Therapeutic Goods Administration

As per the TGAct, the TGR, and the G-CTHandbook, the Therapeutic Goods Administration (TGA) is the regulatory authority responsible for clinical trial approvals, oversight, and inspections in Australia at the national level. The TGA allows for the supply of unapproved therapeutic goods to be used in clinical trials for experimental purposes in humans in accordance with the provisions in the TGAct and the TGR. There are two (2) regulatory schemes for supplying unapproved therapeutic goods in clinical investigations, which are more fully examined in the Scope of Assessment section.

As per AUS-28, the TGA is part of the Health Products Regulation Group (HPRG) within the Australian Department of Health and Aged Care. The TGA’s Pharmacovigilance Branch is responsible for evaluating and authorizing certain clinical trials for all types of therapeutic products. According to the G-TrialsSOP and AUS-32, the TGA also regulates the supply, import, export, manufacturing, and advertising of therapeutic goods. Per AUS-31, therapeutic goods include prescription medicines, vaccines, sunscreens, vitamins and minerals, medical devices, blood, and blood products.

The TGA manages the Australian Register of Therapeutic Goods (ARTG) (AUS-22), a public database of therapeutic goods that can be legally supplied in Australia. According to the TGAct, the TGA grants exemptions from inclusion in the ARTG for unapproved therapeutic goods to be supplied in clinical trials.

Other Considerations

According to AUS-74, the TGA closely aligns its regulatory approaches to therapeutic products with those of comparable international regulatory counterparts, including the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), the European Medicines Agency (EMA), and the United States Food & Drug Administration (FDA), wherever possible. For more information on the international scientific guidelines adopted in Australia, see AUS-74.

Contact Information

Per AUS-23 and AUS-47, the contact information for the TGA is as follows:

Postal Address:
P.O. Box 100
Woden ACT 2606
Australia

For general questions:

Phone: 1 800 020 653 (free call within Australia) or +61 2 6289 4124 (international calls)
Fax: 02 6203 1605
E-mail: use online form (see AUS-11)

For clinical trial questions:

Phone: Same as the general questions numbers
E-mail: clinical.trials@health.gov.au

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 (MoH). 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 MoH 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

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 the NRCC as the National Research Registration Committee.)

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.

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

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

Telephone: +255 22 2700749

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

Overview

In accordance with the G-CTHandbook, the G-TrialsSOP, and AUS-47, the Therapeutic Goods Administration (TGA) allows for the supply of unapproved therapeutic goods to be used in clinical trials under two (2) regulatory schemes—the Clinical Trial Notification (CTN) scheme and the Clinical Trial Approval (CTA) scheme. The G-CTHandbook specifies that the scope of the TGA’s assessment includes all clinical trials (Phases I-IV).

Under either regulatory scheme, per the TGR, the G-CTHandbook, the G-TrialsSOP, and AUS-47, an ethics committee (EC) (Human Research Ethics Committee (HREC) in Australia) must approve the research protocol. The G-NatlStmt further specifies that any research that involves greater than low risk must be reviewed by an EC.

According to AUS-40, all public and private health organizations must also undertake a site-specific assessment (SSA) of each research project. This allows the institution to consider whether the project is suitable for the site and whether it has the capacity to conduct the research at that site. Per the G-TrialsSOP, the SSA and ethics review may occur in parallel. However, EC approval must be obtained and submitted to the research governance officer (RGO) of each participating institution before institutional authorization is granted.

For summaries of the clinical trials regulatory environment, legislation, and guidance, see AUS-40.

Clinical Trial Review Process

Per the G-CTHandbook, the sponsor is responsible for the overall decision as to whether the CTN or CTA scheme should be used. Consulting the EC responsible for protocol approval may assist the sponsor in making the decision. The main difference between the CTN and CTA schemes is the TGA’s level of involvement in reviewing data about the therapeutic goods before the clinical trial commences.

See AUS-27 for more information on choosing a clinical trial scheme.

CTN Scheme

As per the G-CTHandbook, the G-TrialsSOP, and AUS-47, under the CTN scheme, the sponsor must notify the TGA of its intention to sponsor a clinical trial involving an unapproved therapeutic good. The TGA does not assess any data relating to the proposed trial at the time of submission. As further indicated in AUS-47, sponsors may submit the CTN to the TGA concurrently with the EC’s and institution’s review and approval/authorization. However, it is the sponsor’s responsibility to ensure that all relevant approvals and authorizations are in place before commencement of the trial.

The G-CTHandbook indicates that a clinical trial is deemed to be notified as soon as the online CTN form (via the TGA Business Services (TBS) webpage (AUS-36)) has been submitted and the relevant fee has been paid. If there are any changes to the trial details notified to the TGA (such as a change in the details of the principal investigator (PI), the address of the site, or the therapeutic good), the sponsor must update the relevant fields on the online CTN form.

The G-CTHandbook further states that the TGA may request additional information if the trial raises any concern, or ask specific questions to address any deficiencies. Specifically, the TGA can request certain information or documents from the sponsor relating to the supply and handling of the goods, as well as the monitoring and results of the supply of the goods. If the TGA directs a trial notified under the CTN scheme not to be conducted or becomes aware that conducting or continuing the trial would be contrary to the public interest, then the goods used in the trial would no longer be exempt from inclusion in the Australian Register of Therapeutic Goods (ARTG) (AUS-22) and cannot be lawfully supplied. This may occur if the TGA becomes aware that allowing the trial to proceed or continue carries an unacceptable risk of death, serious illness, or serious injury.

CTA Scheme

According to AUS-47, parties that are considering submitting a CTA application are strongly encouraged to contact the TGA at clinical.trials@health.gov.au for advice regarding the application process (some class IV biologicals must be submitted under the CTA scheme). Pre-submission meetings with the TGA may be requested through the forms found on AUS-17.

AUS-47 indicates that the CTA scheme consists of a two (2)-part process. Part 1 constitutes the formal CTA application, which the sponsor completes and submits directly to the TGA. Part 2 requires the sponsor to notify the TGA when a trial commences and alert the TGA to new sites in ongoing CTA trials.

As per the G-CTHandbook, the TGA reviews relevant, but limited, scientific data, and its primary responsibility is to review the safety of the product. In addition, the TGA can request certain information or documents from the sponsor about therapeutic goods approved under the CTA scheme relating to the supply and handling of the goods, as well as the monitoring and results of the supply of the goods.

AUS-47 further specifies that the evaluation of a CTA application includes consideration of the manufacturing and quality and safety data in conjunction with the trial's usage guidelines, to inform a risk-benefit decision by the TGA on whether or not to approve the clinical trial. Any significant changes to the information provided in support of the trial are considered a variation and need to be approved, since they have the potential to affect the initial decision to approve a trial. The TGA advises clinical trial sponsors to contact them via clinical.trials@health.gov.au if they intend to change a previously approved CTA application.

The G-CTHandbook further states that the TGA can revoke an approval of a clinical trial under the CTA scheme where the conditions of approval are not met.

Inspection

According to the G-GCP-Inspect, clinical trials of medicines and biologicals regulated under the CTN or CTA schemes are subject to the TGA’s Good Clinical Practice (GCP) inspection program. The TGA can conduct a GCP inspection at any stage of the clinical trial lifecycle from the early phase of participant recruitment to completed trials. Additionally, the TGA can request certain information or documents about therapeutic goods exempt under the CTN scheme or approved under the CTA scheme. This can include the investigator’s brochure and protocol, further information about safety reports, clarification about the safety profile of a specific therapeutic good, and/or details of problems or complaints. The TGA will normally give advance notice of its intention to conduct a GCP inspection but has the right to perform an inspection at any time. In exceptional circumstances, the TGA can perform an inspection without notice.

See the G-GCP-Inspect for more details on how the TGA prioritizes and schedules GCP inspections, the kinds of inspections the TGA might conduct, the inspection process, and how the TGA reports and follows up on inspections.

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. If authorization is not granted, an appeal may be submitted to the TMDA within 60 days of the TMDA’s decision. If no appeal is submitted by the applicant within this period or, if after consideration of any comments submitted, the TMDA is still not satisfied, it must reject the application. In an appeal, the applicant must give grounds for review for each reason given for the rejection of a clinical trial. The grounds for the appeal request must be based on the information that was submitted in the application. Any additional or new information that was not earlier submitted will only be considered upon submission of a new application. The TMDA may review, reject, or vary its own decision.

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 principal investigator (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.

Therapeutic Goods Administration

As per the TGR, the sponsor is responsible for paying a fee to the Therapeutic Goods Administration (TGA) to submit an application under the Clinical Trial Notification (CTN) or Clinical Trial Approval (CTA) scheme for evaluation. Per the G-FeesCharges, the fees are as follows:

• $429 Australian dollars for unapproved medicines CTN, and for each notification of one (1) or more additional trial sites
• $2,046 Australia dollars for unapproved medicines CTA (30-day evaluation)
• $562 Australian dollars for unapproved medicines CTA – variation (30-day evaluation)
• $25,426 Australian dollars for unapproved medicines CTA (50-day evaluation)
• $6,940 Australian dollars for unapproved medicines CTA – variation (50-day evaluation)
• $429 Australian dollars for unapproved biologicals CTN, and for each notification of one (1) or more additional trial sites
• $30,964 Australian dollars for unapproved biologicals CTA
• $8,448 Australian dollars for unapproved biologicals CTA – variation

According to AUS-47, a higher fee is applicable to clinical trial applications under the CTA scheme due to the more complex nature of the evaluation process. Certain variations to an existing CTN may incur a fee, such as the addition of a new site, change to a previously notified therapeutic good that creates separate and distinct goods, or the addition of a new therapeutic good to a previously notified trial. For additional fee information, refer to Schedules 9 and 9A of the TGR and the G-FeesCharges.

Payment Instructions

AUS-66 indicates that regulatory fees and charges may be paid online or by bank transfer (electronic funds transfer (EFT)). Online payment by credit card is the preferred payment option, and all payments must be in Australian dollars.

As stated in AUS-25, online payment is made via the TGA Online Payment Portal (AUS-16). Once the payment has been finalized, the Portal will confirm that the payment has been successful. The user may request an email confirmation. Certain payments, including a CTN fee and a variation to a medicine (e.g., a therapeutic good), may be made online without an invoice. See AUS-25 for more information on TGA fees and payments. Also see AUS-49 for additional guidance and system screenshots related to paying CTN fees.

AUS-66 further indicates that to ensure all payments made by EFT are correctly allocated, the organization’s Identification Number (e.g., TGA00xxxxx) should be included in the payment ‘Reference’ field. Bank transfer fees are the payer’s responsibility. Additionally, bank transfers must be accompanied by a remittance advice, which must be issued within 24 hours for all bank transfers. Remittance advices must be emailed to TGARemittanceAdvices@health.gov.au and contain the organization’s Identification Number in the subject field. The TGA’s bank account details are as follows:

Bank: Commonwealth Bank of Australia
BSB: 062-909
Account Number: 10215498

Per AUS-66, payments from overseas can only be accepted in Australian denominations. Payers must ensure that their payment covers any international banking fees. The TGA’s international banking details are as follows:

IBAN: 06290910215498
Swift Code: CTBAAU2S

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

The Pay-Overseas reiterates that overseas customers must make all payments via GEPG. Before making any payment, TMDA customers should receive the special payment identification number (Control Number) indicated on a Proforma Invoice issued by the TMDA as per the TMMDAFees. The TMDA’s external customers who pay for services from abroad must fill the relevant payment form (swift form), especially item/section No. 70 by ensuring that no other information is entered in this section except the payment identification number (Control Number). However, the payer should select “OUR” in the charge mode section 71A. Any payment made without a Control Number will not be reflected in any invoice. Further, payments of more than one (1) Control Number(s) cannot be combined. Note that deposited money in the TMDA’s account cannot be refunded.

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

As indicated in the TGAct, the TGR, the G-CTHandbook, the G-NatlStmt, and AUS-47, Australia has a decentralized process for the ethics review and approval of clinical trial research. According to the TGR, the G-CTHandbook, the G-TrialsSOP, and AUS-47, Australia requires human research protocols to be reviewed by an institutional-level ethics committee (EC). The G-NatlStmt further specifies that any research that involves greater than low risk must be reviewed by an EC. (Note: Institutional ECs are referred to as Human Research Ethics Committees (HRECs) in Australia.)

The G-NatlStmt indicates that one (1) or more institutions can individually or jointly establish an EC or any other ethics review body. Institutions that establish an EC are responsible for adequately resourcing and maintaining it, including providing sufficient administrative support. Per the TGAct and AUS-20, ECs are required to be constituted and operate in accordance with the guidelines issued by the National Health and Medical Research Council (NHMRC), and to have notified the NHMRC of their existence. According to the TGR, the G-NatlStmt, the G-TrialsSOP, and AUS-20, institutional ECs ensure that clinical trial research complies with the NHMRC’s ethical standards published in the G-NatlStmt. See the Oversight of Ethics Committees section for more information on notification.

For summaries of the clinical trials regulatory environment, legislation, and guidance, see AUS-40.

Ethics Committee Composition

As stated in the G-NatlStmt, an EC must be composed of at least eight (8) members in the following categories:

• A chairperson with suitable experience
• Two (2) people who bring a broader community or consumer perspective and have no paid affiliation with the institution
• One (1) person with knowledge of and current experience in the professional care, counseling, and/or treatment of people
• One (1) person who performs a pastoral care role in the community
• One (1) qualified lawyer, who may or may not be currently practicing and, where possible, is not engaged to advise the institution on research-related or any other matters
• Two (2) people with current research experience relevant to the research proposals to be considered at the meetings they attend

The G-NatlStmt further states that wherever possible, one (1) or more of the members listed above should be experienced in reflecting on and analyzing ethical decision-making. As far as is practicable, institutions should ensure that their EC’s membership at each meeting has diversity, including gender diversity, and at least one third of those participating in each meeting are from outside of the institution. ECs that review research about Aboriginal and Torres Strait Islander people or communities should appoint one (1) or more members who have knowledge of research with Aboriginal and Torres Strait Islander peoples or are familiar with relevant cultural knowledge, if such a person has not already been appointed.

Per the G-NatlStmt, ECs may also include other members with the above areas of expertise or with additional areas of expertise. Institutions are encouraged to establish a pool of appointed EC members to draw on as needed to help meet minimum membership requirements and/or provide additional experience or expertise. The institution should ensure that its EC has access to the expertise necessary to properly review research, which may necessitate going outside of the EC’s membership.

