of Reference, Review Procedures, and Meeting Schedule

National Health Sciences Research Committee

The G-NHSRC states that the MOH’s Research Unit serves as a secretariat for NHSRC, and is responsible for preparing materials and meeting logistics. Research proposals must be distributed to NHSRC members two (2) weeks before the scheduled meetings to allow members time to adequately review the submitted proposals. Half of the NHSRC’s membership constitutes a quorum of any meeting, and the meeting is rescheduled within the following two (2) weeks if a quorum is not reached. Half of the ordinary quorum forms a quorum for the rescheduled meeting if no ordinary quorum is reached. Otherwise, the meeting must be rescheduled.

As delineated by the G-NHSRC, NHSRC decisions are reached by consensus. If there is no consensus, a decision is made by simple majority of members present through an open ballot. In the event of a tie, the chairperson casts a vote.

According to the G-NHSRC, when new NHSRC members have been appointed, they may attend the first one (1) or two (2) meetings as an observer in order to learn about the workings of the NHSRC before being assigned reviewer responsibility. Such members will undergo NHSRC orientation sessions covering guidelines and standard operating procedures (SOPs) of the committee and any practical matters with the secretariat and chairperson. Continuing education for all members in matters of health research ethics and related disciplines in human research protections is also essential, and the chairperson is responsible for fostering local and international networks, links, and partnerships for the purposes of continuing the NHSRC’s education and development.

Per the G-NHSRC, NHSRC members must serve on the committee for three (3) years and are required to renew their appointments if requested by their organizations. The G-NHSRC and the G-HlthResConduct also indicate that the NHSRC meets once every two (2) months.

College of Medicine Research and Ethics Committee

COMREC requires written SOPs to be maintained, and all relevant records (e.g., SOPs, reports, curriculum vitaes (CVs), meeting minutes, and correspondence) to be archived for three (3) years following the study’s completion, as delineated in the G-COMREC. The COMREC secretariat must compile all the relevant documents and materials required for review of a proposal and circulate them to the members at least 14 days before the date of the scheduled meeting. Quorum of any meeting is achieved when a majority of the members attend. The quorum should preferably include members of both genders, a member whose primary area of expertise is in a non-scientific area, and at least one (1) member who is independent of the COM. If the quorum cannot be achieved, the meeting must be rescheduled within two (2) weeks of the failed meeting. If the subsequent meeting does not achieve quorum, then the chairperson must make a decision based on the expertise and number of members present.

The G-COMREC further states that COMREC’s final decision will be reached through a consensus. If there is no consensus, a decision is made through a majority vote.

Per the G-COMREC, COMREC members must receive initial and continuing training regarding the ethics and science of research. The appointment of committee members is valid for three (3) years, and a member may be reappointed to serve another three (3) year term. According to the G-COMREC and the G-HlthResConduct, COMREC meets every month.

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, NatHREC-Charter, TZA-5, 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, controlling, coordinating, evaluating, and promoting health research in Tanzania or elsewhere on behalf of or for the benefit of 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 the NatHREC.

As delineated in NatHREC-Charter, NatHREC provides ethical review and clearance of health research protocols and monitors and evaluates research studies. In addition, NatHREC conducts the following activities:

• Receiving and registering all health research carried out in Tanzania
• Ensuring that all health research protocols are thoroughly reviewed to safeguard the dignity, rights, safety, and well-being of research participants
• Advising researchers on the risks and responsibilities of conducting research
• Recommending to the MRCC for ethics clearance approval, all health research protocols that have complied with the country’s ethics regulations and guidelines
• Monitoring and coordinating all approved health research conducted in Tanzania
• Advocating for and overseeing all issues pertaining to health research data and material sharing and/or transfer
• Supporting health research institutions in Tanzania to establish institutional ECs or Institutional Review Boards (IRBs)
• Accrediting health research institutions’ ECs

Per the G-AppConductCT, G-EthicsHR-TZA, the G-ResearchIntegrity, the G-RevPrtcl, 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, approval must still be obtained from the NatHREC. For all health research involving foreign collaborators, the applicant must get both the institutional EC and NatHREC’s ethical approval. TZA-5 states that both institutional ECs and NatHREC review and approval are also required for clinical trials, research dealing with vulnerable, special, or marginalized groups, sensitive topics, or indigenous communities. The NatHREC-Charter indicates that institutional and zonal ECs complement NatHREC’s function of issuing institutional ethics clearance certificates and monitoring the approved research at their institutions. According to TZA-18, not all human participant research requires review and approval at the national level, and consequently, institutional ethics review is complementary to NatHREC’s national-level review.

The G-EthicsHR-TZA further states that institutional ECs should monitor their hosted research activities to ensure compliance. Institutional ECs may function at the institutional, zonal, or national levels. ECs act as independent reviewers of any proposed study on human research participants, to ensure ethical conduct of research, and that participant’s rights and welfare are not violated. The major responsibility of ECs is to safeguard the rights, safety, and well-being of research participants. See the Oversight of Ethics Committees section for information on the registration and accreditation of ECs by NatHREC.

Ethics Committee Composition

National Health Research Ethics Committee

Per the G-EthicsHR-TZA and TZA-5, the Director General of NIMR is responsible for appointing NatHREC members. Members are selected based on their capacity, interest, ethical and scientific knowledge, and expertise, as well as their commitment and willingness to volunteer the necessary time and effort for the NatHREC’s work. NatHREC must consist of not less than nine (9) and up to 15 members with the relevant qualifications and experience to review and evaluate the science, medical, and ethical aspects of health research protocols. In addition, NatHREC must be composed of members with varying backgrounds to promote a complete and adequate review of health research protocols commonly received by the NatHREC. Per TZA-5, committee members must include medical scientists, biomedical scientists, social scientists, legal representatives, unaffiliated community representatives, representatives of religious or faith-based organizations, a representative from the President’s Office-Regional Administration and Local Government (PO-RALG), and a representative from the Tanzania Ministry of Health. The Director General may appoint additional members depending on the need for expertise and/or representation and not exceeding the maximum number of members. See TZA-5 for additional information on NatHREC’s standard operating procedures (SOPs).

Per the G-TMRCC, the 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, institutional ECs must have members capable of providing a competent and thorough review of research protocols. Membership typically includes physicians, scientists, laboratory experts, nurses, lawyers, ethicists, and other professionals. In addition, the above membership also includes community members or representatives of patients’ groups who can represent the cultural and moral values of study participants. When a proposed study involves vulnerable individuals or groups, as may be the case in research involving prisoners or illiterate persons, representatives of relevant advocacy groups should be invited to meetings where such protocols will be reviewed. Regular rotation of members is desirable for balancing the advantage of experience with that of fresh perspectives. In addition, each institutional EC must include at least one (1) member who is not affiliated with the institution and is not part of the immediate family of a person who is affiliated with the institution. Further, an EC may invite individuals with competence in particular areas to assist in the review of issues, which require expertise beyond, or in addition to that available in the EC; these individuals do not vote with the EC.

Per IERC-Accredit, following are the membership requirements for ECs accredited with NIMR:

• The Chairperson must have adequate experience in health research, leadership, and have basic knowledge of bioethics
• An EC must comprise at least five (5) members or more, and the total must be an odd number
• At least one-third of the members of the EC must be of either gender
• At least one (1) member should come from outside the institution
• At least two (2) members should have research expertise and experience, and one (1) of these should be in the health field
• At least one (1) member should represent a lay group
• For ECs reviewing clinical research, the committee should have representation from medicine, laboratory, pharmacy, and nursing as needed; a clinician who is active in clinical practice (with a valid practicing license) or in clinical research is mandatory
• At least one (1) member of the EC should possess knowledge and understanding of Tanzanian law
• Where an EC has been formed to serve more than one (1) institution, the institution hosting the Secretariat is responsible for the functioning of the EC in all aspects
• Where multiple institutions are involved in one (1) EC, the appointing authority must make appointments in consultation with the relevant heads of the respective institutions

The G-ResearchIntegrity recommends that composition should not only be multi-disciplinary and multi-sector but should also balance scientific expertise, age, and gender distribution, and should have a non-technical member representing community interests. The institution should determine the type of members needed and establish procedures for selecting/appointing members and number of persons. It is recommended that ECs have seven (7) to 15 members. See the G-ResearchIntegrity and TZA-23 for additional recommendations.

Terms of Reference, Review Procedures, and Meeting Schedule

National Health Research Ethics Committee

The G-TMRCC and TZA-5 state that the NatHREC must operate within written standard operating procedures (SOPs), including a process to be followed for conducting reviews. The G-TMRCC states that 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. Per TZA-5, the SOPs facilitate and support ethical review by improving the standard and uniformity of decision-making and assuring and gaining the confidence of the public in the NatHREC. Membership must be for three (3) years, renewable once, under the discretion of the MRCC Chairperson. A member of the NatHREC may resign by submitting an official letter of resignation to the MRCC Chairperson. A member of the NatHREC may also be disqualified from membership should the appointing authority provide adequate written reasons to the NatHREC and there is unanimous agreement. The NatHREC must request a replacement of any member when there is protracted illness that prevents the member from participating; persistent absenteeism or missing three (3) consecutive committee meetings; voluntary withdrawal or resignation; and/or ethical misconduct.

According to TZA-5, the NatHREC Secretary oversees the daily operations of the Secretariat and arranges training and educational programs to new and continuing committee members and the scientific community on health research ethics. The training must include programs about the basic principles of human participant protection, current literature, and regulations and guidelines affecting the committee and NIMR. Further, the Secretary assists in recruiting new committee members, as well as preparing and submitting an annual committee operational budget and plan to NIMR in consultation with the Chair. See TZA-5 for details on the functions of the NatHREC Secretariat.

Per TZA-5, NatHREC members must fulfill the following responsibilities:

• Review, discuss, and consider health research protocols submitted for ethical clearance evaluation
• Review research study progress reports and monitor on-going studies as appropriate
• Review reports on adverse events, serious adverse events, and/or suspected unexpected serious adverse reactions, as well as any other safety reports and recommend appropriate actions
• Maintain professional confidentiality of documents and deliberations of the committee review proceedings and meetings
• Declare conflicts of interest when they exist
• Participate in continuing education activities in biomedical ethics and research
• Undertake committee duties assigned to them by the NatHREC Chairperson
• Attend NatHREC meetings regularly and participate actively during deliberations
• Participate in the review of NatHREC SOPs
• Conduct research site monitoring visits as deemed necessary

According to TZA-5, the NatHREC must convene at least once a month with a quorum of at least half the number of committee members. The NatHREC Secretary, with support from the Secretariat, must prepare an annual almanac of meetings. The meeting package must include the agenda; all research protocols; and all related materials including, but not limited to, copies of the protocols, informed consent materials, continuing and final reviews, and safety reports. The Secretariat must keep a record of attendance as well as meeting deliberations, indicating which members were present and the discussions of review applications. If members have reviewed a protocol and identified issues that require the principal investigator (PI) to be present during the meeting for further deliberations, then the PI of that research protocol may be invited to answer questions or clarify issues. The meeting members must reach decisions by a consensus; however, if a consensus cannot be achieved, a formal vote must be taken. All members have the right to vote. The committee must provide formal recommendations to the MRCC on the approval of applications, along with minutes that include protocol title and date of review, a checklist of documents reviewed, and a decision reached by the committee, whether approved, approved with stipulation, recommended for resubmission after revision, or not recommended with reasons. For detailed NatHREC procedures and information, see TZA-5.

Institutional Ethics Committees

Per the G-EthicsHR-TZA, the EC members are appointed by institutional appointing authorities. The EC must be constituted according to a document that specifies the manner in which members and the Chair will be appointed, reappointed, and replaced. EC members must regularly update their knowledge about the ethical conduct of health-related research. If committees do not have the relevant expertise to adequately review a specific protocol, they must consult external persons with the required skills or certification. Each EC member must undergo at least one (1) basic training in research ethics within one (1) year of appointment and, thereafter, should undergo continued ethics training at least once every two (2) years. Members of an EC must serve for a term of three (3) years. EC members must guard against any tendencies of unethical conduct on their part. For example, they must protect the confidentiality of research projects, documents, and discussions; an EC member must not appropriate the submitted protocol for their own use; and they must not compel investigators to submit to an unnecessary repetition of review.

In addition, as delineated in the G-EthicsHR-TZA, ECs are responsible for determining whether the research objectives are responsive to the health needs and priorities of the proposed study population, particularly in Tanzania. The ability to judge the ethical acceptability of various aspects of a research protocol requires a thorough understanding of a community’s customs and traditions. For example, the EC should include members that are able to indicate suitable community members to serve as intermediaries between investigators and research participants and to advise on whether material benefits or inducements may be regarded as appropriate considering a community’s gift exchange and other customs and traditions. ECs must have mechanisms to ensure the independence of their operations. They must avoid undue influence and minimize and manage conflicts of interest. ECs must require that their members disclose to the committee any interests that could constitute a conflict of interest or otherwise bias their evaluation of a research protocol. ECs must evaluate each study considering any disclosed interests and ensure appropriate steps are taken to mitigate possible conflicts of interest. ECs may receive a fee for reviewing protocols, and this need not constitute a conflict of interest.

As required in the G-EthicsHR-TZA, ECs should hold meetings as frequently as possible to facilitate timely ethical clearance. ECs must review proposed research at convened meetings where at least 50 percent of the members are present, including at least one (1) member who represents the interests of the community. The Chairperson may be given powers to approve minor matters on behalf of the EC but ensure that the papers are made available to the rest of the EC members at the next meeting. ECs should have the power to co-opt professional or lay members where necessary. For a research protocol to be approved, it must receive the approval of a simple majority of those members present at the meeting; the only exception to the simple majority requirement is in the case of expedited review. 

Regarding documentation, per the G-EthicsHR-TZA, the institution must ensure that the EC prepares and maintains adequate documentation and retain the records for at least five (5) years after the completion of the study. All records must be accessible for inspection and copying by authorized representatives, including the following:

• Detailed written procedures for the EC
• Copies of all research protocols reviewed, scientific evaluations that accompany the protocols, approved sample consent documents, progress reports submitted by the investigator(s), reports of injuries to research participants, etc.
• Minutes of EC Meetings that must be in sufficient detail to show attendance at the meetings; actions taken by the IRB; the vote on these actions, including the number of members voting for, against, and abstaining; the basis for requiring changes in or disapproving research; and a written summary of the discussion of controversial issues and their resolution
• Records of continuing review activities
• Copies of all correspondence between the EC and investigator(s)
• Statements of significant new findings that were provided to research participants

Per the G-ResearchIntegrity, institutions should have clear documentation of candidacy requirements and procedures for identifying or recruiting EC members. The recruitment methods, duration of membership, terms of service, qualifications, disqualifications, resignation procedures, re-appointment/renewal, and other duties and responsibilities should be documented in EC SOPs. Appointment of EC members must be done at the institutional managerial level in consultation with experts, relevant boards, and peer institutions. Institutions should minimize conflicts of interest and establish mechanisms for maximizing transparency and confidentiality of review processes. These qualities may be enhanced by rotation and turnaround of members to allow inflow of new ideas and accountability. The conditions of appointment must clearly indicate the decision on whether to release professional profiles to the public, level of accessibility, members’ cost recovery ceilings for EC-related activities, confidentiality, and any other mechanisms geared to enhancing confidence over the EC’s operations. The pros and cons of each option must be carefully considered and communicated to candidates. Both scientific and support staff must sign a confidentiality agreement and declare any conflicts of interest from the outset.

Overview

According to the G-NHSRC and the G-COMREC, the primary scope of information assessed by the two (2) National Commission for Science and Technology (NCST)-approved ethics committees (ECs)—the National Health Sciences Research Committee (NHSRC) and the College of Medicine Research and Ethics Committee (COMREC)—relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial.

The G-HlthResConduct states that scientific design; recruitment of research participants; care and protection of research participants; ethical consideration; and community consideration are essential elements that the NHSRC and COMREC must review in a clinical trial application. Per the G-NHSRC, the NHSRC 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).

The G-HlthResConduct and the R-HlthResCoord indicate that COMREC, as a subsidiary of NHSRC, only reviews and approves studies involving or originating from the College of Medicine (COM) or Kamuzu College of Nursing (KCN) (now known collectively as the Kamuzu University of Health Sciences (KUHeS), per MWI-62) faculty members and students, and their collaborators/coinvestigators/affiliates. The NHSRC has the sole jurisdiction to review studies with a national interest and multicenter studies, including those from COM and KCN, as well as studies from all other researchers and institutions.

Role in Clinical Trial Approval Process

The R-HlthResCoord indicates that before submitting a clinical trial application to the Pharmacy and Medicines Regulatory Authority (PMRA), the sponsor or principal investigator (PI) must obtain full ethical approval from either the NHSRC or COMREC. Parallel submissions of a clinical trial application to an EC and the PMRA are prohibited.

Moreover, as specified in the R-HlthResCoord, for all studies originating outside Malawi, the sponsor or the PI is required to obtain approval from an EC based in their country prior to submitting an application to the NHSRC or COMREC for ethical review and approval.

Per the G-NHSRC and the G-COMREC, the applicable EC will screen submitted applications for completeness, and help determine the type of review to be conducted.

The G-NHSRC states that new studies submitted to the NHSRC are generally reviewed by a fully convened NHSRC meeting. The following studies will be reviewed by the full NHSRC:

• All high-risk studies
• Studies involving vulnerable populations (including pregnant women, prisoners, mentally incompetent patients, etc.)
• Any clinical interventional study that randomly assigns human participants to alternative experimental or placebo groups
• Studies involving sensitive information connected to personal identifiers
• Studies previously reviewed that require major issues to be addressed

The G-NHSRC and the G-COMREC indicate that following the NHSRC’s or COMREC’s review, the EC will decide to approve the research, stipulate minor changes for approval, or not approve the research. A negative decision on an application must be supported by clearly stated reasons. In addition, the G-NHSRC states that if the NHSRC determines that substantive changes/clarifications must be made before approval may be granted, the study will be deferred for a full NHSRC meeting.

The G-COMREC specifies that the COMREC’s approval of a new application is valid for one (1) year. However, the R-HlthResCoord indicates that EC approval of a study is valid for the period of the study as described in the protocol, which is effective from the date of approval as indicated in the approval letter.

The R-HlthResCoord, the G-NHSRC, and the G-COMREC state that the EC must review and approve any protocol amendments prior to those changes being implemented. See MWI-52 and MWI-44 for the NHSRC and COMREC amendment request forms, respectively. Any changes cannot be implemented until approved by the EC.

The G-COMREC requires that COMREC follow the progress of studies for which a positive decision has been reached and establish a subcommittee responsible for monitoring ongoing studies. The follow-up review intervals are determined by the nature of the research project. However, each protocol should undergo a follow-up review at least once a year. As part of its monitoring process, COMREC conducts inspections of institutions and study sites.

