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

This profile covers the role of the Department of Health & Human Services (HHS)’s Food & Drug Administration (FDA) in reviewing and authorizing investigational new drug applications (INDs) to conduct clinical trials using investigational drug or biological products in humans in accordance with the FDCAct, 21CFR50, and 21CFR312. Regulatory requirements for federally funded or sponsored human subjects research, known as the Common Rule (Pre2018-ComRule and RevComRule), which the HHS and its Office for Human Research Protections (OHRP) implements in subpart A of 45CFR46, are also examined. Lastly, additional HHS requirements included in subparts B through E of 45CFR46 are described in this profile, where applicable, using the acronym 45CFR46-B-E. (Please note: ClinRegs does not provide information on state level requirements pertaining to clinical trials.)

Food & Drug Administration

As per the FDCAct, 21CFR50, and 21CFR312, the FDA is the regulatory authority that regulates clinical investigations of medical products in the United States (US). According to USA-92, the FDA is responsible for protecting public health by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, and medical devices.

An overview of the FDA structure is available in USA-33. Several centers are responsible for pharmaceutical and biological product regulation, including the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). Additionally, per USA-88, the Office of Clinical Policy (OCLiP) develops good clinical practice and human subject protection policies, regulation, and guidance.

See USA-47 for a list of FDA clinical trials related guidance documents.

Office for Human Research Protections and Common Rule Agencies

Per USA-93, the OHRP provides leadership in the protection of the rights, welfare, and well-being of human research subjects for studies conducted or supported by the HHS. The OHRP helps ensure this by providing clarification and guidance, developing educational programs and materials, maintaining regulatory oversight, and providing advice on ethical and regulatory issues in biomedical and social-behavioral research.

USA-65 states that the Common Rule (Pre2018-ComRule and RevComRule) outlines the basic provisions for institutional ethics committees (ECs) (referred to as institutional review boards (IRBs) in the US), informed consent, and Assurances of Compliance. See USA-65 for a list of US departments and agencies that follow the Common Rule, which are referred to as Common Rule departments/agencies throughout the profile.

The RevComRule applies to all human subjects research that is federally funded or sponsored by a Common Rule department/agency (as identified in USA-65), and: 1) was initially approved by an EC on or after January 21, 2019; 2) had EC review waived on or after January 21, 2019; or 3) was determined to be exempt on or after January 21, 2019. (Per USA-55 and USA-74, the RevComRule is also known as the “2018 Requirements.”) For 2018 Requirements decision charts consistent with the RevComRule, including how to determine if research is exempt, see USA-74. For more information about the RevComRule, see USA-66.

Per the RevComRule, the Pre2018-ComRule requirements apply to research funded by a Common Rule department/agency (as identified in USA-65) that, prior to January 21, 2019, was either approved by an EC, had EC review waived, or was determined to be exempt from the Pre2018-ComRule. Institutions conducting research approved prior to January 21, 2019 may choose to transition to the RevComRule requirements. The institution or EC must document and date the institution's determination to transition a study on the date the determination to transition was made. The research must comply with the RevComRule beginning on that date. For pre-2018 Requirements decision charts consistent with the Pre2018-ComRule, including how to determine if research is exempt, see USA-74.

See USA-54 for additional information regarding compliance with the Pre2018-ComRule and the RevComRule.

USA-65 indicates that the FDA, despite being a part of the HHS, is not a Common Rule agency. Rather, the FDA is governed by its own regulations, including the FDCAct and 21CFR50. However, the FDA is required to harmonize with the Pre2018-ComRule and the RevComRule whenever permitted by law.

If a study is funded or sponsored by HHS, and involves an FDA-regulated product, then both sets of regulations will apply. See G-RevComRule-FDA for additional information.

Other Considerations

Per USA-16, the US is a founding regulatory member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The US has adopted several ICH guidance documents, including the E11(R1) Addendum: Clinical Investigation of Medicinal Products in the Pediatric Population (US-ICH-E11), E17 General Principles for Planning and Design of Multiregional Clinical Trials (US-ICH-E17), and E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) (US-ICH-GCPs), which are cited throughout this profile.

Contact Information

Food & Drug Administration

As per USA-81, USA-91, and USA-90, the contact information for the FDA is as follows:

Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993
Telephone (general inquiries): (888) 463-6332

CDER Telephone (drug information): (301) 796-3400
CDER Email: druginfo@fda.hhs.gov

CBER Telephone: (800) 835-4709 or (240) 402-8010
CBER Email (manufacturers assistance): Industry.Biologics@fda.hhs.gov
CBER Email (imports): CBERimportinquiry@fda.hhs.gov
CBER Email (exports): CBERExportCert@fda.hhs.gov

Office for Human Research Protections

Per USA-82, the contact information for the OHRP is as follows:

Office for Human Research Protections
1101 Wootton Parkway, Suite 200
Rockville, MD 20852
Telephone: (866) 447-4777 or (240) 453-6900
Email (general inquiries): OHRP@hhs.gov

Department of Health & Human Services

According to USA-83, the contact information for the HHS is as follows:

US Department of Health & Human Services
Hubert H. Humphrey Building
200 Independence Avenue, S.W.
Washington, D.C. 20201
Call Center: (877) 696-6775

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.

Overview

In accordance with the FDCAct, 21CFR50, and 21CFR312, the Food & Drug Administration (FDA) has authority over clinical investigations for drug and biological products regulated by the agency. 21CFR312 specifies that the scope of the FDA’s assessment for investigational new drug applications (INDs) includes all clinical trials (Phases 1-4). Based on 21CFR56 and 21CFR312, institutional ethics committee (EC) review of the proposed clinical investigation may be conducted in parallel with the FDA review of the IND. However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial. (Note: Institutional ECs are referred to as institutional review boards (IRBs) in the United States (US)).

As delineated in 21CFR312 and USA-42, sponsors are required to submit an IND to the FDA to obtain an agency exemption to ship investigational drug(s) across state lines to conduct drug or biologic clinical trial(s). An IND specifically exempts an investigational drug or biologic from FDA premarketing approval requirements that would otherwise be applicable. 21CFR312 states that “‘IND’ is synonymous with ‘Notice of Claimed Investigational Exemption for a New Drug.’"

According to USA-42, the FDA categorizes INDs as either commercial or non-commercial (research) and classifies them into the following types:

• Investigator INDs - Submitted by physicians who both initiate and conduct the investigation, and who are directly responsible for administering or dispensing the investigational drug.

• Emergency Use INDs - Enable the FDA to authorize experimental drugs in an emergency situation where normal IND submission timelines cannot be met. Also used for patients who do not meet the criteria of an existing study protocol, or if an approved study protocol does not exist.

• Treatment INDs - Submitted for experimental drugs showing potential to address serious or immediately life-threatening conditions while the final clinical work is conducted and the FDA review takes place.

Per the G-PharmeCTD, non-commercial products refer to products not intended to be distributed commercially and include the above listed IND types.

As indicated in the G-IND-Determination, in general, human research studies must be conducted under an IND if all of the following research conditions apply:

• A drug is involved as defined in the FDCAct

• A clinical investigation is being conducted as defined in 21CFR312

• The clinical investigation is not otherwise exempt from 21CFR312

The G-IND-Determination states that biological products may also be considered drugs within the meaning of the FDCAct.

Further, per 21CFR312 and the G-IND-Determination, whether an IND is required to conduct an investigation of a marketed drug primarily depends on the intent of the investigation and the degree of risk associated with the use of the drug in the investigation. See 21CFR312 and the G-IND-Determination for detailed exemption conditions for marketed drugs.

Clinical Trial Review Process

As delineated in 21CFR312, the FDA's primary objectives in reviewing an IND are to ensure human participant safety and rights in all phases of the investigation. Phase 1 submission reviews focus on assessing investigation safety, and Phase 2 and 3 submission reviews also include an assessment of the investigation’s scientific quality and ability to yield data capable of meeting marketing approval statutory requirements. An IND may be submitted for one (1) or more phases of an investigation.

As per USA-41 and USA-94, the FDA’s Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) receive IND submissions for drugs, therapeutic biological products, and other biologicals. Per the FDCAct and 21CFR312, an IND automatically goes into effect 30 calendar days from receipt, unless the FDA notifies the sponsor that the IND is subject to a clinical hold, or the FDA has notified the sponsor earlier that the trial may begin. A clinical hold is an order the FDA issues to delay or suspend a clinical investigation. If the FDA determines there may be grounds for imposing a clinical hold, an attempt will be made to discuss and resolve any issues with the sponsor prior to issuing the clinical hold order. See 21CFR312 for more information on clinical holds.

According to USA-41, with respect to sponsor-investigators, once the FDA receives the IND, an IND number will be assigned and the application will be forwarded to the appropriate reviewing division. A letter will be sent to the sponsor-investigator providing notification of the assigned IND number, date of receipt of the original application, address where future submissions to the IND should be sent, and the name and telephone number of the FDA person to whom questions about the application should be directed.

As indicated in 21CFR312, the FDA may at any time during the course of the investigation communicate with the sponsor orally or in writing about deficiencies in the IND or about the FDA's need for more data or information. Furthermore, on the sponsor's request, the FDA will provide advice on specific matters relating to an IND.

21CFR312 indicates that once an IND is in effect, a sponsor must submit a protocol amendment if intending to conduct a study that is not covered by a protocol already contained in the IND, there is any change to the protocol that significantly affects the safety of subjects, or a new investigator is added to carry out a previously submitted protocol. A sponsor must submit a protocol amendment for a new protocol or a change in protocol before its implementation, while protocol amendments to add a new investigator or to provide additional information about investigators may be grouped and submitted at 30-day intervals. See 21CFR312 for more information on protocol amendments.

As per 21CFR312, if no subjects are entered into a clinical study two (2) years or more under an IND, or if all investigations under an IND remain on clinical hold for one (1) year or more, the IND may be placed by the FDA on inactive status. An IND that remains on inactive status for five (5) years or more may be terminated. See 21CFR312 for more information on inactive status.

21CFR312 indicates that the FDA may propose to terminate an IND based on deficiencies in the IND or in the conduct of an investigation under an IND. If the FDA proposes to terminate an IND, the agency will notify the sponsor in writing, and invite correction or explanation within a period of 30 days. If at any time the FDA concludes that continuation of the investigation presents an immediate and substantial danger to the health of individuals, the FDA will immediately, by written notice to the sponsor, terminate the IND. See 21CFR312 for more information on FDA termination.

For more information on CDER and CBER internal policies and procedures for accepting and reviewing applications, see USA-96 and USA-95, respectively.

Expedited Processes

USA-84 further indicates that the FDA has several approaches to making drugs available as rapidly as possible:

• Breakthrough Therapy – expedites the development and review of drugs which may demonstrate substantial improvement over available therapy
• Accelerated Approval – allow drugs for serious conditions that fill an unmet medical need to be approved based on a surrogate endpoint
• Priority Review – a process by which the FDA’s goal is to take action on an application within six (6) months
• Fast Track – facilitates the development and expedites the review of drugs to treat serious conditions and fill an unmet medical need

See USA-84 and USA-85 for more information on each process. Additionally, see the FDCAct, as amended by the FDORA, for changes to the accelerated approval process.

Other Considerations

The G-RWDRWE-Reg, issued as part of the FDA’s Real-World Evidence (RWE) Program (see USA-17), discusses the applicability of the 21CFR312 IND regulations to various clinical study designs that utilize real-world data (RWD). See the G-RWDRWE-Reg for more information.

For information on the appropriate use of adaptive designs for clinical trials and additional information to provide the FDA to support its review, see G-AdaptiveTrials.

For research involving cellular and gene therapy, see the guidance documents at USA-80.

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.

Food & Drug Administration

The Food & Drug Administration (FDA) does not levy a fee to review investigational new drug submissions.

However, per the FDCAct, FDARA, and USA-45, the FDA has the authority to assess and collect user fees from companies that produce certain human drug and biological products as part of the New Drug Application (NDA). Per USA-43, the NDA is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the United States. The data gathered during the animal studies and human clinical trials of an investigational new drug become part of the NDA.

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

As indicated in 21CFR50, 21CFR56, and 21CFR312, the United States (US) has a decentralized process for the ethics review of clinical investigations. The sponsor must obtain institutional level ethics committee (EC) approval for each study. (Note: Institutional ECs are referred to as institutional review boards (IRBs) in the US.)