Terms of Reference, Review Procedures, and Meeting Schedule

As delineated in the G-NatlStmt, institutional ECs must ensure that it documents, implements, and publicizes standard operating procedures (SOPs) that promote good ethics review, including:

• Meeting frequency, attendance, and conduct
• Minutes and agenda preparation
• Timely distribution of materials to members before meetings
• Timely consideration of applications
• Methods of deliberation and decision-making
• Processes, if any, for reviewing applications from unaffiliated or international researchers
• Disclosure of interests and management of conflicts of interest
• Appropriate confidentiality of the content of applications and the deliberations of review bodies
• Prompt notification of decisions to researchers
• Communicating with researchers, including face to face, by telephone and in writing, (including available forms of electronic communication)
• Record keeping
• Monitoring of approved research
• Reporting and handling of adverse events
• Receiving and handling of complaints
• Advising the institution(s) of decisions to suspend or withdraw ethics approval of research projects
• Attendance of people other than members at meetings

Pursuant to the G-NatlStmt, EC members should be familiar with the G-NatlStmt and other relevant guidelines; prepare for and attend EC meetings or, if unavailable, provide opinions before the meetings; and attend research ethics training programs or continuing education at least every three (3) years. Members should be appointed to an EC using open and transparent processes, and institutions should consider reviewing appointments to the EC at least every three (3) years.

The G-NatlStmt states that as far as possible, each EC meeting should be arranged to enable attendance of all members of the minimum membership categories listed above and other relevant appointed members, either in person or via available technology. Meeting papers should be provided enough in advance to enable members to be fully informed. An EC’s decision about whether a research proposal meets the requirements of the G-NatlStmt must be informed by an exchange of opinions from all members of the EC participating in the meeting. The exchange should, ideally, take place at a meeting with all those members present. Where there is less than full attendance of the minimum membership categories at a meeting, the chairperson must be satisfied, before a decision is reached, that the views of those absent who belong to the minimum membership have been received and considered. The EC should attempt to reach decisions by general agreement or consensus. Voting is neither required nor prohibited. Some decisions may not be unanimous, and a dissent should be recorded in the minutes of the meeting. Where requested by a dissenting member, the reasons for the dissent should also be recorded in the minutes of the meeting.

According to the G-NatlStmt, ECs may invite researchers, and researchers may request, to be present for discussion of their proposed research. In addition, ECs may seek advice from external experts to help in considering a research proposal. Communication between the sponsor and the EC is not prohibited but should be restricted so that it does not inappropriately influence the review of any relevant research proposals.

As delineated in the G-NatlStmt, ECs must maintain a complete record of all research proposals received and reviewed. Approved project documentation and any relevant correspondence must also be retained. Records must be maintained in accordance with the requirements of relevant Commonwealth and state or territory legislation and guidelines. See G-NatlStmt for detailed records requirements.

For more details on the governance and responsibilities of Australian institutional ECs, see the G-NatlStmt.

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, all health research involving foreign collaborators must get ethics approval from both the institutional EC and NatHREC. In addition, TZA-5 specifies that the following also require review by both NatHREC and the zonal or institutional EC: all clinical trials; research dealing with vulnerable, special, or marginalized groups; and sensitive topics or indigenous communities. Protocols that do not involve foreign collaborators and non-clinical trials of investigational products (IP) can be reviewed and given ethics clearance at the zonal or institutional level. NatHREC may request zonal or institutional EC reviewers to assist in review or joint review of protocols when needed. 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. TZA-18 states that if there is no institutional EC available, the approval must be obtained from NatHREC.

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. Regarding leadership, the NatHREC Chairperson must be elected from among appointed members but must not be an employee of NIMR. The NatHREC Secretary, however, must always be an employee of NIMR. 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 (MoH)
• 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 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-NatlStmt, the institutional ethics committee (EC) (Human Research Ethics Committee (HREC) in Australia) is responsible for protecting the interests of research participants and for promoting good research by ensuring adherence to the values of research merit and integrity, beneficence, justice, and respect for persons throughout the conduct of the research project. The EC must review the recruitment and consent processes, weigh the benefits and risks of the research, and consider the impact of the research on certain groups of participants deemed to merit special consideration. Additionally, ECs may conduct both scientific and ethics review or may delegate scientific review to a sub-committee.

Pursuant to the G-NatlStmt, the establishment and maintenance of ethics review processes and processes for assessing the risk level of the research are part of an institution’s overall governance responsibility. In addition to ethics approval, research must also be authorized by each institution with responsibility for oversight of the research before it can proceed. See the Oversight of Ethics Committees, Submission Process, Submission Content, Timeline of Review, and Initiation, Agreements & Registration sections for more information on research governance requirements.

Role in Clinical Trial Approval Process

According to the G-CTHandbook, the G-TrialsSOP, and AUS-47, ECs are responsible for reviewing and approving protocols involving unapproved therapeutic goods under one (1) of two (2) regulatory schemes—the Clinical Trial Notification (CTN) scheme or the Clinical Trial Approval (CTA) scheme—prior to the sponsor initiating a trial. According to AUS-40, all public and private health organizations must also undertake a site-specific assessment (SSA) of each research project. This allows the institution to consider whether the project is suitable for the site, and whether it has the capacity to conduct the research at that site. Per the G-TrialsSOP, the SSA and ethics review may occur in parallel. However, EC approval must be obtained and submitted to the research governance officer (RGO) of each participating institution before institutional authorization is granted.

The G-CTHandbook states that a CTN scheme is a notification scheme under which the Therapeutic Goods Administration (TGA) does not review or evaluate any data relating to the clinical trial. The EC is responsible for assessing the scientific validity of the trial design, the balance of risk versus harm of the therapeutic good(s), and the overall ethical acceptability of the trial. Per AUS-47, EC and institutional review and approval/authorization may be conducted in parallel to the CTN form submission to the TGA; however, it is the sponsor’s responsibility to ensure that all relevant approvals and authorizations are in place before commencement of the trial.

Under the CTA scheme, as delineated in the G-CTHandbook, the TGA reviews relevant, but limited, scientific data, while the EC is responsible for considering the scientific and ethical issues of the proposed trial protocol.

Per the G-CTHandbook, the sponsor determines whether to conduct a clinical trial under the CTN or CTA scheme. Consulting the EC responsible for protocol approval may assist the sponsor in making the decision. One of the determining factors for an EC is whether the committee has access to appropriate scientific and technical expertise in order to assess the safety of the product. If an EC feels that it requires additional expertise to review a CTN, it may seek advice from external authorities or it may seek to collaborate with another EC that has the required expertise. An EC may also determine that it does not have access to the appropriate scientific and technical expertise to review the proposed trial under the CTN scheme and recommend review under the CTA scheme.

AUS-14 states that prior to approving a clinical trial, the EC must be satisfied that the trial protocol complies with the following requirements:

• G-NatlStmt
• Declaration of Helsinki (AUS-52)
• AU-ICH-GCPs
• TGA requirements, including the G-CTHandbook and the G-SafetyDataMgt
• Any relevant Australian Government and/or state/territory laws

The G-CTHandbook and the TGR state that during its review, the EC also needs to be aware of relevant state and territory laws pertaining to the supply of therapeutic goods or other clinical trial-related matters. The G-CTHandbook further indicates that ECs have a high level of independence and are responsible for establishing their own processes for reviewing research proposals. According to the G-CTHandbook and the AU-ICH-GCPs, if requirements specified in the G-NatlStmt appear to differ from those specified in the AU-ICH-GCPs, the TGA recommends compliance with the G-NatlStmt.

As stated in AUS-20, ECs also consider the protection of privacy for humans participating in research and their data. ECs do this by considering whether the research proposal conforms to relevant legislation, principles, and guidelines, including federal and/or state/territory legislation as well as the G-PrivacyAct95 and G-PrivacyAct95A guidelines. See the Personal Data Protection section for more information.

Per the G-NatlStmt, an EC may approve, request modification of, reject, or withdraw approval of a research proposal. The EC must clearly communicate its decision to the researcher(s):

• Where a proposal is approved or rejected, or where approval is withdrawn, communication must be in writing (which may include electronic formats) and should include an explicit statement that the proposal meets or did not meet the requirements of the G-NatlStmt. If rejecting or withdrawing approval of a research proposal, the EC should provide the rationale for its decision, including citing the provisions of the G-NatlStmt or relevant institutional policy that underpins its decision, if relevant.
• Where modifications are requested, communication may be written or, where appropriate, informal; however, a record should be kept of any informal communication, and guidance should be clearly communicated regarding to whom the researcher’s response should be directed .

According to the G-NatlStmt, varying processes may be used for the review and approval of project extensions, amendments to an approved project, progress reports, and renewal of project approval. Appropriate processes depend on the nature of the original project and any proposed changes, but any process authorized by an institution for these purposes must prioritize the safety and well-being of participants, researchers, and/or the community.

Pursuant to the G-CTHandbook and the TGR, when the EC approves a trial protocol, it takes responsibility for monitoring the progress and conduct of the trial. However, the G-NatlStmt indicates that each institution has ultimate responsibility for ensuring, via its research governance arrangements, that all its authorized research is monitored. Monitoring arrangements should be commensurate with the risk, size, and complexity of the research. Monitoring responsibilities that are performed by the institution’s EC should be based on the EC’s review of the project. However, where research that will take place at multiple sites has been reviewed by only one (1) EC, the ECs of the other institutions participating in the project do not have knowledge of the project. In such cases, only the reviewing EC can take on those elements of monitoring a research project that are commonly performed by ECs.

Per the G-NatlStmt, if the EC or institution has reason to believe that continuance of a research project would compromise participants' welfare, or if the conditions of ethics approval for the project are not being adhered to, it should immediately seek to establish whether ethical approval for the project should be suspended or withdrawn. If an institution or EC considers that suspension of research is necessary, the instruction to stop should come from the management of the institution. If ethics approval for a research project is suspended, the researcher, the institution(s), and, where possible, the participants should be informed of the suspension.

As indicated in the G-NatlStmt, ECs may require researchers to amend research procedures to protect participants. If an EC determines that such changes cannot achieve that end, the EC may decline to grant an extension to project approval or decide to withdraw approval for the research. Where ethics approval for a research project is withdrawn:

• The researcher, the institution(s), and, where possible, the participants should be informed of the withdrawal
• Continuation of the research project is subject to re-application and re-approval by the EC

See the G-NatlStmt for more details on institutional and EC responsibilities regarding research monitoring.

External Ethics Approval and the National Mutual Acceptance Scheme

The G-NatlStmt encourages the minimization of unnecessary duplication of ethics review, including for research conducted in multiple Australian jurisdictions or across international boundaries. Institutions may accept an ethics review conducted by an entity external to the institution (including overseas review bodies) and should determine their criteria for this acceptance.

Per the G-NatlStmt, researchers who wish to submit evidence of ethics approval by an external EC in support of single ethics review should be aware of existing national or international programs, protocols, policies, standards, and guidance that may be relevant to the institutional decision to accept the review. To facilitate the efficient ethics review of research, researchers must inform any EC of:

• All sites at which the research will be conducted
• Any information on local site circumstances that is relevant to the ethics review
• Any other body that will be considering ethical issues related to the research
• Any previous decisions to approve, re-consider, or deny approval of the research by another review body in Australia or elsewhere

See the G-NatlStmt for more information on external ethics approval.

As described in AUS-21 and AUS-41, the National Mutual Acceptance (NMA) scheme further supports the acceptance of a single scientific and ethical review of multicenter research conducted in publicly funded health services. All state and territory-certified public health organizations in Australia are part of the NMA scheme.

Per AUS-68, in order for ethics reviews of human research to be accepted under NMA, the EC conducting the review must be certified under the National Health and Medical Research Council (NHMRC) National Certification Scheme of Institutional Processes Related to the Ethical Review of Multi-centre Research (National Certification Scheme), and also be a “Certified Reviewing HREC” under the NMA scheme.

For more information on submissions to ECs under the NMA scheme and the National Certification Scheme, see the Submission Process and Oversight of Ethics Committees sections.

Exemption from Ethics Review

As stated in the G-NatlStmt, some research may be eligible for exemption from ethics review. Where appropriate, exemption is granted, or not, by the institution responsible for the research. Where there is no institution providing oversight of the research, researchers should request a grant of exemption from an EC. Research that may be eligible for exemption from ethics review includes research that carries a lower risk to participants or the community, and satisfies one (1) or more of the following conditions:

• The research involves the use of collections of information or data from which all personal identifiers have been removed prior to being received by the researchers, and where researchers explicitly agree: (i) not to attempt to re-identify those with whom the information or data is associated; (ii) to take all reasonable steps to prevent re-identification of the information or data for unauthorized purposes or access to the information or data by those who are not authorized; and (iii) that any sharing of any research data during or after the project will not create any additional risks of re-identification of the information or data
• The research is restricted to surveys and observation of public behavior using information that was or will be collected and recorded without personal identifiers and is highly unlikely to cause distress to anyone associated with the information or the outcomes of the research
• Is conducted as part of an educational training program in which the research activity is for training purposes only and where any outcomes or documentation are for program use only
• The research uses only information that is publicly available through a mechanism set out by legislation or regulation and that is protected by law, such as mandatory reporting information, information obtained from registries of births and deaths, coroner’s investigations, or reports of the Australian Bureau of Statistics

The G-NatlStmt indicates that institutions or other granting bodies must keep a record of any decision to grant exemption from ethics review. See the G-NatlStmt for more information on ethics review exemption.

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) (also referred to as the National Health Research Management Information System (NHRMIS)), 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 via mail at 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

The G-NatlStmt indicates that when establishing an ethics committee (EC) (Human Research Ethics Committee (HREC) in Australia), an institution must set out and publicize its terms of reference, including its schedule of fees charged, if any, for ethics review. The institution is responsible for ensuring that its EC operates in accordance with the G-NatlStmt, which includes being satisfied that any fees charged for EC review do not discourage research that the institution has an obligation to support.