Studies of National Interest

All studies of national interest, as defined in the G-NHSRC, the G-COMREC, and the R-HlthResCoord to include all vaccine trials and stem cell research, should be referred to the NHSRC, regardless of the origin of the protocol. The NHSRC may form a standing committee for that specific project, which will monitor the project through to its conclusion, composed of members to be drawn on the basis of their expertise.

Multicenter Studies

As delineated in the R-HlthResCoord, the NHSRC is designated and mandated to review and approve multicenter clinical trials, including those originating outside Malawi. The NHSRC will conduct a full initial review of the same protocols for a multicenter study submitted by different investigators provided that such protocols are submitted simultaneously. Protocols for the same multicenter trial to be implemented at different institutions may also be merged into one (1) protocol that the NHSRC will treat as a joint submission for review.

Continuing Review

According to the G-NHSRC and the G-COMREC, all approved studies running for more than one (1) year are subject to continuing annual review by the approving EC (the NHSRC or COMREC). If the materials for continuing EC review are not received within one (1) month following the expiration date of the previous approval, then the study will be classified as lapsed and inactive. If a study has lapsed, the EC will order that all study-related operations cease, except those necessary for the welfare of the participants. Per the G-NHSRC, if the PI wants to continue an NHSRC-reviewed study that has lapsed for two (2) months, the PI must submit a new application for NHSRC review and wait for approval before resuming research under the protocol. MWI-53 indicates that the NHSRC follows, at a minimum, the regulations set forth in the Declaration of Helsinki (MWI-42) and the Council for International Organizations of Medical Sciences (CIOMS) guidelines as the criteria for continuing review of a study. The PI is responsible for timely submission of a continuing review application to prevent any lapse in NHSRC approval. NHSRC regulations do not provide for exceptions to the requirement for continuing review. The NHSRC’s continuing review application form is available at MWI-53.

Expedited Review

Per the G-NHSRC and the G-COMREC, research studies that have previously been reviewed by a fully convened committee and require the PI to address minor issues, may be approved through the NHSRC’s or COMREC’s expedited processes. Studies by students may also be considered for expedited review. Expedited review can be considered for continuing review of research previously approved by the NHSRC or COMREC, where the research is permanently closed to the enrollment of new subjects, and all subjects have completed all research related interventions.

Per the G-COMREC, COMREC’s review period for such a resubmission must not exceed 14 days from the date of the resubmission. The G-NHSRC further indicates that the NHSRC will also consider expedited review for continuing review of research previously approved by NHSRC where no subjects have been enrolled and no additional risks have been identified, or where the remaining research activities are limited to data analysis and report writing.

For more information on each EC’s expedited review procedures, see the G-NHSRC and the G-COMREC.

Exemption from Review

As delineated in the G-NHSRC and the G-COMREC, certain types of human participants research may be exempted from NHSRC or COMREC review. Exemption may be considered for research involving the collection or study of existing data, documents, records, program evaluation, pathological specimens, or diagnostic specimens, if the sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified directly or through identifiers linked to the subjects.

Suspension or Termination of Study/Approval

Per the G-NHSRC, the NHSRC chairperson or the convened NHSRC may suspend a study at any time if it is determined that the study requires further review or evaluation. This determination may be made in the event of an adverse event, non-compliance, or other danger to human participants. The study will be reviewed at the next convened meeting to determine if it requires changes. The NHSRC must notify the PI and the sponsor in writing specifying reasons for suspension or termination with a copy to the National Research Council of Malawi (NRCM). The NRCM must be informed of all the suspended or terminated studies with detailed reasons for the decision. In the event of documented serious adverse events and any unanticipated problems as documented by the researcher, the NHSRC must terminate the study and order the investigator to follow up with study participants. In the case of any officially or unofficially reported noncompliance, protocol violation, or deviation by the researcher, the NHSRC must suspend the study to ensure safety of the study participants and carry out an investigation. Upon investigation of the problem prompting the suspension of the study, the convened NHSRC must terminate the study if convinced beyond any reasonable doubt that there was noncompliance, deviation, or violation of the protocol.

The G-COMREC states that COMREC may recommend to COM management suspension or termination of approval of research that is not being conducted in accordance with the guidelines, or that has been associated with unexpected serious harm to participants. Any suspension or termination of approval must include a statement of the reasons for COMREC's action and must be reported promptly to the investigator, appropriate institutional officials, Dean of Postgraduate Studies and Research, and the Principal of the COM. The Principal of the COM must then send a report of suspended or terminated studies with the reasons contained therein to the NCST and the PMRA, or any other government agency responsible for research policy matters.

Overview

According to the G-TMRCC and the G-EthicsHR-TZA, the primary scope of information assessed by the National Health Research Ethics Committee (NatHREC) and the institutional ethics committees (ECs) relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in health research studies. The 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).The NatHREC is responsible for ensuring an independent, timely, and competent review of all ethical aspects of the clinical trial protocol. TZA-5 states that the NatHREC must function in accordance with national and international standards and guidelines on health research, and guided specifically by the ethical principles expressed in the Declaration of Helsinki (TZA-30), international ethical guidelines such as the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (TZA-13), and the G-EthicsHR-TZA.

As indicated in the G-ResearchIntegrity, institutional ECs review, approve, and recommend for approval, research proposals that have met scientific merit, ethical, and professional standards. The institutional ECs are expected to provide recommendations on proposals that would need approval from a nationally overseeing ethics body where available. Per the G-EthicsHR-TZA, institutional ECs act as independent reviewers of any proposed study on human research participants to ensure ethical conduct of research and that participant’s rights and welfare are not violated. The major responsibility of institutional ECs is to safeguard the rights, safety, and well-being of research participants. In addition, it is essential that they review the scientific soundness of the research protocols, which involves a proper scientific review to verify that a competent expert body has determined the research to be scientifically sound, or consult with qualified experts to ensure that the research design and methods are appropriate. If the EC does not have expertise to judge science or feasibility, they must draw on relevant expertise. See G-EthicsHR-TZA for more information on the scientific review.

Role in Clinical Trial Approval Process

National Health Research Ethics Committee

As per the TMMDAct, the CT-Regs, and the G-AppConductCT, the Tanzania Medicines and Medical Devices Authority (TMDA) and the 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. According to the G-AppConductCT and TZA-4, 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.

As described in TZA-31, the NatHREC’s ethics review is managed through its Research Ethics Information Management System (REIMS) (TZA-32), 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. The G-RevPrtcl indicates that the NatHREC Secretariat will validate submissions for completeness upon receipt in REIMS. The G-RevPrtcl recommends the following review sequence after the materials are checked for completeness: write comments in an MS Word document; read the PI’s cover letter, the institution’s commitment letter, and other supporting letters; review the abstract/summary; review the application form, protocol, and appendices; and synthesize and submit comments online through REIMS (TZA-32). Per TZA-5, following successful validation of an application to the REIMS, the system generates a unique protocol number/identifier; this unique identifier must be used in reference to all communications to the PI or applicant regarding the application. Depending on the research area of the submitted protocols, at least two (2) primary reviewers must be assigned to review a new protocol by the NatHREC Secretariat. Comments from reviewers will reach the PI within two (2) days, depending on the type of study protocol. If the applicant fails to respond to the comments within 30 days, the NatHREC Secretariat must notify the PI of its intent to remove the protocol from the REIMS. Once the research protocol is removed from the REIMS, the PI must re-apply for ethical clearance and pay the application fee. For clinical trial applications, reviewers’ comments and the outcome of the NatHREC meeting must be forwarded to the PI within 30 days from the date of acceptance by the NatHREC. If the research protocol is cleared and the ethical clearance certificate is issued, the PI must receive it through mail to the institution’s postal address. Additionally, the PI may be able to download the soft copy of the ethical clearance certificate from the REIMS account. A PI may appeal a decision in writing to the Medical Research Coordination Committee (MRCC) Chairperson within 30 days of receipt of the decision, stating the precise issues upon which the appeal is based. The MRCC will respond to PIs in writing within 30 days or upon scrutiny of the appeal. The MRCC Chairperson may invite the PI to appear in person to the MRCC within 30 days of receiving the written appeal.

Expedited Review

TZA-5 delineates the categories of research that qualify for NatHREC 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 the NatHREC
• Research that aligns with disease outbreaks or public health emergencies

TZA-5 states that expedited review must be conducted by two (2) or more experienced reviewers designated by the Secretariat. The expedited review must include a review of the complete study protocol with all required attachments. Results of the review process may be communicated to the PI even before being reported to the NatHREC. Expedited reviewers may exercise all the authorities of the committee except that the NatHREC reviewers may not disapprove of the research. Any research activity may be disapproved only after reviewing the protocol in accordance with the non-expedited procedure. Approval for expedited protocols is given by the MRCC through the Chairperson upon recommendation for approval from the reviewers. Once expedited approval has been granted, the protocol may be implemented as approved. Clinical trials with investigational products (IP) are not eligible for expedited review but may be considered for accelerated review. The final decision for a protocol to undergo an expedited review is determined by the NatHREC Chairperson, the NatHREC Secretariat, and/or the MRCC Chairperson, as needed. The Secretariat must notify the NatHREC of all expedited reviews at the next scheduled meeting through a listing in the meeting agenda.

Reviews During Public Health Events

Per TZA-5, rapid review of public health research and clinical trials may be implemented during public health events of national and/or international concern. During public health emergencies, the declaration will come from the public health authority of the country or an internationally recognized organization responsible for international public health. To expedite commencement of the research, many of the preliminary research processes (drafting of documents, translations, approvals) will be allowed to happen in parallel. Protocols should be sent to reviewers within 24 hours of submission by the Secretariat, and reviewers should complete their reviews within three (3) days. The consolidated review and suggested revisions (or approval) should be communicated to the PI(s) within five (5) days. The PI should respond to the review notification within 48 hours. See TZA-5 for additional details on the emergency review requirements.

Approval Duration

Regarding duration of the NatHREC approval, per TZA-5, the NatHREC Secretariat determines how often the committee must re-evaluate the research study, appropriate to the degree of risk, but not less than once per year. Studies whose approval has expired must be suspended until an extension through a renewal process is approved. The PI must submit an electronic continuing review report through REIMS with a frequency as indicated in the terms and conditions of the ethics clearance certificate. The NatHREC Secretary must place the continuing review report on the next meeting’s agenda for review. The NatHREC may provide directives or guidance to the study following review that will be communicated to the PI. In addition, the committee may recommend that the research study is halted.

Protocol Amendments

Per TZA-5, the NatHREC recognizes certain protocol amendments as minor/insubstantial or major/substantial; see TZA-5 for examples of each type. Amendments made to protocols may not be implemented until approved by the NatHREC. Upon receipt of the amendment package, the Secretariat must follow the receiving and validation procedures of submitted protocols. After review of the amendment submission, the Secretariat must determine whether the protocol requires expedited or full review. The amended protocol will be sent to the reviewers of the original submission; in absence of the original reviewers, the Secretariat must appoint and send the amendment application to another reviewer with the same or similar expertise. The number of reviewers will range from one (1) to three (3), depending on the number of the amendments. Minor amendments may be reviewed by members of the Secretariat. If the committee requires modifications to any of the documents, specific changes required must be communicated to the PI with instructions to make the necessary changes and resubmit the documents to the Secretariat. If the committee does not recommend approval of the protocol amendment, this information will be communicated to the MRCC who will review the decision and make the final decision on the approval. If an application is not approved, the PI must be informed of the reasons for not approving the amendment.

Institutional Ethics Committees

Per the G-EthicsHR-TZA, ordinary review is the institution’s normal process for reviewing minimal or more than minimal risk studies. For research that is externally sponsored, the ethical standards should not be less stringent than they would be for research carried out in the country of the sponsoring organization. Local ECs must be fully empowered to disapprove a study they believe is unethical. An EC must require that information given to research participants as part of informed consent complies with the general requirements for informed consent. However, the EC may require that more information be given to the research participants, provided such additional information would meaningfully add to the protection of the rights and the welfare of the research participants. An EC must generally require documentation of the informed consent process. For certain types of research, however, the EC may need the investigator to administer a comprehension test (or test of understanding) to ensure that prospective research participants have acquired adequate knowledge of the relevant facts and consequences of participation in the study. Within 14 days of its review, the EC must notify investigators in writing of the outcome of the research protocol review. If an EC does not approve a research activity, it must include in its written notification a statement of the reasons for its decision.

The G-ResearchIntegrity states that ECs must review protocols in accordance with their standard operating procedures (SOPs) and in a timely and professional manner. Names, titles, and institutional affiliation of reviewers for each proposal will be kept confidential. The decision should be communicated to the investigators in a written letter that is signed or stamped by the EC chair. The letter should include the research/study title as written in the application, the name of the applicant, research site, draft number, date submitted, name and date of EC sitting for that proposal, suggested changes, and a clear statement of final decision by EC. The investigators must notify the EC of protocol amendments, unforeseen circumstances affecting the study, termination of the study, progress reporting, and study termination before or at completion. ECs should also establish monitoring and/or inspection mechanisms for ongoing research projects to ensure compliance with approved criteria.

Expedited Review

As delineated in the G-EthicsHR-TZA, expedited review is a process by which studies that involve no more than minimal risk may be reviewed and approved in a timely manner by an individual EC member or a designated subset of the full EC. Relevant authorities or ECs must establish a list of criteria for protocols that qualify for an expedited review process. Further, relevant authorities or ECs may establish procedures for the expedited review of research protocols, which should specify the following:

• The nature of the applications, amendments, and other considerations that will be eligible for expedited review
• The minimum number of committee members required for expedited review
• The status of decisions (for example, subject to confirmation by a full EC or not)

Accelerated Review

Per the G-EthicsHR-TZA, an accelerated review process may be used for a clinical trial protocol submitted for ethical approval. In reviewing a clinical trial, reviewers may exercise all the authorities of the committee to recommend approval of the submitted protocol. Final approval for protocol is granted in accordance with the standard procedures outlined above. However, applications for accelerated review of clinical trial protocols will be reviewed on a case-by-case basis by the EC, and the applicant may be required to undergo an ordinary review process due to the nature of the trial or else, as determined by the EC.

Continuing Review

As required in the G-EthicsHR-TZA, the EC must conduct additional reviews on approved studies as necessary, particularly if there are significant changes in the protocol that require re-consent by participants or affect the safety of participants, or if other ethical matters emerge during the study. These further reviews include amendments, progress reports submitted by researchers, and possible monitoring of researchers’ compliance with approved protocols. For approved studies, ECs must conduct continuing review of research at intervals appropriate to the degree of risk, but not less than once a year, and must have authority to observe or have a third party observe the informed consent process. The EC must investigate research fraud and take appropriate action where scientific fraud has been suspected or proven.

Suspension or Termination

Per the G-EthicsHR-TZA, the EC has the authority to halt, suspend, or terminate approval of research that is not being conducted in accordance with the EC’s requirements, or research that has been associated with unexpected serious harm to research participants. For example, the EC may suspend research when:

• It finds that the investigator has implemented significant changes in the research protocol without the prior approval of the EC
• The investigator has failed to follow specific procedures or requirements articulated by the EC in its initial review of the research protocol
• When there is severe unexpected harm to the research participants, including, but not limited to, serious physical injury or death

Per the G-EthicsHR-TZA, any suspension or termination of ethics approval must include a written statement of the reasons for the EC’s action. It must be reported promptly to the investigator(s), appropriate institutional officials, and the National Institute for Medical Research (NIMR) Director General.

Multicenter Research

For multicenter research, the G-EthicsHR-TZA states that the study must be conducted in a methodologically identical way at each center, and ECs at individual centers have the authority to adapt the informed consent document provided by the lead institution to make it culturally appropriate. To avoid lengthy procedures, multicenter research within Tanzania should be reviewed by only one (1) EC and other applicable ECs should accept that review. To be informed of the necessary approach, the study team should be consulted. In cases of multicenter research, if a local review committee proposes changes to the original protocol that it believes are necessary to protect the research participants, these changes must be reported to the research institution or sponsor responsible for the whole research program for consideration and possible action. This should ensure that all persons are protected and that the research will be valid across sites. Ideally, review procedures should be harmonized, which may decrease the time needed for review and, accordingly, speed up the research process. Joint reviews may be organized and requested by the study team or sponsor across country borders or institutions in compliance with guidelines. Joint reviews are based on voluntary cooperation between the relevant national regulatory authorities and ECs. In the case of multi-country joint reviews, each country is solely responsible for granting regulatory or ethics approval to the sites within its borders. To harmonize review processes and to maintain sufficient quality of these processes, ECs should develop quality indicators for ethical review.

Exemption

Per the G-EthicsHR-TZA, some studies may be exempt from EC review. If an investigator considers that their research project satisfies the requirements for exemption from ethics review, the EC must ensure that the proposed research satisfies the requirements for exemption from EC review and grant exemption through procedures set by the EC. The following studies may be exempt from EC review:

• Research with negligible risk that involves using existing collections of data or records that contain only non-identifiable data about human beings
• Use of publicly available unlinked data that does not identify individuals or communities
• Use of existing collections of data or records that contain only non-identifiable data about human beings
• Quality assurance/evaluation activities undertaken in the normal course of conducting the business of the institution, i.e., educational assessments, student feedback surveys, audits of organizational activities and systems, and quality assurance reviews
• Emergency use of a test article provided that such emergency use is reported to the EC within five (5) working days; any subsequent use of the test article at the institution is subject to EC approval
• Health systems research if public officials are interviewed in their official capacity on issues that are in the public domain

National Health Sciences Research Committee

According to MWI-4 and MWI-15, non-Malawian researchers must pay $150 USD or its equivalent in Malawian Kwacha to the National Health Sciences Research Committee (NHSRC) upon submission of a research proposal. Malawian students (Masters and below) are required to pay 5000 Malawian Kwacha.

The G-NHSRC and MWI-5 indicate that following the protocol’s approval, the principal investigator must also pay the Ministry of Health (MOH) a fee of 10% of the total budget indicated in the proposal to cover NHSRC institutional capacity strengthening and administrative operating expenses. MWI-15 further specifies that the fee, referred to as a 10% NHSRC Human Subject Protection (HSP) fee, must be paid by PhD students and above.

MWI-5 clarifies that the NHSRC fee and the Pharmacy and Medicines Regulatory Authority (PMRA)’s Clinical Trial Review Committee (CTRC) fees are included in the 10%. Payment of the 10% fee must be made for all NHSRC-approved research projects prior to commencement of the research study.