As set forth in 21CFR50, 21CFR56, and 21CFR312, all clinical investigations for drug and biological products regulated by the Food & Drug Administration (FDA) require institutional EC approval.

The Pre2018-ComRule and the RevComRule also require that human subjects research receive institutional EC approval. However, note that these regulations’ definition of “human subject” does not include the use of non-identifiable biospecimens. Therefore, the use of non-identifiable biospecimens in research does not, on its own, mandate the application of the Pre2018-ComRule to such research. However, the RevComRule does require federal departments or agencies implementing the policy to work with data experts to reexamine the meaning of “identifiable private information” and “identifiable specimen” within one (1) year of the effective date and at least every four (4) years thereafter. In particular, these agencies will collaboratively assess whether there are analytic technologies or techniques that could be used to generate identifiable private information or identifiable specimens.

(See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

Per the RevComRule, for non-exempt research (or exempt research that requires limited EC review) reviewed by an EC not operated by the institution doing the research, the institution and the EC must document the institution's reliance on the EC for research oversight and the responsibilities that each entity will undertake to ensure compliance with the RevComRule. Compliance can be achieved in a variety of ways, such as a written agreement between the institution and a specific EC, through the research protocol, or by implementing an institution-wide policy directive that allocates responsibilities between the institution and all ECs not operated by the institution. Such documentation must be part of the EC’s records. The G-HHS-Inst-Engagemt can help an institution to determine if a research study can be classified as non-exempt.

Ethics Committee Composition

As stated in 21CFR56, the Pre2018-ComRule, and the RevComRule, an EC must be composed of at least five (5) members with varying backgrounds to promote complete and adequate research proposal review. The EC must be sufficiently qualified through member experience, expertise, and diversity, in terms of race, gender, cultural backgrounds, and sensitivity to issues such as community attitudes, to promote respect for its advice and counsel in safeguarding human participants’ rights and welfare. EC members must possess the professional competence to review research activities and be able to ascertain the acceptability of proposed research based on institutional commitments and regulations, applicable laws, and standards. In addition, if an EC regularly reviews research involving vulnerable populations, the committee must consider including one (1) or more individuals knowledgeable about and experienced in working with those participants. See the Vulnerable Populations section for details on vulnerable populations.

At a minimum, each EC must also include the following members:

• One (1) primarily focused on scientific issues
• One (1) focused on nonscientific issues
• One (1) unaffiliated with the institution, and not part of the immediate family of a person affiliated with the institution

No EC member may participate in the initial or continuing review of any project in which the member has a conflicting interest, except to provide EC requested information.

Terms of Reference, Review Procedures, and Meeting Schedule

As delineated in 21CFR56, ECs must follow written procedures for the following:

• Conducting initial and continuing reviews, and reporting findings and actions
• Determining which projects require review more often than annually, and which projects need verification from sources other than the investigator that no material changes have occurred since the previous EC review
• Ensuring that changes in approved research are not initiated without EC review and approval except where necessary to eliminate apparent immediate hazards to participants
• Ensuring prompt reporting to the EC, institution, and FDA of changes in research activity; unanticipated problems involving risks to participants or others; any instance of serious or continuing noncompliance with these regulations or EC requirements or determinations; or EC approval suspension/termination

Per the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, ECs must establish and follow written procedures for the following:

• Conducting initial and continuing reviews, and reporting findings and actions to the investigator and the institution
• Determining which projects require review more often than annually, and which projects need verification from sources other than the investigator that no material changes have occurred since the previous EC review
• Ensuring prompt reporting to the EC of proposed changes in research and ensuring that investigators conduct the research in accordance with the terms of the EC approval until any proposed changes have received EC review and approval, except where necessary to eliminate apparent immediate hazards to participants
• Ensuring prompt reporting to the EC, the institution, the FDA, and the Department of Health & Human Services (HHS)’ Office for Human Research Protections (OHRP) of any unanticipated problems involving risks to participants or others; any instance of serious or continuing noncompliance with these regulations or EC requirements or determinations; or EC approval suspension/termination.

21CFR56, the Pre2018-ComRule, and the RevComRule further require that an institution, or where appropriate an EC, prepare and maintain adequate documentation of EC activities, including copies of all research proposals reviewed. The applicable records must be retained for at least three (3) years after completion of the research. For more details on the EC records included in this requirement, see the Pre2018-ComRule, the RevComRule, and 21CFR56.

See G-IRBProcs for detailed FDA guidance on EC written procedures to enhance human participant protection and reduce regulatory burden. The guidance includes a Written Procedures Checklist that incorporates regulatory requirements as well as recommendations on operational details to support the requirements.

Per 21CFR56, the Pre2018-ComRule, and the RevComRule, proposed research must be reviewed during convened meetings at which a majority of the EC members are present, including at least one (1) member whose primary concerns are nonscientific, except when an expedited review procedure is used. Research is only considered approved if it receives the majority approval of attending members.

Refer to the Pre2018-ComRule, the RevComRule, 21CFR56, the G-IRBProcs, and the G-IRBFAQs for detailed EC procedural requirements.

In addition, per the Pre2018-ComRule, the RevComRule, and the G-HHS-Inst-Engagemt, any institution engaged in non-exempt human subjects research conducted or supported by a Common Rule department/agency (as identified in USA-65) must also submit a written assurance of compliance to OHRP. According to USA-59, the Federalwide Assurance (FWA) is the only type of assurance of compliance accepted and approved by OHRP for HHS-funded research. See USA-57 for more information on FWAs.

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

Overview

21CFR56, 21CFR312, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs state that the primary scope of information assessed by the institutional ethics committee (EC) (referred to as an institutional review board (IRB) in the United States (US)) relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial. As delineated in 21CFR56, the Pre2018-ComRule, and the RevComRule, the EC 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 EC is also responsible for ensuring a competent review of the research protocol, evaluating the possible risks and expected benefits to participants, and verifying the adequacy of confidentiality safeguards.

See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.

Role in Clinical Trial Approval Process

In accordance with 21CFR56 and 21CFR312, the Food & Drug Administration (FDA) must review an investigational new drug application (IND) and an EC must review and approve the proposed study prior to a sponsor initiating a clinical trial. The institutional EC review of the clinical investigation may be conducted in parallel with the FDA review of the IND. However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial. According to 21CFR56, the Pre2018-ComRule, and the RevComRule, the EC may approve, require modifications in (to secure approval), or disapprove the research.

Refer to the G-RevComRule-FDA for information on the impact of the RevComRule on studies conducted or supported by the Department of Health & Human Services (HHS) that must also comply with FDA regulations.

Per 21CFR56, the Pre2018-ComRule, the RevComRule, and the G-IRBContRev, an EC has the authority to suspend or terminate approval of research that is not being conducted in accordance with the EC’s requirements or that has been associated with unexpected serious harm to participants. Any suspension or termination of approval will include a statement of the reasons for the EC’s action and will be reported promptly to the investigator, appropriate institutional officials, and the department or agency head (e.g., the FDA). See the G-IRBContRev for additional information and FDA recommendations on suspension or termination of EC approval.

Expedited Review

21CFR56, the Pre2018-ComRule, and the RevComRule indicate that the FDA and HHS maintain a list of research categories that may be reviewed by an EC through an expedited review procedure (see the G-IRBExpdtdRev for the list). An EC may use the expedited review procedure to review the following:

• Some or all of the research appearing on the list and found by the reviewer(s) to involve no more than minimal risk
• Minor changes in previously approved research during the period (of one (1) year or less) for which approval is authorized
• Under the RevComRule, research for which limited EC review is a condition of exemption

21CFR56, the Pre2018-ComRule, and the RevComRule specify that under an expedited review procedure, the review may be carried out by the EC chairperson or by one (1) or more experienced reviewers designated by the chairperson from among the EC’s members. In reviewing the research, the reviewers may exercise all of the authorities of the EC except that the reviewers may not disapprove the research. A research activity may be disapproved only after review in accordance with the EC’s non-expedited review procedure.

Continuing Review and Re-approval

21CFR56 and the G-IRBContRev state that any clinical investigation must not be initiated unless the reviewed and approved study remains subject to continuing review at intervals appropriate to the degree of risk, but not less than once a year. The G-IRBContRev notes that when continuing review of the research does not occur prior to the end of the approval period specified by the EC, EC approval expires automatically. A lapse in EC approval of research occurs whenever an investigator has failed to provide continuing review information to the EC, or the EC has not conducted continuing review and re-approved the research by the expiration date of the EC approval. In such circumstances, all research activities involving human participants must stop. Enrollment of new participants cannot occur after the expiration of EC approval.

In addition, per the G-IRBContRev, research that qualified for expedited review at the time of initial review will generally continue to qualify for expedited continuing review. For additional information and FDA recommendations regarding continuing review, see the G-IRBContRev.

The Pre2018-ComRule similarly indicates that the EC must conduct reviews at intervals appropriate to the degree of risk, but not less than once per year. However, the RevComRule provides the following exceptions to the continuing review requirement, unless an EC determines otherwise:

• Research eligible for expedited review
• Research reviewed by the EC in accordance with the limited EC review described in Section 46.104 of the RevComRule
• Research that has progressed to the point that it involves data analysis and/or accessing follow-up clinical data from procedures that are part of clinical care

Exemptions under the Revised Common Rule

Per the RevComRule, certain categories of research are exempt from EC review, and some “exempt” activities require limited EC review or broad consent. Users should refer to Section 46.104 of the RevComRule for detailed information on research categories specifically exempt from EC review, or exempt activities requiring limited EC review or broad consent.

Per USA-54, for secondary research that does not qualify for an exemption under the RevComRule, the applicant must either apply for a waiver of the informed consent requirement from the EC, obtain study-specific informed consent, or obtain broad consent.

Further, the RevComRule modifies what constitutes research to specifically exclude the following types of research:

• Scholarly and journalistic activities
• Public health surveillance activities authorized by a public health authority to assess onsets of disease outbreaks or conditions of public health importance
• Collection and analysis of information, biospecimens, or records by or for a criminal justice agency for criminal investigative activities
• Authorized operational activities in support of intelligence, homeland security, defense, or other national security missions

See the G-IRBFAQs, the G-OHRP-IRBApprvl, and USA-54 for frequently asked questions regarding EC procedures, approval with conditions, example research, expedited review, limited review, and continuing review.

Other Considerations

Per the FDA’s G-IRBReview, an EC may review studies that are not performed on-site. When an institution has a local EC, the written procedures of that EC or of the institution should define the scope of studies subject to review by that EC. A non-local EC may not become the EC of record for studies within that defined scope unless the local EC or the administration of the institution agree. Any agreement to allow review by a non-local EC should be in writing. For more information, see G-IRBReview.

Cooperative Research Studies

In the event of multicenter clinical studies, also known as cooperative research studies, taking place at US institutions that are subject to the RevComRule, the institutions must rely on a single EC to review that study for the portion of the study conducted in the US. The reviewing EC will be identified by the Common Rule department/agency (as identified in USA-65) supporting or conducting the research or proposed by the lead institution subject to the acceptance of the department/agency. The exceptions to this requirement include: when multicenter review is required by law (including tribal law) or for research where any federal department or agency supporting or conducting the research determines that the use of a single EC is not appropriate.

Designed to complement the RevComRule, per the NIHNotice16-094 and the NIHNotice17-076, the National Institutes of Health (NIH) issued a final policy requiring all institute-funded multicenter clinical trials conducted in the US to be overseen by a single EC, unless prohibited by any federal, tribal, or state law, regulation, or policy.

For more information on multicenter research, see the FDA’s G-CoopRes. For more information on how new sites added to ongoing cooperative research can follow the same version of the Common Rule, see the HHS Office for Human Research Protections (OHRP)’s G-ComRuleCnsstncy.

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.

Many institutional ethics committees (ECs) (referred to as institutional review boards (IRBs) in the United States (US)) charge fees to review research proposals submitted by industry-sponsored research or other for-profit entities. However, this varies widely by institution. Neither the Department of Health & Human Services (HHS) nor the Food & Drug Administration (FDA) regulate institutional EC review fees. Because each EC has its own requirements, individual ECs should be contacted to confirm their specific fees.

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

As delineated in 21CFR56 and 45CFR46-B-E, the Department of Health & Human Services (HHS) and the HHS’ Food & Drug Administration (FDA) have mandatory registration programs for institutional ethics committee (ECs), referred to as institutional review boards (IRBs) in the United States (US). A single electronic registration system (USA-28) for both agencies is maintained by HHS’ Office for Human Research Protections (OHRP).