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-17, the fees are as follows:

• Tanzanian researchers, expedited review – 3,875,000 Tanzanian Shillings
• Tanzanian researchers, ordinary review – 2,625,000 Tanzanian Shillings
• Tanzanian researchers, amendment – 750,000 Tanzanian Shillings
• Tanzanian researchers, extension – 300,000 Tanzanian Shillings
• Tanzanian students, expedited review – 390,625 Tanzanian Shillings
• Tanzanian students, ordinary review – 390,625 Tanzanian Shillings
• Tanzanian students, amendment – 250,000 Tanzanian Shillings
• Tanzanian students, extension – 125,000 Tanzanian Shillings
• International researchers, expedited review – $5,125 USD
• International researchers, ordinary review – $2,625 USD
• International researchers, amendment – $750 USD
• International researchers, extension – $300 USD
• International students, expedited review – $548 USD
• International students, ordinary review – $548 USD
• International students, amendment – $375 USD
• International students, extension – $125 USD

See TZA-17 for appeal fees and late renewal penalties.

Payment Instructions

No information is current available regarding payment instructions for the NatHREC.

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

As per the TGAct, the G-TrialsSOP, and the G-CTHandbook, the National Health and Medical Research Council (NHMRC) is responsible for receiving applications from ethics committees (ECs) (Human Research Ethics Committees (HRECs) in Australia) to be registered. The NHMRC was established by the NHMRCAct. Per the NHMRCAct, the NHMRC’s activities are designed to raise the standard of individual and public health throughout Australia; to foster the development of consistent health standards between the various states and territories; to foster medical and public health research and training throughout Australia; and to foster consideration of ethical issues relating to health.

Research Governance

Pursuant to the G-NatlStmt, institutions may fulfill their research governance responsibilities by establishing and overseeing different levels of ethics review. One (1) or more institutions can individually or jointly establish an EC or any other ethics review body. Institutions that establish an EC are responsible for adequately resourcing and maintaining it, including providing sufficient administrative support.

According to the G-NatlStmt, institutions should ensure that all ethics review processes and the criteria that are used for determining the appropriate process are clear, transparent, and published to enable researchers to submit their research proposals efficiently.

The G-NatlStmt further states that institutions should clearly publicize their policy for access to their EC or other ethics review processes by researchers who are not affiliated with the institution. Additionally, institutions should regularly assess all their ethics review processes, including the criteria for allocating research to different levels of review, to ensure that those processes continue to enable the institution to meet its responsibilities under the G-NatlStmt. Where possible this assessment should be informed by the documented experience of research participants and/or by involving participants or the wider community in the assessment.

Furthermore, as delineated in the G-NatlStmt, institutions should have in place an auditing process to confirm that research is being reviewed at the levels of review that their criteria require and research is being exempted from review only in accordance with the criteria set out in the G-NatlStmt. See the Scope of Review section for more information on exemption criteria.

Registration, Auditing, and Accreditation

According to the G-NatlStmt, institutions that have responsibility for oversight of research and maintain ECs must register their ECs with the NHMRC. ECs that are not associated with institutions must register themselves with the NHMRC.

Per AUS-20, registration means that the EC has notified the NHMRC of its existence and declared that it meets the requirements of the G-NatlStmt. In order to review and monitor clinical trials of unregistered therapeutic goods, an EC must be notified to the NHMRC, and constituted and operating in accordance with the G-NatlStmt. Forms for registering an EC, notifying the NHMRC of changes to the EC, or terminating an EC’s registration are available at AUS-20.

As per the G-NatlStmt, an institution and its EC must report annually, or upon request, to the NHMRC. The NHMRC, through the Australian Health Ethics Committee (AHEC), will review the activities of ECs to ensure conformance with the G-NatlStmt. Reportable information may include:

• Membership/membership changes
• Number of meetings
• Confirmation of participation in meetings by members in minimum membership categories
• The number of research proposals presented, the number approved, the number requiring modification prior to approval, and the number rejected
• Monitoring procedures that are in place and any problems encountered with monitoring of projects
• Complaints procedures and number of complaints handled
• Any other relevant policies, procedures, or processes as determined by the NHMRC

The G-NatlStmt further indicates that failure to comply with the requirements of the G-NatlStmt may result in the EC being removed from the list of ECs registered with NHMRC. See AUS-20 for more information and the list of registered ECs.

National Certification Scheme

According to AUS-21, the NHMRC developed the National Certification Scheme of Institutional Processes Related to the Ethical Review of Multi-centre Research (National Certification Scheme) to enable the single ethics and scientific review of human research occurring at multiple institutions in Australia. Under this scheme, certified institutions can have their ethics review accepted by other institutions participating in the research project. As part of the National Certification Scheme, certified institutions and their ECs are required to report to the NHMRC on their multicenter research activities.

As per AUS-21, the NHMRC assesses each institution’s interest in certification on a case-by-case basis. Certification respects institutional decisions about research governance matters, including whether research should be conducted at a given site. Before commencing steps to apply for certification, institutions should contact HREC.admin@nhmrc.gov.au.

For more information on the National Certification Scheme and the NHMRC’s continuous certification process, see AUS-21.

As stated in AUS-68, EC certification under the National Certification Scheme is required in order for ethics reviews of human research to be accepted under the National Mutual Acceptance (NMA) scheme. The NMA scheme facilitates single scientific and ethical review of clinical trials conducted in participating jurisdiction’s public health organizations. See the Scope of Review section for more information on NMA.

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 (MoH). 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 research requires 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

In accordance with the G-CTHandbook, the G-TrialsSOP, and AUS-47, Australia requires the sponsor to obtain clinical trial authorization from the Therapeutic Goods Administration (TGA) for the supply of unapproved therapeutic goods for clinical trials for experimental purposes in humans. The sponsor can apply under two (2) regulatory schemes—the Clinical Trial Notification (CTN) scheme and the Clinical Trial Approval (CTA) scheme.

Under either regulatory scheme, per the TGR, the G-CTHandbook, the G-TrialsSOP, and AUS-47, an ethics committee (EC) (Human Research Ethics Committee (HREC) in Australia) must approve the research protocol. The G-NatlStmt further specifies that any research that involves greater than low risk must be reviewed by an EC. AUS-47 indicates that the review and approval/authorization by an EC and institution may be conducted in parallel to the CTN form submission to the TGA, but it is the sponsor’s responsibility to ensure that all relevant approvals and authorizations are in place before commencement of the trial.

According to AUS-40, all public and private health organizations must also undertake a site-specific assessment (SSA) of each research project. This allows the institution to consider whether the project is suitable for the site, and whether it has the capacity to conduct the research at that site. Per the G-TrialsSOP, the SSA and ethics review may occur in parallel. However, EC approval must be obtained and submitted to the research governance officer (RGO) of each participating institution before institutional authorization is granted. While there is no submission language requirement stated in the requirements, the official language of Australia is English.

Regulatory Submission

Per AUS-17, sponsors may request pre-submission meetings with the TGA. See AUS-17 for the applicable forms.

CTN Scheme

According to AUS-47 and AUS-30, CTN forms are submitted online through the TGA Business Services (TBS) webpage (AUS-36). The sponsor must have or obtain a TGA Client Identification Number.

As per AUS-49, to submit the online CTN form successfully through AUS-36, the sponsor must accept a declaration to assume responsibility for the trial. After accepting the declaration, a webpage will advise the sponsor that the CTN submission has been successful. According to AUS-47, the TGA does not send an acknowledgement letter by email since this information is available for viewing and printing via the online portal. The TGA advises clinical trial sponsors to obtain and save a printout of notification at each stage of the submission process.

AUS-49 indicates that the sponsor may delegate duties and correspondence with the TGA to an authorized agent, which is able to create and submit a CTN on behalf of a sponsor. If an agent has submitted a CTN on the sponsor’s behalf, the sponsor will not have access to view or vary the CTN. Access is only granted to the agent.

See AUS-30 and AUS-49 for additional information on using and submitting the online form.

CTA Scheme

According to AUS-47, the sponsor must complete and submit two (2) forms (AUS-56 and AUS-57) to the TGA via email at clinical.trials@health.gov.au. Supporting data for the CTA application should be provided in electronic format, preferably on USB or CD-ROM via post. The trial commencement notification form (AUS-57) must be sent to the TGA within 28 days of commencing supply of the unapproved therapeutic goods.

Per AUS-47, those with queries regarding the CTA scheme are encouraged to contact the TGA directly at clinical.trials@health.gov.au.

Ethics Review Submission

AUS-46 indicates that the National Health and Medical Research Council (NHMRC) developed the Human Research Ethics Application (HREA) form (AUS-9) as a concise application to facilitate timely and efficient ethics review for research involving humans. The HREA assists researchers in considering the ethical principles of the G-NatlStmt in relation to their research and is accepted by institutions that participate in the National Mutual Acceptance (NMA) scheme, which facilitates single ethics review by multiple public health organizations for most human research.

According to the G-CTHandbook, trial sponsors and researchers should use the HREA unless advised otherwise. AUS-19 contains resources for using the HREA.

Per AUS-46, research proposals should be submitted to ECs associated with public health institutions in New South Wales, Queensland, South Australia, Australian Capital Territory, and Victoria, as well as Mater Research, via the Research GEMS system (AUS-55), the Ethical Review Manager (ERM) website (AUS-8), and/or the Research Ethics and Governance Information System (REGIS) (AUS-10), depending on which jurisdictions are involved. For research in the Northern Territory, Tasmania, or Western Australia, the EC should be contacted for their local submission requirements.

The G-CTHandbook further states that ECs have a high level of independence and are responsible for establishing their own processes for receiving research proposals.

Research Governance

According to the G-NatlStmt, institutions should publish (such as on their website) clear policies and procedures for institutional authorization of research. As noted in the G-CTHandbook, individual jurisdictions have specific requirements as a part of their SSA and authorization processes. South Australia sites use the online SSA form found in the Research GEMS system (AUS-55), while the ERM website (AUS-8) is used for SSA form submission for Mater Research, Queensland, and Victoria. New South Wales and the Australian Capital Territory use REGIS (AUS-10) for site governance applications.

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). All clinical trials must get ethics approval from both the institutional EC and the NatHREC. TZA-18 states that if there is no institutional EC available, the approval must be obtained from 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 NatHREC's acknowledgement of receipt for the study protocol. In addition, the TMDA's approval will only be finalized once NatHREC approval is obtained.

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 CTAs 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 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) (also referred to as the National Health Research Management Information System (NHRMIS)).

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

Clinical Trial Notification (CTN) Scheme

As delineated in AUS-49, the following information must be submitted to the Therapeutic Goods Administration (TGA) through the online form on the TGA Business Services (TBS) webpage (AUS-36):

• Sponsor name and address
• Sponsor declaration
• Notification fee (See Regulatory Fees section)
• Organization-nominated contact’s name, phone number, and email
• An optional alternative contact, which may be chosen from the contacts for the agent or sponsor organization submitting the CTN. An Australian contact number is required to be listed with either the primary sponsor contact or the alternate sponsor contact
• Protocol number
• Expected trial start and completion dates
• Potential use of restricted goods
• Study title and description, which must be a minimum of 250 characters (spaces included) and up to a maximum of 2,500 characters
• “This Trial” check boxes indicating whether the trial involves the use of a medicine, a medical device, and/or a biological. For a medicine or biological, additional information must be provided, such as dosage form, route of administration, indication, and the good manufacturing practice (GMP) license/clearance number of a relevant exemption
• Trial type
• Whether the trial is a first in human trial
• Whether the trial, in part or as a whole, has been halted/stopped/withdrawn or rejected in another country due to safety concerns
• Total number of trial participants
• Therapeutic area
• Investigational product (IP) details
• Whether it is a multi-center trial
• Whether the trial is being conducted in other countries
• Preceding trial details
• Trial site details

See AUS-49 for detailed descriptions of each required item.

Clinical Trial Approval (CTA) Scheme

AUS-47 states that the CTA scheme application consists of two (2) forms – Part 1: the application (AUS-56), and Part 2: Notification of the conduct of a trial under the CTA scheme (AUS-57).

The Part 1 CTA application form (AUS-56) requires general information (sponsor name, data details, and sponsor declaration) and details on the medicine (active ingredient)/biological be submitted to the TGA.

The Part 2 CTA application form (AUS-57) requires trial sponsor information (name and client ID code), the IP or biological, and the notification type, as well as trial and trial site details (title of study and trial type). The form also requires signed certifications from the sponsor, the principal investigator (PI), the ethics committee (EC) (Human Research Ethics Committee (HREC) in Australia), and the authority approving the conduct of the trial.

Ethics Committee Requirements

Per the G-CTHandbook, the EC and the institution are responsible for establishing what information should be provided in support of an application. The EC should request any additional information that it believes is necessary to undertake review of the proposed research. Unless advised otherwise, trial sponsors and researchers should use the Human Research Ethics Application (HREA) for submitting proposals for research involving humans to ECs.

AUS-46 indicates that the HREA assists researchers in considering the ethical principles of the G-NatlStmt in relation to their research. The G-NatlStmt requires that those who conduct and approve human research to consider:

• How the research question/theme is identified or developed
• The alignment between the research aims and methods
• How the researchers and the participants will engage with one another
• How the research data or information are to be collected, stored, and used
• How the results or outcomes will be communicated
• What will happen to the data and information after the project is completed

For more information on the HREA, see the Submission Process section.

The G-NatlStmt further specifies that in an application for review of their research, researchers should determine and state in plain language:

• The research question or questions that the project is intended to explore
• The potential benefit of exploring the question or questions including to whom that potential benefit is likely to flow, and whether that benefit is a contribution to knowledge or understanding, improved social or individual wellbeing, or the skill and expertise of researchers
• The basis for that potential benefit as described in either relevant literature or a review of prior research unless, due to the novelty of the question, there is scarce literature or prior research
• How the design and methods of the project will enable adequate exploration of the research questions and achieve the aims of the research
• How the design of the project will maintain respect for the participants
• Where relevant, that the research meets the requirements of any relevant regulations or guidelines authorized by law (such as those related to privacy and reporting requirements for disclosure of child abuse)
• Whether or not the project has been reviewed by a formally constituted academic, scientific, or professional review process, and, if so, the outcome of that review

Research Governance

According to the G-NatlStmt, institutions should publish (such as on their website) clear policies and procedures for institutional authorization of research. See the Research GEMS system (AUS-55), the Ethical Review Manager (ERM) (AUS-8), and the Research Ethics and Governance Information System (REGIS) (AUS-10) websites for public health organization site-specific assessment (SSA) forms, which may differ between institutions and states or territories.