Payment Instructions

Per MWI-15, the application fee and the 10% HSP fee may be paid at the MOH Headquarters Cash Office or through the following bank details:

Account Name: NCST Review Fees
Account Number: 1001670847
Bank Name: National Bank of Malawi
Bank Address: Capital City Branch, Lilongwe 3, Malawi
Swift Code: NBMAMWMW008

College of Medicine Research and Ethics Committee

As per MWI-5, non-Malawian researchers must pay $150 USD and Malawian researchers must pay 500 Malawian Kwacha to the College of Medicine Research and Ethics Committee (COMREC) upon the submission of a research proposal. COMREC is also mandated to charge a College of Medicine (COM) fee of 10% of the total budget indicated in the proposal. As delineated in MWI-1, the COM’s Dean of Postgraduate Studies and Research can grant waivers for the 10% fee.

However, the G-COMREC states that the COM’s processing fee is $100 USD for each new protocol submission and resubmission for the fourth time, and that eligible investigators may apply to management for exemption from paying the fee.

Payment Instructions

No information is currently available regarding payment instructions for COMREC.

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.

As per TZA-33, the fees are as follows:

• Tanzanian researchers, expedited review – 3,100,000 Tanzanian Shillings
• Tanzanian researchers, ordinary review – 2,100,000 Tanzanian Shillings
• Tanzanian researchers, amendment – 500,000 Tanzanian Shillings
• Tanzanian researchers, extension – 200,000 Tanzanian Shillings
• Tanzanian students, expedited review – Not applicable
• Tanzanian students, ordinary review – 1,100,000 Tanzanian Shillings
• Tanzanian students, amendment – 250,000 Tanzanian Shillings
• Tanzanian students, extension – 200,000 Tanzanian Shillings
• International researchers, expedited review – $4,100 USD
• International researchers, ordinary review – $2,100 USD
• International researchers, amendment – $500 USD
• International researchers, extension – $200 USD
• International students, expedited review – Not applicable
• International students, ordinary review – $750 USD
• International students, amendment – $250 USD
• International students, extension – $200 USD

Payment Instructions

Per TZA-33, to pay for NatHREC ethical clearance, applicants should fill out the payment form (TZA-33) and send it to nimrethics@gmail.com. To inquire about how to make the payment with the form, contact the 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. Per the G-ResearchIntegrity, ECs should delineate procedures for the fee structure, mode of payment, and proof of payment in their standard operating procedures (SOPs). Applicants should contact ECs individually for specific fees and payment instructions.

Overview

The R-HlthResCoord indicates that the National Commission for Science and Technology (NCST) is the central statutory body responsible for coordinating and regulating all research, science, and technology related activities in Malawi, as mandated by the SciTechAct.

The R-HlthResCoord further specifies that the NCST provides oversight to the National Health Sciences Research Committee (NHSRC) and the College of Medicine Research and Ethics Committee (COMREC). The NCST’s core responsibilities in this capacity include:

• Participating as an ex-officio member for the NHSRC and COMREC by having a voting representative from the NCST sit on both committees
• Reviewing and approving the ethics committees’ (EC) guidelines and standard operating procedures
• Monitoring the ECs’ performance and adherence to relevant national policies, laws, regulations, and guidelines

Registration, Auditing, and Accreditation

No information is available on registration, auditing, and accreditation responsibilities by the NCST.

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 IERC-Accredit, the G-EthicsHR-TZA, 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 the National Health Research Ethics Committee (NatHREC), which is a subcommittee of the 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 the NatHREC. For detailed information on NatHREC responsibilities, see the G-TMRCC, the G-EthicsHR-TZA, and TZA-5.

TZA-5 acknowledges that not all human subjects require review and approval at the national level—i.e., research that does not involve investigational products or collaboration with foreign institutions. For studies that may not need national review, the local ethics committee (EC) must submit quarterly reports listing studies that were approved by the local EC. The NatHREC may request any information related to approved research studies at the institutional level, and ECs are subject to audit.

Registration, Auditing, and Accreditation

Per the G-EthicsHR-TZA, institutions that intend to establish an institutional EC must make a written request to the Director General of NIMR and, upon approval, submit quarterly and annual progress reports to NIMR. In the initial request, the institution must indicate that it will comply with the following minimum requirements:

• A statement of principles governing the institution's discharge of its responsibilities for protecting the rights and welfare of human research participants of research conducted at or sponsored by the institution; this may include an appropriate existing code, declaration, or statement of ethical principles or a statement formulated by the institution itself
• Details on ensuring meeting space availability and sufficient staff and resources to support the EC’s review and record-keeping duties
• A list of members identified by name, qualifications, profession, representative capacity, indicators, or experience such as board certification, and licenses
• Written procedures for monitoring the conduct of studies approved by the EC

As delineated in the IERC-Accredit, institutional ECs may apply for accreditation. Registered and accredited ECs support the NatHREC function of facilitating institutional ethical clearance and monitoring the approved research studies at the level of the institutions to which they belong or are affiliated. ECs are not mandated to approve research protocols for clinical trials and those involving foreign collaborators. These types of research are cleared at the national level only. Following are the EC accreditation assessment criteria:

• Suitability of infrastructure and office space for EC activities
• Adequacy of equipment to support ethics review management
• Adequacy of qualified EC Secretariat staff (technical and support staff) to manage the ethics review procedures
• Appropriateness of the EC governance and structure
• Plan for capacity building/training program for the EC Secretariat, members, and reviewers
• Plan for monitoring of research activities by the EC
• Adequacy of institutional support services
• Appropriateness of EC standard operating procedures (SOPs)

The IERC-Accredit indicates that ECs approved for full accreditation will be published on the NIMR website. The duration of accreditation is three (3) years from the date of notification (certification) by NIMR. Applications for renewal must be made six (6) months before the expiry of the accreditation period. Failure to renew accreditation or failure to maintain the appropriate standards for continuity of accreditation will mean that the accreditation status of the EC will lapse at the end of the current accreditation period and the committee must cease to function. Accreditation must be terminated if NIMR, in consultation with NatHREC, finds that the accredited EC has failed to maintain the required standards. See IERC-Accredit for additional accreditation information, including application procedures and reporting.

See the Tanzania Commission for Science and Technology’s (COSTECH) and the G-ResearchIntegrity for institutional guidance on the introduction and strengthening of research integrity mechanisms. When such mechanisms are well established, institutional ECs can advance to a stage of accreditation.

Overview

According to the G-CTARevVacBiol, the R-HlthResCoord, and MWI-50, the Pharmacy and Medicines Regulatory Authority (PMRA) requires the applicant to obtain PMRA approval and ethics committee (EC) approval of a clinical trial application.

The R-HlthResCoord indicates that before submitting a clinical trial application to the PMRA, the sponsor or principal investigator (PI) must obtain full ethical approval from either of the two (2) National Commission for Science and Technology (NCST)-approved ECs—the National Health Sciences Research Committee (NHSRC) or the College of Medicine Research and Ethics Committee (COMREC). Parallel submissions of a clinical trial application to an EC and the PMRA are prohibited.

Regulatory Submission

According to MWI-60, an electronic or soft copy of the clinical trial application dossier must be sent to registration@pmra.mw and info@pmra.mw.

As per the G-CTARevVacBiol and MWI-9, applicants must submit three (3) copies of the clinical trial application to the PMRA. MWI-60 further requires that the three (3) dossier hard copies be submitted in a lever arch file to the Director General. Each section of the dossier must be well demarcated for ease of reference by PMRA reviewers. The application may be made by a sponsor or the sponsor’s agent, who must submit a power of attorney (MWI-33) attesting to be a duly appointed agent.

There is no specified language requirement for the clinical trial documents to be submitted to the PMRA.

Ethics Review Submission

National Health Sciences Research Committee

As stated in the G-HlthResConduct and MWI-15, the applicant is required to bind and submit application materials (plus an electronic copy, per MWI-15) to the NHSRC at least three (3) weeks before the date of the review meeting.

MWI-15 states that applications should be submitted to the NHSRC at the following address:

The Chairperson
National Health Sciences Research Committee
Ministry of Health Research Department Area 2/124
P.O. Box 30377
Lilongwe 3, Malawi
Tel: +265 1 789 400

The electronic copy should be submitted to research@mail.gov.mw at the same time. However, per MWI-55, applicants should submit applications to research@health.gov.mw and mohdoccentre@gmail.com.

MWI-15 indicates that three (3) copies of each item indicated in the NHSRC Checklist (MWI-4) must be submitted in the research proposal package to the NHSRC (See the Submission Content section for a list of these items). Three (3) copies for Malawian student proposals (up to master’s level) must also be submitted to the NHSRC secretariat for expedited review. The submission must be bound in the order indicated by MWI-4 as one (1) PDF document. (See the Submission Content section for more details on the individual elements of the NHSRC research proposal submission.)

According to MWI-15 and MWI-4, the data collection tools and informed consent forms must be provided to the NHSRC in both English and Chichewa (or the appropriate local language).

The R-HlthResCoord indicates that for multicenter trials, sponsors and PIs may plan to hold a pre-clinical trial submission and authorization meeting with the NHSRC, at their own choice and cost. The sponsor or PI must write to the NHSRC secretariat of the review committee to request the meeting’s arrangement at least four (4) weeks in advance of the suggested meeting date. For more information, see the R-HlthResCoord.

College of Medicine Research and Ethics Committee

Per the R-HlthResCoord, COMREC may at its own discretion allow a pre-clinical trial application procedure, where applicable, at the request and cost of the sponsor. As stated in the G-HlthResConduct, the applicant is required to submit application materials to COMREC at least three (3) weeks before the date of the review meeting.

According to MWI-10, protocol submissions to COMREC may be made through the National Research Information Management System (NRIMS) (MWI-19). Following submission, the protocol will be reviewed, and feedback will be given through the applicant’s registered email address. See MWI-10 for more information on the NRIMS submission portal.

MWI-19 provides the following additional contact information for COMREC:

Tel: +265 888 118 993
Email: comrec@medcol.mw

However, MWI-1 indicates that all documents should be submitted to COMREC by email to comrec@medcol.mw in one (1) PDF file, if the file size does not exceed 5MB. If the file size is over 5MB, then the file should be sent as a compressed zipped file. The data collection tools and informed consent forms must be provided in both English and Chichewa (or the appropriate local language).

Overview

According to the TMMDAct, the CT-Regs, and the G-AppConductCT, the Tanzania Medicines and Medical Devices Authority (TMDA) requires the sponsor, the designated contract research organization (CRO), or the investigator to obtain TMDA approval. Per TZA-5, the principal investigator (PI) is required to submit an application for ethical review of a research study to the national ethics committee (EC), the National Health Research Ethics Committee (NatHREC). According to the G-AppConductCT and TZA-4, 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 institutional EC and NatHREC 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 TZA-4 and 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 the TMDA at the following address:

Mabibo External along Mandela Express way
P.O. Box 77150
Dar es Salaam, Tanzania

In addition, 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 MS Word format, Bookman Old Style font size 11 and submitted on CD-ROM. TZA-36 requires electronic format on 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 CTD highlighted in the G-AppConductCT. The overall organization of the CTD format should not be modified.

Per the G-AppConductCT and per TZA-4, 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 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 a research permit, the researcher 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 the 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. PIs or applicants must submit all required documents at least two (2) months prior to the commencement of the research study, and they must select either an expedited or ordinary review (for the case of clinical trials, an accelerated review) and pay the relevant fee. 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 the G-RevPrtcl, TZA-5, and TZA-31, applicants should submit the form to the online Research Ethics Information Management System (REIMS) (TZA-32).

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

Institutional Ethics Committees

While the submission requirements will vary by institution, the G-ResearchIntegrity indicates that the lead researcher or PI is responsible for submitting a research proposal to the EC. The institutional EC’s procedures for receiving an application should be clearly stated, and could include some of the following submission elements:

• The name and/or title of the EC member who will receive applications
• Application template or standard forms for submitting applications
• Recommended channel for submissions (e.g., email) and format (e.g., MS word)
• Proper submission of supporting documents with the application
• Use of appropriate language (as recommended) and number of copies
• Name and addresses of contact person for follow up with comments
• Fee structure, mode of payment, and process for submitting proof of payment
• Applicable procedures for proposal amendments, submissions, and supporting tools

Regulatory Authority Requirements

As per the G-CTAProcsVacBiol, the G-CTARevVacBiol, and MWI-60, the following documentation must be submitted to the Pharmacy and Medicines Regulatory Authority (PMRA) in an application to conduct a clinical trial (Note: The sources provide overlapping and unique elements so each of the items listed below will not necessarily be in each):

• Comprehensive table of contents for the entire application, including a complete list of all documents provided in the application. The location of each document should be identified by tab identifiers. In general, the name for the tab identifier should be the name of the document
• Cover letter signed by the principal investigator (PI) or sponsor
• Proof of payment of the application and registration fees
• Signed and stamped Clinical Trial Application (Form CT 8) (MWI-9)
• Current version of the study protocol signed and dated by the sponsor and investigator (in the format provided in the International Council for Harmonisation’s (ICH) good clinical practice (GCP) guidelines and/or in line with Attachment 1 of MWI-60)
• Investigator’s Brochure (IB), where applicable (in the format provided in the ICH GCP guidelines)
• Certificate of Good Manufacturing Practice (GMP) of the investigational product (IP) (also referred to as an investigational medicinal product (IMP) in Malawi) and/or placebo, or evidence of manufacture quality, safety, and consistency
• Mock-up labels for the IP
• Blank case report forms (CRFs) and serious adverse events (SAEs) reporting form to be used in the study
• Investigational Medicinal Product Dossier (IMPD) or alternative as provided in Attachment 2 of MWI-60
• Stability data of the IP and auxiliary medicine(s) for climatic zone IVa if not registered in Malawi by the PMRA
• Evidence of registration of the IP or auxiliary medicines in a country with Stringent Regulatory Authority (SRA) and/or Certificate of Pharmaceutical Product (CoPP), i.e., if IP/auxiliary medicines are not registered by the PMRA
• Summary of Product Characteristics (SmPC) for IP and auxiliary medicines
• Pharmacy plan
• Report summaries of prior clinical trials with the IP (part of IB if it is in the ICH format)
• Capacity building plans including training and updating of staff involved in the trial
• Informed consent form (ICF) (in ICH format)
• Declaration of intent by the national PI or contact person (MWI-31)
• Signed and completed declaration by investigators (MWI-32)
• Investigator(s) Curriculum Vitae(s) (CVs), including that of pharmacist(s)
• Financial declaration by sponsor and PI (MWI-59)
• Ethical clearance certificate from an independent ethics committee (EC) recognized by the laws of Malawi
• Certified copy of clinical trial insurance for study participants endorsed by the National Commission for Science and Technology (NCST)
• Malpractice insurance for investigators and associated staff endorsed by the NCST
• Evidence of accreditation or equivalent of the designated laboratories (see the World Health Organization (WHO)’s guidance on Good Clinical Laboratory Practice (MWI-30))
• Completed PMRA Material Transfer Agreement Form on Shipping of Samples (MWI-14)
• Description of the site facilities (pictorial presentations may be included)
• Evidence of registration of investigators with appropriate bodies
• Evidence of registration of pharmacists with the PMRA
• Evidence of GCP training by investigators and pharmacists in the last three (3) years
• Batch release certificate
• Authorization of the clinical trial from the country of origin, if applicable
• Full, legible copies of key, peer-reviewed published articles supporting the application
• Any other requirement as may be determined by the PMRA

If any above items are not submitted, justification for not submitting the document must be provided. The application may be made by a sponsor or the sponsor’s agent, who must submit a power of attorney (MWI-33) attesting to be a duly appointed agent. See MWI-60 for more details. According to MWI-34, the guidance in the G-CTARevVacBiol and the G-CTAProcsVacBiol also apply to clinical trials of drugs.

Ethics Committee Requirements

National Health Sciences Research Committee

According to the G-NHSRC, MWI-4, and MWI-15, any proposals submitted to the National Health Sciences Research Committee (NHSRC) must be accompanied by the following (Note: The sources provide overlapping and unique elements so each of the items listed below will not necessarily be in each):

• The NHSRC checklist (MWI-4)
• Cover letter from the PI
• The NHSRC application form (MWI-15)
• Research proposal summary, maximum four (4) pages
• Full/main research proposal (see the G-NHSRC, MWI-4, and MWI-15 for details)
• Data collection instruments in both English and Chichewa (or other appropriate local language)
• Informed consent in both English and Chichewa (or other appropriate local language)
• Letter of approval from foreign EC, where applicable (for all students studying in foreign universities)
• Support letters from affiliating institutions (e.g., universities, hospitals, research institutions, or companies where the study is going to take place)
• A copy of the receipt for the paid application fee
• CVs for all the investigators
• Proof of funding from the sponsor/funder (where applicable)

MWI-4 requires that if any of the above items are not included in the submission to the NHSRC, an explanation must be provided.

College of Medicine Research and Ethics Committee

MWI-1 indicates that for submissions to the College of Medicine Research and Ethics Committee (COMREC), a single PDF file should include the following information in the following order:

• Completed copy of the COMREC checklist (MWI-1)
• Cover letter from the PI
• Protocol
• ICFs in both English and Chichewa for adult participants ages 18 and above, parental consent forms for all minors, and assent forms (in addition to the parental consent forms) for all minors between the ages of 7 and 17
• Data collection tools (those that will involve obtaining information from research participants should be translated into Chichewa)
• Material transfer agreement forms and documents
• Waiver letter for the 10% College of Medicine (COM) overhead fee, if applicable
• Information regarding whether the research proposal has been submitted to another EC
• Letter of support from COM head of the principal department hosting the research
• Letter(s) of support from heads of all other departments and institutions in which any research work will be done
• Evidence of current active registration with the Medical Council of Malawi for the PI and other investigators
• Investigator(s) CV(s)

MWI-1 further indicates that the proposal should not be submitted unless every item on the checklist is included, or unless a reason can be provided for the absence of any item. The completed checklist must be attached to the front of the submission. See the G-COMREC and MWI-1 for more information.

Clinical Protocol

As delineated in the G-CTAProcsVacBiol, the clinical protocol should comply with the format provided in the ICH's GCP guidelines. Per MWI-25, clinical trials in Malawi are required to follow the ICH's Guideline for Good Clinical Practice E6(R2) (MWI-22). In addition, MWI-60 provides recommended items to address in a clinical trial protocol and related documents, based on SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidance.