Registration, Auditing, and Accreditation

In accordance with the G-IRBReg-FAQs and USA-61, EC registration with the HHS OHRP system (USA-28) is not a form of accreditation or certification by either the FDA that the EC is in full compliance with 21CFR56, or by the HHS that the EC is in full compliance with 45CFR46-B-E. Neither EC competence nor expertise is assessed during the registration review process by either agency.

Food & Drug Administration

According to 21CFR56 and the G-IRBReg-FAQs, the FDA requires each EC in the US, that either reviews clinical investigations regulated by the agency under the FDCAct or reviews investigations intended to support research or marketing permits for agency-regulated products, to register electronically in the HHS OHRP system (USA-28). Only individuals authorized to act on the EC’s behalf are permitted to submit registration information. Non-US ECs may register voluntarily. The G-IRBReg-FAQs also indicates that while registration of non-US ECs is voluntary, the information the FDA receives from them is very helpful.

As stated in 21CFR56 and the G-IRBReg-FAQs, any EC not already registered in the HHS OHRP system (USA-28) must submit an initial registration prior to reviewing a clinical investigation in support of an investigational new drug application (IND). The HHS OHRP system (USA-28) provides instructions to assist users, depending on whether the EC is subject to regulation by only the OHRP, only the FDA, or both the OHRP and the FDA.

21CFR56 and the G-IRBReg-FAQs indicate that FDA EC registration must be renewed every three (3) years. EC registration becomes effective after review and acceptance by the HHS.

See 21CFR56 and the G-IRBReg-FAQs for detailed EC registration submission requirements. See the G-IRBInspect for FDA inspection procedures of ECs.

Office for Human Research Protections

Per the Pre2018-ComRule and RevComRule, institutions engaging in research conducted or supported by a Common Rule department/agency (as identified in USA-65) must obtain an approved assurance that it will comply with the Pre2018-ComRule or RevComRule requirements and certify to the department/agency heads that the research has been reviewed and approved by an EC provided for in the assurance.

Per USA-59, a Federalwide Assurance (FWA) of compliance is a document submitted by an institution (not an EC) engaged in non-exempt human subjects research conducted or supported by HHS that commits the institution to complying with Pre2018-ComRule or RevComRule requirements. FWAs also are approved by the OHRP for federalwide use, which means that other federal departments and agencies that have adopted the Federal Policy for the Protection of Human Subjects (Pre2018-ComRule or RevComRule) may rely on the FWA for the research that they conduct or support. Institutions engaging in research conducted or supported by non-HHS federal departments or agencies should consult with the sponsoring department or agency for guidance regarding whether the FWA is appropriate for the research in question.

Per USA-54, institutions do not need to change an existing FWA because of the RevComRule. See USA-57 for more information on FWAs.

Per 45CFR46-B-E and USA-61, all ECs that review human subjects research conducted or supported by HHS and are to be designated under an OHRP FWA must register electronically with the HHS OHRP system (USA-28). An individual authorized to act on behalf of the institution operating the EC must submit the registration information. EC registration becomes effective for three (3) years when reviewed and approved by OHRP.

Per USA-59, an institution must either register its own EC (an “internal” EC) or designate an already registered EC operated by another organization (“external” EC) after establishing a written agreement with that other organization. Additionally, each FWA must designate at least one (1) EC registered with the OHRP. The FWA is the only type of assurance of compliance accepted and approved by the OHRP.

See 45CFR46-B-E, USA-58, and USA-61 for detailed registration requirements and instructions.

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

Overview

As delineated in 21CFR312, USA-42, and USA-52, the United States (US) requires the sponsor to submit an investigational new drug application (IND) for the Food & Drug Administration (FDA)'s review and authorization to obtain an exemption to ship investigational drug or biological products across state lines and to administer these investigational products in humans. Per 21CFR312 and the G-IND-Determination, whether an IND is required to conduct an investigation of a drug to be marketed (this includes biological products under the FDCAct) primarily depends on the intent of the investigation, and the degree of risk associated with the use of the drug in the investigation. See the Scope of Assessment section for more information.

In addition, per 21CFR56 and 21CFR312, institutional ethics committee (EC) (institutional review board (IRB) in the US) review of the clinical investigation may be conducted in parallel with the FDA review of the IND. However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial.

Regulatory Submission

According to 21CFR312, meetings between a sponsor and the FDA may be useful in resolving questions and issues raised during the course of a clinical investigation. The FDA encourages such meetings to the extent that they aid in the evaluation of the drug and in the solution of scientific problems concerning the drug, to the degree the FDA's resources permit. See 21CFR312 for more information on meetings with the FDA.

A sponsor who is conducting a clinical trial to support a future marketing application may ask to meet with the FDA for a special protocol assessment (SPA) to help ensure the clinical trial can support the application. For more information, see G-SPA.

Additionally, the G-FDAComm describes the FDA’s philosophy regarding timely interactive communication with IND sponsors, the scope of appropriate interactions between review teams and sponsors, the types of advice appropriate for sponsors to seek from the FDA in pursuing their drug development programs, and general expectations for the timing of FDA response to sponsor inquiries. See the G-FDAComm for more information.

According to the G-PharmeCTD, which implements FDCAct requirements, and as described in USA-34 and USA-53, commercial IND submissions must be submitted in the Electronic Common Technical Document (eCTD) format. Noncommercial INDs are exempt from this eCTD format submission requirement. “Noncommercial products” refer to products not intended to be distributed commercially, including investigator-sponsored INDs and expanded access INDs (e.g., emergency use and treatment INDs). However, the G-AltrntElecSubs indicates that sponsors and applicants who receive an exemption or a waiver from filing in eCTD format should still provide those exempted or waived submissions electronically, in an alternate format.

The G-AltrntElecSubs and USA-35 indicate that for both eCTD and alternate electronic formats, submissions should include only FDA fillable forms and electronic signatures. Scanned images of FDA fillable forms should not be submitted. In addition, before making an electronic submission, a pre-assigned application number should be obtained by contacting the FDA’s Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER). See USA-35 for more information on requesting an application number.

For more information and detailed requirements on eCTD submissions, see the G-PharmeCTD, the G-eCTDTech, USA-35, and USA-36. Additionally, the G-CBER-ElecINDs provides instructions on how to submit an IND using an electronic folder structure on a CD-ROM.

According to the G-eCTDspecs and USA-7, eCTD submissions sized 10 GB and under for most applications must be submitted via the FDA Electronic Submissions Gateway (ESG) (USA-44). However, the G-eCTDspecs adds that the FDA also recommends the use of USA-44 for submissions greater than 10 GB when possible. See USA-8 for information on how to create an account.

As indicated in the G-eCTDspecs, physical media greater than 10 GB should be submitted using a USB drive. For specific instructions on how to submit physical media, email CDER at esub@fda.hhs.gov or CBER at esubprep@fda.hhs.gov. See the G-eCTDspecs for additional physical media information.

The IND must be submitted in English. As indicated in 21CFR312, the sponsor must submit an accurate and complete English translation of each part of the IND that is not in English. The sponsor must also submit a copy of each original literature publication for which an English translation is submitted.

According to USA-41 and USA-94, paper submissions of INDs should be sent to CDER or CBER at the following locations, as appropriate:

Drugs (submitted by Sponsor-Investigators):

Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Central Document Room
5901-B Ammendale Rd.
Beltsville, MD 20705-1266

Therapeutic Biological Product (submitted by Sponsor-Investigators):

Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Therapeutic Biological Products Document Room
5901-B Ammendale Rd.
Beltsville, MD 20705-1266

Center for Biologics Evaluation and Research-Regulated Products:

Food and Drug Administration
Center for Biologics Evaluation and Research (CBER)
Document Control Center
10903 New Hampshire Avenue
WO71, G112
Silver Spring, MD 20993-0002

(Note: Per USA-94, CBER also accepts electronic media via mail, but electronic or email submission is preferred.)

Based on information provided in 21CFR312, for paper IND submissions, the sponsor must submit an original and two (2) copies, including the original submission and all amendments and reports.

For more information on CDER and CBER internal policies and procedures for accepting and reviewing applications, see USA-96 and USA-95, respectively.

Ethics Review Submission

Each EC maintains its own procedures and processes for review. Consequently, there is no stated regulatory requirement for clinical trial submission processes.

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.

Regulatory Authority Requirements

As specified in 21CFR312, an investigational new drug application (IND) to the Food & Drug Administration (FDA) must include the following documents, in the order provided below:

• Cover sheet (Form FDA 1571 (USA-76)) (including, but not limited to: sponsor contact information, investigational product (IP) name, application date, phase(s) of clinical investigation to be conducted, and commitment that the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) will conduct initial and continuing review and approval of each study proposed in the investigation)
• Table of contents
• Introductory statement and general investigational plan
• Investigator’s brochure (IB)
• Protocols
• Chemistry, manufacturing, and control data
• Pharmacology and toxicology data
• Previous human experience with the IP
• Additional information (e.g., drug dependence and abuse potential, radioactive drugs, pediatric studies)
• Relevant information (e.g., foreign language materials and number of copies - see Submission Process section for details)

For detailed application requirements, see 21CFR312. In addition, see USA-40 for other IND forms and instructions.

Furthermore, for information on the appropriate use of adaptive designs for clinical trials and additional information to provide to the FDA to support its review, see G-AdaptiveTrials.

The G-RWDRWE-Doc states that to facilitate the FDA’s internal tracking of submissions that include real-world data (RWD) and real-world evidence (RWE), sponsors and applicants are encouraged to identify in their submission cover letters certain uses of RWD/RWE. For more information, see the G-RWDRWE-Doc.

The FDCAct, as amended by the FDORA, requires sponsors to submit diversity action plans for certain clinical trials, such as a clinical investigation of a new drug that is a phase 3 study. See the FDORA for more details. (Note: The FDA’s guidance on diversity action plans is currently in draft. The ClinRegs team will continue to monitor this requirement and incorporate any updates as appropriate).

According to the G-PedStudyPlans, a sponsor who is planning to submit to the FDA a marketing application (or supplement to an application) for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration is required to submit an initial pediatric study plan (iPSP), if required by the Pediatric Research Equity Act (PREA). An exception to this is if the drug is for an indication granted an orphan designation. For additional details and recommendations to sponsors regarding the submission of an iPSP, see the G-PedStudyPlans.

Ethics Committee Requirements

Each EC has its own application form and clearance requirements, which can differ significantly regarding application content requirements. However, the requirements listed below comply with 21CFR56 as well as the US-ICH-GCPs and are basically consistent across all US ECs.

As per 21CFR56, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, the EC should obtain the following documents and must ensure the listed requirements are met prior to approving the study (Note: The regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

• Clinical protocol
• Informed consent forms (ICFs) and participant information (the RevComRule also requires information regarding whether informed consent was appropriately sought and documented, or waived)
• Participant recruitment procedures
• IB
• Safety information
• Participant payments and compensation
• Investigator(s) current Curriculum Vitaes (CVs)
• Additional required EC documentation
• Risks to participants are minimized and are reasonable in relation to anticipated benefits
• Participant selection is equitable
• Adequate provisions are made to protect participant privacy and maintain confidentiality of data, where appropriate; the Department of Health & Human Services (HHS) will issue guidance to assist ECs in assessing what provisions are adequate to protect participant privacy and maintain the confidentiality of data

Per the RevComRule, where limited EC review applies, the EC does not need to make the determinations outlined above. Rather, limited EC review includes determinations that broad consent will be/was obtained properly, that adequate protections are in place for safeguarding the privacy and confidentiality of participants, and (for secondary studies) that individual research results will not be returned to participants. See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.

See 21CFR56, the Pre2018-ComRule, the RevComRule, and section 3 of the US-ICH-GCPs for additional EC submission requirements.

Clinical Protocol

According to the US-ICH-GCPs, the clinical protocol should contain the following elements:

• General information
• Background information
• Trial objectives and purpose
• Trial design
• Participant selection/withdrawal
• Participant treatment
• Efficacy assessment
• Safety assessment
• Statistics
• Direct access to source data/documents
• Quality control/quality assurance
• Ethics
• Data handling/recordkeeping
• Financing/insurance
• Publication policy
• For complete protocol requirements, see section 6 of the US-ICH-GCPs.

Per the NIHNotice17-064, and provided in USA-29 and USA-27, the National Institutes of Health (NIH) and the FDA developed a clinical trial protocol template with instructional and example text for NIH-funded investigators to use when writing protocols for phase 2 and 3 clinical trials that require IND applications.