Clinical Protocol

The G-TrialsSOP indicates that where the investigator is responsible for the protocol development, the investigator must ensure the protocol follows the outline in the AU-ICH-GCPs. Specific content of a protocol will vary depending on the research area, the level of risk to participants, the phase of the research and study design, and whether a medicinal product or a device or a therapeutic intervention is being researched. If satellite sites for a teletrial are involved in the study, no specific additional wording is required in the protocol, as relevant considerations will be addressed in other study-specific documents which may be annexed to the protocol.

The AU-ICH-GCPs provides the following outline of the protocol:

• 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
• Financing and insurance
• Publication policy

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, CRFs, 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

In accordance with the G-CTHandbook, the G-TrialsSOP, and AUS-47, the Therapeutic Goods Administration (TGA) is responsible for authorizing the supply of unapproved therapeutic goods for clinical trials under two (2) regulatory schemes—the Clinical Trial Notification (CTN) scheme and the Clinical Trial Approval (CTA) scheme. According to the TGR, the G-CTHandbook, the G-TrialsSOP, and AUS-47, under either regulatory scheme, an ethics committee (EC) (Human Research Ethics Committee (HREC) in Australia) must approve research protocols. The G-NatlStmt further specifies that any research that involves greater than low risk must be reviewed by an EC. AUS-47 indicates that the review and approval/authorization by an EC and institution may be conducted in parallel to the CTN form submission to the TGA, but it is the sponsor’s responsibility to ensure that all relevant approvals and authorizations are in place before commencement of the trial.

According to AUS-40, all public and private health organizations must also undertake a site-specific assessment (SSA) of each research project. Per the G-TrialsSOP, the SSA and ethics review may occur in parallel.

Regulatory Authority Approval

AUS-47 states that the TGA’s target time to process online CTNs is five (5) to seven (7) working days, but the agency tries to process the notification as soon as possible. This timeframe does not include the time taken for TGA finance to match the payment (if required) to a submission. For information on how to check the status of a CTN, see AUS-49.

No timeline information is available for applications under the CTA scheme. Per AUS-47, parties that are considering submitting a CTA application are strongly encouraged to contact the TGA at clinical.trials@health.gov.au for advice regarding the application process.

Ethics Committee Approval

The EC review and approval process timeline varies by institution. However, according to the G-NatlStmt, the institutional EC must implement standard operating procedures that promote good ethics review, including timely consideration of applications.

Research Governance

The G-GovHndbk indicates that ethical review and site assessment, both components of research governance, are two (2) distinct processes relating to the ethical approval and institutional authorization of research involving humans. However, because evidence of EC approval is a component of the site assessment process, institutional authorization of a research project cannot be given until EC approval has been provided. The G-TrialsSOP further specifies that EC approval must be obtained and submitted to the research governance officer (RGO) of each participating institution before institutional authorization is granted.

While some parts of the research governance review must occur after the EC review, the G-GovHndbk recommends that as part of the national approach to single ethical review, institutions establish processes to facilitate parallel review. Project documentation processes related to site assessment may be considered as falling into these categories:

• That which can be assessed independent of ethical review, such as evidence of research qualifications, supporting department approval forms, contracts, budgets, and insurance and indemnity documents
• That which is subject to ethical review, but can be submitted prior to or in parallel with ethical review to enable independent assessment of other documentation, such as initial project application documents
• That which can only be assessed subsequent to ethical approval, such as approved project application documents, fully signed regulatory documents, and a certificate of ethical approval

See the G-GovHndbk for additional National Health and Medical Research Council (NHMRC) guidance on best practices in the governance of multicenter human research as part of the national approach to single ethical review.

The NHMRC also developed the GPP-SiteAssess to help institutions streamline the research governance process and shorten clinical trial start-up times. See the GPP-SiteAssess for more information.

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). If authorization is not granted, an appeal may be submitted to the TMDA within 60 days of the TMDA’s decision. If no appeal is submitted by the applicant within this period or, if after consideration of any comments submitted, the TMDA is still not satisfied, it must reject the application.

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) (also referred to as the National Health Research Management Information System (NHRMIS)), 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

In accordance with the G-TrialsSOP, the G-CTHandbook, and AUS-47, clinical trials involving unapproved therapeutic goods can only commence under the Clinical Trial Notification (CTN) scheme or the Clinical Trial Approval (CTA) scheme. According to the G-GovHndbk and the G-TrialsSOP, under either scheme, both institutional ethics committee (EC) (Human Research Ethics Committees (HRECs) in Australia) approval and research governance authorization are required before a research project can commence at a site.

Research Governance

Per the G-GovHndbk, research must be governed by the institution at all stages of a project. Ethical review and site assessment, both components of research governance, are two (2) distinct processes relating to the ethical approval and institutional authorization of research involving humans. According to AUS-40, all public and private health organizations must undertake a site-specific assessment (SSA) of each research project. This allows the institution to consider whether the project is suitable for the site, and whether it has the capacity to conduct the research at that site. Pursuant to the G-NatlStmt, authorization of research by the institution should consider, but not re-review, any issues raised during the ethics review of the research proposal, and each institution should have a process or processes for assessing the risk level of the research. These processes may involve seeking advice from relevant clinical or administrative staff, members of an EC, or a full meeting of the EC. All research should be developed, reviewed, authorized, conducted, and monitored in accordance with a research governance framework as described in an institution’s policy. For more information on institutional responsibilities, see the Site/Investigator Selection section.

The G-TrialsSOP states that in the case of a teletrial, the principal investigator (PI) must ensure that a robust site assessment is undertaken that fully quantifies the capabilities of each satellite site to inform the extent to which trial related activities can be delegated to the site. This may include a pre-commencement assessment before a specific trial is proposed so that the process of trial start up is expedited when a suitable trial is identified.

Per the G-TrialsSOP, prior to a study’s commencement, the PI must:

• Submit the primary site's Clinical Trial Research Agreement (CTRA), EC approval, the SSA form, evidence of any relevant good clinical practice (GCP) training, and any other required documentation to the institution’s research governance officer (RGO)
• Ensure all documentation and correspondence pertaining to the submission and approval processes is filed in the study master file (SMF) (see Appendix 8 of the G-TrialsSOP)
• Ensure each satellite site completes and submits to their RGO a clinical trial sub-contract and a SSA form
• Await site specific RGO authorization before any study related activity can occur at that site
• Ensure the satellite site files all documentation in the satellite site study file (SSSF)

The G-TrialsSOP further states that prior to the initiation of a study, the investigator must also mutually agree with the sponsor on a scheduled date, time, and location for a study initiation visit at the participating site to ensure the site is prepared to commence the study. In the case of a teletrial, this may be at the primary site only, or could include (remotely) the satellite site(s) as determined by the study complexity by the sponsor/PI.

See the G-TrialsSOP for more information on site initiation requirements for primary and satellite sites.

The G-GovHndbk further indicates that in the national approach to single ethical review, site assessment and project authorization are the responsibility of each institution participating in a multicenter human research project while ethical review is provided by a single EC using certified ethical review processes. Each institution collaborating in a multicenter project utilizing the outcome of a single ethical review must individually authorize the commencement of research at their institution. To avoid unnecessary delays in research commencing at all collaborating centers and sites, each institution should consider relevant local matters prior to or in parallel with ethical review.

Clinical Trial Agreement

As delineated in the AU-ICH-GCPs, the sponsor must sign an agreement between all involved parties, including investigators, institutions, contract research organizations, and others for documentation purposes. Further, the sponsor should obtain the investigator’s/institution's agreement:

• To conduct the trial in compliance with good clinical practice, with the applicable regulatory requirement(s), and with the protocol agreed to by the sponsor and given approval/favorable opinion by the EC
• To comply with procedures for data recording and reporting
• To permit monitoring, auditing, and inspection
• To 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.

For the purposes of the G-TrialsSOP, the CTRA for the primary site and the sub-contract for each satellite site constitute part of a research governance application, which is submitted to the RGO. The CTRA covers matters such as confidentiality, intellectual property, ownership of data, insurance, and indemnity. The Medicines Australia CTRA (see AUS-38) is the recommended standard form.

Clinical Trial Registration

The G-NatlStmt requires that clinical trials be registered on a publicly accessible register complying with international standards before recruitment of the first participant. For information on these standards, see the World Health Organization (WHO)’s International Clinical Trials Registry Platform (ICTRP) (AUS-67). Per AUS-15, the Australian and New Zealand Clinical Trials Registry (ANZCTR) (AUS-12) recommends applying for registration at the same time as ethics submission.

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 indicates 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

According to the G-SftyRpt, the following definitions provide a basis for a common understanding of Australia’s safety reporting requirements:

• Adverse Event (AE) – Any untoward medical occurrence in a patient or clinical trial participant administered a medicinal product and that does not necessarily have to have a causal relationship with this treatment
• Adverse Reaction (AR) – Any untoward and unintended response to an investigational medicinal product related to any dose administered
• Unexpected Adverse Reaction (UAR) – An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., investigator's brochure (IB) for an unapproved investigational medicinal product)
• Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) – Any adverse event/adverse reaction that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect
• Suspected Unexpected Serious Adverse Reaction (SUSAR) – An adverse reaction that is both serious and unexpected
• Significant Safety Issue (SSI) – A safety issue that could adversely affect the safety of participants or materially impact the continued ethical acceptability or conduct of the trial
• Urgent Safety Measure (USM) – A measure required to be taken in order to eliminate an immediate hazard to a participant’s health or safety (Note: This type of SSI can be instigated by either the investigator or sponsor and can be implemented before seeking approval from ethics committees (ECs) or institutions)

Safety Reporting Requirements

Investigator Responsibilities

As specified in the G-SftyRpt, the investigator is responsible for recording and assessing all AEs that occur at the site. The investigator is also required to inform the sponsor of all SAEs, and all USMs instigated by the site, within 24 hours of becoming aware of the event. All safety critical events must be reported to the sponsor, and for reported deaths, the investigator should supply the sponsor with any additional requested information. Further, the investigator must report to the institution all SSIs and SUSARs arising from the local site within 72 hours of becoming aware of the event.

However, the G-TrialsSOP states that the investigator must also report any SUSARs to the sponsor within 24 hours of becoming aware of the event, and USMs instigated by the investigator or site must be reported to the sponsor within 72 hours. Furthermore, the investigator must report all other significant issues to the sponsor within 15 days of instigating or becoming aware of the event. The investigator must notify the sponsor promptly regarding any changes significantly affecting the conduct of the trial, and/or increasing the risk to participants. The investigator must also be available to meet with the sponsor to discuss study progress, issues, and safety.

The G-TrialsSOP requires that within 72 hours of instigating or becoming aware of the event, the investigator must notify the institution of:

• USMs
• SUSARs arising from the local site
• Any information received from the sponsor that may be new and have an impact on the continued ethical acceptability of the trial or may indicate the need for amendments to the trial protocol, including monitoring of safety

The G-TrialsSOP indicates that for satellite site(s) in teletrials, staff must report safety issues directly to the sponsor as per the timelines specified in the clinical trial protocol and the safety monitoring plan or similar document, in the same way as the primary site. Certified copies of the relevant safety reports/documentation generated at the satellite site must be sent to the primary site for filing in a study master file.

According to the G-TrialsSOP, the principal investigator (PI) must ensure that study staff, including those at teletrial satellite sites, are trained in the protocol, investigator’s brochure (IB), study procedures, and AE/SAE reporting. The PI must also ensure that a system for safety reporting duties is in place for all study staff. For more information on investigator responsibilities related to standard operating procedures (SOPs), see the G-TrialsSOP.

Sponsor Responsibilities

As delineated in the G-SafetyDataMgt, the G-SftyRpt, and the G-CTHandbook, the sponsor is required to expedite reporting of SUSARs to the Therapeutic Goods Administration (TGA).

The G-SafetyDataMgt indicates that other situations requiring expedited reporting may include information that might materially influence the benefit-risk assessment of an investigational product, or that would be sufficient to consider changes in the administration or conduct of a clinical trial.

According to the G-SftyRpt and the G-TrialsSOP, expedited reporting requires the sponsor to file reports to the TGA in the following specified timelines:

• For an Australian SUSAR that is fatal or life-threatening, immediately, but no later than seven (7) calendar days, with any follow-up information within eight (8) calendar days
• For all other Australian SUSARs, no later than 15 calendar days after becoming aware of the case

The G-SftyRpt and the G-TrialsSOP further indicate that the TGA, the EC, and investigators must also be notified of all SSIs that adversely affect the safety of participants, or materially impact the continued ethical acceptability or conduct of the trial. SSIs that meet the definition of a USM should be reported within 72 hours, and all other SSIs should be reported within 15 calendar days of the sponsor being made aware of the issue. It is strongly recommended that the sponsor contact the TGA within 24 hours of a USM being taken, and if initial contact is by telephone, it should be followed up with a written notification provided by e-mail within 72 hours. See AUS-53 for additional information on SSIs and USMs.

Per the G-SftyRpt, submitting individual reports of AEs, SAEs, and SUSARs to ECs, institutions, and investigators are no longer required. However, according to the G-TrialsSOP, the sponsor must provide the EC with an updated IB at least annually that supports trial oversight, depicts a clear picture of the evolving trial safety profile, and provides evidence that the sponsor is conducting its safety monitoring appropriately.

The G-CTHandbook and the G-SftyRpt further require the sponsor to maintain records of all other single case AEs and submit them to the TGA upon request. The G-CTHandbook indicates that the TGA does not require sponsors to submit individual SUSARs from outside Australia. Sponsors should continually monitor the safety of their clinical program and advise the TGA of any SSIs that arise from their analysis of overseas reports, or of any action that has been taken by another country’s regulatory agency. Investigators and ECs should also be informed of this information, and sponsors must be able to provide the TGA with the clinical details of any individual overseas AE reports if requested.

According to the G-TrialsSOP, the sponsor’s plans for safety data monitoring should be documented in a safety monitoring plan or similar document and be given to the PI prior to commencement of the clinical trial. The plan must be continually reviewed and updated during the trial, as real-time assessments of safety data are performed, and outcomes are made available.