Per the G-HlthResConduct, MWI-60, MWI-1, and MWI-22, the following elements should be included in the protocol (Note: the sources provide overlapping and unique elements so each of the items listed below will not necessarily be in each):

• Cover page
• General information (protocol title, identifying number, and date; registry name; contact information for the sponsor, medical expert, investigator(s), trial site(s), qualified physician(s), and laboratory and/or institutions involved in the study, along with role responsibilities)
• Protocol summary/abstract
• Background and justification
• Investigator(s) CV(s) and contact information
• IP description (See the Investigational Products topic for detailed coverage of this subject)
• Form, dosage, route, method, and frequency of administration and treatment period
• Summary of potential risks and known benefits to research participants
• Hypothesis
• Trial objectives and purpose
• Study setting
• Trial design, random selection method, and blinding level
• Work plan/Gantt chart
• Participant selection/withdrawal, timeline, and sample size
• Participant treatment
• Safety and efficacy assessments
• Literature review
• Adverse event reporting requirements (See the Safety Reporting section for additional information)
• Statistics and methods to track trial data
• Sponsor specifications for direct access to source data/documents
• Quality control/quality assurance procedures and practices
• Data monitoring, including composition of a data monitoring committee, and auditing
• Ethical considerations, including confidentiality, and plans for seeking EC approval
• Plans for communicating important protocol modifications to relevant parties
• Data management and recordkeeping
• Dissemination of findings
• Financing and insurance details
• Publication policy
• Consent form, and information on who will obtain consent
• Plans for collection, laboratory evaluation, and storage of biological specimens

For more detailed protocol requirements and recommendations, refer to MWI-60, MWI-22, MWI-1, and the G-HlthResConduct.

Regulatory Authority Requirements

Tanzania Medicines and Medical Devices Authority

As per the CT-Regs and the G-AppConductCT, 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
• 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 the TMDA to access related files
• Copies of key, peer-reviewed published articles supporting the application
• Completed, 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 different clinical trials. The applicant must include a statement indicating that all the 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 sponsor or sponsor’s agent must submit the following to the TMDA:

• 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: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• A full research proposal, including a summary, abstract, introduction, research objectives, 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 the 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, the G-RevPrtcl, 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: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Application Form for Ethics Approval (see Form 3 in TZA-5 and the Research Ethics Information Management System (REIMS) (TZA-32))
• Full protocol, including benefits sharing, placebo rationale, information on randomization/blinding, and a commitment to register the trial in a public registry
• 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
• Information on the study site(s)
• Review of the known risks and if they are acceptable for the expected benefit
• Interim analysis and stopping rules
• Dissemination of research results
• Commitment letter from affiliated institution and/or local government officials
• Letter from student supervisors
• 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)

Per TZA-5, a request for amendment of a previously approved protocol must describe the requested amendment, provide the rationale for the amendment, and describe the impact, if any, of the amendment on the protocol’s risk-benefit profile.

Institutional Ethics Committees

While the submission requirements vary by institution, the G-ResearchIntegrity indicates that the following are typically required:

• Completed application, signed by the lead investigator/researcher(s)
• Full proposal completed in all sections with supporting documents
• A lay summary of the application and/or a flow chart representing key milestones
• Description of ethical issues pertaining to the research, and how they will be managed
• Tools for operationalizing the research and how they will be applied
• Safety issues related to the use of instruments, materials, and research data
• Investigators’ CVs, up to date and signed
• Research context, including criteria for identifying research participants, research environment, and relevant protection measures
• Information to be provided to participants, which may include tools and use of local translators, if needed
• Procedures for informed consent by participants
• Compensation plans for research participants, if any
• Description of indemnity and/or insurance coverage for participants, if applicable
• A history of rejection of the same research protocol, reasons for rejection, and measures taken to address the concerns; withholding such information should be regarded as misconduct and managed in accordance with misconduct guidelines

Clinical Protocol

The G-AppConductCT indicates that the protocol should state the background, rationale, and objectives of the trial, and describe its design, methodology and organization, including statistical considerations, and the conditions under which it is to be performed and managed. In addition, Tanzania 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

The G-EthicsHR-TZA states that research protocols submitted for ethics review and approval must, at the least, include the following information:

• A clear statement of the objectives of the research, the present state of knowledge, and a justification for undertaking the research
• A precise description of all proposed procedures and interventions, including the duration of the study
• A statistical analysis plan
• Description of the study population, including the number of study participants to be recruited
• The inclusion and exclusion criteria for study participants and procedures for the withdrawal of individual participants
• Complete details of the informed consent process, including the proposed means of obtaining informed consent (or assent in case of minors)
• Evidence that the investigators are appropriately qualified and experienced, and have adequate facilities for the safe and efficient conduct of the research
• Provisions that will be made to protect the confidentiality of information/data obtained from research participants
• The study tool (s) (e.g., questionnaires, case report forms, videos, flip charts, and other data collection tools)

Also see the G-RevPrtcl for additional guidance on the NatHREC’s review of the protocol.

Overview

As stated in the R-HlthResCoord, one (1) of the two (2) government approved ethics committees (ECs), the National Health Sciences Research Committee (NHSRC) or the College of Medicine Research and Ethics Committee (COMREC), must review and approve a clinical trial application prior to the Pharmacy and Medicines Regulatory Authority (PMRA) initiating its review and approval process. Parallel submissions of a clinical trial application to an EC and the PMRA are prohibited.

Regulatory Authority Approval

According to the G-CTARevVacBiol, the PMRA review process takes approximately six (6) weeks.

As per the G-CTARevVacBiol and the G-CTAProcsVacBiol, once the dossier is submitted to the PMRA, the application is screened for completeness. According to the G-CTARevVacBiol, the result of the screening will be communicated to the applicant within 10 working days after receipt of the application, and the screening form will be forwarded by fax. The applicant will have 10 working days to forward any outstanding documents to the PMRA. The PMRA’s technical staff then reviews the application or may forward it to an expert or evaluator for scientific review, with an allocated review period of three (3) weeks.

However, the G-CTAProcsVacBiol specifies that the application is evaluated by three (3) PMRA-appointed expert clinical trial reviewers who will provide a written report within 14 days to the designated registration office, also known as the “Focal Point” division. The Focal Point will then collate and present the expert reviews to the PMRA Clinical Trial Review Committee (CTRC). The CTRC then reviews all the available documentation and provides a recommendation for approval or rejection. The PMRA considers the CTRC’s recommendation and issues a written approval or rejection.

Per MWI-34, the guidance in the G-CTARevVacBiol and the G-CTAProcsVacBiol also apply to clinical trials of drugs.

Ethics Committee Approval

National Health Sciences Research Committee

The G-NHSRC indicates that in the case of an approval with no changes, the chairperson must inform the investigator in writing within seven (7) days. The NHSRC’s timeline for review of research proposals is not otherwise specified in the requirements.

College of Medicine Research and Ethics Committee

According to the G-COMREC, COMREC must ensure that submitted complete proposals are reviewed in a timely manner, i.e., within the month of submission. A written decision is provided to the applicant within two (2) weeks of the meeting at which the decision was made.

Overview

Based on the TMMDAct, the CT-Regs, and the G-AppConductCT, 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, TMDA and NatHREC reviews may be conducted in parallel. However, the TMDA application must include a copy of the 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 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. The 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. The CTC-Time validates the timelines in the G-AppConductCT.

As set forth in the TMMDAct, the CT-Regs, and the 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 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, the 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; and 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 the research commencement date.

Ethics Committee Approval

National Health Research Ethics Committee

As set forth in the G-TMRCC and TZA-5, the NatHREC meets once a month to evaluate application submissions. TZA-5 indicates an e-mail notification acknowledging receipt and successful validation of the clinical trial application must be sent to the PI or applicant by NatHREC within two (2) working days from the date of receipt. Comments from reviewers will reach the PI within two (2) days through the Research Ethics Information Management System (REIMS) (TZA-32), depending on the type of study protocol. If the PI or applicant fails to respond to the committee’s and reviewers’ comments within 30 days, the NatHREC Secretariat must notify the PI of intent to remove the protocol from the REIMS. For clinical trials applications, reviewers’ comments and the outcome of the NatHREC meeting must be forwarded to the PI within 30 days from the date of acceptance by the NatHREC. A PI may appeal that decision in writing to the Medical Research Coordination Committee (MRCC) Chairperson within 30 days of receipt of the decision. The MRCC will respond to PIs in writing within 30 days or upon scrutiny of the appeal. The MRCC Chairperson may invite the PI to appear in person to the MRCC within 30 days of receiving the written appeal. For protocol reviews during public health events of national and/or international concern, protocols should be sent to reviewers within 24 hours of submission by the Secretariat. Reviewers should complete their reviews within three (3) days. The consolidated review and suggested revisions (or approval) should be communicated to the PI(s) within five (5) days. The PI should respond to the review notification within 48 hours.

Per TZA-18, the whole process of receiving, reviewing, and approving the protocols takes a maximum of six (6) weeks.

Institutional Ethics Committees

According to TZA-5, the institutional EC review may occur prior to the proposal review by the NatHREC as the application to the 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). As required in the G-EthicsHR-TZA, the EC must notify investigators in writing of the review decision within 14 days of its review.

Overview

According to the G-CTARevVacBiol, the R-HlthResCoord, and MWI-50, the Pharmacy and Medicines Regulatory Authority (PMRA) requires the applicant to obtain PMRA approval and ethics committee (EC) approval before initiating a clinical trial.

The R-HlthResCoord indicates that before submitting a clinical trial application to the PMRA, the sponsor or principal investigator (PI) must obtain full ethical approval from either of the two (2) National Commission for Science and Technology (NCST)-approved ECs—the National Health Sciences Research Committee (NHSRC) or the College of Medicine Research and Ethics Committee (COMREC).

In addition, as per the PMRAAct and the D-ImprtRelIMPs, the sponsor is required to obtain an import permit for the shipment of the investigational product (IP) to be used in the trial. (See the Manufacturing & Import section for additional information.)

Clinical Trial Agreement

The G-CTAProcsVacBiol requires the sponsor to sign a letter of agreement with the participating institution(s) before the trial begins. In addition, the investigators and the sponsor or the contract research organization must sign an agreement specific to the clinical trial.

Per MWI-25, clinical trials in Malawi are required to follow the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (MWI-22). MWI-22 indicates that the sponsor should obtain the investigator’s/institution’s agreement to:

• Conduct the trial in compliance with good clinical practices (GCPs), with the applicable regulatory requirement(s), and with the approved protocol
• Comply with procedures for data recording/reporting
• Permit monitoring, auditing, and inspection
• Retain the trial related essential documents until the sponsor informs the investigator/institution these documents are no longer needed

The sponsor and the investigator/institution should sign the protocol, or an alternative document, to confirm this agreement.

Clinical Trial Registration

No clinical trials registry exists at this time and there is no stated requirement to register in an international registry.

Overview

In accordance with the TMMDAct, the CT-Regs, and the G-AppConductCT, 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 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 TMMDAct, the CT-Regs, the TFDCA-ImptExpt, and the G-AppConductCT, 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. G-EthicsHR-TZA also states that the PI must sign the protocol and holds primary responsibility for managing and ensuring the integrity of the research study from initiation to finalization.

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 and the G-AppConductCT, 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 in 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 the TMDA.

Safety Reporting Definitions

In accordance with the G-SAEs-PMRA, the following definitions provide a basis for a common understanding of Malawi’s safety reporting requirements:

• Adverse Event (AE) – Any AE associated with the use of a medicine in humans, and which does not necessarily bear a causal relationship to the treatment. This may include an AE occurring in the following circumstances: during use in professional practice; from an overdose, whether accidental or intentional; from drug abuse; from drug withdrawal; and as a result of any failure of expected pharmacological action.
• Adverse Drug Reaction (ADR) – A reaction characterized by the suspicion of a causal relationship between the drug and the occurrence.
• Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (SADR) – An adverse experience occurring at any dose that results in death, is life-threatening, requires or extends patient hospitalization, results in persistent or significant disability, is a birth defect or congenital anomaly; or is an important medical event that, based upon appropriate medical judgment, may jeopardize the participant, and may require intervention to prevent one (1) of the listed outcomes.

Safety Reporting Requirements

As stated in the G-SAEs-PMRA, the sponsor or the investigator(s) is required to report all SAEs that meet the Pharmacy and Medicines Regulatory Authority (PMRA)’s reporting requirements as soon as possible (within 24-72 hours) following site awareness using the SAE Form (MWI-12). All deaths that are assessed as definitely, probably, or possibly related must be reported to the PMRA within 24 hours of site awareness, and the SAE Form (MWI-12) must be submitted within three (3) working days of site awareness. See the G-SAEs-PMRA for additional details on reporting timelines for different reportable SAE situations.

The G-NHSRC indicates that the National Health Sciences Research Committee (NHSRC) requires the investigator to submit a written report for any occurrence of an AE. In the event of documented SAEs and any unanticipated problems as documented by the researcher, the NHSRC must terminate the study and order the investigator to follow up with study participants. Per the G-COMREC, AE and SAE reports must also be submitted to the College of Medicine Research and Ethics Committee (COMREC).

Form Completion & Delivery Requirements

As per the G-SAEs-PMRA, all SAEs that meet reporting requirements must be reported to the PMRA on an SAE Form (MWI-12). The G-SAEs-PMRA indicates that the form must be submitted to the PMRA office by email or hand delivered to the offices at the following address:

The Director General
Pharmacy and Medicines Regulatory Authority
P.O. Box 30241
Lilongwe 3, Malawi
Tel: 265-1755166/165
Email: info@pmra.mw, registration@pmra.mw

According to the G-NHSRC, AE reports submitted to the NHSRC must provide the following details:

• Title of protocol
• NHSRC assigned reference number
• Name of investigator
• Local affiliating institution for studies originating from outside Malawi
• Subject identifier
• Date and site/place of event
• Description of event (i.e., nature of injury or other adverse occurrence, assessment of severity, and assessment of relationship of the event to the study)
• Action taken by the researcher
• Signature of the principal investigator (PI)

See MWI-2 for the NHSRC SAE Reporting Form.

Safety Reporting Definitions

In accordance with the CT-Regs, the G-ReptSafetyData, and the G-AppConductCT, 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.

Per the G-EthicsHR-TZA, the severity of an AE must be graded as follows:

• Mild: Includes events that do not interfere with activities of daily living and do not require treatment
• Moderate: Includes events that have minimal effect on activities of daily living and usually require out-patient treatment
• Severe: Includes activities that significantly affect activities of daily living and may require inpatient hospitalization
• Life-threatening: Includes all events that are life threatening and usually require emergency procedures
• Death

The G-EthicsHR-TZA states that an AE must be deemed unexpected if:

• It is previously unobserved or undocumented in humans under the health research intervention (or one substantially similar)
• The nature or severity is not consistent with information in the investigator’s brochure or other safety information known at the time
• The event is observed with higher frequency or severity than previously documented

See the G-EthicsHR-TZA for additional details on grading AEs.

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. TZA-5 requires the principal investigator (PI) to ensure that the protocol includes all required elements for safety monitoring, including assessment and reporting of any anticipated or unanticipated AEs and SAEs. Ethics committees (ECs) (both the National Health Research Ethics Committee (NatHREC) and institutional ECs) must review and address AEs, SAEs, and/or SUSARs. Investigators must be familiar with the regulations, policies, and procedures concerning reporting and continuing review requirements, as well as timelines for submission of notifications and reports.

The CT-Regs states that the 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 the PI 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.

The G-EthicsHR-TZA requires the investigator to promptly investigate all SAEs, take appropriate measures to ensure the safety of all research participants, and report these and any other information that is likely to affect the safety of the research participants or the conduct of the research events, to the regulatory authority, institutions, and sponsor within timelines as stated in standard operating procedures. Specifically, the investigator must report the following to the EC and TMDA:

• All SAEs irrespective of relationship to the health-related intervention
• All unexpected events of greater than moderate severity irrespective of relationship to health-related intervention
• All events associated with protocol violations irrespective of severity and relationship to health-related intervention
• When criteria for stopping or pausing a study as stipulated in the protocol are met
• Any event mandated by regulatory authorities
• Any event stipulated in the protocol as reportable to the regulatory bodies

Per the G-EthicsHR-TZA, all SAEs must be reported to the local EC as soon as possible and in any case no later than seven (7) days of becoming aware of the event. Thereafter, a detailed report of the SAE should be submitted within eight (8) days. All other reportable AEs should be reported to the EC as soon as possible and in any case not later than 15 days. TZA-5 requires the investigator to submit an initial report on SAE to NatHREC within 24 hours of its occurrence and a final or follow up report on the SAE within 14 days of its occurrence.

Further the G-EthicsHR-TZA requires the investigator to clearly outline in the protocol how management of both foreseeable and unforeseeable AEs will be done. Certain categories of interventions whose long-term effects are not known or cannot be extrapolated will require extended monitoring for AEs, such as genetically modified substances, gene therapy, and DNA-based therapies.

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 CT-Regs and the G-ReptSafetyData 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 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, the 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

Per MWI-25, clinical trials in Malawi are required to follow the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (MWI-22). MWI-22 notes that the investigator should promptly provide written reports to the sponsor and the institutional ethics committee (EC) on any changes significantly affecting the conduct of the trial, and/or increasing the risk to participants.

According to the G-NHSRC, the National Health Sciences Research Committee (NHSRC) requires an initial submission of a progress report within three (3) months of approval of the study, and an annual report for medium to long-term studies.

The G-COMREC requires that the College of Medicine Research and Ethics Committee (COMREC) follow the progress of studies for which a positive decision has been reached and establish a subcommittee responsible for monitoring ongoing studies. As part of the monitoring process, every approved study must submit annual reports by November 30, regardless of the date of its approval.

As required in MWI-58, the principal investigator (PI) must submit an annual progress report to the Pharmacy and Medicines Regulatory Authority (PMRA). All sections of the Clinical Trial Annual Progress Reporting Form for Investigators (MWI-58) must be completed in typescript and submitted together with accompanying documents to the PMRA Director General at info@pmra.mw. Both hard and soft (electronic) copies must be submitted.

The G-NHSRC and the G-COMREC further state that all approved studies continuing for more than one (1) year are subject to continuing review by the approving EC. As part of this review, applicant(s) are required to submit a progress report describing the number of participants enrolled, any problems that occurred during the prior approval period, any new knowledge regarding the study, and any procedural changes.

See MWI-54 and MWI-8 for the NHSRC and COMREC report forms, respectively.

Final Report

As required by the G-NHSRC and the G-COMREC, the applicant is required to submit a final report to the approving EC when a study is completed.

According to the G-NHSRC, the investigator must submit three (3) copies of the final technical report when submitting written notice of the completion of the study to NHSRC.

Other Considerations

The G-NHSRC states that all data originating from a research study conducted in Malawi are the property of the Malawi Government irrespective of the source of funds for carrying out the study. Therefore, investigators are required to submit copies of their reports to NHSRC for review prior to submitting for publication within or outside of Malawi. Investigators are expected to have plans for disseminating research findings in Malawi.

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. In addition, TMDA provides a six (6)-month progress report form for clinical trials of investigational products (TZA-3). The CT-Regs states that progress reports should be submitted annually, or more frequently, as required by the TMDA.

Per the G-EthicsHR-TZA, researchers must submit progress reports to the ethics committee (EC). The investigator must ensure appropriate and timely feedback on the research process including progress reports at regular intervals as stipulated by the EC. Periodic progress reports enable the EC to determine whether the research study is progressing according to the approved protocol.