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

As delineated in 21CFR56 and 21CFR312, institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) review of the clinical investigation may be conducted in parallel with the Food & Drug Administration (FDA)'s review of the investigational new drug application (IND). However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial.

Regulatory Authority Approval

Per the FDCAct and 21CFR312, initial INDs submitted to the FDA’s Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER) automatically go into effect in 30 calendar days, unless the FDA notifies the sponsor that the IND is subject to a clinical hold, or the FDA has notified the sponsor earlier that the trial may begin. As indicated in 21CFR312, the FDA will provide the sponsor with a written explanation of the basis for the hold as soon as possible, and no more than 30 days after the imposition of the clinical hold. See 21CFR312 for more information on clinical hold timelines. For more information on CDER and CBER internal policies and procedures for reviewing applications, see USA-96 and USA-95, respectively.

According to USA-41 and USA-42, clinical studies must not be initiated until 30 days after the FDA receives the IND, unless the FDA provides earlier notification that studies may begin.

Ethics Committee Approval

Each EC maintains its own procedures and processes for review. Consequently, there is no stated regulatory requirement for a standard timeline of review and approval of the clinical trial. However, according to the US-ICH-GCPs, the institutional EC should review a proposed clinical trial within a reasonable time.

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.

Overview

In accordance with 21CFR312, USA-41, and USA-42, a clinical trial can only commence after the investigational new drug application (IND) is reviewed by the Food & Drug Administration (FDA), which will provide a written determination within 30 days of receiving the IND. No waiting period is required following the 30-day FDA review period, unless the agency imposes a clinical hold on the IND or sends an earlier notification that studies may begin. Per 21CFR312 and 21CFR56, ethics approval from an institutional ethics committee (EC) (known as institutional review board (IRB) in the United States (US)) is also required before a clinical trial can commence.

As per 21CFR312, once an IND has been submitted and following the 30-day review period, the sponsor is permitted to import an investigational product (IP). (See the Manufacturing & Import section for additional information).

See the G-CTDiversity for FDA recommendations to sponsors on increasing enrollment of underrepresented populations in their clinical trials.

Clinical Trial Agreement

Prior to the trial’s commencement, as addressed in the 21CFR312 and the G-1572FAQs, the sponsor must obtain from the investigator(s) a signed Statement of Investigator, Form FDA 1572 (USA-77). This form serves as the investigator’s agreement to provide certain information to the sponsor and to ensure compliance with the FDA’s clinical investigation regulations. Refer to the 21CFR312, the G-1572FAQs, and USA-40 for further information.

The US-ICH-GCPs indicates that the sponsor must obtain the investigator’s/institution’s agreement:

• To conduct the trial in compliance with good clinical practice (GCP), 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/reporting;
• To permit monitoring, auditing, and inspection; and
• 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 must sign the protocol, or an alternative document, to confirm this agreement.

Clinical Trial Registration

The FDAMA, the FDAAA, and 42CFR11 require the responsible party, either the sponsor or the principal investigator (PI) designated by the sponsor, to register electronically with the ClinicalTrials.gov databank (USA-78). Per the FDAAA and 42CFR11, the sponsor/PI must register no later than 21 calendar days after the first human participant is enrolled in a trial.

42CFR11 expands the legal requirements for submitting clinical trial registration information and results for investigational products that are approved, licensed, or cleared by the FDA.

The National Institutes of Health (NIH) issued NIHTrialInfo to complement 42CFR11 requirements. This policy requires all NIH-funded awardees and investigators conducting clinical trials, funded in whole or in part by the NIH, regardless of study phase, type of intervention, or whether they are subject to the regulation, to ensure that they register and submit trial results to ClinicalTrials.gov (USA-78).

See 42CFR11, the NIHTrialInfo, and USA-49 for detailed information on ClinicalTrials.gov (USA-78). See also the FDA’s G-DataBankPnlty for clarification on the types of civil money penalties that may be issued for failing to register a clinical trial.

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.

Safety Reporting Definitions

In accordance with 21CFR312, the G-IND-Safety, 42CFR11, and USA-38, the following definitions provide a basis for a common understanding of safety reporting requirements in the United States (US):

• Adverse Event – Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related
• Suspected Adverse Reaction – Any adverse event where there is a reasonable possibility that the drug caused the adverse event
• Adverse Reaction – Any adverse event caused by a drug. Adverse reactions are a subset of all suspected adverse reactions where there is reason to conclude that the drug caused the event
• Serious Adverse Event/Serious Suspected Adverse Reaction – An adverse event/suspected adverse reaction that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, causes persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, or leads to a substantial disruption of the participant’s ability to conduct normal life functions
• Unexpected Adverse Event/Unexpected Suspected Adverse Reaction – An adverse event/suspected adverse reaction that is not listed in the investigator’s brochure (IB), or is not listed at the specificity or severity that has been observed; or if an IB is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the application
• Life-threatening Adverse Event/Life-threatening Suspected Adverse Reaction – An adverse event/suspected adverse reaction is considered “life-threatening” if its occurrence places the participant at immediate risk of death. It does not include an adverse event/suspected adverse reaction that, had it occurred in a more severe form, might have caused death

According to the G-HHS-AEReqs, the Department of Health & Human Services (HHS)’s 45CFR46 regulations (the Pre2018-ComRule, the RevComRule, and 45CFR46-B-E) do not define the terms “adverse event” or “unanticipated problems.” However, the Pre2018-ComRule and the RevComRule do contain requirements relevant to reviewing and reporting these incidents. See the G-HHS-AEReqs, the G-IRBRpting, the Pre2018-ComRule, and the RevComRule for further information.

See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.

Safety Reporting Requirements

Investigator Responsibilities

As delineated in 21CFR312 and the G-IND-Safety, the investigator must comply with the following reporting requirements:

• Serious adverse events, whether or not considered drug related, must be reported immediately to the sponsor
• Study endpoints that are serious adverse events must be reported in accordance with the protocol unless there is evidence suggesting a causal relationship between the drug and the event. In that case, the investigator must immediately report the event to the sponsor
• Non-serious adverse events must be recorded and reported to the sponsor according to the protocol specified timetable
• Report promptly to the ethics committee (EC) all unanticipated problems involving risk to human participants or others where adverse events should be considered unanticipated problems

Sponsor Responsibilities

As delineated in 21CFR312, the G-IND-Safety, and USA-38, the sponsor must report any suspected adverse reaction or adverse reaction that is both serious and unexpected. An adverse event is only required to be reported as a suspected adverse reaction if there is evidence to suggest a causal relationship between the drug and the adverse event.

The sponsor is required to notify the Food & Drug Administration (FDA) and all participating investigators in a written safety report of potential serious risks, from clinical trials or any other source, as soon as possible, but no later than 15 calendar days after the sponsor determines the information qualifies for reporting. Additionally, the sponsor must notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but no later than seven (7) calendar days following receipt of the information. The sponsor is required to submit a follow-up safety report to provide additional information obtained pertaining to a previously submitted safety report. This report should be submitted without delay, as soon as the information is available, but no later than 15 calendar days after the sponsor initially receives the information.

Per 21CFR312 and the G-IND-Safety, the sponsor must also report the following:

• Any findings from epidemiological studies, pooled analyses of multiple studies, or clinical studies (other than those reported in the safety report), whether or not conducted under an investigational new drug application (IND), and whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to the drug
• Any findings from animal or in vitro testing, whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to the drug
• Any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or IB

In each safety report, the sponsor must identify all safety reports previously submitted to the FDA concerning a similar suspected adverse reaction and must analyze the significance of the suspected adverse reaction in light of previous, similar reports, or any other relevant information. Refer to 21CFR312 and the G-IND-Safety for more details on these safety reporting requirements.

As part of the clinical trial results information submitted to ClinicalTrials.gov (USA-78), 42CFR11 requires the responsible party, either the sponsor or the principal investigator (PI) designated by the sponsor, to submit three (3) tables of adverse event information. The tables should consist of the following summarized data:

• All serious adverse events
• All adverse events, other than serious adverse events, that exceed a frequency of five (5) percent in any arm of the trial
• All-cause mortalities

Per 42CFR11 and USA-70, this information must be submitted no later than one (1) year after the primary completion date of the clinical trial. Submission of trial results may be delayed as long as two (2) years if the sponsor or PI submits a certification to ClinicalTrials.gov (USA-78) that either: 1) the FDA has not yet approved, licensed, or cleared for marketing the investigational product (IP) being studied; or 2) the manufacturer is the sponsor and has sought or will seek approval within one (1) year.

See 42CFR11 for detailed adverse event reporting requirements.

Form Completion & Delivery Requirements

As per 21CFR312, the G-IND-Safety, and USA-38, the sponsor must submit each safety report in a narrative format on Form FDA 3500A (USA-75), or in an electronic format that the FDA can process, review, and archive, and be accompanied by Form FDA 1571 (USA-76) (cover sheet).

As per the G-IND-Safety and USA-38, the submission must be identified as follows:

• “IND safety report” for 15-day reports
• “7-day IND safety report” for unexpected fatal or life-threatening suspected adverse reaction reports
• “Follow-up IND safety report” for follow-up information

The report must be submitted to the appropriate review division (i.e., Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER)). Per USA-38, the FDA recommends that sponsors submit safety reports electronically. Other means of rapid communication to the respective review division’s Regulatory Project Manager (e.g., telephone, facsimile transmission, email) may also be used. Per USA-90, fatality reports to CBER should be sent to fatalities2@fda.hhs.gov.

Additionally, 21CFR312 and the G-IND-Safety indicate that the FDA will accept foreign suspected adverse reaction reports on CIOMS Form I (See USA-13 and USA-3) instead of Form FDA 3500A (USA-75). See USA-38 and USA-48 for additional information.

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

Interim and Annual Progress Reports

As per the US-ICH-GCPs, the investigator should promptly provide written reports to the sponsor and the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) on any changes significantly affecting the conduct of the trial, and/or increasing the risk to participants.

As specified in 21CFR312, the investigator must furnish all reports to the sponsor who is responsible for collecting and evaluating the results obtained. In addition, per 21CFR56 and the US-ICH-GCPs the investigator should submit written summaries of the trial status to the institutional EC annually, or more frequently, if requested by the institutional EC.

21CFR312 states that the sponsor must submit a brief annual progress report on the investigation to the Food & Drug Administration (FDA) within 60 days of the anniversary date that the investigational new drug went into effect. The report must contain the following information for each study:

• Title, purpose, and description of patient population, and current status
• Summary of the participants screened (e.g., failed screenings; participants enrolled, withdrawn, or lost to follow-up; and other challenges)
• Summary information - including information obtained during the previous year’s clinical and nonclinical investigations
• Description of the general investigational plan for the coming year
• Updated investigator’s brochure, if revised
• Description of any significant Phase 1 protocol modifications not previously reported in a protocol amendment
• Brief summary of significant foreign marketing developments with the drug
• A log of any outstanding business for which the sponsor requests a reply, comment, or meeting

As indicated in 42CFR11, trial updates must be submitted to ClinicalTrials.gov (USA-78) according to the following guidelines:

• Not less than once every 12 months for updated general trial registration information
• Not later than 30 calendar days for any changes in overall recruitment status
• Not later than 30 calendar days after the trial reaches its actual primary completion date, the date the final participant was examined or received an intervention for the purposes of final collection data for the primary outcome

Final Report

As indicated in 21CFR312, an investigator must provide the sponsor with an adequate report shortly after completion of the investigator’s participation in the investigation. There is no specific timeframe stipulated for when the report should be completed.

The US-ICH-GCPs also states that upon the trial’s completion, the investigator should inform the institution and the investigator/institution should provide the EC with a summary of the trial’s outcome, and supply the FDA with any additional report(s) required of the investigator/institution.

Additionally, per 42CFR11 and USA-70, the sponsor or the principal investigator (PI) designated by the sponsor must submit results for applicable investigational product (IP) clinical trials to USA-78 no later than one (1) year following the study’s completion date. Submission of trial results may be delayed as long as two (2) years if the sponsor or PI submits a certification to USA-78 that indicates either: 1) the FDA has not yet approved, licensed, or cleared the IP being studied for marketing; or 2) the manufacturer is the sponsor and has sought or will seek approval within one (1) year. The results information must include data on the following:

• Participant flow
• Demographic and baseline characteristics
• Outcomes and statistical analysis
• Adverse events
• The protocol and statistical analysis plan
• Administrative information

See USA-49 for more information and 42CFR11 for more detailed requirements. See NIHTrialInfo for specific information on dissemination of NIH-funded clinical trial data.