Other Safety Reports

The G-SftyRpt delineates that the sponsor must provide the EC with an annual safety report including a clear summary of the evolving trial safety profile. The annual safety report should generally include:

• A brief description and analysis of new and relevant findings
• For investigational products (IPs) not on the Australian Register of Therapeutic Goods (ARTG) (AUS-22), a brief analysis of the safety profile of the IP and its implications for participants
• A brief discussion of the implications of the safety data to the trial’s risk-benefit ratio
• A description of any measures taken or proposed to minimize risks

A Development Safety Update Report (DSUR) or other similar document may also serve as the annual safety report. See the G-SftyRpt for more information.

Form Completion & Delivery Requirements

As per the G-CTHandbook, all SUSARs from Australian sites must be reported to the TGA using one (1) of three (3) formats:

• The Electronic Data Interchange (EDI) functionality, which allows sponsors to submit AE reports directly from their system to the TGA (more information can be found at AUS-26)
• The online reporting form, which can be accessed from AUS-51
• The CIOMS Form I (AUS-4) or the TGA’s Blue Card Adverse Reaction Reporting Form (AUS-3)

Per AUS-3, the Blue Card form may be emailed to adr.reports@tga.gov.au or mailed to Pharmacovigilance and Special Access Branch, Reply Paid 100, Woden ACT 2606. More information about reporting to the TGA may be found at AUS-7.

See AUS-37 for the SSI/USM 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 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 the timelines 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 an SAE to NatHREC within 24 hours of its occurrence and a final or followup 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 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

As per the AU-ICH-GCPs, the G-NatlStmt, and the G-TrialsSOP, the investigator(s) is responsible for submitting progress reports to the ethics committee (EC) (known as Human Research Ethics Committee in Australia) annually, or more frequently if requested. The AU-ICH-GCPs and the G-TrialsSOP state that if there are significant changes in trial conduct or safety, the investigator should submit a written report to the sponsor, the EC, and where applicable, the institution. The G-NatlStmt indicates that at regular periods (reflecting the degree of risk, and at least annually), researchers should provide reports to the relevant EC(s) and institution(s), including information on:

• Progress to date
• The security of project-related data and information
• Compliance with the approved proposal
• Compliance with any conditions of approval

According to the G-NatlStmt, progress report forms should be designed to collect information that can provide meaningful assistance to reviewers in determining whether continuation of ethics approval is warranted. See the G-NatlStmt for more details.

Final Report

AUS-47 indicates that for trials conducted under the Clinical Trial Approval (CTA) scheme, the CTA clinical trial completion advice form (AUS-58) is used to notify the Therapeutic Goods Administration (TGA) of the trial completion. AUS-58 indicates that upon completion, the form may be emailed to the TGA at clinical.trials@tga.gov.au (preferred) or faxed to 02 6232 8112.

Per AUS-49, for trials conducted under the Clinical Trial Notification (CTN) scheme, a completion advice should be submitted through the TGA Business Services (TBS) webpage (AUS-36). The completion advice must include the date the trial was completed at all Australian sites, as well as the completion reason. See AUS-49 for additional information on the completion advice.

The AU-ICH-GCPs and the G-TrialsSOP indicate that the investigator should provide the EC with a final clinical study report. As per the G-TrialsSOP, the investigator must also notify the research governance officer that the trial has been terminated/closed. At the completion of the project, a report with the same information as described above for progress reports (per G-NatlStmt) must also be provided to the relevant EC(s) and institution(s), but it should include information on the outcome of the completed research.

Additionally, the TGA has adopted the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)’s Topic E 3: Structure and Content of Clinical Study Reports (AUS-81). For more information, see AUS-81.

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, the 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 AU-ICH-GCPs and the G-TrialsSOP, 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.

In accordance with the AU-ICH-GCPs, Australia permits a sponsor to transfer any or all of its trial-related duties and functions to a contract research organization (CRO). Any trial-related duties and functions transferred to a CRO should be specified in a written agreement, and the sponsor should ensure oversight of such transferred responsibilities. Any trial-related duties and functions not specifically transferred to and assumed by a CRO are retained by the sponsor. The sponsor retains overall responsibility for the trial data’s quality and integrity, as well as the conduct of the trial. As stated in the G-TrialsSOP, the sponsor is also responsible for ensuring that appropriate approvals are obtained prior to the commencement of the clinical trial, that conditions of any approvals are adhered to during the course of the clinical trial, and that the ethics principles of research merit and integrity, justice, beneficence, and respect are applied to the conduct of clinical trials.

According to the G-CTHandbook, if the investigator initiates and organizes the trial, the role of trial sponsor is assumed. If another party (such as a pharmaceutical company) provides the IP or other support for an investigator-led trial, that party is not required to assume the sponsor role.

As per the G-CTHandbook, the G-TrialsSOP, and AUS-47, a sponsor must be an Australian entity.

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

As set forth in the AU-ICH-GCPs, the sponsor should select the investigator(s) and the institution(s) for the clinical trial, taking into account the appropriateness and availability of the study site and facilities. The sponsor must also ensure that the investigator(s) are qualified by training and experience. 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.

According to the G-TrialsSOP, the principal investigator (PI) must ensure that all required staff who assist with the clinical trial are informed about and trained on the protocol, any investigational product (IP), and their research-related duties and functions. This can be in the form of an initiation meeting held by any communication means, including face-to-face, videoconference, telehealth, etc. The PI must also have sufficient time to properly conduct and complete the research within the specified period, as well as an adequate number of qualified staff and adequate facilities for the foreseen duration of the research. When a teletrial is being conducted, the PI, who is always at the primary site and never at the satellite site, remains responsible for the trial across the cluster. For more information on PI site staff training and qualification requirements, see the G-TrialsSOP.

See AUS-64 for additional clinical trial and researcher resources.

Research Governance

The G-NatlStmt indicates that institutions must ensure that any human research for which they are responsible is designed, reviewed, approved, authorized, conducted, and monitored in accordance with the G-CodeConduct and the G-NatlStmt, along with any policies that they have developed that form part of their research governance framework. Each institution should be satisfied that the human research for which it is responsible meets both relevant ethical standards and scholarly or scientific standards, and ensure that those conducting the research (i) are either adequately experienced and qualified, or supervised; (ii) understand the need to assess risks to their own safety and that of participants; and (iii) are aware they are free to withdraw from research on conscientious grounds. Institutions should publish (such as on their website) clear policies and procedures for ethics review and approval and institutional authorization of research. They may establish their own processes for ethics review of research or use the review processes of another institution or external ethics review body.

Per AUS-63, the Australian Commission on Safety and Quality in Health Care developed the National Clinical Trials Governance Framework (AUS-63), which embeds clinical trials into routine health service provisions and strengthens the clinical and corporate governance arrangements for parties that deliver clinical trials. All jurisdictions have agreed to implement the framework in health service organizations, meaning the organizations will be assessed concurrently for clinical and corporate services and clinical trial service provisions. The framework describes the systems and processes that should be in place to implement an effective governance system considering local needs, values, and the context in which services are provided. For more information about implementation timing and assessments under the National Safety and Quality Health Service (NSQHS) standards, see AUS-63.

Foreign Sponsor Responsibilities

As per the G-CTHandbook, the G-TrialsSOP, and AUS-47, a sponsor must be an Australian entity.

Data Safety Monitoring Boards

G-DSMB indicates that the sponsor may establish a Data Safety Monitoring Board (DSMB) (also referred to as Data Monitoring Committees (DMCs)) to review accumulating trial data in order to monitor the progress of a trial. The role of a DSMB is to provide advice on safety and/or trial conduct issues by making recommendations to the sponsor or trial steering committee on whether to continue, modify, or stop a trial. Per the AU-ICH-GCPs, the DSMB should have written standard operating procedures (SOPs) and maintain written records of all its meetings.

According to the G-TrialsSOP, the sponsor may utilize a DSMB or independent individuals (e.g., a medical monitor) to:

• Review accruing trial safety data in either an unblinded or blinded manner to assess treatment exposure
• Access, assess, and review emerging efficacy data for the trial
• Assess the balance of risks and benefits within the trial
• Document the outcome of these reviews

Additionally, the Therapeutic Goods Administration (TGA) has adopted the European Medicines Agency (EMA)’s Guideline on Data Monitoring Committees (AUS-78), which discusses the key issues involved when sponsors include DSMBs as part of their trial management. For more information, see AUS-78.

Multicenter Studies

As delineated in the AU-ICH-GCPs, in the event of a multicenter trial, the sponsor must ensure that:

• All investigators conduct the trial in strict compliance with the protocol that was agreed to by the sponsor and the TGA (if required), and that was approved by the ethics committee (EC)
• The case report forms (CRFs) capture the required data at all multicenter trial sites
• The responsibilities of coordinating investigator(s) and the other participating investigators are documented prior to the start of the trial
• All investigators are given instructions on following the protocol, on complying with a uniform set of standards to assess clinical and laboratory findings, and on completing the CRFs
• Communication among investigators is facilitated

As noted in the G-TeletrialPrncpls, Australian jurisdictions agree that “traditionally” multicenter clinical trials assume one (1) PI per geographic site, differing from teletrials. However, for the purposes of teletrials, multicenter trials may include some sites that have satellite sites supervised under teletrial guidance, including the Clinical Oncology Society of Australia (COSA)’s Australasian Tele-trial Model (AUS-2), the G-TeletrialPrncpls, and the G-TrialsSOP. Sponsor responsibilities in teletrials, as described in the G-TrialsSOP, are discussed throughout the Australia profile alongside other clinical trial regulations and guidance. See each section of the Sponsorship topic for additional applicable information.

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

The AU-ICH-GCPs and the G-NatlStmt state that the sponsor should provide insurance in accordance with applicable regulatory requirements. In addition, according to the G-NatlStmt, institutions must ensure that sponsors have insurance arrangements in accordance with applicable regulatory requirements. The federal documents cited here do not explicitly require insurance.

Per the G-GovHndbk, the institution and investigator are responsible for managing risks of any proposed research, including providing appropriate insurance coverage.

Compensation

Injury or Death

According to the G-NatlStmt, institutions must ensure that sponsors have indemnity and compensation arrangements in accordance with applicable regulatory requirements, and that arrangements are in place to compensate trial participants for harm resulting from negligence in research. The AU-ICH-GCPs further indicates that the sponsor must explain to participants the compensation and/or treatment available to them in the event of trial-related injuries. The federal documents cited here do not explicitly require indemnity.

The G-TrialsSOP states that if the investigator is notified or becomes aware that a trial participant intends to make a claim against the institution or sponsor for injuries arising as a result of participating in a clinical trial undertaken at the institution (or any of the satellite sites under supervision by the institution in a teletrial), the investigator must promptly notify the following parties in writing that such an action is intended:

• The institution’s authority
• The coordinating principal investigator (CPI)/principal investigator (PI)/associate investigator, as relevant
• The sponsor

In addition, if the institution is notified or becomes aware that a trial participant intends to make a claim for compensation against the institution or sponsor for injuries arising as a result of participating in a clinical trial undertaken at the institution (or any of the satellite sites under supervision by the institution in a teletrial), the institution must promptly notify the institution’s insurer in writing that such an action is intended.

See AUS-39 for indemnity and injury compensation guidelines for commercially-sponsored trials.

Trial Participation

The G-NatlStmt states that it is generally appropriate to reimburse participants for the costs associated with taking part in research including travel, accommodations, and parking. Sometimes participants may also be paid for time involved. However, payment may not be disproportionate to the time involved, or include other incentives that encourage participants to take risks. Further, payment or reimbursement decisions should consider customs and practices of the community in which the trial will be conducted.

According to the G-ResearchPayment, any proposal for payment of participants should be considered by the ethics committee (EC) reviewing the research. The EC should be provided with a payment plan that includes:

• A rationale for the proposed payments
• The method and timing of any disbursements, including how they have been calculated, and
• Information about how prospective participants will be advised of the provision of payment

Payment of participants is ethically appropriate if it is equitable and proportionate to the burden of the research, and does not:

• Undermine a participant’s capacity to provide voluntary and informed consent
• Unduly influence a participant to accept a risk or burden that is greater than they would otherwise accept in everyday living or to compromise their fundamental values
• Unduly influence a participant to make false representations about or conceal information that is relevant to their eligibility for the research, their contribution to the research, or the risks related to participation

To minimize the likelihood of a payment acting as an undue influence, the G-ResearchPayment further indicates that payment of participants should generally be limited to reimbursement of documented expenses and remuneration for time and inconvenience. Payment may be offered as an incentive to participate in cases where the research offers little or no benefit to individuals or where the research requires the participation of target populations that are difficult to recruit. In these cases, adequate processes must be in place to promote valid consent. For more information and examples of payment models, see the G-ResearchPayment.

According to the AU-ICH-GCPs, payments to a participant should be prorated and not wholly contingent on completion of the trial by the participant.

Post-Trial Access

Per the G-NatlStmt, researchers must make clear to the participant if there are any intended therapeutic benefits from the trial, and if the treatment will be available only through participation in the trial. In addition, researchers must make it clear to the participant whether they will have access to the treatment or information they received after completion of the trial.

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 the 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

As per the TGR and the AU-ICH-GCPs, 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.

According to the AU-ICH-GCPs, 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 accept
• Documenting quality management activities and communicate to those involved in or affected by these activities
• Periodically reviewing risk control measures to ascertain whether the implemented quality management activities are effective and relevant
• Describing the quality management approach implemented in the trial and summarize important deviations from the predefined quality tolerance limits and remedial actions taken in the clinical study report

The G-RBMgmtMntring provides further guidance on the application of risk-based trial processes, particularly as a reference to sponsors of non-commercial trials.

The AU-ICH-GCPs further indicates that the sponsor is responsible for implementing and maintaining quality assurance (QA) and quality control (QC) systems with written standard operating procedures (SOPs) to ensure that trials are conducted and data generated, recorded, and reported in compliance with the protocol, the AU-ICH-GCPs, and the applicable regulatory requirements. 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. The sponsor should implement a system to manage quality throughout all stages of the trial process, and QC should be applied to each stage of data handling to ensure that all data are reliable and have been correctly processed. Any agreements between the sponsor and investigator, or with any other parties involved in the clinical trial, should be written, either within the protocol or in a separate agreement.

As per AUS-74, the Therapeutic Goods Administration (TGA) has adopted certain guidelines released by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), the European Medicines Agency (EMA), and the United States Food & Drug Administration (FDA) regarding quality management and technical aspects of clinical trials. See each of these documents for additional details:

· ICH Guideline E8 (R1) on General Considerations for Clinical Studies (AUS-76)

· Guideline on Strategies to Identify and Mitigate Risks for First-in-Human Clinical Trials with Investigational Medicinal Products (AUS-77)

· Guideline on Clinical Trials in Small Populations (AUS-79)

· ICH E11(R1) Guideline on Clinical Investigation of Medicinal Products in the Pediatric Population (AUS-80)

· Use of Electronic Health Record Data in Clinical Investigations - Guidance for Industry (AUS-82)

· Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drug and Biological Products - Guidance for Industry (AUS-83)

· ICH Topic E 10 Choice of Control Group in Clinical Trials (AUS-84)

· ICH Topic E 9 - Statistical Principles for Clinical Trials (AUS-85)

See AUS-74 for more information on, as well as a list of, the international scientific guidelines adopted by the TGA.

Responsible Research Conduct

The G-CodeConduct outlines principles, responsibilities, and expectations for institutions and researchers to facilitate responsible research practices. Australian institutions must establish and maintain good governance and management practices for responsible research conduct. In addition, researchers must comply with the relevant laws, regulations, disciplinary standards, ethics guidelines, and institutional policies related to responsible research conduct. Compliance with the G-CodeConduct is a requirement to receiving funding from the National Health and Medical Research Council (NHMRC) or the Australian Research Council (ARC).

The G-CodeBreaches describes the preferred model for institutions to use to investigate and manage potential code breaches, to determine any corrective actions, and when a finding of research misconduct may be made. The Australian Research Integrity Committee uses the G-CodeBreaches as a guide for reviewing how NHMRC- and ARC-funded institutions manage potential code breaches.

The G-RptBreachGCP requires the sponsor to notify the reviewing ethics committee (EC) (Human Research Ethics Committee (HREC) in Australia) within seven (7) days of confirming a serious breach of good clinical practice (GCP). A serious breach is defined as one that is likely to affect to a significant degree: the safety or rights of a trial participant or the reliability and robustness of the data generated in the trial. Sponsors should also develop documented processes for managing serious breaches. The G-TrialsSOP notes that although all deviations or breaches of the protocol must be reported by the investigator to the sponsor, only serious breaches must be reported to the EC. Serious breaches should also be reported by the principal investigator (PI) to their institution, as they may have an impact on medico-legal risk, the responsible conduct of research, or adherence to contractual obligations.

The supplementary guidance G-RptBreachGCP should be read alongside the G-CodeConduct and the G-CodeBreaches.

Monitoring Requirements

As part of its QA system, the AU-ICH-GCPs notes 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, the AU-ICH-GCPs, 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 its own SOPs and that the auditor’s observations are documented.

Per the G-TrialsSOP, the PI must ensure audit/inspection readiness throughout the study, have oversight of any audit or inspection of the trial at both primary and satellite sites, and ensure any deficiencies identified through audit or inspection are actively managed to ensure continuous improvement.

The TGR further states that the sponsor must provide a written assurance to comply with any trial-related requests by an authorized TGA officer(s), which includes allowing inspection of clinical trial sites. The PI is required to comply with requests and answer any questions the authorized officer(s) may have. According to the G-GCP-Inspect, clinical trial sites that have been notified of a GCP inspection should prepare for the inspection by:

· Ensuring their authorizing institution, trial sponsor, and clinical team are advised of the inspection (the G-GCP-Inspect notes that although the TGA does not require that the sponsor be informed, there is generally a requirement in the contract between the site and the sponsor to share this type of information)

· Ensuring access for the inspectors to clinical trial records and source documents is arranged for the time of the inspection

· Ensuring their IT processes allow them to grant view-only access to the inspectors

The G-GCP-Inspect adds that ECs and trial sponsors are not included in the scope of the TGA’s GCP inspection program. The site PI can invite the sponsor representative(s) to attend the inspection opening and closing meeting. See the Scope of Assessment section and the G-GCP-Inspect for more information on TGA inspections.

Premature Study Termination/Suspension

As per the G-CTHandbook, procedures following the TGA’s revocation of approval under the Clinical Trial Approval (CTA) scheme or a breach of the conditions of the Clinical Trial Notification (CTN) scheme would be determined on a case-by-case basis based on the impact on participants and their ongoing safety. The AU-ICH-GCPs states that if a trial is prematurely terminated or suspended, the sponsor should promptly inform the investigator(s), institution(s), the EC, and the TGA. The sponsor should provide the reason(s) for the termination or suspension. Additionally, as indicated in the G-CTHandbook, the sponsor must notify all sites in the case of a multicenter trial. A lead EC in a multicenter study will need to liaise with the sites and sponsor when determining which, if any, are affected and the actions they need to apply.

According to the G-TrialsSOP, if a trial is prematurely terminated or suspended for any reason, the investigator must:

• Promptly inform the sponsor, EC, research governance officer, associate investigator, any satellite site, and the TGA by providing a detailed written explanation of the premature termination or suspension
• Promptly inform the trial participant and the participant’s primary care physician where the trial participant has consented, of the termination or suspension and, if applicable, of the investigational product (IP) and dose that was administered
• Assure appropriate therapy and follow up for the participant’s continued care

As per the G-NatlStmt, if an institution or EC considers that suspension of research is necessary, the instruction to stop should come from the management of the institution. Where ethics approval for a research project is suspended:

• The institution must ensure that the researcher promptly suspends the research and makes arrangements to meet the needs of participants, such as ensuring that appropriate counselling support or the provision of standard care continues
• The research may not be resumed unless: (i) the research is modified to provide sufficient protection or participants or address the concerns that led to the suspension; or (ii) the researcher establishes to the satisfaction of the EC that continuation of the research will not compromise participants’ welfare; and (iii) the institution authorizes the continuation of the research

The G-NatlStmt further indicates that if ethics approval for a research project is withdrawn, the researcher must promptly halt the research, make arrangements to meet the needs of participants, and notify the institution that these steps have been taken.

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 the G-EthicsHR-TZA, the investigator is responsible for documenting all steps in data management to allow a step-by-step retrospective assessment of the quality of the data and the performance of the research study.

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 (ECs). 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

The G-AppConductCT states that the sponsor should ensure that the protocol or other written agreement specifies that the investigator(s)/institution(s) will permit Tanzania Medicines and Medical Devices Authority (TMDA) inspection(s) and provide direct access to source data/documents. 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 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, the 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 the 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, the National Health Research Ethics Committee (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

When using electronic trial data handling systems, the sponsor must ensure and document that the electronic data processing system conforms to its established requirements for completeness, accuracy, reliability, and consistent intended performance, and that standard operating procedures (SOPs) are maintained for using these systems. Refer to the AU-ICH-GCPs for additional information.

The Therapeutic Goods Administration (TGA) has adopted the United States Food & Drug Administration (FDA)’s Use of Electronic Health Record Data in Clinical Investigations - Guidance for Industry (AUS-82). For more information, see AUS-82.

Records Management

According to the G-CodeConduct and the G-DataInfoMgt, institutions must provide access to facilities for the safe and secure storage and management of research data, records, and primary materials.

The G-DataInfoMgt requires that institutional policy include guidance for managing research data and primary materials that addresses the following:

• Ownership, stewardship, and control
• Storage, retention, and disposal
• Safety, security, and confidentiality
• Access by interested parties

Furthermore, institutional policies on ownership of, and access to, databases and archives must require that:

• Researchers are informed of relevant confidentiality agreements and restrictions on the use of research data
• Computing systems are secure
• Information technology personnel understand their responsibilities for network security and access control
• Those holding primary material, including electronic material, understand their responsibilities for security and access

The G-CodeConduct and the G-DataInfoMgt further state that researchers must retain clear, accurate, secure, and complete records of all research including research data and primary materials. Additionally, the G-NatlStmt indicates that when multiple researchers are collaborating on the collection, storage, and/or analysis of data or information, they should agree to the arrangements for custodianship, storage, retention, and destruction of those materials, as well as the rights of access, rights to analyze/use and re-use the data or information, and the right to produce research outputs based upon them.

According to the G-TrialsSOP, the investigator must maintain adequate source documents and trial records, including all key observations on each of the trial participants. The investigator must also store all trial related documents in a study master file (SMF) and take measures to prevent accidental or premature destruction of these documents. In the case of a teletrial, the SMF is stored at the primary site, and the principal investigator (PI) must have control of all essential documents and records generated by the investigator(s), institution, and satellite site(s) before, during, and after the trial. The PI must also establish the maintenance rules of the SMF and relationship between the primary site’s SMF and any satellite site study files. For more information on the SMF, see the G-TrialsSOP.

As set forth in the annotated AU-ICH-GCPs, the TGA requires that the sponsor retain records for 15 years following the completion of a clinical trial. However, product liability is the overriding consideration, and the sponsor should be able to produce records at any time, including possibly beyond the life of a product, in the event of an adverse event claim. The sponsor should inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed.

The TGA has adopted the European Medicines Agency (EMA)’s Guideline on the Content, Management and Archiving of the Clinical Master File (Paper and/or Electronic) (AUS-75). For more information on the clinical trial master file, see AUS-75.

Data Management Plan

According to the G-NatlStmt and the G-DataInfoMgt, researchers should create a data management plan, which should be developed as early as possible in the research process and should include details regarding:

• Physical, network, system security, and any other technological security measures
• Policies and procedures
• Contractual and licensing arrangements and confidentiality agreements
• Training for members of the project team and others, as appropriate
• The form in which the data or information will be stored
• The purposes for which the data or information will be used and/or disclosed
• The conditions under which access to the data or information may be granted to others
• What information from the data management plan, if any, needs to be communicated to potential participants

The G-NatlStmt states that in the data management plan, researchers should also clarify whether they will seek extended or unspecified consent for future research, or permission from a review body to waive the requirement for consent. In addition, the security arrangements specified in the plan should be proportional to the risks of the research project and the sensitivity of the information.

In accordance with the G-NatlStmt, researchers must comply with all relevant legal and regulatory requirements that pertain to the data or information collected, used, or disclosed as well as the conditions of the consent provided by participants. Data, information, and biospecimens used in research should be disposed of in a manner that is safe and secure, consistent with the consent obtained and any legal requirements, and appropriate to the research design.

The G-NatlStmt indicates that in the absence of justifiable ethical reasons and to promote access to the benefits of research, researchers should collect and store data, or information generated by research projects, in such a way that they can be used in future research projects. A justification must be provided when a researcher believes there are valid reasons for not making data or information accessible. More details are provided in the G-NatlStmt.

In addition, for details related to secondary use and sharing of data or information, see the G-NatlStmt.

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

Per AUS-70, the PrivacyAct regulates how certain health service providing organizations collect and handle personal information, including health information. It also includes provisions that generally allow an individual to access information held about them.

According to the PrivacyAct, agencies and organizations as defined in the PrivacyAct must comply with the Act and the Australian Privacy Principles (APP), found in Schedule 1, and are referred to as APP entities.

Data Protection

Per the PrivacyAct’s APP, an APP entity must have a clearly expressed and up-to-date policy about the management of personal information by the entity. Individuals must have the option of not identifying themselves or of using a pseudonym, and an APP entity must not collect sensitive information about an individual unless the individual consents to the collection of the information.

The APP outline further requirements for the consideration of personal information privacy; the collection of personal information; dealing with personal information; the integrity of personal information; and access to, and correction of, personal information. For the full list of APP, see Schedule 1 of the PrivacyAct.

Consent for Processing Personal Data

The PrivacyAct’s APP indicate that if an APP entity holds personal information about an individual that was collected for a particular purpose, the entity must not use or disclose the information for another purpose unless consent is obtained from the individual. There are limited exceptions to this requirement, which can be found in Schedule 1 of the PrivacyAct.

AUS-70 notes that in certain circumstances, the PrivacyAct permits the handling of health information and personal information for health and medical research purposes, where it is impracticable for researchers to obtain individuals' consent, recognizing: the need to protect health information from unexpected uses beyond individual healthcare, and the important role of health and medical research in advancing public health. To promote these ends, the Office of the Australian Information Commissioner (OAIC) approved the National Health and Medical Research Council (NHMRC)’s legally binding guidelines, G-PrivacyAct95 and G-PrivacyAct95A, which researchers must follow when handling health information for research purposes without individuals' consent. The guidelines also assist ethics committees (ECs) (known as the Human Research Ethics Committees in Australia) in deciding whether to approve research applications. The guidelines are:

• G-PrivacyAct95, which sets out procedures that ECs and researchers must follow when personal information is disclosed from a federal agency for medical research purposes
• G-PrivacyAct95A, which provides a framework for ECs to assess proposals to handle health information held by organizations for health research (without individuals' consent). It ensures that the public interest in the research activities substantially outweighs the public interest in the protection of privacy

See the PrivacyAct, the G-PrivacyAct95, and the G-PrivacyAct95A for more information.

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 Australian clinical trials, valid consent is required from each participant in accordance with the requirements set forth in the AU-ICH-GCPs and the G-NatlStmt. According to the AU-ICH-GCPs, if requirements specified in the G-NatlStmt appear to differ from those specified in the AU-ICH-GCPs, the Therapeutic Goods Administration (TGA) recommends compliance with the G-NatlStmt.

As per the AU-ICH-GCPs, the informed consent form (ICF) (also referred to as a participant information sheet and consent form (PICF) in Australia) is viewed as an essential document that must be reviewed and approved by an institutional ethics committee (EC) (known as a Human Research Ethics Committee in Australia) and kept on file before the trial commences. (See the Required Elements section for details on what should be included in the form.)

According to the G-TrialsSOP, the principal investigator (PI) for any research project retains overall responsibility for ensuring a participant’s consent has been obtained in the correct manner prior to the participant’s entry into the project. This includes where consent is obtained from participants at satellite sites in a teletrial. The PI can delegate the duty for obtaining consent to a suitably qualified associate investigator at the PI’s discretion, but the PI remains responsible for any delegated activity. Furthermore, the investigator must ensure that institutional authorization is obtained, inclusive of approval by an appropriate EC, for all written information and any other media used to provide information to potential participants prior to their usage to obtain consent from any participant.

The AU-ICH-GCPs states that the investigator must provide detailed research study information to the participant or legal representative/guardian. The ICF content should be as non-technical as practical and understandable to the participant or legal representative/guardian. The G-TrialsSOP further indicates that the ICF and relevant EC-approved participant information documents can be provided in person, by telehealth, or by telephone and email or weblink. If informed consent is obtained by telephone, this must be recorded on the ICF and in the participant’s health and medical record, and/or source document, stating (as an example): “The protocol was discussed with [participant’s name] via telephone on [DD/MM/YYYY].”

According to the G-TrialsSOP, e-consent may be the preferable option for teletrials, as consent signatures can be obtained contemporaneously at both primary and satellite sites. For more information on obtaining consent using telehealth, see the G-TrialsSOP.

As per the AU-ICH-GCPs, the ICF content should be clearly presented orally, or in a written language that is easy to understand, and commensurate with the age and comprehension level of the research participant. The participant and legal representative/guardian should also be given adequate time to consider whether to participate. According to the G-NatlStmt, information should also be presented to potential participants in ways that help them make informed choices. To this end, the researcher should take into account cultural and language barriers, the need for accurate and reliable translation, the participant’s educational background, the participant’s age and maturity level, and whether there is a visual, hearing, or communication impairment. See AUS-65 for researcher guidance on how to talk to potential participants.

Furthermore, as delineated in the G-TrialsSOP, the PI or delegate must assess the potential participant’s understanding of what they are agreeing to, that they are aware of the purpose of the study, what will be involved, and any risks that may exist. The participants must demonstrate that they fully understand the implications of decisions that may be made within the course of the research.

Per the G-NatlStmt, where a potential participant lacks the capacity to consent, a person or appropriate statutory body exercising lawful authority for the potential participant should be provided with relevant information and decide whether the individual will participate. That decision must not be contrary to the individual’s best interests. Researchers should bear in mind that the capacity to consent may fluctuate, and even without that capacity, people may have some understanding of the research and the benefits and burdens of their participation. Additionally, within some communities, decisions about participation in research may involve not only individuals but also properly interested parties such as formally constituted bodies, institutions, families, or community elders. See the Emergencies, Vulnerable Populations, Children/Minors, Prisoners, and Mentally Impaired sections for additional information about these populations.

As per the AU-ICH-GCPs, none of the oral and written information concerning the research study, including the written ICF, should contain any language that causes the participant or 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 representative(s) from liability for negligence. Per the G-NatlStmt, no person should be subject to coercion or pressure in deciding whether to participate in a trial.

The G-NatlStmt indicates that consent may be:

• Specific – limited to the specific project under consideration
• Extended – given for the use of data or tissue in future research projects that are: (i) an extension of, or closely related to, the original project; or (ii) in the same general area of research (for example, genealogical, ethnographical, epidemiological, or chronic illness research)
• Unspecified – given for the use of data or tissue in any future research

The G-NatlStmt further states that when unspecified consent is sought, its terms and wide-ranging implications should be clearly explained to potential participants. When such consent is given, its terms should be clearly recorded. Subsequent reliance, in a research proposal, on existing unspecified consent should describe the terms of that unspecified consent. See the G-NatlStmt for more information on consent to future use of data and tissue in research. Additionally, see the Consent for Specimen section for more information on consent related to use of tissue in research.

Re-Consent

According to the AU-ICH-GCPs and the G-TrialsSOP, any change in the ICF that is relevant to the participant’s consent should be approved by the EC prior to implementing any changes. The participant or 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. The G-TrialsSOP further specifies that unless there is a significant safety concern, ECs will not usually require that participants be recontacted immediately since there are potential implications related to blinding. If approved by the EC, continued consent may be obtained verbally and recorded in the participant’s medical records and relevant documents. Re-consent may also be obtained by telephone if approved by an EC.

The G-NatlStmt notes that in some research, consent may occasionally need to be renegotiated or confirmed, especially where projects are complex or long-running, or participants are vulnerable. Research participants should be told if there are changes to the terms to which they originally agreed and given the opportunity to continue their participation or withdraw.

Language Requirements

Pursuant to the G-NatlStmt, methods for presenting research information to participants should take into account the need for accurate and reliable translation into the participant’s first language or dialect, as well as culture and its effects on the communication process. According to the G-TrialsSOP, in cases where translation is required, a professional interpreter should facilitate the process.

Documenting Consent

The AU-ICH-GCPs and the G-TrialsSOP state that the participant or legal representative(s)/guardian(s) and the investigator(s) must sign and date the ICF. Where the participant is unable to read or the legal representative/guardian is unable to read, an impartial witness should be present during the entire informed consent discussion. After the following steps have occurred, the witness should sign and date the ICF attesting that the information in the ICF was accurately explained to, and apparently understood by the participant or legal representative/guardian:

• The written ICF and any other written information to be provided to the participant is read and explained to the participant or legal representative/guardian
• The participant or legal representative/guardian has 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 legal representative/guardian should receive a copy of the signed and dated ICF.

The G-TrialsSOP further indicates that where consent is obtained by telehealth or telephone, once the ICF is signed and dated by both the participant and the investigator (and any other person present, for example an interpreter), the participant must select the statement identifying that consent was obtained by telehealth or telephone with the name of the investigator. Similarly, the investigator must select the statement identifying that consent was obtained by telehealth or telephone with the name of the participant. For more information on informed consent documentation, see the G-TrialsSOP.

According to the G-NatlStmt, consent may be expressed orally, in writing, or by some other means (such as return of a survey or conduct implying consent), depending on the nature, complexity, and level of risk of the research, and the participant’s personal and cultural circumstances.

Waiver of Consent

The G-NatlStmt specifies that although voluntary consent is a requirement for every trial, the EC may approve an alteration to the consent requirements. Limited disclosure to participants of the aims and/or methods of research may be justifiable. However, only an EC can review and approve research that involves active concealment or planned deception or aims to expose illegal activity.

Per the G-NatlStmt, it may be appropriate to use an opt-out approach for participant recruitment when obtaining explicit consent is neither practical nor feasible. An opt-out approach is a method used in the recruitment of research participants where information is provided to the potential participant regarding the research and their involvement, and where their participation is presumed unless they take action to decline to participate. An EC may approve the use of an opt-out approach for research if the study satisfies all of the following conditions:

• It involves only low risk to participants
• The public interest in the proposed activity substantially outweighs the public interest in the protection of privacy
• The research activity is likely to be compromised if the participation rate is not near complete, and the requirement for explicit consent would compromise the necessary level of participation
• Reasonable attempts are made to provide participants with appropriate plain language information explaining the nature of the information to be collected, the purpose of collecting it, and procedure to decline participation or withdraw from the research
• A reasonable time period is allowed between the provision of information to prospective participants and the use of their data so that an opportunity for them to decline to participate is provided before the research begins
• A mechanism is provided for prospective participants to obtain further information and decline to participate
• The data collected will be managed and maintained in accordance with relevant security standards
• There is a governance process in place that delineates specific responsibility for the project and for the appropriate management of the data
• The opt-out approach is not prohibited by state, federal, or international law

According to the G-NatlStmt, only an EC may grant a waiver of consent for research using personal information in medical research, or personal health information. However, other review bodies may grant a waiver of consent for other research. In order to help maintain public confidence in the research process, each institution must make publicly accessible summary descriptions of all its research projects for which consent has been waived.

As stated in the G-NatlStmt, an EC may waive the requirement for consent if the study satisfies all of the following conditions:

• Involvement in the research carries no more than low risk to participants
• The benefits from the research justify any risks of harm associated with not seeking consent
• It is impracticable to obtain consent (for example, due to the quantity, age, or accessibility of records)
• There is no known or likely reason for thinking that participants would not have consented if they had been asked
• There is sufficient protection of their privacy
• There is an adequate plan to protect the confidentiality of data
• There is, where practicable, a plan for making information arising from the research available to participants in cases where the results have significance for their welfare
• The possibility of commercial exploitation of derivatives of the data or tissue will not deprive the participants of any financial benefits to which they would be entitled
• The waiver is not prohibited by state, federal, or international law

See the G-NatlStmt for more information on conditions for the opt-out approach or waiving consent.

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 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 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 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.

Regarding secondary use of materials or data in databases, registries, and repositories, the G-EthicsHR-TZA states that in the absence of broad consent to future use of material or data, including images, for research purposes, the following is recommended:

• The nature of the previously obtained consent should be determined to ascertain whether subsequent usage was envisaged and whether it falls within the scope of the current protocol. If so, new consent is not required
• If the scope of the current protocol is different, then new consent may be required
• If samples are anonymous and the results of research would not place any individual, family, or community at social, psychological, legal, or economic risk of harm, then new consent is not required
• If the link to identifiers exists but is not provided to the research team and the results of research will not place any individual, family, or community at social, psychological, legal, or economic risk of harm, then new consent is not required. The person who holds the code or link should sign an explicit written agreement not to release the identifiers to the research team. This agreement should be submitted to the EC
• If the samples can be linked to identifiers, the EC must decide on a case-by-case basis whether expedited or full review is necessary

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 and Kiswahili.

Documenting Consent

The G-AppConductCT and the G-EthicsHR-TZA state that the participant 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 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.

Based on the AU-ICH-GCPs and the G-NatlStmt, both the informed consent discussion and the written informed consent form (ICF) (also referred to as a participant information sheet and consent form (PICF) in Australia) 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):

• That the trial involves research
• The purpose of the trial
• The trial treatment(s) and the probability for random assignment to each treatment
• The trial procedures to be followed, including all invasive procedures
• The participant's responsibilities
• Those aspects of the trial that are experimental
• The reasonably foreseeable risks or inconveniences to the participant and, when applicable, to an embryo, fetus, or nursing infant
• The reasonably expected benefits, including to the wider community. When there is no intended clinical benefit to the participant, the participant should be made aware of this
• The alternative procedure(s) or course(s) of treatment that may be available to the participant, and their important potential benefits and risks
• The compensation and/or treatment available to the participant in the event of trial-related injury, including provision of services to participants adversely affected by the research
• The amounts and sources of funding for the research, as well as financial or other relevant declarations of interests of researchers, sponsors, or institutions
• The anticipated prorated payment, if any, to the participant for participating in the trial
• The anticipated expenses, if any, to the subject for participating in the trial
• That participation in the trial is voluntary and that the participant may refuse to participate or withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is otherwise entitled
• Any implications of withdrawal from the trial, and whether it will be possible to withdraw data
• How the research will be monitored
• 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 informed consent form, the participant or legal representative/guardian is authorizing such access
• That records identifying the participant will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly available. If the results of the trial are published, the participant’s identity will remain confidential
• That the participant or legal representative/guardian will be informed in a timely manner if information becomes available that may be relevant to the participant's willingness to continue participation in the trial
• The person(s) to contact for further information regarding the trial and the rights of trial participants, and whom to contact in the event of trial-related injury
• Contact details of a person to receive complaints and of the researchers
• The foreseeable circumstances and/or reasons under which participation in the trial may be terminated
• The expected duration of participation in the trial
• The approximate number of participants involved in the trial
• The likelihood and form of dissemination of the research results, including publication
• Any other relevant information, including research-specific information required under other chapters of the G-NatlStmt

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 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
• 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

In accordance with the AU-ICH-GCPs and the G-NatlStmt, Australia’s ethical standards protect participants’ rights and promote respect for human beings, research merit and integrity, justice, and beneficence. The G-NatlStmt further recognizes that state or territory authorities may have additional statutes regarding the use of human tissues, guardianship, and illegal and unprofessional conduct. Furthermore, a participant’s rights must be clearly addressed in the informed consent form (ICF) (also referred to as a participant information sheet and consent form (PICF) in Australia).

The Right to Participate, Abstain, or Withdraw

As stated in the AU-ICH-GCPs and the G-NatlStmt, 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 G-TrialsSOP further specifies that participants may withdraw their consent at any time without giving a reason.

Per the G-NatlStmt, the participant should be informed of any implications of withdrawal and whether it is possible to withdraw data.

The Right to Information

As per the AU-ICH-GCPs and the G-NatlStmt, a potential research participant 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 or treatment in the case of injury, and any significant new information regarding the research study.

The Right to Privacy and Confidentiality

According to the AU-ICH-GCPs and the G-NatlStmt, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right. Privacy is also subject to national, state, and territory laws, including the PrivacyAct. As per the G-TrialsSOP, if telehealth is used, all measures must be taken to ensure privacy and confidentiality of the participant’s identity.

See the Personal Data Protection section for more details on personal information collection and handling requirements.

The Right of Inquiry/Appeal

The AU-ICH-GCPs and the G-NatlStmt state that the research participant or the legal representative/guardian should be provided with contact information for the individual responsible for addressing trial-related inquiries and/or rights.

AUS-45 provides information on who the participant or the legal representative/guardian may contact regarding a concern with the clinical trial. The options include contacting the researcher(s) directly, the ethics committee (EC) (known as Human Research Ethics Committee in Australia), the institution, the healthcare complaints entity in the state or territory, or the National Health and Medical Research Council (NHMRC). Concerns may also be reported to the Therapeutic Goods Administration (TGA). See AUS-45 for more information on the types of concerns that may be reported to each party.

See the G-NatlStmt for more information on institutional requirements for receipt of complaints.

The Right to Safety and Welfare

The AU-ICH-GCPs (which upholds the Declaration of Helsinki (AUS-52)) and the G-NatlStmt clearly state that a research participant’s right to safety and protection of health and welfare must take precedence over the interests of science and society.

See the Required Elements and Vulnerable Populations sections for additional information regarding requirements for participant rights.

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 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 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.

The AU-ICH-GCPs states that in emergency situations, when prior consent of the participant is not possible, the consent of the legal representative/guardian, if present, should be requested. When prior consent of the participant is not possible, and the legal representative/guardian is not available, enrollment of the participant should require measures described in the protocol and/or elsewhere, with documented approval/favorable opinion by the ethics committee (EC) (known as the Human Research Ethics Committee in Australia), to protect the rights, safety, and well-being of the participant and to ensure compliance with applicable regulatory requirements, including the G-NatlStmt. Per the AU-ICH-GCPs, the participant or legal representative/guardian should be informed about the trial as soon as possible, and consent to continue and other consent should be requested, as appropriate.

The G-NatlStmt recognizes that in emergency care research, recruitment into a research project often must be achieved rapidly. Where the research involves emergency treatment and meets the G-NatlStmt’s requirements for research involving people highly dependent on medical care, consent for the research may be waived. See the Vulnerable Populations section for more information on people highly dependent on medical care, and the Documentation Requirements section for more details 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

The AU-ICH-GCPs characterizes vulnerable populations as those who may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation in a clinical trial, or of a retaliatory response for not participating. Examples are 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 subjects include patients with incurable diseases, residents of nursing homes, unemployed or impoverished persons, patients in emergency situations, homeless persons, nomads, refugees, minors, and those incapable of giving consent. Per the G-NatlStmt, people who may be involved in illegal activities, Aboriginal and Torres Strait Islander peoples, ethnic minority groups, and people in other countries are other groups for which specific ethical considerations are required.

People Highly Dependent on Medical Care

According to the G-NatlStmt, research involving people who are highly dependent on medical care may be approved where:

• It is likely that the research will lead to increased understanding about, or improvements in, the care of this population
• The requirements of relevant jurisdictional laws are taken into account
• Either: 1) any risk or burden of the proposed research to this particular participant is justified by the potential benefits, or 2) where participants have capacity to consent, any risk or burden is acceptable to them and justified by the potential benefits of the research

The G-NatlStmt indicates that when a researcher is also the treating health professional, it should be considered whether an independent person should seek the consent of potential participants who are highly dependent on medical care. In addition, the participant and/or the participant’s relatives and an authorized representative should be informed of the participant’s inclusion in the research and of the option to withdraw from it without any reduction in quality of care.

The G-NatlStmt states that when neither the potential participant nor the legal representative/guardian can consider the proposal and give consent, an ethics committee (EC) (known as the Human Research Ethics Committee in Australia) may, having taken account of relevant jurisdictional laws, approve a research project without prior consent if:

• There is no reason to believe that, were the participant or legal representative/guardian to be informed of the proposal, the participant would be unwilling to consent
• The risks of harm to individuals, families, or groups linked to the participant, or to their financial or social interests, are minimized
• The project is not controversial and does not involve significant moral or cultural sensitivities in the community

And, where the research is interventional, these additional conditions apply:

• The research supports a reasonable possibility of benefit over standard care
• Any risk or burden of the intervention to the participant is justified by its potential benefits
• Inclusion in the research project is not contrary to the interests of the participant

The G-NatlStmt further provides specific requirements related to conducting research on participants in terminal care, which is characterized by the short remaining life expectancy of the participants and their vulnerability to unrealistic expectations of benefits. Terminal care research should be designed so that the benefits of research justify any burden, discomfort, or inconvenience to the participants; the prospect of benefit from research participation is not exaggerated; the needs and wishes of participants to spend time as they choose are respected; and the entitlement of those receiving palliative care to participate is recognized.

Aboriginal and Torres Strait Islander Peoples

The G-NatlStmt states that research involving Aboriginal and Torres Strait Islander Peoples must be reviewed and approved by an EC and include assessment and advice from: people who have networks with and/or knowledge of Aboriginal and Torres Strait Islander Peoples; and people familiar with the culture and practices of the relevant Aboriginal and Torres Strait Islander community(ies). In addition, the researcher should ensure the following:

• Research methods are respectful and acknowledge the cultural distinctiveness of participating Aboriginal and Torres Strait Islander communities and groups
• There is evidence of support for the research project from relevant Aboriginal and Torres Strait Islander communities or groups and the research methodology engages with their social and cultural practices
• The research methods provide for mutually agreed mechanisms for recruitment, information provided about the research, notification of participants’ consent and of research progress, and final reporting
• Procedures and actions have been taken to monitor and, where appropriate, minimize any potential negative consequences of the proposed research

For more information on research involving Aboriginal and Torres Strait Islander Peoples, see the G-AboriginalEthic, the G-EthicsRsrchTrackII, and the G-AIATSISCode.

People in Dependent Groups

The G-NatlStmt cautions that dependent or unequal relationships that might compromise the voluntary character of a participant’s decision should be considered. Examples of such relationships include caregivers and people with chronic conditions/disabilities; health care professionals and their patients; teachers and their students; prison authorities and prisoners; governmental authorities and refugees; employers/supervisors and their employees (including members of police and Defense Forces); and service-providers and especially vulnerable communities to whom the services are provided. Where potential participants are especially vulnerable or powerless, consideration should be given to the appointment of a participant advocate.

Per the G-NatlStmt, when a researcher and potential participant have a pre-existing relationship, it should be considered whether an independent person should seek the consent of the participant.

People Who May Be Involved in Illegal Activities

The G-NatlStmt provides specific requirements related to conducting research on participants who may be involved in illegal activities. Research that is intended to study or expose, or likely to expose, illegal activity should be reviewed and approved by an EC. Researchers should be satisfied that participants who are subject to criminal justice processes are aware that the research may discover illegal activity and do not have unrealistic expectations of benefit from their participation. Finally, research designed to expose illegal activity should only be approved where the illegal activity bears on the discharge of a public responsibility or the fitness to hold public office, the risks are justified by the benefits, and the research meets the other requirements in the G-NatlStmt.

People in Other Countries

The G-NatlStmt states that research involving people in other countries must be reviewed and approved by an EC and comply with the G-NatlStmt. The research design, protocol, and consent process should take into consideration the local cultural values, yet still result in participants being treated with no less respect and protection than what is provided in the G-NatlStmt. Additional details are provided in the G-NatlStmt.

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 a 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 FamLawAct defines a child as a person who is under 18 years of age. Per AUS-71, different states or territories may have specific legislation about a parent/guardian providing consent to medical treatment for a minor; otherwise, the FamLawAct has provisions that may apply.

According to AUS-71, children under 16 cannot give legal consent, which must be given by a parent/guardian, but they can and should be involved in the decision. Young people over 16 can give legal consent to medical treatment; however, they usually cannot provide legal consent to participate in research until they are 18. Nonetheless, some ethics committees (ECs) (known as Human Research Ethics Committees in Australia) do allow mature young people under 18 to give their consent for some kinds of research.

The AU-ICH-GCPs states that minors should be informed to the extent compatible with their maturity and understanding, and if capable, they should sign and personally date the informed consent form (ICF) (also referred to as a participant information sheet and consent form (PICF) in Australia). In accordance with the G-NatlStmt, consent requirements for conducting clinical trials follow the general requirements listed in the Required Elements section.

The G-NatlStmt states before including a child or young person in research, researchers must establish that there is no reason to believe that such participation is contrary to that child's or young person's best interest. Furthermore, a child or young person's refusal to participate in research should be respected wherever the child or young person has the capacity to give consent to that same research. Where a child or young person lacks this capacity, the child or young person’s refusal may be overridden by the judgement of the parent/guardian as to what is in the child's best interest.

The G-NatlStmt indicates that an EC may approve research to which only the child or young person consents if it is satisfied that:

• The child or young person is mature enough to understand the relevant information and give consent
• The research involves low risk
• The research aims to benefit children or young people
• The child or young person is estranged or separated from the parent/guardian and the researcher ensures the child or young person’s safety, security, and well-being in the research conduct; or it would be contrary to the best interests of the child or young person to seek consent from the parent/guardian, and the researcher ensures the child or young person’s safety, security, and well-being in the research conduct

In addition, as stated in the G-NatlStmt, children and young people who are not of sufficient maturity to consent should only participate in clinical studies when: the research is likely to advance knowledge about the health or welfare of, other matters relevant to, children and young people; or their participation is indispensable to the conduct of the research. When considering the inclusion of children and young people in research, the researchers and EC must consider their level of maturity to ensure adequate protections for their welfare.

Assent Requirements

AUS-71 indicates that when a parent/guardian gives consent for their child to take part in a clinical trial, researchers may also ask the child for their permission or agreement, also referred to as assent. The researchers must do this in an age-appropriate manner. Both the parent/guardian and the child should have the chance to ask any questions before agreeing to participate and at any time during a trial. In order for a child to provide their consent or assent they must:

• Understand the research process
• Understand the purpose of the trial
• Be told what they are expected to do or what will happen to them during the trial

AUS-71 further states that children should be able to express their views and any worries they might have about participating in a trial, and have their questions answered. Children should always be given information in a form that they can understand. Additionally, AUS-80 indicates that refusal to assent or withdrawal of assent by a child should be respected. Over the course of a clinical study, it may be necessary to reassess the assent of a child in recognition of their advancing age, evolving maturity, and competency, especially for long-term studies or studies that may require sample retention. During clinical studies, it is required to obtain adequate informed consent for continued participation from pediatric participants once a child reaches the age of legal consent. Local regulations related to confidentiality and privacy of pediatric participants must be followed.

Furthermore, the G-NatlStmt states that except in cases involving standing parental consent, specific consent must be obtained from the child or young person whenever the child or young person has the capacity to make this decision, and either one (1) parent, except when the EC decides that the risks require the consent of both parents, or the child or young person’s parent/guardian.

Per the G-NatlStmt, researchers must respect the developing capacity of children and young people to be involved in decisions about participation in research. The child or young person's particular level of maturity has implications for whether consent is necessary and/or sufficient to authorize participation. However, it is not possible to attach fixed ages to each level of maturity, which may vary from child to child. The following guidelines on maturity and corresponding capacity to consent are provided:

• Infants, who are unable to take part in discussion about the research and its effects
• Young children, who are able to understand some relevant information and take part in limited discussion about the research, but whose consent is not required
• Young people of developing maturity, who are able to understand the relevant information but whose relative immaturity means that they remain vulnerable; the consent of these young people is required, in addition to consent from a parent or guardian
• Young people who are mature enough to understand and consent, and are not vulnerable through immaturity in ways that warrant additional consent from a parent or guardian

See the G-NatlStmt for more information on consent and assent involving children and young people.

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.

As per the G-NatlStmt, studies involving pregnant women, fetuses, and neonates require additional safeguards to ensure that the research assesses the risks to the pregnant women, fetuses, and neonates. The wellbeing and care of the woman who is pregnant and of her fetus always takes precedence over research considerations, and research involving a fetus or fetal tissue should be conducted in a manner that maintains a clear separation between the woman’s clinical care and the research. Additionally, research should be designed to minimize pain or distress for the fetus, include steps for monitoring for signs of fetal pain or distress, and include steps for suspending or ceasing the research if necessary.

In accordance with the G-NatlStmt, consent requirements for conducting clinical trials follow the general requirements listed in the Required Elements section. However, except for therapeutic innovative therapy cases, the process of providing information and obtaining consent for participating in research should be clearly separate from clinical care if the woman is pregnant and the fetus is in utero. Further, per the G-NatlStmt, the woman should be informed of the following:

• That she should consider whether to seek consent to the proposed research from any other person (e.g., the other parent)
• Whether it is possible to store the fetus or fetal tissues for later use in research
• That she is free to withdraw her consent to the research at any time, whether before or after a termination or other loss of a fetus
• Whether there is potential for commercial application of outcomes of the research, including the development of cell lines
• That she will not be entitled to a share in the profits of any commercial applications
• Whether fetal organs or stem cell lines developed from them will be exported to another country

In addition, the G-NatlStmt states that if, for research purposes, fetal cells are to be derived from the fetal tissue and stored or propagated in tissue culture, or tissues or cells are to be used in human transplantation, the woman's consent is required. Others whom the woman identifies may also need to be involved in decisions about these matters.

For requirements related to assisted reproductive technology, including research involving the creation of human embryos using precursor cells from a human embryo or a human fetus, see the G-EthicsART.

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

The G-NatlStmt refers to prisoners and prison authorities as an example of people who may be in dependent or unequal relationships.

Per the G-NatlStmt, a research study involving people in dependent or unequal relationships (such as prisoners) should, wherever possible, invite prospective participants to discuss their participation with someone who is able to support them in making their decision. If prospective participants are especially vulnerable, researchers should consider appointing a participant advocate.

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

Cognitive Impairment, Intellectual Disability, or Mental Illness

The G-NatlStmt discusses the requirements for research involving participants with cognitive impairment, intellectual disability, and mental illness together, noting that many of the ethical issues they raise about research participation are similar. An ethics committee (EC) (known as Human Research Ethics Committee in Australia) must review and approve research involving such participants, except where the research uses collections of non-identifiable data and involves negligible risk.

Per the G-NatlStmt, the research design should take into account factors that may affect the capacity to receive information, to consent to the research, or to participate in it. Additionally, care should be taken to determine whether the participant’s cognitive impairment, intellectual disability, or mental illness increases the susceptibility to some forms of discomfort or distress. Ways of minimizing effects of this susceptibility should be described in the research proposal.

As delineated in the G-NatlStmt, the participant must consent if the participant has the capacity, or the participant’s legal representative/guardian must consent on behalf of the participant. Where a legal representative/guardian has given consent, the researchers still must explain to the participant what the research is about and what participation involves. If the participant recovers the capacity to consent, the researcher should offer the opportunity to continue participation or withdraw. Refusal or reluctance to participate in a research project should be respected.

The G-NatlStmt states that if the participant’s impairment, disability, or illness is temporary or episodic, researchers should seek consent when the condition does not interfere with the capacity to give consent. This consent should occur in the presence of a witness who is familiar with the participant, is independent from the research, and understands the research’s merits, risks, and procedures.

Research Involving Unconscious Persons

The G-NatlStmt states when prior consent is not possible for research involving unconscious persons, consent should be provided by the participant’s legal representative/guardian. However, relevant jurisdictional laws must be taken into account. Because of their extreme vulnerability, unconscious persons should be excluded from all but minimally invasive research, or in research designed both to be therapeutic for them and to improve treatment for the condition from which they suffer.

The G-TrialsSOP notes that as per the Declaration of Helsinki (AUS-52), for research involving participants who are physically or mentally incapable of giving consent (e.g., unconscious patients/participants), the study must be relevant to the physical or mental condition of the participant(s) that prevents them from being able to consent to participate in the study.

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

According to the AU-ICH-GCPs and the G-TrialsSOP, an investigational 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. This includes a product with a marketing authorization when used or assembled (formulated or packaged) in a different way from the approved form; when used for an unapproved indication; or when used to gain further information about an approved use.

In Australia, IPs are also referred to as unapproved therapeutic goods. As per the G-CTHandbook and AUS-47, an unapproved therapeutic good includes:

• Any medicine, biological, or medical device not entered on the Australian Register of Therapeutic Goods (ARTG) (AUS-22), including any new formulation, strength or size, dose, name, indications, directions for use or type of container of a medicine already in the ARTG
• Any therapeutic good already in the ARTG to be used in a manner not covered by the existing ARTG entry

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