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 the 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 the NatHREC on a Close-out Form (Form 08 in TZA-5) 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 closeout will be provided to the investigator and a copy retained in the proposal file. Further, the G-EthicsHR-TZA requires researchers to submit a final report to the institutional EC containing a summary of the study's key findings, recommendations, and conclusions.

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 D-ImprtRelIMPs and the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (MWI-22), a sponsor is defined as an individual, company, institution, or organization that takes responsibility for the initiation, management, and/or financing of a clinical trial. Per MWI-25, clinical trials in Malawi are required to follow MWI-22. MWI-22 goes on to specify that a sponsor-investigator is an individual who both initiates and conducts, alone or with others, a clinical trial, and under whose immediate direction the investigational product is administered to, dispensed to, or used by a participant. The term does not include any person other than an individual (e.g., it does not include a corporation or an agency). The obligations of a sponsor-investigator include both those of a sponsor and those of an investigator.

In accordance with MWI-22, a sponsor may transfer any or all of its trial-related duties and functions to a contract research organization (CRO) and/or institutional site(s). However, the ultimate responsibility for the trial data’s quality and integrity always resides with the sponsor. Any trial-related responsibilities transferred to a CRO should be specified in a written agreement. The CRO should implement quality assurance and quality control.

A sponsor may be domestic or foreign. As specified in the R-HlthResCoord, a sponsor that is a foreign company, organization, or individual(s), must first be affiliated with a local Malawian institution that is recognized by the National Commission for Science and Technology (NCST) prior to commencing any operations in the country.

Per the CT-Regs and the G-AppConductCT, 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. 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.

As required in the G-EthicsHR-TZA, the sponsor is responsible for providing all the necessary financial support for the initiation and completion of the research study. Additional sponsor responsibilities include developing the final study report; providing forms for safety monitoring and reporting; securing compensation or indemnity in the event of research-related injuries, disability, or death; and managing matters related to the investigational new drug.

The G-EthicsHR-TZA states that research may be externally sponsored, meaning that it is sponsored, financed, and sometimes wholly or partly carried out by an external organization with the collaboration or agreement of the appropriate authorities of the host community.

Overview

The G-CTAProcsVacBiol specifies that the investigator(s) must be qualified, experienced, and have specific good clinical practice (GCP) training. The principal investigator (PI) should have acted as a sub-investigator in at least one (1) prior clinical study. The investigator must also commit to complying with the clinical trial protocol, have no conflicts of interest, and have no history of GCP noncompliance.

Per MWI-25, clinical trials in Malawi are required to follow the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (MWI-22). MWI-22 provides the following guidance to sponsors on investigator and site selection:

• The sponsor is responsible for selecting the investigator(s)/institution(s). Each investigator should be qualified by training and experience and should have adequate resources to properly conduct the trial for which the investigator is selected. If organization of a coordinating committee and/or selection of coordinating investigator(s) are to be utilized in multicenter trials, their organization and/or selection are the sponsor’s responsibility.
• Before entering an agreement with an investigator/institution to conduct a trial, the sponsor should provide the investigator(s)/institution(s) with the protocol and an up-to-date Investigator’s Brochure, and should provide sufficient time for the investigator/institution to review the protocol and the information provided.

As stated in the G-CTAProcsVacBiol, all clinical trials must also be conducted in a laboratory that can provide evidence of accreditation with a recognized control authority to conduct the specified test. In the absence of an accreditation authority, proof of Good Laboratory Practice compliance and validation of assay methods should be provided.

Foreign Sponsor Responsibilities

According to the G-NHSRC, foreign researchers must be affiliated to a local institution and provide a supporting letter from the institution as evidence. Additionally, they must have a local collaborator. The R-HlthResCoord further indicates that any foreign-based institution or organization must first be affiliated with a local Malawian institution that is recognized by the National Commission for Science and Technology (NCST) prior to commencing any operations in the country.

Data and Safety Monitoring Board

Although not specified as a sponsor requirement, the G-CTAProcsVacBiol states that a Data Safety Monitoring Board (DSMB) or a similar body must be established and empowered to regularly assess the trial and to recommend a pause or termination of the trial for safety reasons. MWI-22 notes that a DSMB may be established to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial.

Multicenter Studies

As delineated in MWI-22, 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 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 among investigators is facilitated

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 sufficient time is available 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 (GCPs) 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.

Per G-EthicsHR-TZA, institutions hosting research are overall accountable for research projects within their institutions. The institution must work closely with the investigators and monitor implementation of the research activities. Specifically, the host institution must ensure that they have qualified and competent investigators to carry out the research studies at the institution; facilitate the smooth implementation of research studies conducted at the institution; and take appropriate disciplinary action against investigators for non-compliance.

Foreign Sponsor Responsibilities

The G-EthicsHR-TZA states that research may be externally sponsored. The ethical standards should not be less stringent than they would be for research carried out in the country of the sponsoring organization. Local ethics committees (ECs) are fully empowered to disapprove a study they believe is unethical.

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

Per the G-EthicsHR-TZA, all Phase I, II, and III clinical trials, including drug efficacy trials, conducted in Tanzania must have a safety monitoring plan and Data and Safety Monitoring Board (DSMB) or a Data Monitoring Committee (DMC). Other interventional studies, such as community trials, may be required to set up DSMBs on a case-by-case basis. The National Health Research Ethics Committee (NatHREC) must ensure the establishment of a DSMB in all clinical trials to periodically assess the progress of implementation of safety data and the efficacy endpoints and to recommend to the sponsor whether to continue, modify, or terminate a trial. See the G-EthicsHR-TZA for details on the DSMB composition, qualifications, affiliation, terms of reference, and reporting.

As delineated in TZA-5, NatHREC considers DSMBs to be relevant in the following kind of studies:

• Controlled studies with mortality and/or severe morbidity as a primary or secondary endpoint
• Randomized controlled studies focused on evaluating the clinical efficacy and safety of a new intervention
• Early studies of a high-risk intervention
• Studies in the early phases of a novel intervention with very limited information on clinical safety
• Studies where the design or expected data accrual is complex, particularly studies with a long duration
• Studies carried out in emergency situations

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 the 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 must include regional representation, and a Tanzanian must be among the members. Where necessary, NatHREC may request that the sponsor submit the most recent report from the DSMB. 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/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 or 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

Per the G-EthicsHR-TZA, for multicenter studies, the study must be conducted in a methodologically identical way at each center. See the Scope of Review section for more details on 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-CTInsurance-MWI, the G-CTAProcsVacBiol, the G-CTARevVacBiol, and the G-COMREC, the sponsor or the investigator(s) are responsible for providing insurance coverage for any unforeseen injury to research participants. Before a clinical trial begins, the sponsor should also provide insurance or indemnify the investigator and the institution against claims arising from malpractice or negligence. See the G-CTInsurance-MWI, the G-CTAProcsVacBiol, the G-CTARevVacBiol, and the G-COMREC for detailed information on when insurance is required.

As per the G-CTInsurance-MWI, the sponsor or the investigator(s) must provide the participants with a no-fault insurance policy and certificate for the duration of the trial, and for five (5) years following the trial’s completion. “No-fault” is defined as insurance for which proof of negligence or other wrongful conduct need not be established. However, the causal connection between the trial and harm, bodily injury, or death must be proven to trigger the obligation to make a compensation payment. The National Health Sciences Research Committee (NHSRC), the College of Medicine Research and Ethics Committee (COMREC), or the Pharmacy and Medicines Regulatory Authority (PMRA)'s Clinical Trial Review Committee are responsible for determining which clinical trials fall within the scope of this requirement.

Per the G-CTInsurance-MWI, obtaining and submitting insurance is a requirement and a prerequisite to obtaining clinical trial ethics and regulatory approval. The insurance documentation must be included as part of the application package submitted to either the NHSRC or COMREC, and the PMRA. As specified in the G-CTAProcsVacBiol, the sponsor or the investigator(s) must also comply with the insurance and compensation requirements delineated in the Association of the British Pharmaceutical Industry’s guidelines (MWI-21 and MWI-20).

The PMRA’s Indemnity Form for Conducting Clinical Trials (Form CT 10) is available at MWI-18.

Compensation

Injury or Death

As specified in the G-CTInsurance-MWI, the G-CTAProcsVacBiol, and the G-COMREC, the sponsor is responsible for providing compensation to research participants and/or their legal heirs in the event of trial-related injuries or death. Per MWI-25, clinical trials in Malawi are required to follow the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (MWI-22). MWI-22 provides guidance for sponsors on providing compensation to research participants in the event of trial-related injuries or death. The sponsor must explain to participants the compensation and/or treatment available to them in the event of trial-related injuries.

As per the G-CTAProcsVacBiol, the sponsor must follow the principles set forth in the Association of the British Pharmaceutical Industry’s guidelines (MWI-21 and MWI-20) to comply with Malawi’s participant compensation and treatment requirements due to trial-related injuries. The guidelines state that the sponsor should furnish written assurance to the investigator that the sponsor will agree to pay compensation to participants and/or the legal heirs in the event of trial-related injuries or death. The investigator, in turn, communicates this information to the relevant ethics committees (ECs).

MWI-21 provides several basic principles to guide sponsors in fulfilling their compensation obligations. Compensation should be paid as follows:

• When it can be demonstrated that a causal relationship exists between a participant’s injury and participation in a trial
• When a child is injured in utero through participation by the child’s mother in a clinical trial
• When the injury results in permanent injury or disability to the participant
• When there is an adverse reaction to a medicinal product under trial, and injury is caused by a procedure adopted to deal with that adverse reaction

MWI-21 states that the likelihood of an adverse reaction, or the fact that the participant has freely consented (whether in writing or otherwise) to participate in the trial should not exclude the participant from being eligible for compensation. The amount of compensation paid to the participant should be appropriate to the nature, severity, and persistence of the injury. The compensation should also be generally consistent with the amount of damages commonly awarded for similar injuries.

According to MWI-21, the amount paid in 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

Per MWI-21, in any case where the sponsor agrees to pay the participant, but the two (2) parties differ on what is the appropriate level of compensation, it is recommended that the sponsor agree to seek the opinion of a mutually acceptable independent expert at the sponsor’s own cost. This opinion should then be made available to the participant(s), and the expert’s opinion should be given substantial weight by the sponsor in reaching a decision on the payment amount.

Additionally, any participant claims pursuant to MWI-21, should be made to the sponsor, preferably via the investigator. The participant should include details on the nature and background of the claim, which the sponsor should review expeditiously. The review process may be delayed if the participant requests an authority to examine any medical records relevant to the claim.

Trial Participation

Per G-BioSampCompense, participants may also be reimbursed for trial-related expenses, if allowed by the EC. However, payments to participants that are construed to affect the voluntary participation of the subjects are not allowed. Furthermore, lump sum payments for research participation are not allowed. Participants who incur direct costs from trial participation must be reimbursed if required by the EC. Such reimbursable expenses include travel and communications costs associated with routine clinical trial evaluations. During review of the protocol, the EC will make a case-by-case determination if the study should provide any form of acceptable recompense.

Insurance

As set forth in the CT-Regs, the G-AppConductCT, the G-CTInsurance-TZA, and TZA-5, the sponsor or the 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 state 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.) The G-EthicsHR-TZA requires that insurance issues are clearly described in all clinical trial protocols, and that sponsors and investigators comply with the G-CTInsurance-TZA.

As per the CT-Regs and the G-CTInsurance-TZA, the sponsor or the 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 deemed necessary by the protocol. The sponsor and the institution’s chief executive officer must sign the indemnity. 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 (EC)-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 and the G-EthicsHR-TZA, the sponsor or the designated 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-EthicsHR-TZA states that research study participants must not be asked to waive the right to compensation and must retain the legal rights to seek monetary compensation for research-related injuries including settlements out of court, in accordance with applicable laws in Tanzania.

Per TZA-5, investigator(s) must ensure participants (or their dependents in case of participant death) are equitably compensated should they sustain unexpected serious injuries (physical, psychological, or social harm) that are judged to be related to the investigational product (IP) or study procedure. Participants must not be compensated if they sustain expected adverse events or those related to other licensed medicines appropriately prescribed during the trial.

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.

The G-EthicsHR-TZA indicates that research study participants may be reimbursed for lost earnings, travel costs, lunch, and other expenses incurred in taking part in a study; they may also receive free medical services. Research participants, particularly those who receive no direct benefit from the research, will be compensated for inconvenience and time spent. Compensation must not be so large as to induce potential participants to consent to participate in the research study against their better judgement (undue inducement). A local EC must approve reimbursement and compensation for research study participants. Incentives to research study participants for their participation in research studies must not be considered a research benefit, but a recruitment incentive, and should not present undue influence on potential research participants.

Post-Trial Access

Per the study protocol template in the G-AppConductCT and TZA-42, details on post-trial access to products must be provided in the study protocol.

Per the G-EthicsHR-TZA, where appropriate, the clinical trial protocol should include a provision for the involvement of the community in the research process including the post-research period. The community in this context may be geographical or study population. Further, there should be optimization of collateral benefits to the research communities including access to the products of the research. If the investigational product is found to be beneficial, the investigator should assist to secure its provision, without charge, to participants in the research study following the conclusion of the study.

Quality Assurance/Quality Control

Per MWI-25, clinical trials in Malawi are required to follow the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (MWI-22). MWI-22 guides sponsors on quality, data, and records management.

Per MWI-22, 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:

• During protocol development, identification of processes and data that are critical to ensure participant protection and the reliability of trial results
• Identification of risks to critical trial processes and data
• Evaluation of the identified risks against existing risk controls
• Decisions on which risks to reduce and/or which risks to accept
• Documentation of quality management activities and communication to those involved in or affected by these activities
• Periodic review of risk control measures to ascertain whether the implemented quality management activities are effective and relevant
• In the clinical study report, a description of the quality management approach implemented in the trial and a summary of important deviations from the predefined quality tolerance limits and remedial actions taken

See also MWI-61 for information on Pharmacy and Medicines Regulatory Authority (PMRA) procedures for conducting and reporting Good Clinical Practice (GCP) inspections.

Monitoring Requirements

As part of its quality assurance (QA) system, the G-CTAProcsVacBiol notes that the sponsor should perform a clinical trial audit. The purpose of the audit should be to evaluate trial conduct and compliance with the protocol, standard operating procedures (SOPs), and other applicable regulatory requirements. The sponsor should appoint auditors to review the clinical trial. The sponsor should ensure that the auditors are qualified by training and experience, and the auditor’s qualifications should be documented. The sponsor must also ensure that the audit is conducted in accordance with the sponsor’s own SOPs, the auditor observations are documented, and data are available as needed for the PMRA to review. No specific timeframe is provided for the audit process.

Per MWI-22, 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).

Premature Study Termination/Suspension

According to MWI-22, 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. Refer to MWI-17 for the National Health Sciences Research Committee (NHSRC)’s protocol termination form.

The G-COMREC states that if a study is prematurely suspended/terminated, the applicant should notify the College of Medicine Research and Ethics Committee (COMREC) of the reasons for suspension/termination, and a summary of the results obtained should be communicated to the committee.

Quality Assurance/Quality Control

As stated in the CT-Regs and the G-AppConductCT, 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 G-EthicsHR-TZA, during the conduct of clinical trials, deviations from the original study might occur, such as changes in the sample size or analysis of the data as described in the protocol. Deviations must be reported to ethics committees (EC). In the case of permanent deviations, researchers may write an amendment. The EC must decide whether a deviation is accidental or purposeful. Protocol violations are deviations from the original protocol that significantly affect the rights or interests of research participants and the scientific validity of the data. In the case of protocol violations, study participants must be informed and provisions made to protect their safety and welfare. ECs may halt the continuation of a previously approved protocol if they find protocol violations or other misconduct. Any serious or continuing non-compliance with ethical standards in the conduct of previously approved research projects must be reported to the sponsor and institutional or governmental authorities by the study’s principal investigator (PI) and the Data and Safety Monitoring Board (DSMB).

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 communicating 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

Further, TZA-13 indicates 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. 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 any custom 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 are 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.

Per Pub-Rpts, to promote transparency of clinical trial oversight in the country, TMDA will publish to its website clinical trial public assessment reports (CTPAR) and clinical trial public inspection reports (CTPIR) of all approved and ongoing clinical trials on an annual basis. The publication will only be undertaken after obtaining the consent of the respective PIs and sponsors. The PIs and sponsors are required to provide their consent within 14 days from TMDA’s notification letter. Failure to respond is assumed to mean that the PIs and sponsors have consented to the publication of the CTPAR and CTPIR. For further clarification on this notice, contact TMDA at clinicaltrials@tmda.go.tz or info@tmda.go.tz.

Premature Study Termination/Suspension

The CT-Regs and the G-AppConductCT state that if a trial is prematurely terminated or suspended, the 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.

The G-EthicsHR-TZA also indicates that in the event of early termination of the research study, the investigator must inform, in writing, the appropriate EC, the National Institute for Medical Research (NIMR), the TMDA, and the research sponsor of the early termination and the underlying reason for such termination. Per TZA-5, NatHREC should be notified if the investigator chooses to suspend the study. To resume a suspended study regardless of who initiated the suspension, the PI must submit a request to the Medical Research Coordination Committee (MRCC) with a report on the progress of addressing corrective actions. Research studies may be terminated based on the recommendation of the NatHREC, zonal or institutional ECs, DSMB, study sponsor, PI, or regulatory authority. In addition, a research study can be terminated due to an arising conflict of interest among investigators or financial misuse, which negatively affects implementation of the research project.

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 EC should also be informed promptly and provided the reason(s) for the termination or suspension by the sponsor.

Electronic Data Processing System

Per MWI-25, clinical trials in Malawi are required to follow the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (MWI-22). As per MWI-22, 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. 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 standard operating procedures (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 MWI-22 for additional information.

Records Management

As set forth in MWI-22, sponsor-specific essential documents should be retained until at least two (2) years after the last approval of a marketing application, until there are no pending or contemplated marketing applications, or at least two (2) years have elapsed since the formal discontinuation of the investigational product’s clinical development. The sponsor should inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed.

In addition, MWI-22 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.

According to MWI-15, consent forms must be kept for three (3) years after the completion of the investigation, unless otherwise stipulated by the National Health Sciences Research Committee (NHSRC).

Electronic Data Processing System

As stated in the CT-Regs and the G-AppConductCT, 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 standard operating procedures (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

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. Further, documentation should be retained for at least two (2) years after the last approval of a marketing application. The sponsor should inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed. See the CT-Regs for detailed record retention requirements. As set forth in 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.

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.

Responsible Parties

For the purposes of data protection requirements, PDP-Act delineates that the “data controller” (i.e., the natural/legal person or public body designated by law) is responsible for determining the purpose and means of processing personal data. The "data processor" processes personal data on behalf of the data controller. The “data protection officer” is an individual appointed by the data controller or data processor to ensure compliance with the PDP-Act and its regulations. Data controllers and processors must be registered with the Personal Data Protection Commission (PDPC). See the PDP-Reg-TZA for detailed procedures on registering with PDPC.

Data Protection

Per the PDP-Act, the data controller or data processor must protect personal data by ensuring that it is:

• Processed lawfully, fairly, and transparently
• Collected for explicit, specified, and legitimate purposes and not further processed in a manner incompatible with those purposes
• Adequate, relevant, and limited to what is necessary in relation to the purposes for which it is processed
• Accurate and where necessary, kept up to date, with every reasonable step taken to ensure that any inaccurate personal data is erased or rectified without delay
• Stored in a form which permits identification of data subjects for no longer than is necessary for the purposes for which the personal data is processed
• Processed in accordance with the rights of a data subject
• Processed in a manner that ensures appropriate security of the personal data, including protection against unauthorized or unlawful processing and against any loss, destruction or damage
• Not transferred abroad contrary to the provisions of the PDP-Act

Regarding transborder data flow, the PDP-Act prohibits the transfer of personal data outside of Tanzania except under the following circumstances:

• If the data is transferred to a country that also has a data protection law enacted
• If the country does not have a data protection law, data may only be transferred outside of Tanzania based on several factors, including the recipient state's federal legal frameworks, security and privacy principles, the type of information being shared, the data transfer mechanisms in place, the specific reason for the transfer, and the proposed length of data processing (See the PDP-Act for more details)

See the PDP-Reg-TZA for detailed implementation requirements.

Consent for Processing Personal Data

Per the PDP-Act, before collecting data, a data controller must ensure that the data subject is aware of the purposes for which the personal data is collected; the fact that collection of the personal data is for authorized purposes; and any intended recipients of the personal data. However, the data controller is not required to inform the data subject if the personal data is publicly available, the data subject concerned authorizes the collection of the personal data from a third party, compliance is not reasonably practicable in the circumstances of the particular case, non-compliance is necessary per other written laws, or compliance would prejudice the lawful purpose of the collection.

As required in the PDP-Act, sensitive personal data must not be processed without obtaining prior written consent of the data subject, which may be withdrawn by the data subject at any time and without any explanation or charges. If the data subject is a minor, a person of unsound mind, or any other person unable to consent, such person’s consent must be obtained or sought from the legal representative(s)/guardian(s). Exceptions to this rule apply where the processing is necessary in these circumstances:

• Compliance with other written laws
• To protect the vital interests of the data subject or of another person, where the data subject is incapable of giving consent or is not represented by a legal representative
• Necessary for the institution, trial, or defense of legal claims
• Relates to personal data that has been made public by the data subject
• The purposes of scientific research and the PDPC has, by special guidelines, specified the circumstances under which such processing may be carried out
• For the purposes of medical reasons in the interest of the data subject and the sensitive personal data concerned is processed under the supervision of a health professional in accordance with the law

Further, the PDP-Act delineates that data collected may only be disclosed if the data subject has consented to such disclosure and if the disclosure is authorized or required by law, directly related to the purpose for which such data was collected, and/or would preserve health or reduce harm to another person or the society. Disclosure of information may also be permitted where the data subject is not identified for statistical or research purposes and where it is guaranteed that such data will not be published in a manner that will identify the data subject. Additionally, data collectors must establish a code of ethics for personal data protection during collection or processing of personal data, and they must maintain a proper security system.

Per the PDP-Reg-TZA, the rights of participants regarding their personal data are the autonomous right to control their personal data, the right to communicate and exercise their data rights, and the right to human intervention to minimize biases that automated processes may create. In addition, per the G-EthicsHR-TZA, researchers using online and digital tools must protect the individual’s right to privacy and confidentiality including whether they knew or were expected to know that records and data were being kept. If individuals have reasonable expectations of privacy and impermanence of their online activities, then researchers may need to take specific measures to inform the respondents and obtain their consent to use their data for research. Further, if studies use artificial intelligence, the participant’s “right to be forgotten” must be protected by enabling their ability to request that a search engine remove information about them.

Obtaining Consent

In all Malawian clinical trials, a freely given informed consent is required to be obtained from each participant in accordance with the requirements set forth in the G-NHSRC and G-COMREC-IC. The G-BioSampCompense also confirms that a participant’s voluntary informed consent is required. Also, per MWI-25, clinical trials in Malawi are required to follow the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (MWI-22).

As per the G-NHSRC, the G-CTAProcsVacBiol, the G-CTARevVacBiol, the G-COMREC, and MWI-22, the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by one (1) of the two (2) National Commission for Science and Technology (NCST)-approved ethics committees (ECs)—the National Health Sciences Research Committee (NHSRC) and the College of Medicine Research and Ethics Committee (COMREC)—and provided to the Pharmacy and Medicines Regulatory Authority (PMRA) with the clinical trial application. (See the Required Elements section for details on the contents to be included in the form.)

The G-NHSRC, the G-COMREC-IC, and MWI-22 state that the participant and/or the legal representative(s) or guardian(s) must be provided with detailed research study information. Per the G-NHSRC, the ICF content should be presented orally and in writing, in a manner that is easy to understand, commensurate with the comprehension level of the research participants, and without coercion. When drafting and presenting the ICF, special consideration must be taken with regard to the participant’s culture, traditional values, intelligence, and education.

As per the G-NHSRC and MWI-22, 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 the legal representative(s) or guardian(s) to waive or appear to waive the participant’s 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. The G-BioSampCompense also confirms that researchers must not duly induce participants to participate in any proposed research. Rather, they must design and implement their studies in a manner that calls for the participants’ informed voluntary consent to participate.

Re-Consent

According to MWI-22, the written ICF and any other written information to be provided to participants should be revised whenever important new information becomes available that may be relevant to the participant’s consent. Any revised written ICF and written information should receive the EC's approval/favorable opinion in advance of use. The participant and/or the legal representative(s) or guardian(s) should 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, and the participant and/or the legal representative(s) or guardian(s) should receive a copy of the signed and dated ICF updates, including a copy of any amendments to the written information provided to the participants.

Language Requirements

As stated in the G-NHSRC, the G-COMREC, and the G-COMREC-IC, the ICF should be written in English and any other relevant local languages that the participant is able to understand.

Documenting Consent

The G-NHSRC and MWI-22 specify that the participant and/or the participant’s legal representative(s) or guardian(s) must sign the ICF. The G-NHSRC indicates that where the participant is illiterate, the NHSRC will permit the participant to provide a thumbprint in the presence of a witness, who must also sign the ICF. NHSRC also permits the participant to provide verbal consent in cases where the participant is illiterate. However, the script or information sheet to be read to the potential participant must be approved by NHSRC and be signed for by the participant’s legal representative(s) or guardian(s).

MWI-22 states that where the participant is illiterate and/or the legal representative(s) or guardian(s) is illiterate, an impartial witness should be present during the entire informed consent discussion. The witness should sign and date the ICF after the following steps have occurred:

• The written ICF and any other written information provided to the participant is read and explained to the participant and the legal representative(s) or guardian(s)
• The participant and the legal representative(s) or guardian(s), have orally consented to the participant’s involvement in the trial, and has signed and dated the ICF, if capable of doing so

Before participating in the study, the participant or the legal representative(s) or guardian(s) should receive a copy of the signed and dated ICF.

According to MWI-15, consent forms must be kept for three (3) years after the completion of the investigation, unless otherwise stipulated by the NHSRC.

Waiver of Consent

Per the G-NHSRC, the NHSRC may waive the requirement for the investigator to obtain a signed ICF in cases where circumstances warrant such a waiver. The following conditions may be considered for a waiver:

• The research presents no more than a minimal risk of harm to the participants and involves no procedures for which written consent is normally required outside of the research context
• The research could not practically be carried out without the consent waiver and obtaining informed consent is not practicable
• The consent document is the only link between the participant and the research and the principal risk of harm would come from a breach of confidentiality
• Waiver is consistent with the individual’s rights

The G-NHSRC indicates that in lieu of a signed ICF, the NHSRC may require the investigator to provide participants with a written statement regarding the research in the form of an information or fact sheet. This statement should contain, at a minimum:

• A statement verifying that the project involves research
• A description of the level of involvement and amount of time expected from participants
• A description of the study
• A description of the risks and benefits to the participants
• A statement describing the participant’s rights
• A description of the compensation to be provided to participants
• Contact information for both the investigator and NHSRC chairperson

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 CT-Regs, the G-AppConductCT, and the G-EthicsHR-TZA. 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 the designated representative, must provide detailed research study information to the participant and/or the legal representative/guardian. The G-AppConductCT, the G-EthicsHR-TZA, and TZA-5 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 the legal representative/guardian, should also be given adequate time to consider whether to participate. The G-EthicsHR-TZA indicates that informed consent protects the individual’s freedom of choice and respects the individual’s autonomy. The consent process should be a flow of information exchange between the researcher and research participants during the whole research process. The information provided should be adequate, and clearly understood by the research participants. Seeking consent must be carried out under circumstances that provide the prospective research participant or the representative sufficient opportunity to consider whether to participate and minimize the possibility of coercion or undue influence. The information given to the research participant or the representative, whether it is conveyed orally, in writing, or another delivery mechanism, must be in a language and form understandable to the participant or the legal representative/guardian.

As per the G-AppConductCT and the G-EthicsHR-TZA, 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 the legal representative/guardian to waive or to appear to waive their 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.

Per the G-EthicsHR-TZA, for verbal consent, the procedures used to obtain consent must be described within the ethics application, and the verbal consent must still contain all of the elements required for informed 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 the NatHREC and the TMDA prior to implementing any changes. The participant and/or the legal representative/guardian 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.

Per the G-EthicsHR-TZA, the investigator must ensure that there is continued adequacy of the informed consent process and renewal of informed consent if there are significant changes in the conditions or procedures of the research project or if new information becomes available that could affect the research participant’s willingness to continue in the research project.

Language Requirements

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

Documenting Consent

The G-AppConductCT and the G-EthicsHR-TZA state that the participant and/or the legal representative/guardian, and the person who conducted the informed consent discussion must sign and date the ICF. Where the participant is illiterate and/or the legal representative/guardian 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 G-AppConductCT states that the participant and/or the legal representative/guardian 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.

Per the G-EthicsHR-TZA, the study participant may imply consent by voluntary actions (e.g., express consent verbally or sign (written consent form)). A verbal or oral consent process is where the researcher and participant have a conversation to give information and obtain consent. Usually, oral consent is used when it is not possible to get written consent. The verbal consent may be deemed appropriate and applied under the following situations where:

• The study is deemed to be of minimal risk
• There are cultural or political concerns with signing contract-like documents
• The researcher and or participants could be put at risk by the existence of a paper record
• The study is conducted remotely via video conferencing software, telephone, etc.
• It may not be feasible in large information-taking settings (e.g., some focus group discussions (FGDs)); however, documentation of verbal consent for participants in FGDs must be written down to include the names of participants who consented verbally and those that did not

Waiver of Consent

Per the G-EthicsHR-TZA, for research that is no more than minimal risk, the EC may approve a request to waive some or all of the required elements of informed consent under specific circumstances. Waivers of informed consent are primarily requested for projects involving the secondary analysis of existing data. To waive or alter informed consent elements, the following conditions must be met:

• The study could not practicably be carried out without the waiver or alteration (whenever appropriate the study participants will be provided with additional pertinent information after participation)
• In situations where deception needs to be applied to achieve the objectives of the study
• The only record linking the study participant and the study would be the consent document and the principal risk to the research participant would be potential harm resulting from a breach of confidentiality
• The study participant presents in an emergency situation and informed consent cannot be reasonably obtained (See the Emergencies section for more information)

The G-EthicsHR-TZA states that if a waiver of written informed consent is granted by the EC, then each study participant should be asked whether they wish to have documentation that links them with the study; and the participant’s wishes must govern.

Per MWI-25, clinical trials in Malawi are required to follow the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (MWI-22). MWI-22 provides guidance on the elements to include in the informed consent form (ICF). The G-NHSRC and MWI-22 state that information about the research study should be clearly presented in both written and oral form.

Based on the G-NHSRC, the G-COMREC-IC, the G-NHSRC-ICF, MWI-22, and MWI-13, the ICF should include the following statements or descriptions, as applicable (Note: the sources provide overlapping and unique elements so each of the items listed below will not necessarily be in each):

• The study title, purpose, procedures, and duration
• Experimental aspects of the study
• The responsibilities and expected duration of the participant's participation
• The trial treatment(s) and the probability for random assignment to each treatment
• Any expected risks or discomforts to the participant, and when applicable, to an embryo, fetus, or nursing infant
• Any expected benefits to the participant, others, or to the country as a whole that may reasonably be expected from the research
• Description of procedures, including data collection, that will be followed
• Identification of any experimental procedures
• Disclosure of alternate procedures or treatments available to participants that might be advantageous to the participant
• Compensation and/or treatment available for the participant in the case of trial-related injury
• The anticipated prorated payment, if any, to the participant for participating in the trial
• The anticipated expenses, if any, to the participant for participating in the trial
• That participation is voluntary, and that the participant can refuse to participate or withdraw from the study at any time without penalty or loss of benefits, including medical treatment, to which the participant is otherwise entitled
• That the monitor(s), the auditor(s), the ethics committee (EC), and the regulatory authority(ies) will be granted direct access to the participant's original medical records for verification of clinical trial procedures and/or data, without violating the confidentiality of the participant, to the extent permitted by the applicable laws and regulations and that, by signing a written ICF, the participant or the participant's legally acceptable representative is authorizing such access
• The extent to which confidentiality of records identifying the participant will be maintained
• Name and contact details of institutions that have approved the study
• Contact information for the sponsor and investigator in the event of participant problems or trial-related injuries
• EC contact information
• Foreseeable circumstances under which the investigator(s) may remove the participant without the participant’s consent
• The consequences of a participant’s decision to withdraw from the research, and procedures for orderly withdrawal by the participant
• That the participant and/or the 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
• Any additional costs to the participant that may result from participation in the research
• The site of the study
• Consent and signature or thumb print, including the last sentence, which should explicitly read “I voluntarily agree”

See the Vulnerable Populations and Consent for Specimen sections for further 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: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• 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, with a description of such compensation/treatment and where further information may be obtained
• 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
• A statement of the extent of the investigator’s responsibility, where applicable, to provide medical services to the study participant
• A statement of the nature, form, and extent of compensation for study participation (e.g., reimbursement for transport, time, and meals)
• A brief description of the research project sponsors and the investigators’ institutional affiliation
• 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 the legal representative/guardian 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; these contacts must speak the participant’s language
• Foreseeable circumstances under which the investigator(s) may remove the participant without consent
• Consequences of a participant’s decision to withdraw from the research, and procedures for orderly withdrawal by the participant
• The participant and/or the legal representative/guardian 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
• A statement that study participants will get feedback on findings and the progress of the study and that any new information that affects the study or data that has clinical relevance to the participants will be made available to the participants or their health care providers
• Where necessary (e.g., illiterate, mentally incapacitated, or physically disabled study participants), the provision for a witness at appropriate stages of the informed consent process should be ensured
• A statement that the study has been approved by a recognized Tanzanian-based ethics committee (EC)
• Whether, when, and how any of the products or interventions proven by the study to be safe and effective will be made available to the study participants at the end of the study and whether they will be expected to pay for them
• With regard to research involving the collection of biological/genetic materials, an explanation should be provided on how specimens will be managed at the end of the study; if the samples are stored for future use, separate consent should be obtained
• Additional costs to the participant that may result from participation in the research

Per the G-EthicsHR-TZA, for protocols involving verbal consent, the following minimum information must be communicated to the participant:

• Introduction - who is the caller/interviewer, affiliation, organization
• A statement that the study involves research
• Study purpose
• What the participant will be asked to do and the time commitment
• Any compensation and any information to be collected to make that payment (mailing address, email address, etc.)
• The voluntary nature of participation in the study
• Any risks or benefits associated with participating (leave this out if there are none)
• That notes are being taken or data is being recorded, if applicable
• Whether the information collected will remain confidential or if it is planned to keep identifiers with the research data
• Contact information for the researcher and/or the EC
• Ask if the participant has any questions
• Ask explicitly, “Do you agree to participate in this study?”
• Depending on the nature of the study and the participant pool, the researcher may offer other pertinent information to ensure that participants are fully informed about the study and any risks or benefits from participating in it

Compensation Disclosure

Regarding compensation, TZA-5 states that investigator(s) must ensure participants are aware of the compensation guidelines and that their rights regarding compensation are protected. Participants must not be asked to waive their rights to free treatment or compensation for research-related harms, nor must they be required to show negligence or lack of a reasonable degree of skill on the part of the researcher to claim free treatment or compensation. The informed consent process or form must not contain statements that would absolve a researcher from responsibility in the case of harm, or that would imply that participants waive their right to seek compensation.

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

Overview

Per the G-NHSRC, Malawi’s ethical standards 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. Per MWI-25, clinical trials in Malawi are required to follow the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (MWI-22), which addresses participant rights.

(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-NHSRC, the G-COMREC-IC, and MWI-22, the participant and/or the legal representative(s) or guardian(s) should be informed that participation is voluntary, that the participant 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-NHSRC, the G-COMREC-IC, and MWI-22, a potential research participant and/or the 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-NHSRC, the G-COMREC-IC, and MWI-22, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right. It is the responsibility of the investigator(s) to safeguard the confidentiality of research data to protect the identity and records of research participants.

The Right of Inquiry/Appeal

The G-NHSRC, the G-COMREC-IC, and MWI-22 state that the research participant and/or the legal representative(s) or guardian(s) should be provided with contact information for the sponsor and the investigator(s) to address trial-related inquiries and/or to appeal against a violation of the participant’s rights. (See the Required Elements section for more detailed information regarding participant rights.)

The Right to Safety and Welfare

The Malawi government complies with MWI-22 principles that state a research participant’s right to safety and the protection of the participant’s health and welfare must take precedence over the interests of science and society.

Overview

As stated in the G-AppConductCT, 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 the legal representative/guardian should be informed that participation is voluntary, that the participant 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 the legal representative/guardian 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 G-EthicsHR-TZA states that information about the research study must be communicated in understandable and legally accepted language and format, and in a conducive environment, at all stages of the research.

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

Per MWI-25, clinical trials in Malawi are required to follow the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (MWI-22). MWI-22 makes provisions to protect the rights of a research participant during the informed consent process when the procedure is complicated by medical emergencies.

Per MWI-22, in an emergency, if the signed informed consent form (ICF) has not been obtained from the research participant and/or the legal representative(s) or guardian(s), or if an effective treatment is lacking but the investigational product could address the participant’s emergency needs, the clinical trial may be conducted. However, the method used on the participant must be explained clearly in the trial protocol, and the ethics committee (EC) must approve the protocol in advance. The participant and/or the legal representative(s) or guardian(s) should be informed about the trial as soon as possible, and consent to continue and other consent should be requested, as appropriate.

As per the G-NHSRC, a waiver of consent may be justified if the research being conducted could not practically be carried out without the consent waiver, and obtaining informed consent is not practicable. See the Documentation Requirements section for more information on waiver of consent.

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 the legal representative/guardian should be obtained. If prior consent from the participant or the legal representative/guardian 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 National Health Research Ethics Committee (NatHREC) and TMDA requirements. The participant or the legal representative/guardian should provide consent as soon as possible.

In addition, per the G-EthicsHR-TZA, an EC may approve a waiver of consent if the study participant presents in an emergency situation and informed consent cannot be reasonably obtained from the participant or the legal representative/guardian. During a public health emergency of national and international concern, some of the activities focusing on diseases or events threatening national and international health security are considered non-research and need immediate attention. Informed consent may not be required in non-research activities.

Overview

As per the G-NHSRC, in all Malawian 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-NHSRC characterizes vulnerable populations as those who are relatively or absolutely incapable of protecting their own interests due to illiteracy, a lack of education, autonomy, resources, or other necessary attributes. These participants may include children, pregnant women, prisoners, refugees, orphans, sex workers, people living with HIV and AIDS, persons with mental disabilities, and persons in dependent relationships (e.g., some women who culturally must ask their husbands before consenting to participate in a research study).

Per MWI-25, clinical trials in Malawi are required to follow the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (MWI-22). MWI-22 includes the following as vulnerable populations: members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable populations include persons in nursing homes, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.

The G-NHSRC specifies that National Health Sciences Research Committee (NHSRC) members must pay special attention to protecting participants who are from vulnerable populations. Consent for those who are not legally, mentally, and physically able should be sought from their legal representative(s) or guardian(s) in the form of a signature or thumbprint.

As per the G-NHSRC, trials involving vulnerable persons require the research to be directly related to the specific conditions of the vulnerable population involved, and that the participants should personally benefit from the research. In addition, the following elements must be considered when studies are conducted using vulnerable populations:

• The methods of recruitment, selection, and inclusion/exclusion criteria, as well as informed consent, data confidentiality, and the participant’s willingness to volunteer
• Group characteristics such as economic, social, physical, environmental, and cultural conditions
• Applicable local laws that bear on the decision-making abilities of potentially vulnerable participants
• Research studies involving potentially vulnerable population groups should have adequate procedures in place for assessing and ensuring participants’ capacity, understanding, and informed consent or assent
• Safeguards may include NHSRC monitoring of the consent process where possible

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

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. Vulnerable populations include 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, the G-AppConductCT 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, nomads, refugees or displaced persons, people living with disabilities, people with incurable or stigmatized conditions or diseases, and people faced with physical frailty. The G-EthicsHR-TZA additionally identifies children, mature and emancipated minors, street children, prisoners, the homeless, substance abusers, handicapped (mentally and physically), armed forces, and pregnant women. In some cases, willingness to volunteer to participate in research is unduly influenced by the expectation of benefits associated with their participation, or fear of retaliation from interested senior members of the hierarchy in case of refusal to participate. Characteristics that constitute vulnerability with reference to communities include one (1) or more of the following:

• Limited economic empowerment
• Inadequate protection of human rights
• Discrimination on the basis of health status
• Inadequate understanding of scientific research
• Limited availability of health care and treatment options
• Limited ability in the community to provide informed consent

As per the G-EthicsHR-TZA, clinical trials involving vulnerable persons require additional attention to ensure their protection. Where factors relating to vulnerability are an aspect of the research study, ethics committees (ECs) must ensure that researchers specify how that vulnerability would be addressed, particularly:

• Selection of the particular communities is justified by the research goals
• Research study is relevant to the needs and priorities of the community in which it is to be conducted
• Research study is beneficial to that community
• The community can access products of the research
• Where appropriate, feedback of results should be provided to the community
• Study participants must be fully aware that they are participating in the research and should provide informed consent
• Special attention should be paid to the content, language of the consent document, procedures for obtaining informed consent, monitoring of the process, and testing comprehension

TZA-5 requires the investigator to specify in the clinical trial application if a research protocol involves a vulnerable population or special group, provide adequate justification for their involvement, and provide information on how the participants’ rights and welfare will be safeguarded. Further, the investigator should include information about how they will assess the participants’ capacity to consent for themselves. If the participant is not able to consent, the researcher should include information about how consent will be obtained from the participant’s legal representative/guardian and how assent will be obtained from the participant (where appropriate).

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

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

Persons Highly Dependent on Medical Care

Per the G-EthicsHR-TZA, persons highly dependent on medical care, such as those living with disabilities (physical or mental) or terminally ill patients, require special attention because they are prone to being socially marginalized. Therefore, their dignity, rights, and well-being in research must be respected. For persons living with disabilities, careful consideration should be made where proxy consent is used, and where the use of signed consent forms is not feasible, alternative viable methods should be employed. Persons living with disabilities should not be unfairly excluded from participating in research. Researchers should make efforts to address communication, disability, and comprehension constraints. (See Mentally Impaired section for requirements on persons with mental disabilities). For terminally ill patients, their dire state may affect their ability to make voluntary decisions regarding participation in research studies. A research protocol involving terminally ill patients as study participants must meet the following additional requirements: the research can only be conducted with terminally ill patients; if the research objectives of the study cannot be addressed using another non-vulnerable group; and the risk-benefit ratio should be favorable to the patients.

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 be satisfied 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 research studies involving students can be conducted as long as the following conditions are met:

• The tutor involved in the tuition of the student should not be involved in the recruitment and other negotiations on the terms and research conditions
• The informed consent should clearly state that the student may wish at any stage of the research study to withdraw without any undue consequences
• An impression should not be created that acceptance to participate in the study will benefit the student in the passing of their examinations
• An impression should not be created that non-acceptance will result in discrimination and consequences on the student’s studies
• There should not be any form of coercion, pressure, or financial inducement other than that proposed as reimbursements for participants

Homeless Persons

Per the G-EthicsHR-TZA, the category of homeless persons includes street children, adults staying on the street, refugees, and internally displaced persons. In conducting research with people who are homeless, researchers should be guided by the following principles:

• Research must be conducted with respect to the human rights, welfare, and dignity of study participants
• The research study must be conducted in a non-judgmental way regarding the person’s appearance, strategies for making money, or personal habits
• The right to privacy and security must be respected at all times for people who are homeless

Armed Forces

For research involving participants in the armed forces, the G-EthicsHR-TZA requires the following consent conditions:

• Any possible advantages accruing to participants through their participation in the research study (when compared to the general living conditions, medical care, quality of food, amenities, and opportunity for earnings) are not of such magnitude so that it might impair participants’ ability to weigh the risks of the study against the value of these advantages in the military environment
• The risks involved in the research study are commensurate with the risks that would be accepted by non-armed force volunteer participants
• Procedures for the selection of study participants from within the military are fair to all military personnel and insulated from arbitrary intervention by military authorities or by other members of the armed forces
• The information conveyed to the participants is presented in language that is understandable to them
• There is adequate assurance that a participant’s participation or refusal to participate in the study will not be considered in decisions regarding their promotion, pay, or any other career opportunities

The G-NHSRC states that a minor is a person less than 18 years of age. When the research participant is a minor, assent must be obtained in tandem with permission from the legal representative(s) or guardian(s).

Per MWI-25, clinical trials in Malawi are required to follow the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (MWI-22). MWI-22 states that when a clinical trial includes minors, the minors should be informed about the trial to the extent compatible with their understanding and, if capable, they should sign and personally date the written informed consent.

Assent Requirements

As per the G-NHSRC, assent must be obtained from a minor who is deemed capable of providing assent. The National Health Sciences Research Committee (NHSRC) bases its assessment of a minor’s ability to assent on the minor’s age, maturity, and psychological state. In certain cases, the NHSRC may regard assent by minors to represent informed consent without requiring the signature from a legal representative(s) or guardian(s). A typical case is when the minors are emancipated, and may include those that are legally married or are university students under the age of 18.

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 parent/legal guardian.

According to the G-EthicsHR-TZA, research involving greater than minimal risk, but presenting the prospect of direct benefit to a child, may be conducted only if:

• The risk is justified by the anticipated benefit to the child
• The relation of the anticipated benefit to the risk is at least as favorable to the research study participants (children) as that presented by available alternative approaches
• Adequate provisions have been made for the solicitation of the child’s assent and the informed consent of the child’s parent/legal guardian

Further, per the G-EthicsHR-TZA, research that involves greater than minimal risk and entails no prospect of direct benefit to the individual child participant, but is likely to yield generalizable knowledge about the child’s disorder or condition may not be conducted unless:

• The risk represents a minor increase over minimal risk
• The intervention or procedure presents experiences that are commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations
• The intervention or procedure is likely to yield generalizable knowledge about the child’s disorder or condition that is of vital importance for the understanding or amelioration of that disorder or condition
• Adequate provisions have been made for the solicitation of the child’s assent and their parents’/legal guardians’ informed consent
• When the child’s participation is indispensable and participation is not contrary to the child’s best interest

As delineated in the G-EthicsHR-TZA, mature minors are individuals 14 to 17 years of age who are able to demonstrate the ability and capacity to manage their own affairs and to live wholly or partially independent of their parent/legal guardian. This is someone who has not reached adulthood (as defined by country law) but who may be treated as an adult for certain purposes (e.g., consenting to medical care). Emancipated minors refer to persons who have not reached the age of majority (18 years) and are empowered by law to make autonomous decisions. They are free from control by their parent/legal guardian, and the parent/legal guardian is free from the responsibility for the child. Mature and emancipated minors may independently provide informed consent to participate in research if:

• In the ethics committee’s (EC’s) view, the research is not objectionable to parents/legal guardians in the community (established with evidence from the community)
• The research protocol includes clear justification for targeting mature and emancipated minors as participants, and a clear justification for not involving parents/legal guardians in the consent process

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.

Assent Requirements

The G-EthicsHR-TZA, states that the child’s assent takes precedence over the parent’s/legal guardian’s consent. For all research involving children, there must be no financial or other inducements to participate for the parent, guardian, or child, although reimbursements and a token for the child after completion of the study may be acceptable.

Per the G-EthicsHR-TZA, children and adolescents who are minors cannot give legally-valid informed consent, but they may be able to give assent. To give assent means that the child or adolescent is meaningfully engaged in the research study discussion in accordance with their capacities. Assent must be considered as a process and is not merely the absence of dissent. Furthermore, the researcher must involve the child or adolescent in the actual decision-making process and use age-appropriate information. It is particularly important to inform the child or adolescent and obtain assent as described above, preferably in writing for children who are literate. Specific protections to safeguard children and adolescents’ rights and welfare in the study are necessary. Before undertaking research studies involving children and adolescents, the researcher and the ECs must ensure that:

• A parent/legal guardian of the child or adolescent has given permission
• Assent of the child or adolescent has been obtained, after having been provided with adequate information about the study tailored to the child’s or adolescent’s level of maturity
• If children reach the legal age of maturity during the study period, their consent to continued participation should be obtained

Per the G-EthicsHR-TZA, children or adolescents are required to assent if they are between 10 and 17 years old and can read and write, as well as understand the description of the study. In general, the refusal of a child or adolescent to participate or continue in the study must be respected unless, in exceptional circumstances, where participation is considered the best medical option. For research interventions or procedures that have the potential to benefit children or adolescents, the risks must be minimized and outweighed by the prospect of potential individual benefit. For research interventions or procedures that have no potential individual benefits for children/adolescents, the interventions should be studied in adults first, unless the necessary data cannot be obtained without participation of children/adolescents and the risks are minimized.

Per MWI-25, clinical trials in Malawi are required to follow the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (MWI-22). MWI-22 states that the informed consent form should include a statement on the reasonably foreseeable risks or inconveniences to the participant, and when applicable, to an embryo, fetus, or nursing infant.

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 the International Council for Harmonisation's Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (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, research studies relating to pregnant women or fetuses may be undertaken under the following conditions:

• The risk to the fetus is minimal and is the least possible risk for achieving the objectives of the research study, except where the purpose of the research study is to meet the health needs of the mother and the fetus, and the foreseeable benefits outweigh the potential risks
• No procedural changes that could cause greater than minimal risk to the fetus or to the pregnant woman may be introduced into the procedure for termination of the pregnancy
• No inducements, whether financial or any other form, may be offered to terminate the pregnancy for the purposes of the research study
• Appropriate studies on animals and non-pregnant individuals have been completed
• The purpose of the proposed research is to meet the health needs of the mother and the fetus will be placed at risk to the minimum extent necessary to meet these needs or the risk to the fetus is minimal
• The mother and the father are 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 is not required if the purpose of the research is primarily to meet the health needs of the mother, the father’s identity and/or whereabouts are unknown, the father is not available, or the pregnancy resulted from rape or incest

No information available regarding consent requirements for prisoners.

According to the G-EthicsHR-TZA, prisoners are vulnerable to abuse by research because their freedom for consent can easily be undermined, which could affect their ability to make a voluntary decision regarding their participation in research. Research involving prisoners may not be approved unless the proposed research has the intent and a reasonable probability of improving the health and well-being of the study participants, and appropriate knowledgeable persons in penology, medicine, and ethics have been consulted in the course of reviewing the research protocol. Further, research with prisoners can be conducted only if:

• The research offers a distinctly favorable benefit to risk ratio, not because the prisoners are a convenient source of participants
• The research improves the well-being of prisoners while taking great care to protect their health, well-being, and human rights
• The ethics committee (EC) reviews and verifies that the criteria for permissible research are satisfied
• EC members have no association with the prison(s) involved other than their status as members of the EC reviewing the proposed research study
• Where possible, a prisoner or an ex-prisoner should be co-opted to the EC in reviewing the proposed research study
• The risks involved in the research study are commensurate with risks that will be accepted by non-prisoner volunteers
• The procedure for selecting participants in the prison are fair to all prisoners
• There is adequate assurance that a prisoner’s participation or refusal to participate will not be considered in decisions regarding their release or further detention and each prisoner is clearly informed in advance that participation in the research study will have no effect on their release
• Any possible advantages accruing to the prisoner through participation in the research study, when compared to the general living conditions, medical care, quality of food, amenities and opportunity for earnings in the prison, are not of such magnitude that the prisoner’s ability to weigh the risks of the research against the value of these advantages in the prison environment is impaired

Per MWI-25, clinical trials in Malawi are required to follow the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (MWI-22). MWI-22 states that when a clinical trial includes participants with mental impairment (e.g., those with severe dementia), the participants should be informed about the trial to the extent compatible with their understanding and, if capable, they should sign and personally date the written informed consent.

The G-NHSRC states that consent for those who are not mentally able should be sought from their legal representative(s) or guardian(s) in the form of a signature or thumbprint.

As indicated in the G-EthicsHR-TZA, persons living with mental disabilities require special attention because they are prone to being socially marginalized, and therefore, their dignity, rights, and well-being in research must be respected. Careful consideration should be made where proxy consent is used. Where the use of signed consent forms is not feasible, alternative viable methods should be employed. Persons living with disabilities should not be unfairly excluded from participating in research. Researchers should make efforts to address communication, disability, and comprehension constraints. Persons with mental health conditions including psychiatric, cognitive, or developmental conditions, and substance abuse related disorders at times may be hospitalized or institutionalized, which may further compromise their ability to make voluntary decisions to participate in a research project. Research must not be conducted if the purpose of the research is not relevant to the particular health needs of persons living with disabilities, or alternative interventions exist that are at least as advantageous to the individual participant as that under the proposed study. Further, the following should be scrutinized:

• There is sufficient justification for inclusion
• There are appropriate evaluation procedures for ascertaining study participants’ ability to give informed consent; if such study participants are deemed unable to understand and to make an informed decision, then an appropriate proxy should be identified
• An informed consent process that is free from coercion
• Be of no more than minimal risk; if minimal risk is involved, the risk is outweighed by the anticipated benefits of the research study to the participants

The G-EthicsHR-TZA outlines the requirements to safeguard the rights and welfare of adults who are incapable of giving informed consent in research studies. Before undertaking research with adults who are not capable of giving informed consent, the researcher and the EC must ensure that:

• A legal representative of the person who is incapable of giving informed consent has given permission and this permission takes account of the participant’s previously formed preferences and values (if any)
• The assent of the participant has been obtained to the extent of that person’s capacity, after having been provided with adequate information about the study at the level of the participant’s capacity for understanding this information
• If participants become capable of giving informed consent during the study, their consent to continued participation must be obtained; in general, a potential participant’s refusal to enroll in the study must be respected, unless in exceptional circumstances where study participation is considered the best available medical option for an individual who is incapable of giving informed consent

As delineated in the D-ImprtRelIMPs and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (MWI-22), an investigational product (IP) (also referred to as an investigational medicinal product (IMP) in Malawi) is defined as a pharmaceutical form of an active substance 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 unauthorized indication, or when used to gain further information about an approved use. Per MWI-25, clinical trials in Malawi are required to follow MWI-22.

As delineated in the G-AppConductCT, an investigational medicinal product (IP) is defined as a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial. Further per the G-EthicsHR-TZA, an IP refers to a preventative (vaccine), therapeutic (drug or biologic), device, diagnostic, or palliative used in a clinical trial. The G-AppConductCT and the G-EthicsHR-TZA state that an IP 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 PMRAAct, the D-ImprtRelIMPs, and the G-CTARevVacBiol, the Pharmacy and Medicines Regulatory Authority (PMRA) is responsible for authorizing the manufacture of investigational products (IPs) (also referred to as an investigational medicinal products (IMPs)) in Malawi.

Per MWI-25, clinical trials in Malawi are required to follow the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (MWI-22). MWI-22 requires IPs to be manufactured, handled, and stored in accordance with applicable good manufacturing practices (GMPs) and used in accordance with the approved protocol. See MWI-11 for the PMRA’s GMP inspection application form.

Import

The PMRA is also responsible for authorizing the import of IPs. As per the G-CTAProcsVacBiol and the G-CTARevVacBiol, the sponsor may apply for an import permit at the same time that the sponsor submits the clinical trial application to the PMRA. The G-CTAProcsVacBiol further indicates that the applicant must submit proof of payment of a fee for an application to import IPs for the study, if required. Per MWI-34, the guidance in the G-CTAProcsVacBiol and the G-CTARevVacBiol also apply to clinical trials of drugs.

Per the D-ImprtRelIMPs, shipping of IPs should be conducted according to instructions given by or on behalf of the sponsor in the shipping order. A pre-clearance inspection should be carried out at the port of entry by the PMRA. The sponsor must complete the cover sheet contained in Annex 1 of the D-ImprtRelIMPs for the importation and release of IPs.

Please note: Malawi is party to the Nagoya Protocol on Access and Benefit-sharing (MWI-3), which may have implications for studies of IPs developed using certain non-human genetic resources (e.g., plants, animals, and microbes). For more information, see MWI-35.

Manufacturing

According to the TMMDAct, the CT-Regs, and the G-AppConductCT, 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. Also see the GMP-Insp for information on the inspection of manufacturing facilities of human medicinal products.

Import

Per the TMMDAct, the CT-Regs, the TFDCA-ImptExpt, the G-AppConductCT, and the G-ImpExp, the TMDA is also responsible for authorizing the import of IPs. As per the TMMDAct, the TFDCA-ImptExpt, and the G-ImpExp, the sponsor or the principal investigator (PI) may apply for an import license once the clinical trial application has been approved by the TMDA. 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 G-ImpExp states that importation of pharmaceutical products and raw materials must be done by importers whose premises are registered by the TMDA or the relevant government institutions. All importers should import pharmaceutical products and raw materials through authorized ports of entry. A person must not import any pharmaceutical product with a shelf life of more than 24 months whose remaining shelf life is less than 60%, or a pharmaceutical product with a shelf life of less than or equal to 24 months whose remaining shelf life is less than 80%.

The TFDCA-ImptExpt specifies that 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 three (3) copies of the proforma invoice numbered, 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. An online access registration form is available in Annex I of the G-ImpExp.

As delineated in the TFDCA-ImptExpt and the G-ImpExp, the import permit is valid for six (6) months, not transferable, and issued to cover only one (1) shipment. Per the G-ImpExp, in the case of partial shipments, two (2) shipments may be allowed based on the initial import permit. See the TFDCA-ImptExpt and the G-ImpExp for detailed import application requirements.

The TFDCA-ImptExpt and the G-ImpExp identify the authorized ports of entry for pharmaceutical products imported into Tanzania. The TFDCA-ImptExpt states that 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, the inspector may take samples for further investigation.

Investigator's Brochure

In accordance with the G-CTAProcsVacBiol and the G-CTARevVacBiol, the Malawi government requires the sponsor to provide investigators with an Investigator’s Brochure (IB). Per MWI-25, clinical trials in Malawi are required to follow the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (MWI-22). MWI-22 specifies that the IB must contain all of the relevant information on the investigational product(s) (IPs) (also referred to as investigational medicinal products (IMPs) in Malawi) obtained through the earlier research phases, including preclinical, toxicological, safety, efficacy, and adverse event data. The sponsor should also update the IB as significant new information becomes available.

As specified in MWI-22, the IB must include the following sections:

• Table of Contents
• Summary
• Introduction
• Physical, Chemical, and Pharmaceutical Properties and Formulation
• Nonclinical Studies (pharmacology, pharmacokinetics, toxicology, and metabolism profiles)
• Effects in Humans (pharmacology, pharmacokinetics, metabolism, and pharmacodynamics; safety and efficacy; and regulatory and post-marketing experiences)
• Summary of Data and Guidance for the Investigator(s)

See MWI-22 for detailed content guidelines.

Quality Management

MWI-60 requires that an Investigational Medicinal Product Dossier (IMPD) or alternative be submitted in the clinical trial application to the Pharmacy and Medicines Regulatory Authority (PMRA). The IMPD must include information on the quality of any IP, the manufacture and control of the IP, and data from non-clinical studies and from its clinical use.

As per the G-CTAProcsVacBiol, the G-CTARevVacBiol, and the D-ImprtRelIMPs, the PMRA requires the following documents to accompany the IP (Note: The sources provide overlapping and unique elements so each of the items listed below will not necessarily be in each):

• Evidence of manufacture under conditions compliant with current good manufacturing practices (GMPs)
• A release of specifications and tests, including a Certificate of Analysis (CoA) for each batch of IPs, as well as comparator(s), if applicable
• A copy of the PMRA’s letter of approval of the clinical trial
• Batch release certificate
• A copy of a valid Certificate of Manufacture issued by the competent authority in the country of origin
• A copy of a valid World Health Organization certificate of a pharmaceutical product issued by the competent authority in the country of origin

The D-ImprtRelIMPs states that the CoA should identify the product name or code; the sponsor/company name; batch numbers; expiration dates; date of issue; signature, qualification, and title of responsible person; and the results of physical and analytical tests. Per MWI-22, the sponsor must maintain a CoA to document the identity, purity, and strength of the IP(s) to be used in the clinical trial.

The sponsor should complete the cover sheet in Annex 1 of the D-ImprtRelIMPs, include it with each IP shipment, and use the checklist in Annex 2 to ensure the required documentation is attached. As delineated in the D-ImprtRelIMPs, the sponsor should also prepare IP shipping instructions, including information about the shipment’s overall physical condition, for PMRA review and approval. The sponsor should provide information on the acceptable storage temperatures and storage conditions.

Investigator’s Brochure

In accordance with the CT-Regs and the G-AppConductCT, the Tanzanian government follows the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (TZA-13), and requires the sponsor or the designated contract research organization (CRO) to provide investigators with an Investigator’s Brochure (IB). The G-AppConductCT states that the IB should be presented in a concise, simple, objective, balanced, and non-promotional form that enables a clinician, or potential investigator, to understand it and make an unbiased risk-benefit assessment of the appropriateness of the proposed trial. The contents of the IB should be approved by the disciplines that generated the described data and a medically qualified person should generally participate in the editing of an IB. If the investigational product (IP) is locally marketed and its pharmacology is well established and widely understood by medical practitioners, an extensive IB may not be necessary, and a current summary of product characteristics may be submitted as an alternative. If a marketed product is being studied for a new use (i.e., a new indication), an IB specific to that new use should be prepared. The IB should be reviewed at least annually and revised as necessary in compliance with a sponsor’s written procedures. More frequent revision may be appropriate depending on the stage of development and the generation of relevant new information.

TZA-13 specifies that the IB must contain all of the relevant information on the IP(s) 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.

Quality Management

Per the G-AppConductCT, the sponsor must document details regarding the chemistry, manufacturing, and control of the IP as prescribed in Module 3. This should include data to demonstrate the quality of the IP, including relevant batch analyses results. If a comparator medicinal product is used, the proprietary name of the medicinal product, non-proprietary or common name of the active pharmaceutical ingredient, company name, country from which the clinical supplies were obtained (as well as the market status in that country), dosage form(s), and strength(s) should be listed. Batch analysis results for the active pharmaceutical ingredient may be provided in either the quality summary or by providing a copy of the certificate of analysis. The certificate of good manufacturing practice should also be included in the clinical trial application.

Investigational product (IP) labeling in Malawi must comply with the requirements set forth in the D-ImprtRelIMPs. The D-ImprtRelIMPs states that for an IP to be used in a clinical trial, it must be properly labeled in the official language of the country where the trial is being conducted.

As set forth in the D-ImprtRelIMPs, the following labeling information must be included on the outer packaging or on the immediate packaging when there is no outer packaging:

• Wording that clearly indicates the IP is clinical trial material
• Product name or unique code
• Storage temperature and conditions
• Expiration date
• Sponsor contact details

Per MWI-25, clinical trials in Malawi are required to follow the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (MWI-22). The D-ImprtRelIMPs and MWI-22 state that the IP must be coded and labeled in a manner that protects the blinding, if applicable.

Investigational product (IP) labeling in Tanzania must comply with the requirements set forth in the CT-Regs, the TFDCA-ImptExpt, and the G-ImpExp. 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 CT-Regs, the TFDCA-ImptExpt, and the G-ImpExp, the following information must be included on the label (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• 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 a 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.

Per the G-EthicsHR-TZA, the sponsor is responsible for proper labelling of the IP(s). The investigational and comparator products must be labelled in conformity with the research protocol and the labelling must state that the product is for investigational purposes only.

Supply, Storage, and Handling Requirements

Per MWI-25, clinical trials in Malawi are required to follow the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (MWI-22). As defined in the D-ImprtRelIMPs and MWI-22, the sponsor must also supply the investigator(s)/institution(s) with the investigational product(s) (IP(s)), including the comparator(s) and placebo, if applicable. The sponsor should not supply either party with the IP(s) until after obtaining Pharmacy and Medicines Regulatory Authority (PMRA) and ethics committee (EC) approvals.

The D-ImprtRelIMPs and MWI-22 indicate that IPs must be suitably packaged in a manner that will prevent contamination and unacceptable deterioration during transport and storage. Additionally, the sponsor must ensure the following (Note: the sources provide overlapping and unique elements so each of the items listed below will not necessarily be in each):

• IP product quality and stability over the period of use
• IP is manufactured according to any applicable Good Manufacturing Practices (GMPs)
• Proper coding, packaging, and labeling of the IP(s)
• Records are maintained for document shipment, receipt, disposition, return, and destruction of the IP(s)
• Acceptable storage temperatures, conditions, and times for the IP

• Timely delivery of the IP(s)
• Written procedures are established, including instructions for handling and storage of the IP(s), adequate and safe receipt of the IP(s), dispensing of the IP(s), retrieval of unused IP(s), return of unused IP(s) to the sponsor, and disposal of unused IP(s) by the sponsor
• Sufficient quantities of the IP(s) are maintained to reconfirm specifications, should this become necessary

Refer to the D-ImprtRelIMPs for detailed sponsor-related IP requirements.

In addition, the PharmG-InvestDrugs states that the pharmacist at each clinical trial site, designated as the Pharmacist of Record, is the primary individual who is expected to develop and maintain an IP control system, which includes the technical procedures for product ordering, control, dispensing, and accountability. In addition, the Pharmacist of Record is responsible for the establishment of internal policies and procedures for the safe and proper use of IPs. The Pharmacist of Record will perform the day-to-day dispensing and accountability activities. A pharmacy plan must be created by the Pharmacist of Record for each clinical research site, addressing the control and use of IPs. See the PharmG-InvestDrugs for more information.

Record Requirements

In accordance with the D-ImprtRelIMPs, the sponsor is required to maintain a system for retrieving IP(s) and document this retrieval process (e.g., for deficient product recall, reclaim after trial completion, expired product reclaim). The sponsor must also maintain a system for the disposition of unused IP(s) and for the documentation of this disposition. Finally, the sponsor should maintain sufficient quantities of the IP(s) used in the trial to reconfirm specifications, should this become necessary, and maintain records of batch sample analyses and characteristics. Moreover, to the extent stability permits, samples should be retained either until the analyses of the trial data are complete or as required by the applicable regulatory requirement(s), whichever represents the longer retention period.

G-GMP-MWI requires that for IPs, the batch documentation must be retained for at least five (5) years after the completion or formal discontinuation of the last clinical trial in which the batch was used.

Supply, Storage, and Handling Requirements

Per the G-AppConductCT, the sponsor must obtain approval from the Tanzania Medicines and Medical Devices Authority (TMDA) for the investigational product (IP) dossier in the clinical trial application and any changes to the IP that relate to the chemistry and manufacturing information that may affect drug safety and quality. For example, specifications for the IP where limits of the test are relaxed or deleted; where a new impurity or degradation product has been identified; and addition of new raw materials, solvents, reagents, catalysts, or any other materials used in the manufacture of the active pharmaceutical ingredient.

The G-AppConductCT requires researchers to comply with the CT-Regs and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (TZA-13). Per TZA-13, the sponsor must supply the investigator(s)/institution(s) with the IP(s), but not until the sponsor obtains approvals from the TMDA and an ethics committee. The sponsor 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, receipt, disposition, return, and destruction of the IP(s)
• Acceptable storage temperatures, conditions, and times for the IP
• Timely delivery of the IP(s)
• Written procedures including instructions for handling and storage of the IP(s), adequate and safe receipt of the IP(s), dispensing of the IP(s), retrieval of unused IP(s), return of unused IP(s) to the sponsor, and disposal of unused IP(s) by the sponsor
• Maintain sufficient quantities of the IP(s) to reconfirm specifications, should this become necessary

The G-AppConductCT further requires the sponsor to be responsible for the destruction of unused and/or returned IPs. IPs should not be destroyed without prior written authorization by the sponsor. The delivered, used, and recovered quantities of product should be recorded, reconciled, and verified by or on behalf of the sponsor for each trial site and each trial period. Destruction of unused IPs should be carried out for a given trial site or a given trial period only after any discrepancies have been investigated and satisfactorily explained and the reconciliation has been accepted. Requests to dispose IPs must be made to and authenticated by the TMDA. The destruction must be done in accordance with applicable environmental regulations.

The TFDCA-ImptExpt requires that every importer or exporter of a pharmaceutical product must, in respect to the premises, make available the following information to the TMDA: an appropriate inventory control system; an inspection reports file; procedures for handling complaints; and registers for unfit medicines, controlled drugs, recalls, and customers. 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.

Per the G-EthicsHR-TZA, the sponsor must:

• Provide to the ethics committee (EC) and all other regulatory authorities, a description of the investigational and comparator drugs and a dossier
• Ensure that the IP and any comparator products are of appropriate quality and are subject to quality assurance procedures
• Promptly provide the investigator with any relevant new information that arises during the course of the trial, including information relating to IP safety
• Be responsible for proper packaging and labelling of the IP
• Retain sufficient samples of each batch of the IP and a record of analyses and characteristics so that, if necessary, an independent laboratory may check the product for quality control or bioequivalence

Record Requirements

As set forth in the G-AppConductCT, which complies with 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

The G-AppConductCT further requires the sponsor to record and retain destruction operations of IPs. These documents should clearly identify, or allow traceability to, the batches and/or patient numbers involved and the actual quantities destroyed.

See the Data & Records Management section for information about clinical trial-related records retention requirements.

Import/Export

As delineated in the G-CTAProcsVacBiol, MWI-14, and MWI-7, the applicant must obtain approval from the Pharmacy and Medicines Regulatory Authority (PMRA) to import and export human biological specimens into and out of Malawi. The G-CTAProcsVacBiol notes that the applicant may apply to the PMRA for permission to import and/or export materials at the same time that the applicant submits the clinical trial application.

The G-StorExptSpecimens specifies that the sponsor is responsible for shipping specimens, for preparing the required documentation (e.g., nationally authorized import/export permits and dispatch/shipping documents), and for ensuring that the samples collected from research participants are sent through the appropriate carrier to their destination. The sponsor may delegate these functions to the principal investigator (PI). Refer to Annex 1 of the G-StorExptSpecimens for a checklist to be completed by the PI for the proper storage and export of clinical trial samples. As per the G-StorExptSpecimens, the transport of specimens is subject to regulation by the International Air Transport Association.

In cases where investigators are unable to complete all required research tests in Malawi, MWI-14 and MWI-7 state that justification must be provided for the importation and exportation of samples.

Per the G-GenResReqs, the National Health Sciences Research Committee (NHSRC) requires investigators who wish to export biological/genetic materials to apply for a transfer under a material transfer agreement (MTA) that must be reviewed, approved, and signed for by NHSRC. The investigator must provide a satisfactory description of how the privacy and confidentiality of the individuals and communities and the safety of such materials will be maintained. Furthermore, an investigator is not permitted to transfer biological/genetic material to another research group locally and internationally unless NHSRC has approved a collaborative study between the two (2) parties and the material and information provided protects the participants.

Material Transfer Agreement

MWI-14, MWI-16, and MWI-7 indicate that the PMRA, the NHSRC, and the College of Medicine Research and Ethics Committee (COMREC) must ensure a MTA is in place that includes the following:

• Intention of the importation and exportation of samples
• Duration and location of storage
• Appropriate informed consent authorizing the exportation and importation
• Person(s) who will have access to the samples
• The controlling officer of the samples
• Ownership of the samples
• Capacity building (only applicable for MWI-7)

See MWI-14, MWI-16, and MWI-7 for the PMRA, NHSRC, and COMREC MTA forms, respectively.

The G-BioSampCompense also confirms that MTAs remain an instrument to be used by a researcher in requesting the approval of an ethics committee (EC) for the transfer of samples for analysis outside of Malawi.

Other Considerations

According to the G-GenResReqs and MWI-6, COMREC and NHSRC-approved samples can be stored for a maximum of five (5) years during which time all tests/analyses approved for that particular study should be concluded. MWI-6 further states that if the sample is to be used beyond five (5) years, an updated authorization must be provided, which will last another five (5) years before it can be renewed. Per G-BioSampCompense, while samples are primarily allowed to be stored as long as they are needed for the initial study, leftover samples are also permitted to be stored as long as needed for a research endeavor. See G-BioSampCompense for additional details regarding EC approval requirements.

In accordance with the G-StorExptSpecimens, the G-NHSRC, the G-HlthResConduct, and MWI-6, prior to collecting, storing, or using a research participant’s specimen(s), written consent must be obtained from the participant and/or the legal representative(s), and investigators should comply with internationally accepted ethics guidelines for specimen collection and handling. The G-BioSampCompense also confirms that consent must be obtained.

As per the G-GenResReqs, the G-StorExptSpecimens, and the G-NHSRC, a clear explanation and justification for the collection and import/export of specimens must be provided. The investigator(s) are responsible for clarifying to the participant and the legal representative(s) how the sample is to be used, and how the research results might affect their interests. MWI-60 also recommends that the clinical trial protocol submitted to the Pharmacy and Medicines Regulatory Authority (PMRA) include plans for collection, laboratory evaluation, and storage of specimens for genetic or molecular analysis in the current trial and for future use in ancillary studies, if applicable.

The G-StorExptSpecimens states that consent must also be obtained for sample storage and potential future use.

Per G-BioSampCompense, while samples are primarily allowed to be stored as long as they are needed for the initial study, leftover samples are also permitted to be stored as long as needed for a research endeavor. In addition, researchers may use secondary samples with permission of the samples’ custodial entity and if the study receives ethics committee (EC) approval. See G-BioSampCompense additional details regarding EC approval requirements.

Further, the G-GenResReqs, the G-NHSRC, and MWI-6 state that all forms of studies and testing designed to collect and store biological specimens for future unspecified genetic research/analyses, including any scientific retrospective genetic analyses, is not permitted. The G-BioSampCompense also confirms that researchers are not allowed to collect human biological samples for undefined research with the intention of storage for unspecified future use. Furthermore, it states that commercialization of human biological samples is prohibited.

Per the G-NHSRC, investigators should also avoid collecting excess specimens from participants. (See the Required Elements and Participant Rights sections for additional information on informed consent).

The G-GenResReqs states that the investigator(s) must obtain written consent for human genetic research from the participant and the legal representative(s). The informed consent form must include statements on what is being studied and why; details about study procedures; known risks, discomforts, and benefits; and alternatives to participation. In addition, the sponsor or the investigator(s) is required to provide the participant(s), the community(ies), or the tribe(s) with detailed information on how their privacy will be protected, and how the confidentiality of obtained information will be maintained. See the G-GenResReqs for consent requirement details.