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.

As per 21CFR312, 21CFR50, and the US-ICH-GCPs, a sponsor is defined as a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization. The sponsor does not actually conduct the investigation unless the sponsor is a sponsor-investigator. 21CFR312, 21CFR50, and the US-ICH-GCPs define a sponsor-investigator as an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational product is administered or dispensed.

In addition, 21CFR312 and the US-ICH-GCPs state that a sponsor may transfer responsibility for any or all obligations to a contract research organization (CRO).

Any trial-related responsibilities transferred to and assumed by a CRO should be specified in writing, and those obligations not covered by the written description will be deemed not to have been transferred. Further, a CRO that assumes any sponsor obligations must comply with the specific regulations delineated in 21CFR312 and will be subject to the same regulatory action as the sponsor for failure to comply with any obligation assumed under these regulations. However, per the US-ICH-GCPs, although a sponsor may transfer all trial-related duties and functions to a CRO, the sponsor is ultimately responsible for the study data’s quality and integrity.

As indicated in 21CFR312, a sponsor may be either domestic or foreign.

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.

Overview

As set forth in 21CFR312 and the US-ICH-GCPs, 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. Prior to permitting an investigator(s) to conduct a study, the sponsor must obtain the following:

• Signed investigator’s statement (Form FDA 1572 (USA-77))
• Curriculum vitae
• Clinical protocol
• Financial disclosure information

As addressed in the G-1572FAQs, Form FDA 1572 (USA-77) serves as the investigator’s agreement to provide certain information to the sponsor and to assure compliance with the Food & Drug Administration (FDA)'s clinical investigation regulations. Refer to the G-1572FAQs and USA-40 for further information.

In addition, prior to the start of the study, the sponsor must provide the investigator(s) with the protocol and the investigator’s brochure.

See G-InvstgtrResp for more information on investigator responsibilities.

As per the G-InvstgtrAdmin, the FDA may disqualify a clinical investigator from receiving investigational drugs (including biologics) if the FDA determines that the investigator has repeatedly or deliberately violated the agency’s regulations, or submitted false information to the sponsor or FDA in any required report. See the G-InvstgtrAdmin for more details.

Foreign Sponsor Responsibilities

No information is currently available.

Data and Safety Monitoring Board

As per 21CFR50 and the G-DMCs, Data and Safety Monitoring Boards (DSMBs), (also known as a Data Monitoring Committees (DMCs)), are not required by FDA regulations, except in the case of research conducted in emergency settings in which fulfilling the informed consent requirement is unfeasible. In this case, as stated in 21CFR50, the FDA requires the establishment of an independent data monitoring committee to exercise oversight of the clinical investigation. See the G-DMCs for FDA recommendations on DSMB/DMC establishment.

Additionally, the Pre2018-ComRule and the RevComRule indicate that for all human subjects research funded and/or sponsored by a Common Rule department/agency (as identified in USA-65), the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) must ensure that, when appropriate, the research plan makes adequate provisions for monitoring the data collected during the study to ensure participant safety. Moreover, per the NIHDataSftyMntrng and USA-72, all National Institutes of Health (NIH)-funded clinical trials require a Data and Safety Monitoring Plan and monitoring should be commensurate with risk. DSMBs are also required for multi-site clinical trials with interventions that involve potential participant risk. See the NIHDataSftyMntrng and USA-72 for detailed Department of Health & Human Services (HHS)/NIH requirements.

Although not specified as a sponsor requirement, the US-ICH-GCPs states that a DSMB may be established to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial.

Multicenter Studies

For all human subjects research funded and/or sponsored by a Common Rule department/agency, institutions that are located in the US and engaged in multicenter research/cooperative research studies must use a single EC to review the research. See the Scope of Review section, the RevComRule, and G-CoopRes for additional information.

The US-ICH-GCPs indicates that in the event of a multicenter clinical trial, the sponsor must ensure that:

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

See US-ICH-E17 for additional FDA guidance related to multi-regional clinical trials.

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.

Insurance

The United States (US) regulations do not require insurance.

Compensation

The G-IRBFAQs state that institutional policy, not Food & Drug Administration (FDA) regulation, determines whether compensation and medical treatment(s) will be offered and the conditions that might be placed on participant eligibility for compensation or treatment(s).

Injury or Death

According to the US-ICH-GCPs, the sponsor's policies and procedures should address the costs of treatment of trial subjects in the event of trial-related injuries in accordance with the applicable regulatory requirement(s).

As specified in 21CFR50, the Pre2018-ComRule, the RevComRule, and US-ICH-GCPs, for research involving more than minimal risk, participants must be informed as to whether any compensation or medical treatments are available in the event of trial-related injuries. See the Required Elements section for additional information.

Trial Participation

As per the FDA’s G-SbjctPayment, compensation for participation is considered a recruitment incentive and not a benefit, and is often offered when the participant’s health benefits are remote or non-existent. Payment amounts and schedules should be presented to the institutional ethics committee (EC) (institutional review board (IRB) in the US) at the time of the initial review. The EC should ensure the payment amount and the proposed method and timing of disbursement are not coercive or present undue influence and are also included in the informed consent document. Payment to participants who withdraw may be made at the time that they would have completed the study. While the entire payment should not be contingent upon completion of the entire study, a small payment provided as an incentive for completion is acceptable to the FDA. Further, the FDA does not consider reimbursement for travel expenses to and from the clinical trial site and associated costs such as airfare, parking, and lodging to raise issues regarding undue influence.

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.

Quality Assurance/Quality Control

Per the US-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. The quality management system should use a risk-based approach that includes:

• During protocol development, identify processes and data that are critical to ensure participant protection and the reliability of trial results
• Identify risks to critical trial processes and data
• Evaluate the identified risks, against existing risk controls
• Decide which risks to reduce and/or which risks to accept
• Document quality management activities and communicate to those involved in or affected by these activities
• Periodically review risk control measures to ascertain whether the implemented quality management activities are effective and relevant
• In the clinical study report, describe the quality management approach implemented in the trial and summarize important deviations from the predefined quality tolerance limits and remedial actions taken

As stated in the US-ICH-GCPs, 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 US-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. QC 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 all parties agree to the trial protocol, the monitoring and auditing practices, the SOPs, and their respective duties.

Per the G-ICH-E19, the Food & Drug Administration (FDA) has adopted the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)’s E19 guidance, A Selective Approach to Safety Data Collection in Specific Late-Stage Pre-Approval or Post-Approval Clinical Trials. The document describes circumstances in which it may be appropriate to reduce the collection of safety data in late-stage pre-approval and post-approval clinical trials, e.g., long-term outcome trials, when appropriate and with agreement from regulatory authorities. See the G-ICH-E19 for more information.

Furthermore, the FDA’s G-CTEmrgncy provides general considerations to assist sponsors, institutional ethics committees (ECs) (institutional review boards (IRBs) in the United States (US)), and clinical investigators in assuring the safety of trial participants, maintaining compliance with good clinical practice (GCP), and minimizing risks to trial integrity during disasters and public health emergencies that may lead to a major disruption of clinical trial conduct and operations. See the G-CTEmrgncy for more information.

See the G-eHealthRecords for the FDA’s guidance related to the use of electronic health records in clinical research.

Additionally, the G-CovariatesCT provides the FDA’s recommendations for the use of covariates in the analysis of randomized, parallel group clinical trials that are applicable to both superiority trials and noninferiority trials. See the G-CovariatesCT for more information.

The G-RWDRWE-Reg, issued as part of the FDA’s Real-World Evidence (RWE) Program (see USA-17), discusses the applicability of the 21CFR312 IND regulations to various clinical study designs that utilize real-world data (RWD). See the G-RWDRWE-Reg for more information.

Additionally, see USA-47 for a list of FDA clinical trials related guidance documents.

See USA-6 for information on the National Institutes of Health (NIH)’s data management and sharing policy, the NIHDataMngmnt, which applies to all research that is funded or conducted in whole or in part by the NIH, and results in the generation of scientific data.

Monitoring Requirements

As part of its QA system, the US-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 US-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 the sponsor’s own SOPs and the auditor observations are documented. 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 FDA’s G-RiskMntrng states that for each clinical trial, the sponsor should develop a monitoring plan that describes the monitoring methods, responsibilities, and requirements for the trial. The monitoring plan should include a brief description of the study, its objectives, and the critical data and study procedures, with particular attention to data and procedures that are unusual in relation to clinical routine. The monitoring plan should also require training of study site staff. Additionally, the plan should communicate the specific risks to be addressed by monitoring and should provide those involved in monitoring with adequate information to effectively carry out their duties. The FDA also encourages greater use of centralized monitoring practices, where appropriate, with correspondingly less emphasis on on-site monitoring. Centralized monitoring techniques should be used to the extent appropriate and feasible to:

• Supplement or reduce the frequency and extent of on-site monitoring with monitoring activities that can be done as well or better remotely or with monitoring activities that can be accomplished using centralized processes only. Examples include monitoring data quality through routine review of submitted data, as well as completing administrative and regulatory tasks.
• Target on-site monitoring by identifying higher risk clinical sites (e.g., sites with data anomalies or a higher frequency of errors, protocol violations, or dropouts relative to other sites).

For more FDA guidance on a risk-based approach to monitoring and monitoring plans, see the G-RiskMntrng and the G-RiskMntrngQA.

Premature Study Termination/Suspension

As delineated in 21CFR312 and the US-ICH-GCPs, if the sponsor determines the study presents an unreasonable and significant risk to the participants, the sponsor must discontinue the study as soon as possible, and no later than five (5) working days after making the determination. The sponsor must also notify the FDA, all ECs, and all investigators who have participated in the study about the termination. Additionally, the sponsor must ensure the disposition of all remaining drugs and provide the FDA with a full report on the sponsor’s actions.

According to the US-ICH-GCPs, 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.

The G-InfrmdCnsnt, which is the FDA’s discussion of the regulations in 21CFR50, further states that if a study is terminated, participants should be provided with as much information as possible regarding the reason for the termination. Such a discussion provides an opportunity to address questions that participants may have about an investigational product (IP) that was administered to them (e.g., immediate safety concerns, ability to participate in another clinical trial, and appropriate waiting period to do so) and what long-term follow-up may be available or necessary.

21CFR312 indicates that if the FDA terminates an investigational new drug application (IND) based on deficiencies in the IND or in the conduct of an investigation under an IND, the sponsor must end all clinical investigations conducted under the IND and recall or otherwise provide for the disposition of all unused supplies of the drug. See 21CFR312 for more information on FDA termination.

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.

Electronic Data Processing System

Per the US-ICH-GCPs, when using electronic trial data handling processing systems, the sponsor must ensure and document that the electronic data processing system conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistency of intended performance. To validate such systems, the sponsor should use a risk assessment approach that takes into consideration the system’s intended use and potential to affect human subject protection and reliability of trial results. In addition, the sponsor must maintain standard operating procedures (SOPs) that cover system setup, installation, and use. The SOPs should describe system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning, and decommissioning. With respect to the use of these computerized systems, the responsibilities of the sponsor, investigator, and other parties should be clear, and the users should receive relevant training. Refer to the US-ICH-GCPs for additional information.

Records Management

As set forth in 21CFR312 and the US-ICH-GCPs, the sponsor must retain all sponsor-specific essential documents pertaining to the trial for at least two (2) years after a marketing application (known as a new drug application (NDA)) is approved for the drug; or if a NDA is not approved, until two (2) years after shipment and delivery of the drug for investigational use is discontinued and the Food & Drug Administration (FDA) has been notified. The sponsor should also inform the investigator(s)/institution(s) in writing of the need for record retention and when the trial-related records are no longer needed. Additionally, per 21CFR312, the sponsor must upon request from the FDA, permit an officer or employee to access, copy, and verify any records and reports relating to the clinical investigation. Upon written request by the FDA, the sponsor must also submit the records or reports (or copies of them) to the agency.

In addition, the US-ICH-GCPs 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

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.

Responsible Parties

As stated in USA-86, the HIPAA Privacy Rule establishes the conditions under which protected health information (PHI) may be used or disclosed by covered entities for research purposes (Per USA-87, the Privacy Rule is located at 45CFR160 and Subparts A and E of 45CFR164; see USA-87 for more information). The Privacy Rule builds upon protections, described in Department of Health & Human Services (HHS) (the Pre2018-ComRule and the RevComRule) and Food & Drug Administration (FDA) (21CFR50 and 21CFR56) regulations, that help ensure the privacy of participants and the confidentiality of information. (Please note: ClinRegs does not provide information on state level personal data protection requirements.)

Per the Privacy Rule, a covered entity means: a health plan; a health care clearinghouse; or a health care provider who transmits any health information in electronic form in connection with a transaction covered by the Privacy Rule.

Data Protection

According to the FDA’s G-CertCnfdntlty, a Certificate of Confidentiality (CoC) is intended to help protect the privacy of human subject research participants from whom identifiable, sensitive information is being collected or used in furtherance of the research. CoCs must be issued for federally funded human subject research that collects or uses identifiable, sensitive information (mandatory CoCs). For non-federally funded research, issuance of CoCs is not required but may be issued at the discretion of the FDA (discretionary CoCs). If an institutional ethics committee (EC) (institutional review board (IRB) in the United States) determines that data collected in a clinical trial are sufficiently sensitive to warrant requesting a CoC, then the EC may request that a CoC be obtained in order to secure EC approval. Any disagreement between an EC, sponsor, and/or investigators regarding the need to request a CoC for a study should be resolved by communications among the parties. See the G-CertCnfdntlty for more information on CoCs.

NIH Privacy Requirements

The NIHPrvcy indicates that the HHS’ National Institutes of Health (NIH) follows the PrvcyAct, which includes procedures for: 1) protecting records that can be retrieved by personal identifiers such as a name, social security number, or other identifying number or symbol, and 2) persons to access their identifiable records and to request correction(s) of these records. See the NIHPrvcy and the PrvcyAct for more information.

Consent for Processing Personal Data

Per USA-86, the Privacy Rule defines the means by which individuals will be informed of uses and disclosures of their medical information for research purposes, and their rights to access information about themselves held by covered entities. Researchers may obtain, create, use, and/or disclose individually identifiable health information in the course of conducting research. Under the Privacy Rule, covered entities are permitted to use and disclose PHI for research with individual authorization, or without individual authorization under limited circumstances. To use or disclose PHI without authorization by the research participant, a covered entity must obtain one (1) of the following:

• Documented EC or privacy board approval
• Representations from the researcher that the use or disclosure of the PHI is solely to prepare a research protocol (or for similar purposes preparatory to research), the researcher will not remove any PHI from the covered entity, and PHI for which access is sought is necessary for the research purpose
• Research on protected health information of decedents
• Limited data sets with a data use agreement
• Research use/disclosure with individual authorization
• Accounting for research disclosures

See USA-86 for more information on these circumstances.

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.

Obtaining Consent

In all United States (US) clinical trials, a freely given informed consent is required to be obtained from each participant in accordance with the requirements set forth in 21CFR50 for Food & Drug Administration (FDA) regulated clinical trials, and the Pre2018-ComRule or the RevComRule for federally funded or sponsored clinical trials. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on agency-specific compliance.) Department of Health & Human Services (HHS)-funded or sponsored clinical trials must also comply with 45CFR46-B-E. The FDA has also adopted the US-ICH-GCPs as guidance.

As per 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by an institutional ethics committee (EC) (institutional review board (IRB) in the US) and provided to the FDA with the investigational new drug application (IND).

Per the G-RevComRule-FDA, the informed consent requirements of the RevComRule are not inconsistent with FDA regulations. Therefore, there may not be a need for sponsors or investigators to develop, and have ECs review, two (2) separate ICFs for research that must comply with both the RevComRule and FDA regulations. (See the Required Elements section for ICF content details.) Per the RevComRule, which took effect January 21, 2019, for each clinical trial conducted or supported by a federal department or agency, one (1) EC-approved ICF used to enroll subjects must be posted by the awardee or the federal department or agency component conducting the trial on a publicly available federal website that will be established as a repository for such ICFs. According to USA-12, two (2) federal websites have been identified to meet this requirement: ClinicalTrials.gov (USA-78) and a docket folder on Regulations.gov (USA-79). According to the RevComRule, if the federal department or agency supporting or conducting the clinical trial determines that certain information should not be made publicly available on a federal website (e.g., confidential, commercial information), such federal department or agency may permit or require redactions to the information posted. The ICF must be posted on the federal website after the clinical trial is closed to recruitment and no later than 60 days after the last study visit by any subject, as required by the protocol.

According to 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, the investigator must provide detailed research study information to the participant and/or the legal representative(s) or guardian(s). ICF content should be briefly and clearly presented orally and in writing, in a manner that is easy to understand and commensurate with the comprehension level of the research participants, and without coercion or unduly influencing a potential participant to enroll in the clinical trial. The participant and/or the legal representative(s) or guardian(s) should also be given adequate time to consider whether to participate.

As indicated in 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, none of the oral and written information concerning the research study should contain any language that causes the participant and/or the legal representative(s) or guardian(s) to waive or appear to waive legal rights, or that releases or appears to release the investigator, sponsor, institution or its agents from liability for negligence.

Additionally, per the RevComRule, participants must be provided with the information that a “reasonable person” would want to have in order to make an informed decision and an opportunity to discuss that information. Furthermore, the RevComRule requires that the informed consent, except for broad consent, must begin with a concise and focused presentation of the key information and organized to facilitate comprehension. Broad consent may be obtained in lieu of a full informed consent only with respect to the storage, maintenance, and secondary research uses of private identifiable information and identifiable biospecimens. See USA-54 and USA-60 for additional information regarding informed consent and broad consent requirements.

In addition, per 21CFR50, the Pre2018-ComRule, and the RevComRule, the ICF may be presented as either a full length written ICF or as a short form stating the consent requirements have been presented orally. The full length written ICF may be presented orally but must then be provided to the participant and/or a legal representative(s) or guardian(s) to read before it is signed.

See the FDA’s G-ElectronicIC for recommendations on the use of electronic systems and processes that may employ multiple electronic media to obtain informed consent for both HHS-regulated human subject research and FDA-regulated clinical investigations of medical products.

See the G-InfrmdCnsnt for the FDA’s discussion of the regulations in 21CFR50. Also, see USA-54 and USA-60 for additional information regarding informed consent.

Re-Consent

According to 21CFR50, the US-ICH-GCPs, and the G-IRBFAQs, the EC should determine the need to re-consent enrolled participants in the event of an ICF modification due to protocol changes or new information which may, in turn, affect the willingness of already enrolled participants to continue in the study. The communication of this information should be documented.

The G-IRBFAQs indicates that the FDA does not require re-consenting of participants who have completed their active participation in the study, or of participants who are still actively participating when the change will not affect their participation. One such case is when the change will be implemented only for subsequently enrolled participants.

Language Requirements

21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs state that any information provided must be in a language understandable to the participant and/or the legal representative(s) or guardian(s).

As delineated in the FDA’s G-InfrmdCnsnt, when non-English speaking participants are enrolled in a study, ECs and investigators must ensure that the information provided to prospective participants and/or their legal representative(s) or guardian(s) is in a language that is understandable to them. The EC must review and approve all consent documents that are to be used by investigators to document the informed consent. When translation and interpretation are needed for written and oral information to be presented to participants, the FDA recommends that the EC review and approve reasonable procedures for ensuring that the translations will be prepared by a qualified individual or entity, and that interpretation assistance is available. The FDA also recommends that whenever non-English speaking participants are enrolled in a study, appropriate interpreter services be made available throughout the course of the study.

USA-63 also states that when an oral presentation of the ICF is provided, the witness present should be fluent in both English and the participant’s language, and the translator may serve as the witness. See the G-InfrmdCnsnt and USA-63 for detailed information.

Documenting Consent

As set forth in 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, the participant and/or a legal representative(s) or guardian(s) must sign and date an EC-approved written ICF. A written copy of the form must be given to the participant and/or a legal representative(s) or guardian(s). In addition, the RevComRule explicitly allows electronic signatures for consent documentation.

Per 21CFR50, the Pre2018-ComRule, and the RevComRule, if the consent information is only presented orally using the short form, the participant and/or the legal representative(s) or guardian(s) must sign the form, the witness must sign both the short form and a copy of the summary once consent has been provided, and the person obtaining the consent must sign a copy of the summary. A copy of both the summary and the short form must be given to the participant and/or the legal representative(s) or guardian(s). The FDA’s G-InfrmdCnsnt further states that participants who cannot write can instead indicate their consent by "making their mark" on the consent document. In these situations, a note should be included in participant case histories indicating the reason for the lack of a signature and date as required in 21CFR50. The date consent was obtained should be recorded in this note.

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

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

Per the US-ICH-GCPs, before participating in the study, the participant or the legal representative(s)/guardian(s) should receive a copy of the signed and dated ICF.

Waiver of Consent

Per the Pre2018-ComRule and the RevComRule, the EC may waive the requirement to obtain a signed ICF if it finds any of the following:

• The ICF would risk a breach of confidentiality by linking the participant to the study
• The research presents minimal risk and involves no procedures for which written consent is required outside of the study

The RevComRule also adds that the EC may waive the requirements to obtain a signed ICF if the participants are part of a distinct cultural group or community in which signing the form is not the norm, the research presents minimal risk, and there is an alternative approach to document informed consent.

The Pre2018-ComRule and the RevComRule further indicate that in cases where the documentation requirement is waived, the EC may require the investigator to provide the participant or the legal representative(s)/guardian(s) with a written statement regarding the research.

In addition, 21CFR50, the RevComRule, and the Pre2018-ComRule state that for an EC to approve a general waiver or alteration of consent, the EC must find that:

• The research involves no more than minimal risk
• The research could not practicably be carried out without the requested waiver or alteration
• The waiver or alteration will not adversely affect the rights and welfare of the participants
• Whenever appropriate, the participant or the legal representative(s)/guardian(s) will be provided with additional pertinent information after participation

21CFR50 and the RevComRule also state that for an EC to approve the general waiver or alteration of consent, the EC must find that if the research involves using identifiable private information or identifiable biospecimens, the research could not practicably be carried out without using such information or biospecimens in an identifiable format.

In the G-MinRiskWaiver, the FDA informs sponsors, investigators, and ECs that it does not intend to object to an EC waiving or altering informed consent requirements for certain minimal-risk, clinical investigations.

Furthermore, the Pre2018-ComRule, the RevComRule, and the G-MinRiskWaiver specify that although voluntary informed consent is always a requirement for every trial, the EC may approve a waiver or alteration of consent if the study involves a public benefit and service program conducted by or subject to the approval of state or local officials and could not be carried out without the waiver or alteration.

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.

Based on 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, the informed consent form (ICF) must include the following statements or descriptions, as applicable (Note: The regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

• The study purpose, procedures, and expected duration of the trial
• Identification of any experimental procedures
• Any expected risks or discomforts to the participant, and when applicable, to an embryo or fetus
• Any expected benefits to the participant
• Disclosure of appropriate alternative procedures that might be advantageous to the participant
• Confidentiality of records identifying the participant will be maintained and the possibility that the Food & Drug Administration (FDA) may inspect the records
• Compensation and/or treatment available for the participant in the case of trial-related injury
• Contact information for relevant individuals to contact in the event of a trial-related injury
• That participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the participant is otherwise entitled, and that the participant can withdraw from the trial at any time without penalty or loss of otherwise entitled benefits
• Foreseeable circumstances under which the investigator may remove the participant without consent
• Any expenses the participant needs to pay to participate in the trial
• The consequences of a participant’s decision to withdraw from the study, and procedures for orderly withdrawal by the participant
• Any significant new findings developed during the study that may affect a participant’s willingness to continue participation
• Approximate number of participants in the study

As per 21CFR50, for FDA-regulated research, the following statement must be included on the informed consent documents: “A description of this clinical trial will be available on https://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.”

In the G-InfrmdCnsnt, the FDA also recommends the consent document advise participants that data collected on them up until the point of their withdrawal from a study will remain part of the study database and may not be removed. See the G-InfrmdCnsnt for additional FDA discussion of the regulations in 21CFR50.

The RevComRule also requires the following statements to be included in the ICF:

• Whether research results will be disclosed to participants
• Whether or not the participant’s information or biospecimens will be used or distributed for future research
• That participant’s biospecimens (even if identifiers are removed) may be used for commercial profit and if the participant will share in this profit
• Whether biospecimens research may include whole genome sequencing

See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.

Compensation Disclosure

The FDA’s G-InfrmdCnsnt further states that if no compensation in the event of injury is available, the consent process should include a statement informing the participant. See the G-InfrmdCnsnt for an example statement.

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.

Overview

In accordance with 21CFR50, 21CFR312, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, the United States’ (US) ethical standards promote respect for all human beings and safeguard the rights of research participants. A participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process.

The Right to Participate, Abstain, or Withdraw

As set forth in 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, a potential participant and/or a legal representative(s) or guardian(s) must 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 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, a potential research participant and/or a legal representative(s) or guardian(s), has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation for participation or injury/treatment, and any significant new information regarding the research study.

The Right to Privacy and Confidentiality

As per 21CFR50, the Pre2018-ComRule, and the RevComRule, participants should be given a statement describing the extent, if any, to which confidentiality of records identifying them will be maintained. Per the US-ICH-GCPs, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right. It is the responsibility of the investigator(s) to safeguard the confidentiality of research data to protect the identity and records of research participants.

The RevComRule does allow the use of identifiable private information or biospecimens in instances where the institutional ethics committee (EC) (institutional review board (IRB) in the US) determines the research could not practicably be carried out without the information. Furthermore, it removes the requirement for the investigator to seek a waiver of informed consent to obtain information or biospecimens to screen, recruit, or determine eligibility of prospective participants. See USA-54 for additional information on identifiable private information or biospecimens, USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.

The G-InfrmdCnsnt, which is the Food & Drug Administration (FDA)’s discussion of the regulations in 21CFR50, delineates how data should be handled when an enrolled participant decides to withdraw from a trial. Data collected on participants up to the time of withdrawal from clinical investigations of drugs conducted under an investigational new drug application (IND) must remain in the study database to maintain the scientific validity of the research. The FDA recommends that participants be advised in the consent document that the data collected on them up until the point of their withdrawal will remain part of the study database and may not be removed. If a participant withdraws from the interventional portion of the clinical investigation but agrees to continued follow-up not addressed in the original consent document, the investigator must obtain the participant’s informed consent for this limited participation using an EC-approved consent document. If a participant withdraws from the interventional portion of a clinical investigation and does not consent to continued follow-up of associated clinical outcome information, the investigator must not access the participant’s medical record or other confidential records that would require additional consent from the participant. However, such records may be accessed consistent with the original consent process, without additional consent, to obtain information collected prior to the participant’s withdrawal from the study. See the G-InfrmdCnsnt for additional information.

The Right of Inquiry/Appeal

21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs state that the research participant and/or a legal representative(s) or guardian(s), should be provided with contact information for the sponsor and the investigator(s) to address trial-related inquiries and/or to appeal against a violation of the participant’s rights.

The Right to Safety and Welfare

The US-ICH-GCPs clearly states that 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.

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.

21CFR50, 21CFR56, the US-ICH-GCPs, and the G-ICEmrgncyReqs make provisions to protect the rights of a research participant during the informed consent process when the procedure is complicated by life-threatening medical emergencies, public health emergencies, or military operations.

Medical Emergencies

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

Emergency Use Situation

21CFR56 describes emergency use as the use of a test article, such as an IP, on a human participant in a life-threatening situation in which no standard acceptable treatment is available, and in which there is not sufficient time to obtain EC approval.

21CFR50 and the G-EmrgncyUse indicate that even in an emergency use situation, obtaining participant consent is required unless the investigator and a physician not participating in the trial certify in writing the following:

• The participant is confronted by a life-threatening situation
• Informed consent cannot be obtained due to an inability to communicate with the participant
• Time is insufficient to obtain consent from the participant’s legal representative(s) and/or guardian(s)
• No alternative methods of approved or generally recognized therapy are available

Per 21CFR50 and the G-EmrgncyUse, if immediate use of the IP is, in the investigator's opinion, required to preserve the participant’s life and time is not sufficient to obtain an independent physician’s determination prior to using the IP, the investigator’s determinations should be carried out. However, within five (5) working days following the use of the IP, the investigator’s decision must be reviewed and evaluated in writing by a physician not participating in the investigation. According to 21CFR50, 21CFR56, and the G-EmrgncyUse, the investigator must also notify the EC within five (5) working days.

21CFR56, the G-EmrgncyUse, and the G-IRBFAQs further state that following emergency use of the IP, EC review and approval is required for any subsequent use of the IP.

Emergency Research

The G-ICEmrgncyReqs defines emergency research as a planned clinical investigation that requires prior written Food & Drug Administration (FDA) authorization to proceed, and involves participant(s) who are in a life-threatening situation for which available treatments or in vitro diagnostic tests are unproven or unsatisfactory.

21CFR50 and the G-ICEmrgncyReqs delineate that for emergency research, the EC may approve the investigation without requiring the consent of all the participants if the EC (with the concurrence of a licensed physician who is an EC member or EC consultant, and not otherwise participating in the investigation) finds and documents the following:

• The participants are in a life-threatening situation, available treatments are unproven or unsatisfactory, and the collection of valid scientific evidence is necessary to determine the safety and effectiveness of particular interventions
• Obtaining informed consent is not feasible because: (i) the participants will not be able to give their informed consent as a result of their medical condition; (ii) the intervention under investigation must be administered before consent from the participants’ legal representative(s) and/or guardian(s) is feasible; and (iii) there is no reasonable way to identify prospectively the individuals likely to become eligible for participation in the clinical investigation
• Participation in the research holds out the prospect of direct benefit to the participants
• The clinical investigation could not practicably be carried out without the waiver
• The proposed investigational plan defines the length of the potential therapeutic window based on scientific evidence, and the investigator has committed to attempting to contact a legal representative and/or guardian for each participant within that window of time and, if feasible, to asking them for consent within that window rather than proceeding without consent
• The EC has reviewed and approved informed consent procedures and an informed consent document consistent with 21CFR50
• Additional protections of the rights and welfare of the participants will be provided

See 21CFR50 and the G-ICEmrgncyReqs for more details.

USA-60 notes that in certain emergency circumstances, the Department of Health & Human Services (HHS) Secretarial waiver of informed consent under 46.101(i) of the RevComRule may be applicable. The HHS waiver applies to research that may be carried out in human participants who need emergency therapy and for whom, because of the participants’ medical condition and the unavailability of the participants’ legal representative(s) and/or guardian(s), no legally effective informed consent can be obtained. Furthermore, if the research is regulated by the FDA, the HHS waiver permits the research to be conducted under a comparable provision. See the G-HHS-Emrgncy for additional guidance, USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the RevComRule applies to research.

Military Operations

21CFR50 and 10USC55 indicate that in the case of IP administration to a member of the armed forces in connection with participation in a particular military operation, the requirement for the member’s prior consent may be waived only by the US President. The US President may grant the waiver only after determining, in writing, that obtaining consent is not feasible; is contrary to the best interests of the military personnel; or is not in the interests of national security. See 21CFR50 and 10USC55 for detailed requirements.

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

Overview

As per 21CFR56, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, in all United States (US) clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process. Institutional ethics committees (ECs) (institutional review boards (IRBs) in the US) must pay special attention to protecting such participants. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

21CFR56 and the US-ICH-GCPs require special considerations for vulnerable populations and characterize them as those whose willingness to volunteer in a trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response for refusing to participate. Examples of these participants include members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students; subordinate hospital and laboratory personnel; pharmaceutical industry employees; members of the armed forces; and persons kept in detention. Per 21CFR56 and US-ICH-GCPs, other vulnerable subjects include children, pregnant women, physically or mentally disabled persons, patients with incurable diseases, persons in nursing homes, economically or educationally disadvantaged persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.

The Pre2018-ComRule describes children, prisoners, pregnant women, handicapped persons, mentally disabled persons, or economically or educationally disadvantaged persons as vulnerable populations. The RevComRule describes children, prisoners, individuals with impaired decision-making capacity, or economically or educationally disadvantaged persons as vulnerable populations.

For more guidance documents related to vulnerable populations, see USA-64.

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

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 set forth in 21CFR50 and 45CFR46-B-E, children are defined as persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the study will be conducted. USA-25 further states that the age of majority in most states is 18 and therefore for legal purposes, children are those individuals who have not reached the age of 18. See USA-25 for a table delineating the legal age of majority by state in the United States (US).

Per the Pre2018-ComRule and the RevComRule, children require additional safeguards to be included in any research study in order to protect their rights and welfare. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

As delineated in the US-ICH-GCPs, when the research participant is a minor, informed consent should be obtained from a legal representative(s) or guardian(s). All pediatric participants should be fully informed about the trial and its risks and benefits in a language and in terms that they are easily able to understand. If capable, the participant should sign and date the written informed consent.

For all clinical trials that do not involve greater than minimal risk, 21CFR50 and 45CFR46-B-E state that a study may only be conducted if adequate provisions are made to obtain the child’s assent and the permission of their legal representative(s) or guardian(s).

For all clinical trials that involve greater than minimal risk but present the prospect of direct benefit to the child, 21CFR50 and 45CFR46-B-E indicate that a study may only be conducted if the following applies:

• The risk is justified by the anticipated benefit to the child
• The anticipated benefit is greater than or equal to the available alternative approaches
• Adequate provisions are made to obtain the child’s assent and the permission of their legal representative(s) or guardians

For all clinical trials involving children/minors that involve greater than minimal risk and do not present the prospect of direct benefit to the child, but will likely result in increased knowledge about the child’s disorder or condition, 21CFR50 and the 45CFR46-B-E state that a study may only be conducted if the following applies:

• The risk is slightly greater than minimal
• The trial presents experiences that are similar to those associated with the child’s actual or expected medical, dental, psychological, social, or educational situation
• Adequate provisions are made to obtain the child’s assent and the permission of their legal representative(s) or guardian(s)

For all clinical trials that present a reasonable opportunity to further understand, prevent, or alleviate a serious problem affecting the health or welfare of children/minors but is not otherwise approvable per 21CFR50 and 45CFR46-B-E, a study may only be conducted if the following applies:

• The institutional ethics committee (EC) (institutional review board (IRB) in the US) finds that the investigation presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children, and,
• The Commissioner of Food and Drugs consults with an expert panel and has an opportunity for public review and comment to determine that the investigation satisfies the conditions of one (1) of the other earlier described research types, or the following conditions are met: the investigation will be conducted in accordance with sound ethical principles and adequate provisions are made for soliciting the assent of children and the permission of their legal representative(s) or guardian(s)

Per the RevComRule, certain exemptions may apply to observational research involving children. See the RevComRule for details.

For additional Food & Drug Administration (FDA) guidance on clinical research in children, see US-ICH-E11 and USA-60. Additionally, see the G-InfrmdCnsnt for FDA discussion of the regulations in 21CFR50.

Assent Requirements

Per 21CFR50 and 45CFR46-B-E, when determining whether children/minors are capable of providing assent, the EC must consider their age, maturity, and psychological state. Assent from a child/minor is not necessary for proceeding with the clinical trial if the following applies:

• The capability of some or all of the children/minors is so limited that they cannot reasonably be consulted
• The trial presents a potential direct benefit that is important to the health or well-being of the children/minors and is only available through the investigation

Further, the EC may waive assent, even if the children/minors are capable of providing assent, if it finds and documents the following:

• Trial involves no more than minimal risk
• The waiver will not negatively affect the rights and welfare of the children/minors
• The trial could not be implemented without the waiver
• The children/minors will be given additional information after participation, whenever appropriate

When legal representative or guardian permission is necessary, the EC must determine whether the permission of one (1) legal representative or guardian is sufficient, or if permission from both is required. If the EC determines assent is required, it must also determine whether and how assent must be documented. 21CFR50 and 45CFR46-B-E do specify, however, that the consent of both legal representative(s) or guardian(s) is required in the following cases:

• When there is greater than minimal risk to the child with no direct benefit to the child, but the study will likely result in increased knowledge about the child’s disorder or condition
• Research that presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children/minors, but is not otherwise approvable

Exceptions to the two (2) legal representatives’ and/or guardians’ consent requirement are when one (1) legal representative or guardian is deceased, unknown, incompetent, or not reasonably available, or, when only one (1) legal representative or guardian has legal responsibility for the care and custody of the child.

The G-InfrmdCnsnt indicates that when obtaining legal representative or guardian permission, in the event that the legal representative(s) or guardian(s) of a child does not understand English, the permission must be obtained and documented in a language that is understandable to the legal representative(s) or guardian(s). The child who will be participating in the research should not be used as an interpreter for the legal representative(s) or guardian(s), even if the child is fluent in English and may be able to assent. Further, legal representative or guardian permission and child assent should be viewed as an ongoing process throughout the duration of a clinical investigation. If and when a child who was enrolled in a clinical investigation with legal representative or guardian permission reaches the legal age of consent, that participant no longer meets the definition of a child under 21CFR50, and the investigator should obtain the participant’s informed consent prior to performing any further research interventions and/or procedures involving that participant. See the G-InfrmdCnsnt for additional FDA discussion of the regulations in 21CFR50.

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

As per 21CFR50 and 45CFR46-B-E, for studies involving women of childbearing age or who are pregnant, a statement should be provided in the informed consent form (ICF) indicating that the treatment or procedure may involve risks to the participant, embryo, or fetus, which are currently unforeseeable. According to the US-ICH-GCPs, the ICF should include a statement on the reasonably foreseeable risks or inconveniences to the participant, and when applicable, to an embryo, fetus, or nursing infant.

Per the Pre2018-ComRule, pregnant women require additional safeguards to be included in any research study in order to protect their rights and welfare. Furthermore, according to the RevComRule, all of the available exemptions of the RevComRule for observational research may be applied to research involving pregnant women, fetuses, and neonates. See the RevComRule for details. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

All Department of Health & Human Services (HHS)-sponsored or -funded research involving pregnant women, human fetuses, neonates of uncertain viability, or nonviable neonates must comply with Subpart B of 45CFR46-B-E.

Pregnant Women and Fetuses

As per 45CFR46-B-E, pregnant women and fetuses may participate in research if all of the following criteria are met:

• Preclinical and clinical studies have been conducted and provide data for assessing potential risks, where scientifically appropriate
• Risk to the fetus is caused solely by procedures that provide potential direct benefit to the woman or fetus. If there is no potential direct benefit, then the risk to the fetus cannot be greater than minimal, and the intent of the study is to develop important biomedical knowledge that cannot be obtained otherwise
• Least possible risk involved for achieving the research objectives
• Consent is obtained from the woman for studies that provide potential direct benefit to the pregnant woman and/or fetus, and studies with minimal risk to the fetus conducted to develop important biomedical knowledge that cannot be obtained otherwise
• Consent is obtained from the pregnant woman and the father if the study provides potential direct benefit solely to the fetus. Paternal consent is not required if the father is unavailable, incompetent, temporarily incapacitated, or the pregnancy was a result of incest or rape
• All individuals providing consent are fully informed about the foreseeable impact on the fetus or neonate
• No inducements will be offered to terminate a pregnancy
• Participants will not be involved in determining the timing, method, or procedures for terminating a pregnancy
• Participants will not be involved in determining the viability of a neonate

Neonates

45CFR46-B-E states that neonates may not be involved in research unless all of the following criteria are met:

• Preclinical and clinical studies have been conducted and provide data for assessing potential risks, where scientifically appropriate
• All individuals providing consent are fully informed about the foreseeable impact on the neonate

Neonates of uncertain viability may not be involved in research unless the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) determines the following additional conditions are met:

• Research provides the potential for increasing the probability of survival to the point of viability, and involves the least possible risk
• The purpose is to develop important biomedical knowledge that cannot be obtained otherwise and there is no added risk resulting from the research
• Informed consent is obtained from either parent, or if neither parent is able to provide consent, then consent is obtained from the neonate’s legal representative and/or guardian. Paternal consent is not required if pregnancy was a result of incest or rape.

Nonviable neonates may not be involved in research unless the following additional conditions are met:

• Vital functions will not be maintained artificially
• Research will not terminate the heartbeat or respiration
• The purpose is to develop important biomedical knowledge that cannot be obtained otherwise, and there is no added risk resulting from the research
• Consent is obtained from both parents. If neither parent is able to provide consent, informed consent of one (1) parent will suffice. Paternal consent is not required if pregnancy was a result of incest or rape. Consent of a legal representative or guardian of either or both parents will not suffice.

Viable neonates may only be included in research to the extent permitted by and in accordance with the RevComRule and subparts B and D of 45CFR46-B-E.

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

21CFR56, 45CFR46-B-E, and the US-ICH-GCPs include prisoners in their description of vulnerable populations. As set forth in 45CFR46-B-E, a prisoner is defined as any individual involuntarily confined or detained in a penal institution. Prisoners are considered vulnerable because incarceration could affect their ability to make a voluntary decision regarding participation in research.

Per the Pre2018-ComRule and the RevComRule, prisoners require additional safeguards to be included in any research study in order to protect their rights and welfare. As delineated in the RevComRule, none of its observational research exemptions may be applied to research involving prisoners, except for research aimed at involving a broader subject population that only incidentally includes prisoners. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

45CFR46-B-E states that prisoners may participate in biomedical or behavioral research conducted or supported by the Department of Health & Human Services (HHS) only if the following criteria are met:

• The institution conducting the research has certified to the HHS Secretary that the research has been approved by the institutional ethics committees (EC) (institutional review board (IRB) in the United States (US)); research involves minimal risk; and studies focus on the possible causes, effects, and processes of incarceration and criminal behavior, prisons as institutional structures, or prisoners as incarcerated persons
• Research should focus on conditions specifically affecting prisoners as a class, or practices that have the intent and likelihood of improving the health or well-being of participants only after the HHS Secretary has consulted the appropriate experts, and a Federal Register notice is published indicating intent to approve such research

See USA-62 for more HHS information on prisoner research.

As per 45CFR46-B-E, ECs have additional approval responsibilities when reviewing research studies involving prisoners. An EC must only approve these studies if it determines that:

• The research under review represents one (1) of the permissible categories of research delineated in Subpart C
• The prisoner’s judgement will not be impaired by any possible advantages accruing to the prisoner through participation in the research, when compared to the general living conditions, medical care, quality of food, amenities, and opportunity for earnings in the prison
• Research risks are commensurate with those that would be accepted by non-prisoner volunteers
• Procedures for participant selection within the prison are fair to all prisoners and immune from arbitrary intervention by prison authorities or prisoners
• Information is presented in a language understandable to the prisoner population
• Adequate assurance exists that parole boards will not take into account a prisoner's participation in the research in making decisions regarding parole, and each prisoner is clearly informed in advance that participation in the research will have no effect on parole
• As needed, adequate provisions have been made for follow-up examination or care of participants, taking into account the varying lengths of individual prisoners' sentences, and for informing participants of this fact

See Subpart C of 45CFR46-B-E for additional EC requirements related to prisoner research.

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

In accordance with 21CFR56, the Pre2018-ComRule, and the US-ICH-GCPs, an institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) must approve the participation of research participants who are mentally incapable of giving consent. According to the G-InfrmdCnsnt, which is the Food & Drug Administration (FDA)’s discussion of the regulations in 21CFR50, impaired consent capacity may involve partial impairment, impairment that fluctuates over time, or complete impairment. Consent capacity can be affected by a wide range of disorders and conditions, such as dementia, stroke, traumatic brain injury, intellectual and developmental disabilities, serious mental illness, intoxication, and delirium.

Per the Pre2018-ComRule and the RevComRule, this population requires additional safeguards to be included in any research study to protect the rights and welfare of participants likely to be vulnerable to coercion or undue influence. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

USA-60 further indicates that while Department of Health & Human Services (HHS) regulations do not provide specific procedures, it is expected that for research involving adult participants with mental illnesses or cognitive impairments, the EC and investigator(s) must be knowledgeable about the condition and any level of impairment that is likely to be present in the participant population.

As stated in the FDA’s G-InfrmdCnsnt, ECs and investigators should carefully consider whether the inclusion in research of individuals who lack consent capacity is ethically appropriate and scientifically necessary. Considerations that may help address these challenges and provide additional safeguards include:

• Assessing consent capacity of prospective participants, for example, through use of an independent, qualified professional

• Establishing a waiting period in the decision-making process to allow additional time for decision-making

• Using methods to enhance consent capacity, for example through (1) simplification and/or repetition of information, (2) involvement of a participant advocate or trusted family member/friend to assist when sharing information about the clinical investigation, and (3) refraining from discussions during periods of heightened impairment, when possible

• Assessing a participant’s understanding after information about the clinical investigation has been imparted, for example, through use of a questionnaire

• Re-assessing consent capacity after initiation of the clinical investigation for participants with progressive disorders whose cognition may decline

• Involving a legally authorized representative and/or guardian either initially or later in the clinical investigation if consent capacity diminishes

• Assessing whether prospective participants who cannot provide legally effective consent on their own behalf may nonetheless be able to provide some form of oral agreement at the outset of the study and, as appropriate, throughout the course of the research (e.g., for participants with progressive disorders), and how such oral agreement would be documented

• Emphasizing the voluntary nature of the decision to participate and the right to withdraw at any time

• Determining whether the EC or a third party should observe the consent process

See the G-InfrmdCnsnt for additional information and FDA discussion of the regulations in 21CFR50.

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

As delineated in 21CFR312, an investigational new drug is defined as a new drug or biological drug that is used in a clinical investigation. This includes a biological product that is used in vitro for diagnostic purposes. The terms ‘investigational drug’ and ‘investigational new drug’ are deemed to be synonymous for the purposes of this part.

Additionally, the US-ICH-GCPs defines an investigational product as a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use.

Manufacturing

According to the TMMDAct, the CT-Regs, and the G-AppConductCT, the Tanzania Medicines and Medical Devices Authority (TMDA) is responsible for authorizing the manufacture of investigational products (IPs) in Tanzania. The TMDA will approve the manufacture of an IP after the clinical trial application has been approved via the Regulatory Information Management System (RIMS) Customer Self Service Portal (TZA-34). Regarding inspection frequency, the GMP-Insp and TZA-19 state that a domestic manufacturing facility must be inspected once a year to renew its annual business permit. The GMP-Insp also states that a manufacturing facility must be inspected once every three (3) years. However, a facility may be inspected at any time when necessary. See the G-AppConductCT for details on the quality requirements for manufacturing IPs.

Per the GMP-Insp, domestic and foreign manufacturing facilities of human medicinal products must comply with the good manufacturing practice (GMP) in the latest versions of the World Health Organization (WHO)’s Technical Report Series (WHO-TRS). In addition, other guidelines—such as those by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use and Pharmaceutical Inspection Co-operation Scheme—may be used as supplementary guidance when establishing compliance of facilities to GMP requirements. See the GMP-Insp for additional details and information on the inspection of manufacturing facilities of human medicinal products.

Import

Per the TMMDAct, the CT-Regs, the TFDCA-ImptExpt, the G-AppConductCT, and the G-ImpExp, the TMDA is also responsible for authorizing the import of IPs. As per the TMMDAct, the TFDCA-ImptExpt, and the G-ImpExp, the sponsor or the principal investigator (PI) may apply for an import license once the clinical trial application has been approved by the TMDA. The TFDCA-ImptExpt specifies that in order to be granted an import license, the applicant must:

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

The G-ImpExp states that importation of pharmaceutical products and raw materials must be done by importers whose premises are registered by the TMDA or the relevant government institutions. All importers should import pharmaceutical products and raw materials through authorized ports of entry. A person must not import any pharmaceutical product with a shelf life of more than 24 months whose remaining shelf life is less than 60%, or a pharmaceutical product with a shelf life of less than or equal to 24 months whose remaining shelf life is less than 80%.

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

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

Per TZA-34, the import license application can be submitted to the TMDA via TZA-34, which can be accessed by first creating a trader account. An online access registration form is available in Annex I of the G-ImpExp.

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

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

Manufacturing

According to 21CFR312 and USA-42, the Food & Drug Administration (FDA) is responsible for authorizing the manufacture of investigational products (IPs) (also known as investigational new drugs in the United States (US)).

Per 21CFR312, sponsors that use an IP not already subject to a manufacturer’s investigational new drug application (IND) or marketing application are required to provide all of the technical chemistry, manufacturing, and control (CMC) information outlined in the application content and format requirements section of 21CFR312, unless such information may be referenced from applicable scientific literature. Sponsors using an IP already subject to a manufacturer’s application should follow the same general application format but may, if authorized by the manufacturer, refer to the manufacturer’s application to provide the technical (CMC) information supporting the proposed clinical investigation.

Moreover, as stated in 21CFR312, a sponsor may ship an IP to the investigators named in the IND under the following conditions: