South African Health Products Regulatory Authority

As stated in the MRSA and ZAF-9, the South African Health Products Regulatory Authority (SAHPRA) is the regulatory authority overseeing medicines and clinical research, as well as medical devices and radiation safety. As stated in the MRSA and GRMRSA, SAHPRA is responsible for clinical trial oversight, approval, and inspections in South Africa. The agency grants permission for clinical trials to be conducted in South Africa in accordance with the provisions of the GRMRSA.

Per the MRSA and ZAF-39, the SAHPRA is an independent, state-owned entity established to oversee the regulation of medicines in South Africa. According to ZAF-39, this agency is responsible for:

• The regulation of health products intended for human and animal use
• The licensing of manufacturers, wholesalers, and distributors of medicines and medical devices; radiation emitting devices; and radioactive nuclides
• The conduct of clinical trials in a manner that is compatible with national medicines policy

Per the MRSA, SAHPRA is a state-owned entity within the public administration but outside the public service. It acts through a Board appointed by South Africa’s Minister of the National Department of Health (NDOH). For details on the Board appointments, see ZAF-39 and ZAF-38.

As described in ZAF-39 and the SA-GCPs, SAHPRA is tasked with regulating (monitoring, evaluating, investigating, inspecting, and registering) all health products. This includes clinical trials, complementary medicines, medical devices, and in vitro diagnostics (IVDs). Its mission is to promote access to health products and protect human and animal health in South Africa through science-based regulatory decisions. Per ZAF-36, SAHPRA’s Clinical Trial Committee (CTC), within the Clinical Trial Unit, reviews clinical trial applications and bioequivalence studies for human participants and recommends approval of the conduct of clinical trials. SAHPRA also authorizes the importation of unregistered medicine for the purpose of conducting clinical trials. The SA-GCPs also states that SAHPRA is responsible for the following: ensuring efficient, effective, and ethical evaluation or assessment of health products that meet defined standards of quality, safety, efficacy, and performance; ensuring that the process of evaluating or assessing and registering health products is transparent, fair, objective, and concluded in a timely fashion; ensuring periodic re-evaluation and monitoring of health products; and conducting announced and unannounced inspections.

Please note: South Africa is party to the Nagoya Protocol on Access and Benefit-sharing (ZAF-8), which may have implications for studies of investigational products developed using certain non-human genetic resources (e.g., plants, animals, and microbes). For more information, see ZAF-34.

Contact Information

Per ZAF-35, SAHPRA’s postal address is:

South African Health Products Regulatory Authority
Private Bag X828
Pretoria
0001
South Africa

SAHPRA’s physical address is:

Building A
Loftus Park
402 Kirkness Street
Arcadia, Pretoria
South Africa

As provided in the G-CTA-Electronic and ZAF-36, the following are the SAHPRA Clinical Trial Unit emails:

New clinical trials application alert, responses to new clinical trial applications and related queries: ctcresponses@sahpra.org.za
Protocol amendments, responses to amendments and related queries: ctcamendments@sahpra.org.za
Additional investigators and sites, responses to additional and related queries: ctcinvestigators@sahpra.org.za
Bioequivalence (BE) studies, BE amendments, responses to BE studies and related queries: ctcbeprotocols@sahpra.org.za
Notifications and related queries: ctcnotifications@sahpra.org.za
Individual patient serious adverse events and related queries: ctcsaes@sahpra.org.za
Guidelines, forms, and related queries: ctcguidelines@sahpra.org.za

See ZAF-47 for clinical evaluation and management contacts.

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

In accordance with the GRMRSA, the South African Health Products Regulatory Authority (SAHPRA) is responsible for reviewing and approving all clinical trial applications for an unregistered medicine, and for any new indication or dosage regimen of a registered medicine. The scope of the SAHPRA’s assessment includes all clinical trials (Phases I-IV) and bioequivalence/bioavailability studies. Per ZAF-23, the review and approval of clinical trial applications by SAHPRA and an accredited ethics committee (EC) may be conducted in parallel.

ZAF-36 states that the SAHPRA’s Clinical Trial Unit (CTU) provides the legal framework for the review of clinical trials and bioequivalence studies for human participants and recommends approval of the conduct of clinical trials. The unit also authorizes the importation of unregistered medicines for the purpose of conducting clinical trials. As per G-GenInfo, the CTU is responsible for the evaluation of clinical trial applications, clinical trial amendments, and adverse event reports arising from a clinical trial.

Clinical Trial Review Process

Per ZAF-36, the CTU of SAHPRA receives, processes, and evaluates clinical trial applications and any subsequent amendments for approval to conduct a study within South Africa. Researchers must submit a completed application and the prescribed fee on predetermined dates (ZAF-11). The proof of delivery, proof of payments, and cover page must be sent to SAHPRA via email.

As stated in ZAF-36, the CTU completes a preliminary screening of the application and sends an official letter to the applicant with the outcome and follow-up questions on a screening checklist. As indicated in ZAF-23, incomplete documentation or sub-standard submissions will be rejected. Additionally, applications submitted without clinical trial insurance will be rejected. Applicants will be allowed a maximum of two (2) rounds of queries to respond to, and if the responses are not satisfactory the application will be rejected. Per ZAF-36, if an application is rejected, no response is required; the screening checklist should be used as guidance for resubmission during the next review cycle. Next, the CTU’s Clinical Trial Committee (CTC) (which includes an expert committee of specialists, as needed) reviews the proposed clinical trials pursuant to the schedule on SAHPRA’s website. (See ZAF-11 for 2024 dates). Clinical trial reviews will result in one (1) of the following outcomes:

• Category 1A: Approved; no items pending
• Category 1B: Approved; ethics approval pending
• Category 2A: Not approved; for approval by in-house evaluators, 1-2 or more items outstanding as deemed by the committee
• Category 2B: Not approved; for approval by the original evaluator and in-house if a need arises
• Category 3: Not approved; items outstanding to be discussed at the next CTC meeting
• Category 4: Not approved; for referral for specialist opinion
• Category 5: Not approved – technical/scientific deficiencies; applicant to resubmit for the next cycle
• Category 6: Rejected due to administrative and technical items outstanding; applicant to resubmit for the next cycle

If an applicant would like to request a meeting with the CTC, the request should be submitted through the SAHPRA Chief Executive Office pursuant to the procedures in the G-ConsultMtg.

Other Considerations

Per the G-Capacity, SAHPRA will also review clinical trial applications for evidence of plans to build capacity at each study site as well as enhancing research activities and skills of professionals from historically disadvantaged groups. See G-Capacity for detailed information on actions that will comply with this requirement.

In addition, see G-Clin for South Africa's use of a “reliance model” to register medicines based on clinical trial data from other regulatory authorities.

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.

South African Health Products Regulatory Authority

Per the MRSA, the South African Health Products Regulatory Authority (SAHPRA) is authorized to make regulations to collect fees for its various medicine regulatory functions. As delineated in the MRSA-Fees and ZAF-37, applicants are responsible for paying several non-refundable fees to submit a clinical trial application. MRSA-Fees delineates the following fees:

For a clinical trial application for the authorization of the use of unregistered medicines:

• Clinical trial application (safety and efficacy): South African Rand (R)32 400
• Clinical trial application (bioequivalence study): R30 400
• Clinical trial application (postgraduate study): R10 800
• Any other clinical trial application: R5 000

For amendments to clinical trials:

• Technical amendment applications: R7 000
• Administrative amendment applications: R4 100
• Any other application except for the purpose of performing a clinical trial: R350

For licenses:

• New manufacturing license: R25 200
• New import/export license to the holder of certificate of registration: R15 000
• Renewal of manufacturing license: R22 000
• Renewal of import license to the holder of the certificate of registration: R9 200
• Renewal of export license to the holder of the certificate of registration: R9 200
• Annual retention of all licenses: R4 200

For inspections to assess the quality, safety, and efficacy of medicines:

• Local and international manufacturing sites: R1 600 per hour
• Local and international clinical trial sites: R1 600 per hour

Payment Instructions

Per the G-SAHPRAFees, when making payments, applicants should follow these guidelines:

• Applicants should submit a cover page that identifies the services requested using the template provided in ZAF-37
• Payments should be referenced in accordance with the SAHPRA Fee Categorization Guideline (Annexure A of G-SAHPRAFees)
• If the applicable bank limits reference spacing, follow the sequence listed in Annexure A as far as the limitation allows; spacing and dashes (/) may be omitted
• Fee payments may be transferred directly into the bank account of SAHPRA via an electronic or manual deposit process
• No check payments will be accepted
• For administrative control purposes, applicants should make one (1) payment per service
• Payment should only be made once the application and required dossiers are ready for submission
• Payments do not have to be made upon request of an application number; however, the applications and required dossiers should be submitted within a reasonable time upon receipt of an application number or as specified in the relevant application guidelines

• As soon as the fee payment has been made, the proof of payment and cover page should be attached and sent via email to SAHPRA Finance at pop@sahpra.org.za, and the relevant unit(s) processing the application should be copied on the email.

• If the proof of payment has not been submitted, or no details to identify the payment reference as per the G-SAHPRAFees have been provided, and any further attempts to clear these payments fail after 12 months, any liability for SAHPRA to refund these payments will be forfeited
• If a payment has been received without an application, the applicant will be notified to submit the required application within 14 working days, failing which, the amount will be forfeited
• Requests for refunds should be submitted in line with Annex B in the G-SAHPRAFees
• Payment and pro forma invoice queries and requests can be directed to finance@sahpra.org.za or 012 501 0323
• See the G-SAHPRAFees for details on special requests for extensions to the deadline

Per the G-SAHPRAFees, the bank and account details are as follows:

Account name: South African Health Products Regulatory Authority
Special Name: The Medicines Control Council
Account type: Cheque/Current Account
Account number: 40-5939-2080
Bank: ABSA
Bank Branch Code: 632005
Bank physical address: 240 Vermeulen Street, Pretoria, 0001, South Africa
Swift Code: ABSAZAJJ

Fee payment questions can be directed to finance@sahpra.org.za or 012 501 0323.

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

Per ZAF-51, ethics committees (ECs) in South Africa are governed by the National Health Research Ethics Council (NHREC), which is a statutory body established under the NHA. According to ZAF-52, NHREC gives direction on ethical issues relating to health and develops guidelines for the conduct of research involving humans and animals. As delineated in the NHA, the G-EthicsHR-ZAF, and the SA-GCPs, all ECs are required to register with the NHREC in order to undertake the ethical review of a clinical study.

The NHA requires that every institution, health agency, and health establishment at which research is conducted establish an EC or have access to an independent EC. The EC must be registered with the NHREC. The SA-GCPs note that the NHREC accredits and audits the ECs.

Ethics Committee Composition

As delineated in the SA-GCPs and the G-EthicsHR-ZAF, an EC must consist of members who collectively encompass the qualifications and experience required to review and evaluate the scientific, medical, and ethical aspects of all proposed research studies.

The G-EthicsHR-ZAF indicates that an EC should comprise:

• Members who have documented proof of research ethics training, refreshed at least once within the period of appointment
• At least nine (9) members
• At least one (1) layperson
• At least one (1) member with knowledge of, and current experience in the professional care, counselling, or health-related treatment of people; such a medical practitioner, psychologist, social worker, or nurse
• At least one (1) member with professional training and experience in qualitative research methodologies
• Members with professional training and experience in quantitative research methodologies
• A member with expertise in bio-statistics
• A member with expertise in research ethics
• At least one (1) member who is legally qualified

Terms of Reference, Review Procedures, and Meeting Schedule

Per the G-EthicsHR-ZAF, an institution or organization must select EC members according to prescribed recruitment and appointment procedures. Members must receive a formal notice of appointment and assurance that they will be legally protected with respect to any liabilities that may arise during their term. EC quorum should be a simple majority, and where the number of members is more than 15, the quorum may be 33%. An EC must also establish and record written procedures to address several administrative issues including meetings, agenda/minutes preparation, research protocol presentations, application registration, protocol submission requirements, review and decision notification process, adverse event reporting, protocol amendment reporting, and end-of-trials review. A reasonable term of office is between two (2) and four (4) years, renewable twice, after which the person should stand down for at least one (1) term. Further, EC members and researchers are expected to familiarize themselves with the institutional documentation as well as national and international research ethics guidelines and should have documented proof of such familiarity. Training of all EC members is critical, especially for ECs that review high-risk research. Training and refresher courses should be available, and EC members should produce, at least once during a term of appointment, evidence of recent training. This ensures that both expertise and responsibility are distributed and encouraged in a range of members, and that institutional memory is accumulated. The SA-GCPs stipulate that EC members who review clinical trial proposals should have research ethics training and good clinical practice training, evidenced by certificates issued in the last three (3) years.

Per the SA-GCPs, the EC should retain all relevant records for a period of at least three (3) years or as per institutional requirement, whichever period is longer, after completion of the trial and make them available upon request from the applicable regulatory authority. The G-EthicsHR-ZAF indicates that ECs should keep written records of all research protocols received for review in the form in which they were approved. Electronic records are acceptable if the signatures are properly documented and included in the record. EC records must provide a reliable and authoritative record of the EC’s business that will stand up to scrutiny in the event of queries, conflicts, and audits.

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

Per the SA-GCPs, clinical trials should be conducted in accordance with all ethical principles outlined in the Declaration of Helsinki (ZAF-44) and consistent with good clinical practice and other applicable regulatory requirements. In accordance with the NHA, the SA-GCPs, and the G-EthicsHR-ZAF, ethics committees (ECs) must evaluate the ethical and scientific rigor of all research studies to be conducted in the country. An EC’s primary responsibilities are to (Note: the regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

• Review protocols to ensure that research involving human participants has scientific merit and will promote health, and prevent or cure disability and disease; in addition, ensure the research has social merit in light of South Africa’s research priorities or is otherwise justified
• Ensure clinical trials are governed by the ethical principles of beneficence and non-maleficence, distributive justice (equity), and respect for persons (dignity and autonomy)
• Grant approval for research where the protocols meet the ethical standards of the institution, agency, or establishment
• Determine whether and why randomization is relevant, and how this is addressed
• Evaluate the appropriateness of the inclusion/exclusion criteria and the recruitment process in the South African context
• Ensure the feasibility of obtaining meaningful results with the lowest possible risk of harm for participants and whether the risk of harm is appropriately weighed against anticipated benefits for participants or the class of persons from which they are drawn; high risk of harm may be justifiable where the anticipated benefit is of high importance to increase relevant knowledge and appropriate mitigating measures are in place to minimize harm to participants; and attention must be given to harms and benefits beyond the life of the trial itself, especially in respect to early phase studies and (pharmacovigilance) surveillance for chronic and life-threatening conditions

An EC must also pay special attention to protecting the welfare of certain classes of participants deemed to be vulnerable (See the Informed Consent topic for additional information about these populations).

Role in Clinical Trial Approval Process

Per the G-EthicsHR-ZAF, the SA-GCPs, and the NHAParticipants, the principal investigator (PI) or the sponsor must submit a clinical trial application to both the South African Health Products Regulatory Authority (SAHPRA) and a registered EC for review and approval before a study may commence. Per ZAF-23, the review and approval of clinical trial applications by SAHPRA and an accredited EC may be conducted in parallel.

The G-EthicsHR-ZAF indicates that after the deliberative review process, the EC should approve, require amendment to, or reject a research protocol. In considering a research protocol, the EC may seek assistance from experts. EC decisions should be recorded in writing. A decision to approve should include the conditions (e.g., the duration of the approval, the reporting requirements, etc.). Reasons for a decision to require an amendment or to reject a research protocol should be recorded. Outright rejection should be avoided if a researcher can be advised to improve the protocol. Researchers should be encouraged to address the concerns and improve their protocols. ECs should require researchers to report immediately if a project is terminated or suspended before the anticipated date of completion. ECs should require researchers to report immediately anything that might warrant reconsideration of ethical approval of the protocol, including but not limited to:

• Serious or unexpected adverse effects on participants
• Proposed changes in the protocol
• Unforeseen events that might affect continued ethical acceptability of the project

Per the G-EthicsHR-ZAF, ECs may, at their own discretion, recognize prior review and approval of a research protocol by another registered EC to avoid duplication of effort. Reciprocal recognition means that two (2) or more registered ECs decide to recognize each other’s prior review. ECs that recognize prior review in this manner must determine the nature of the documents to be filed locally, which must, at minimum, include a copy of the approval letter from the other ECs. In addition, ECs may establish procedures for expedited review for research that poses no more than minimal risk of harm to participants.

The SA-GCPs requires the EC’s approval of the following before the clinical trial may begin: protocol and any amendments; case report form, if applicable; informed consent form(s); any other written information to be provided to the participants; advertisement for participant recruitment (if used); participant compensation; and any other documents given approval/favorable opinion.

The SA-GCPs mandate that the sponsor receive confirmation of EC review from the investigator(s) or institution(s). The sponsor must receive the following information prior to the trial’s commencement:

• The name and address of the relevant EC registered with National Health Research Ethics Council (NHREC), with its documented approval
• If EC approval is conditional on required modifications, a copy of the modification(s) made and the date the final approval was granted by the EC
• Documentation and dates of any EC re-approvals/re-evaluations

As delineated in the G-EthicsHR-ZAF, ECs have the right to monitor the research it approves, and researchers should provide appropriate information to the EC to facilitate monitoring, including alerts and investigator brochures. The frequency and type of monitoring should reflect the degree and extent of risk of harm to participants or animals. ECs may recommend and adopt any additional appropriate mechanism for monitoring.

Per ZAF-20, if there is an amendment to the protocol, the sponsor must notify the EC and get its approval. This approval should be sent to the SAHPRA using the Application for Protocol Amendment to an Approved Trial (ZAF-20).

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.

Based on the G-EthicsHR-ZAF, ethics committees (ECs) may independently decide whether to charge fees for a protocol review. The G-EthicsHR-ZAF states that an EC should establish and record working procedures concerning fees charged, if any. Researchers without affiliation to an institution or organization with an EC should approach a registered EC to request it to review their health research protocols. If the EC is willing to review external applications, a fee for service may be levied.

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

Per ZAF-51, ethics committees (ECs) in South Africa are governed by the National Health Research Ethics Council (NHREC), which is a statutory body established under the NHA. As delineated in the NHA, the NHREC was created by the Minister of Health to provide ethical oversight of clinical research and to safeguard the rights and welfare of human participants involved in clinical studies. According to ZAF-52, NHREC gives direction on ethical issues relating to health and develops guidelines for the conduct of research involving humans and animals. Further, NHREC upholds the principle that research involving human participants is based on a moral commitment to advancing human welfare, knowledge, and understanding, and to exploring cultural dynamics, especially in large-scale trials conducted in developing countries. Of fundamental importance is the duty to conduct scientifically sound research while acting in the participant’s best interests and respecting and protecting the participant’s autonomy.

As delineated in the NHA, the SA-GCPs, and the G-EthicsHR-ZAF, the NHREC’s core responsibilities center on promoting, ensuring, and monitoring compliance by ECs. According to ZAF-52, the functions of the NHREC include:

• Determine guidelines for the functioning of ECs
• Register and audit ECs
• Set norms and standards for conducting research on humans and animals including clinical trials
• Adjudicate complaints about the functioning of ECs
• Refer to the relevant statutory health professional council matters involving the violation or potential violation of an ethical or professional rule by a health care provider
• Institute such disciplinary action as prescribed
• Advise the national department and provincial departments on any ethical issues concerning research

Registration, Auditing, and Accreditation

As delineated in the NHA, the G-EthicsHR-ZAF, and the SA-GCPs, all ECs are required to register with the NHREC in order to undertake the ethical review of a clinical study. The application to register an EC is available at ZAF-53. ZAF-54 states that the EC registration is recorded and publicly listed by the NHREC. The annual report form that ECs must submit to NHREC is available at ZAF-54. Per the SA-GCPs, the NHREC accredits and audits the ECs.

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

As delineated in the SA-GCPs, the sponsor and the investigator must obtain approval from the South African Health Products Regulatory Authority (SAHPRA) and a registered ethics committee (EC) to begin a clinical trial in South Africa. Per ZAF-23, the review and approval of clinical trial applications by SAHPRA and an accredited EC may be conducted in parallel. Per ZAF-20, the same process applies to the review and approval of an amendment to the protocol.

Regulatory Submission

Per ZAF-36, researchers must submit a completed application (ZAF-23) and the prescribed fee on predetermined dates (ZAF-11) and obtain proof of delivery. The proof of delivery, proof of payments, and cover page must be sent to SAHPRA via email. The G-CTA-Electronic delineates the electronic submission and communication process in SAHPRA’s Clinical Trial Unit (CTU). For new clinical trial applications (excluding bioequivalence studies), upon submission at SAHPRA Reception, applicants are requested to alert the CTU via e-mail at ctcresponses@sahpra.org.za and include a copy of the proof of delivery, proof of payment, and proof of insurance. In the subject of the e-mail, provide type of application, protocol number, SAHPRA predetermined cycle (see ZAF-11), and email number in case of multiple emails (e.g., “email 1 of 5”). Note that the submission email must include organized zipped folders for various sections of the clinical trial application. Individual site documents for each staff member must be uploaded into one (1) document and labelled with the staff name and arranged in folders according to the site which they belong to.

Per G-CTA-Electronic, to respond to SAHPRA’s screening checklist or to CTU’s expert committee review, the applicant must submit all responses by e-mail to ctcresponses@sahpra.org.za and include labelled attachments to the required documents. In the subject of the email, the applicant should provide the type of application, protocol number, and SAHPRA database tracking number. Responses to the CTU’s expert committee recommendations can be in MSWord or PDF formats. All other accompanying documents should be in PDF format v1.4, 1.5, 1.6, or 1.7 and legible with the Acrobat Reader search plugin or any other freeware viewer. PDF files should be saved as “Optimized” to reduce the size and allow faster opening when viewed online. The use of additional software to navigate and work with the files is not acceptable. If PDF files are not produced from an electronic source document but from scanned paper, readability and file size should be balanced; the following is recommended: resolution 300 dpi (photographs up to 600 dpi), avoid grayscale or color where possible, use only lossless compression techniques. The file must be searchable (OCR scanned). In addition, the maximum size of documents allowed per e-mail is 5 MB. As per arrangement with CTU, in case of a big file of documents and documents that need to be couriered, the waybill should indicate the type of application, protocol number, and SAHPRA database tracking number.

Per G-CTA-Electronic, for bioequivalence studies, the application and accompanying documents should be emailed to ctcbeprotocols@sahpra.org.za. The clinical trial application form should be in MS Word format and all other accompanying documents in PDF, as described above. As per arrangement with CTU, in case of a big file of documents and documents need to be couriered, the waybill should indicate the type of application, protocol number and SAHPRA database tracking number. The email subject should include the type of application, protocol number, and SAHPRA database tracking number. See the G-CTA-Electronic for specific examples of labeling the emails.

Per the G-CTAPHEmerg, during a public health emergency, applicants should use the modified clinical trial application form in G-CTAPHEmerg. This form recognizes the constraints on the availability of information posed by the emergency. SAHPRA may accept clinical trial applications with reduced information together with a commitment to update and complete the required information as soon as possible. However, all documents submitted must be organized with zipped folders according to the checklist in G-CTAPHEmerg and correctly labelled to ensure easy validation by SAHPRA (See the Submission Content and Emergencies sections for more details).

The G-CTA-Electronic provides instructions on submitting protocol amendments during the conduct of clinical trials, for additional investigators and sites during the conduct of clinical trials, bioequivalence studies, notifications and notification studies, and individual serious adverse events. The applicant must submit to SAHPRA the application for amendment to an approved trial (ZAF-20), as well as notify and get EC approval. (Also see Site/Investigator Selection and Safety Reporting sections for information about these submittal processes.)

The G-CTA-Electronic and ZAF-23 state that the clinical trial application must be sent to SAHPRA in a submission email (per directions above). However, ZAF-1 provides the following address for delivery of clinical trial applications to SAHPRA Reception:

South African Health Products Regulatory Authority
SAHPRA reception – 2nd floor
Loftus Park, Building A
402 Kirkness St, Arcadia
Pretoria, 0007
South Africa

Per ZAF-1, upon receipt of the clinical trial application at SAHPRA Reception, an acknowledgement of receipt in the form of a stamp and signature will be issued. The waybill from a courier company does not suffice as proof of delivery. SAHPRA’s CTU requires a document, referred to as the ‘stamp page,’ which includes the SAHPRA trial reference number, protocol number, and study title. This document will then be date-stamped and signed by SAHPRA’s Administrative Department and returned as proof.

As per the GRMRSA, all applications and supporting data submitted to the SAHPRA should be presented in English. Original documents that are not in English must be accompanied by an English translation.

Ethics Review Submission

Each EC has its own required submission procedures, which can differ significantly regarding the number of copies to be supplied and application format requirements. Refer to each EC’s website for specific submission procedures (Note: ECs are referred to as health research ethics committees (HRECs) in South Africa).

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

As per ZAF-23, the following documentation must be submitted to the South African Health Products Regulatory Authority (SAHPRA):

• The clinical trial application form (ZAF-23)
• Two (2) cover letters (one (1) signed in PDF and one (1) in MS-Word format)
• Two (2) completed copies of the clinical trial application (one (1) signed in PDF and one (1) in MS-Word format) (ZAF-23 and ZAF-20 (for amendments))
• Checklist
• Protocol
• Patient information leaflets (PILs) and informed consent forms (ICFs); include standardized SAHPRA contact details (Annex 1 of ZAF-23)
• Copy(ies) of recruitment advertisement(s) (if applicable) and questionnaires
• Investigator’s Brochure (IB)/SAHPRA and other regulatory authorities’ approved professional information (Package insert(s))
• Summary of previous trials with the investigational product(s) (IP(s)), if applicable
• Certificate of analysis of the product
• Signed investigator(s) Curriculum Vitae(s) (CV) in SAHPRA format (Annex 2 of ZAF-23)
• Signed declaration(s) by all investigator(s) (Annex 3 of ZAF-23)
• Signed joint financial declaration by sponsor and principal investigator (PI) or national PI (Annex 4 of ZAF-23)
• Signed declaration by applicant and national PI
• Signed declaration by national PI (See page 4 and Annex 3 (ZAF-23)
• Signed declaration by sub-investigators (Annex 5 of ZAF-23)
• CV(s) and signed declaration by regional monitor(s) (Annexes 2 and 6 of ZAF-23)
• Proof of application to register the trial on the South African National Clinical Trials Register (SANCTR) (ZAF-48)
• Active insurance certificate for clinical trial
• Proof of sponsor indemnity for investigators and trial site(s) (Annex 7 of ZAF-23)
• Active Good Clinical Practice (GCP) Certificates
• Workload forms for investigators (Annex 8 of ZAF-23)
• Proof of registration with professional statutory bodies
• Proof of professional indemnity (malpractice insurance) of trialist(s)
• Ethics committee (EC) approval letter or copy of letter submitted to EC
• Study budget
• Electronic copies of key peer reviewed publications following International Committee of Medical Journal Editors (ICMJE) recommendations to support the application (if applicable)
• Proof of payment (bank validated)
• Certificate of good manufacturing practice (GMP) for manufacture of the IP(s) (including placebo and comparator)
• Evidence of accreditation/certifications of the designated laboratories
• Data Safety Monitoring Board charter and composition (where applicable)

See ZAF-36 for additional information on submissions. For phase IV trials of approved products, the applicant must notify SAHPRA following the instructions provided in ZAF-17.

ZAF-20 delineates the contents and requirements for submitting an application for protocol amendment to an approved clinical trial.

Per the G-CTAPHEmerg, SAHPRA states that during a public health emergency, new and experimental treatments may become necessary and clinical trials are essential to provide the evidence to develop appropriate policies for patient treatments. Under these circumstances, there may be limited information available. However, applications need to contain a certain minimum of information to enable a meaningful evaluation and regulatory decisions. To address this, SAHPRA provides an information grading system in the G-CTAPHEmerg wherein required information is labelled. Applicants must attempt to provide the information listed below and justify when this is not available. The required information is graded as follows:

• Essential – Application will not be considered without this
• Important – Necessary information that must be provided later and must be justified if not available
• Not essential – May be omitted from this preliminary application

All incomplete information must be explained, justified, and provided to SAHPRA as a complete application (ZAF-23), when available. This means that repeat evaluations of an application may be necessary.

Ethics Committee Requirements

Each EC has its own application form and clearance requirements which can differ significantly regarding the number of copies to be supplied and application format requirements. However, the requirements list provided below is basically consistent across all South African ECs.

The following list was compiled from ZAF-24, ZAF-22, ZAF-45, ZAF-42, and ZAF-49, to exemplify the common elements shared by the various application forms:

• Cover letter
• Completed EC-specific application form
• Protocol
• Protocol synopsis
• PIL(s) and ICF(s) and process for obtaining informed consent
• Separate assent form required for adolescents/children under the age of 18 (See Children/Minors section for additional information)
• IB and package insert(s) (if applicable)
• SAHPRA approval letter or letter of application and notification
• Approval letter from institution’s scientific committee (if applicable)
• Copy of completed clinical trial application signed by all participating investigators
• All questionnaires and diaries to be used in the study
• Advertisement(s) (if applicable)
• Trial site information (address, telephone numbers, PI names, etc.)
• Trial payment schedule and budget schedule per site/draft financial contract and additional funding details
• Proof of submission fees payment
• Current investigator(s) CVs
• GCP training certificates for PIs and subinvestigators
• Information on registration with SANCTR (ZAF-48)
• Declaration of trialists (PI and sub-investigators) in SAHPRA format
• Insurance certificate

Further, per the MTA-Human, all the providers and recipients of human biological material for use in research or clinical trials under the auspices of ECs must use the “Material Transfer Agreement of Human Biological Materials” in MTA-Human. The agreement must be signed by the research institution’s authorized representative and the EC. (For additional details, see Specimens topic.)

Clinical Protocol

As delineated in ZAF-23 and the SA-GCPs, the clinical protocol should contain the following information (Note: the sources provide overlapping and unique elements so each of the items listed below will not necessarily be in each source.):

• General information
• Background information
• Study rationale and motivation
• Trial objectives, purpose, and endpoints (with justifications)
• Trial design and methodology
• IP information
• Participant eligibility, selection, and withdrawal
• Participant treatment
• Efficacy assessment
• Safety assessment
• Statistics
• Direct access to source data/documents
• Quality control/quality assurance
• Data and safety monitoring plan
• Data handling/recordkeeping
• Statistical measures
• Financing/insurance
• Publication policy

Per the SA-GCPs, the protocol must also provide details on ethical and administrative issues, including how the following matters are addressed:

• Compliance of multi-center/national trials with all South African regulatory requirements
• The trial design must be customized appropriately for the local setting to ensure that local realities are considered and appropriately integrated into the design
• For multi-national trials, whether a reasonable proportion of significant project team members, including scientists and health care professionals, are South African researchers, including those from previously disadvantaged backgrounds
• If South Africa is selected as a clinical trial site but the country of origin or other high-income countries are not, an explanation and reason for this with a clear ethical justification

For detailed information on protocol elements, please refer to ZAF-23 and the SA-GCPs.

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 ZAF-23 and the SA-GCPs, the review and approval of clinical trial applications by the South African Health Products Regulatory Authority (SAHPRA) and an accredited ethics committee (EC) may be conducted in parallel. The applicant must notify each regulatory body of the other’s approval once it has been received.

Regulatory Authority Approval

In general, per ZAF-36, SAHPRA’s Clinical Trial Unit (CTU) aims to process new applications and issue a screening checklist within three (3) weeks of receipt. After that, the expert Clinical Trials Committee (CTC) recommendations will be sent within 10 weeks of the submission due date. There are cases where this turnaround time might be prolonged, such as an unfamiliar investigational product which may be referred to external reviewers or other SAHPRA committees for input.

Per ZAF-1, during the preliminary screening, the CTU screens the application and sends an official letter to the applicant with the outcome and follow-up questions on a screening checklist. The applicant receives the screening checklist within 15 working days after application submission. The applicant must respond within seven (7) working days after receipt of the screening review.

Next, the CTC reviews the proposed clinical trials. ZAF-11 provides the dates of the 2024 CTC meetings and the SAHPRA submission due dates. It is advisable to submit clinical trial applications before these due dates. Once the reviewer approves the application, the CTC presents the committee’s/reviewer’s recommendations to the SAHPRA. ZAF-1 states that applicants receive a response within 10 working days from the CTC meeting, and they must send an answer within seven (7) working days after receipt of comments. If an applicant would like to request a meeting with the CTC, the request should be submitted through the SAHPRA Chief Executive Office pursuant to the procedures in the G-ConsultMtg.

Ethics Committee Approval

As earlier stated, an applicant must also submit the clinical trial application for review and approval by an accredited local EC. Review timelines vary per an individual EC’s procedures.

Governance

In addition, as described in the G-EthicsHR-ZAF and ZAF-6, all clinical trials must obtain site-specific provincial and/or hospital approval to assess the impact the clinical trial will have on the resources of the establishment hosting the trial.

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 GRMRSA, the SA-GCPs, the G-EthicsHR-ZAF, and the NHAParticipants, a clinical trial can only commence in South Africa once an applicant receives approval from the South African Health Products Regulatory Authority (SAHPRA) and from an accredited local ethics committee (EC). There is no waiting period required following the applicant’s receipt of these approvals.

In addition, the principal investigator (PI) for each study site must be a South African-based scientist (resident of South Africa), and should have the appropriate qualifications, training, and experience to assume responsibility for the proper conduct of a trial. The trial must be conducted in compliance with the SA-GCPs, the G-EthicsHR-ZAF, and the GRMRSA. Also, per the SA-GCPs, all clinical trials must be conducted in a laboratory complying with Good Laboratory Practices (GLP). See ZAF-46 for the World Health Organization (WHO)’s handbook on GLPs.

Per the SA-GPPs, pharmacists must be involved in clinical trials, including for example, assisting in the development of protocols, overseeing medicine supplies, monitoring administration protocols, and maintaining registries.

Clinical Trial Agreement

According to the SA-GCPs, all parties involved in the conduct of a trial should be familiar with guidance in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (ZAF-27) and other international guidelines. Before the trial begins, a sponsor must prepare a written agreement. The agreement must be signed by the sponsor and the PI, and any other parties involved (e.g., institutions and contract research organizations) with the trial to confirm the contract terms. Both the sponsor and the PI must commit to providing safety information between each other. The sponsor should also obtain the investigator's agreement to:

• Conduct the trial in compliance with the SA-GCPs, the SAHPRA requirements, ZAF-27, and the EC approved protocol

• Comply with data recording/reporting procedures

• Permit monitoring, auditing, and inspection

• Retain the trial-related essential documents until the sponsor informs the investigator(s) and institution(s) that these documents are no longer needed

In addition, per the SA-GCPs, the financial aspects of the trial should be documented in the agreement. A declaration must be signed by the sponsor and PI stating that sufficient funds are available to complete the study. The sponsor is also responsible for securing agreements to ensure direct access to all trial-related sites, source data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and inspection by domestic and foreign regulatory authorities.

Clinical Trial Registration

According to the SA-GCPs, NHAParticipants, and ZAF-32, the PI or the sponsor must enter the trial information in the South African National Clinical Trials Register (SANCTR) (ZAF-48). The SA-GCPs indicates that the National Department of Health (NDOH) then issues a unique SANCTR National Register Number. ZAF-32 has instructions for registering either online or via email.

ZAF-48 states that SANCTR fulfills the requirements of the International Committee of Medical Journal Editors (ICMJE) publication mandates and has a formal partnership with the Pan African Clinical Trials Registry (ZAF-50), which is recognized by the WHO.

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 SA-GCPs, the G-EthicsHR-ZAF, and the G-SafetyRpt, the following definitions provide a basis for a common understanding of South Africa’s safety reporting requirements:

• Adverse Event/Experience (AE) – Any untoward medical occurrence that may present during treatment with a medicine, but which does not necessarily have a causal relationship with this treatment
• Adverse Drug Reaction or Adverse Reaction (ADR) – A noxious and unintended response to a medicine in humans or animals, including lack of efficacy, and which occurs at any dosage and can also result from overdose, misuse, or abuse of a medicine
• 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 patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect
• Unexpected Adverse Drug Reaction – One in which the nature, specificity, severity, and outcome is inconsistent with the applicable product information (i.e., with the approved package inserts for registered medicines, the investigator’s brochure, or other product information for unregistered medicines being used)

Furthermore, ZAF-30 provides clarification on the definition of a serious suspected unexpected adverse reaction (SUSAR), which is a reporting requirement in the updated G-SafetyRpt. Per ZAF-30, a SUSAR is an adverse reaction that is unexpected but suspected to be drug related. It must fulfil the criteria for “serious” as per the definition of SAEs. In addition, all SUSARs are SAEs but not all SAEs are SUSARs.

Per the G-EmergencyProc, all clinical trial sites must have an emergency standard operating procedure that should be available for inspection by the South African Health Products Regulatory Authority (SAHPRA). In addition, each clinical trial site should have adequately trained investigators to manage medical emergencies. Further, there must be an emergency 24-hour contact number for trial participants who experience an unexpected AE.

Safety Reporting Requirements

Investigator Responsibilities

As specified in the SA-GCPs and the G-EthicsHR-ZAF, the principal investigator (PI) must inform the sponsor immediately, or within the time specified in the protocol, of any serious and/or unexpected AEs occurring during the study. The initial reporting form and any relevant follow-up information should be sent to the sponsor. The G-SafetyRpt directs the investigator to report AEs to the sponsor in a manner defined in the protocol. Per the SA-GCPs, AEs and/or laboratory abnormalities identified in the protocol as critical to safety evaluations must be reported to the sponsor in accordance with the reporting requirement and within the time periods specified in the protocol. In the case of participant deaths, the PI must supply the sponsor, the ethics committee (EC), and SAHPRA with any additional information, as requested. The initial and follow-up reports must identify the affected participants by the participant identification code.

Sponsor Responsibilities

As delineated in the GRMRSA and the G-EthicsHR-ZAF, the sponsor is required to report all expected or unexpected SAEs/SADRs on an expedited basis to all concerned parties, including the investigator(s) and institution(s), the SAHPRA, and the ECs. Pursuant to the G-SafetyRpt, the sponsor is required to submit the following safety reports to SAHPRA:

• Reports of SUSARs occurring in the clinical trial using the SAHPRA SAE form (ZAF-19), CIOMS form (ZAF-15), or Annex B of G-SafetyRpt
• Reports of all SUSAR and trends occurring with the investigational product (IP) in South Africa
• Six-month progress report
• Annual Development Safety Update Reports (DSURs) that includes information gathered from all clinical experience with the IP, whether in South Africa or elsewhere
• Final Progress Report
• Final Study Report

The SA-GCPs states that the sponsor is responsible for performing an ongoing safety evaluation of the IP and must promptly provide written notification to the investigator and SAHPRA of findings that may adversely affect the safety of participants or the conduct of the trial, and/or change the EC's approval to continue the trial. The commitment to provide safety information must be included in the clinical trial agreement signed between the sponsor and the investigator.

The G-SafetyRpt delineates the following reporting timeframes:

• The sponsor should initially report all fatal or life-threatening SAEs in local reports within seven (7) calendar days after first knowledge, using CIOMS format (ZAF-15)/SAHPRA SAE form (ZAF-19). The follow-up report should be submitted within an additional eight (8) calendar days.
• All fatal or life-threatening SAEs in foreign reports should initially be reported within 30 calendar days after first knowledge by the sponsor. The follow-up report should be submitted within an additional six (6) months as part of the progress report. If the SAEs result in premature study closure, the reporting times are shorter—seven (7) days for the initial report and within an additional eight (8) days for the follow-up report. These reports should be in a line listing format. Note that these reporting requirements also cover foreign reports of “special concern,” which is a significant safety issue defined for each clinical trial that requires urgent attention from the regulatory authority. An adverse reaction of special concern from a foreign jurisdiction should be based on the decision of its regulatory authority. A safety issue leading to international regulatory action is considered to be significant at all times and hence reportable.
• Local reports of other serious events (unexpected, not fatal or life threatening) within 15 calendar days of the event and every six (6) months in the CIOMS format (ZAF-15)/SAHPRA SAE form (ZAF-19)
• A line listing of all local reports—serious (unexpected and expected) AEs—and any other issues of special concern outside South Africa should be submitted every six (6) months (using the progress report form in ZAF-18).
• An initial detailed report of new information impacting the risk-benefit profile of the IP or conduct of trial should be submitted within three (3) calendar days; a follow-up report should be submitted within an additional six (6) months.
• An initial detailed report of other major safety concerns (e.g., changes in nature, severity, or frequency of risk factors) should be submitted within 15 days of knowledge of the concern; a follow-up report should be submitted within an additional six (6) months.
• DSURs should be submitted within one year from approval of the study and annually thereafter.

In addition, SAHPRA reserves the right to impose additional reporting timelines on an individual protocol basis, and it may require expedited reporting of AEs of special interest, whether serious or not.

See the G-SafetyRpt for details on the contents of the reports and other safety report requirements.

Form Completion & Delivery Requirements

Per the G-SafetyRpt and ZAF-19, the SAHPRA’s Safety Reporting During Clinical Trials Form (ZAF-19) should be used to complete SAE/ADR reports—for both initial and follow-up safety reports. The G-SafetyRpt indicates that adverse drug reactions occurring during post-marketing studies (Phase 4 and observational studies) should be reported to the Vigilance Unit of SAHPRA, and adverse drug reactions occurring during the use of concomitant and/or comparator medicine in a clinical trial should be reported to the Clinical Trial Unit of SAHPRA. Reportable safety information must be sent to:

• ctcsaes@sahpra.org.za for clinical trials (per ZAF-47, ctcsaes@sahpra.org.za should be used for individual patient SAEs and related queries)
• adr@sahpra.org.za or e2b@sahpra.org.za for post-marketing studies
• section21@sahpra.org.za for reporting of SAEs for medicines used under Section 21

As per ZAF-47, the following is the contact information for pharmacovigilance-related submissions:

• ADR reports in an e2b in an xml format: e2b@sahpra.org.za
• All other ADR reports: adr@sahpra.org.za
• Pharmacovigilance related queries: pvqueries@sahpra.org.za
• Documentation relating to identified safety concerns, responses to recommendations, and Risk Management Plans (RMPs): pvsubmissions@sahpra.org.za

G-CTA-Electronic details the requirements for electronic submission of individual SAEs. All SAEs should be submitted to ctcsaes@sahpra.org.za with a cover letter detailing:

• The title of the study
• The SAHPRA reference number
• Protocol number
• Name of site
• Patient study ID
• Cause of SAE
• Causality and SAE reporting form
• Other applicable information

The email subject line should include the following information: SAE, protocol number, and SAHPRA database tracking number.

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

In accordance with the GRMRSA, the person authorized by the South African Health Products Regulatory Authority (SAHPRA) to conduct a clinical trial (i.e., the sponsor) must submit progress reports to the SAHPRA every six (6) months from the application approval date. The SA-GCPs requires the investigator to submit written progress reports to the ethics committee (EC) annually and to SAHPRA every six (6) months. ECs and SAHPRA may request reports more frequently.

Per the GRMRSA, the SA-GCPs, and G-SafetyRpt, the six-month report (ZAF-18) must include the following (Note: the sources provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

• SAHPRA database tracking number
• Study title
• Protocol number
• Details of the sponsor
• Progress to date or the outcome in case of completed research
• Whether participant follow up is still active or has been completed
• List of all active trial sites, addresses, and principal investigators (PIs)
• Trial information, including date of approval of study, treatment hold (if applicable), and expected date of completion
• Number of participants per site and current enrollment status
• Sponsor comment on progress to date
• Summary Data Safety Monitoring Board or Safety Committee recommendations and relevant safety data
• Serious adverse events and suspected unexpected serious adverse reactions for all participants per site in South Africa, including identification of previous safety reports submitted to SAHPRA concerning a similar suspected adverse reaction and an analysis of their connection
• Any safety issues of special concern outside of South Africa
• Line listing of all critical and major protocol violations/noncompliance and resolutions/actions taken at a site or conditions of approval
• Principal investigator (PI) comment on other major safety concerns
• Signature of the PI
• Signature of the sponsor

Note that the SA-GCPs directs the investigator to promptly provide written reports to the sponsor/applicant, the EC, and where applicable, the institution on changes that significantly affect trial conduct and/or increase the risk of participant harm.

Final Report

The sponsor is required to submit a final progress report to the SAHPRA 30 days following the trial’s completion as stated in the GRMRSA and the G-SafetyRpt. Further, per G-SafetyRpt, a final study report should be submitted within 180 days of clinical trial completion or termination.

In addition, per the SA-GCPs, upon the trial’s end, the investigator must inform the institution (if applicable), the EC, and SAHPRA and provide them with a summary of the trial outcome and other required reports.

The SA-GCPs specifies that the sponsor must ensure that trial results and outcomes are reported to the investigators, SAHPRA, and the National Department of Health (NDOH) via the South African National Clinical Trials Register (SANCTR) (ZAF-48) within one (1) year of the study’s completion. The sponsor and the PI are responsible for appropriate dissemination of the trial findings.

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.

As defined in the SA-GCPs, a sponsor is the person or organization responsible for the initiation, management, or financing of a clinical trial. A sponsor can be a pharmaceutical company, the principal investigator (PI), a funding body, or an individual or organization designated by the funding body or academic institution. An applicant can be an individual, company, institution, or organization that acts on behalf of the sponsor to initiate and manage the trial as its local representative. In the case of an international sponsor, a local applicant designated by the sponsor is responsible for initiation and management of the trial in the local context.

Per the SA-GCPs, a sponsor may transfer any or all trial-related duties and functions to a contract research organization (CRO). However, the sponsor is always ultimately responsible for the study data quality and integrity. Further, per the G-Monitor, the sponsor is solely responsible for adequate oversight of clinical trial conduct, including the justification for and selection of monitoring methods. Any trial-related responsibilities transferred to and assumed by a CRO should be specified in writing. The sponsor retains those responsibilities not specifically transferred to and assumed by a CRO.

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

As set forth in the SA-GCPs, the sponsor is responsible for using qualified individuals (e.g., biostatisticians, clinical pharmacologists, and physicians), as appropriate, throughout all stages of the trial process. Sponsors should select investigator(s) who are qualified by training and experience and have adequate resources to conduct the proposed clinical trial. Further, per the G-Monitor, the sponsor should consider previous experience with the investigator or site, workload of the investigator, and resource availability at the study site during investigator and site selection. Per the G-Capacity, clinical trial applications should include evidence and activity plans to build capacity at each study site as well as enhancing research activities and skills of professionals from historically disadvantaged groups. Mandatory training in Good Clinical Practice (GCP) forms a part of capacity building. To support transformation and capacity building, the South African Health Products Regulatory Authority (SAHPRA) states that the sponsor must have a policy on “Capacity Building and Transformation in Clinical Research in SA” in place, and preferentially select sites that are compliant. See G-Capacity, for detailed information on actions that will comply with this requirement.

According to the SA-GCPs, the sponsor must also define and allocate all study related duties and responsibilities to the investigator prior to initiating the study.

In addition, per ZAF-21, to add or change investigators and/or additional sites to an approved clinical trial, the sponsor must submit a signed application to SAHPRA. See ZAF-21 for details.

Per the G-CTInvestigators, SAHPRA will recognize and approve categories of investigators for trial leadership. The principal investigator (PI) must be a South Africa-based scientist, who has sole or joint responsibility for the design, conduct, and delegation of trial responsibilities, analysis, and reporting. The PI is accountable to the sponsor and regulatory authorities. The PI can designate and supervise sub-principal investigator(s) (Sub-PI) of which at least one (1) must be a clinician and registered with the appropriate statutory entity to provide clinical oversight within their scope of practice. Further, the SAHPRA recognizes a category of co-principal investigator (co-PI), which allows for a team consisting of two (2) co-PIs to lead a study at a site. At least one (1) of the co-PIs must be a clinician registered with the appropriate statutory body and qualified to provide clinical oversight within their scope of practice. For multi-center studies, there must be a national PI appointed, who may or may not be a site PI. The national PI must have appropriate experience and expertise in that field and must be responsible for the application to the SAHPRA to conduct the study. The national PI must meet all other requirements to be a PI and sign a declaration accepting the responsibility as national PI and sign off on the clinical trial application. For more information on PI requirements, roles, and responsibilities, see the G-CTInvestigators.

Per the SA-GCPs, all parties involved in the conduct of a trial should be familiar with the guidance in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (ZAF-27) and other international guidelines. Additionally, the investigator must agree to conduct the trial in compliance with the SA-GCPs, ZAF-27, SAHPRA requirements, and the ethics committee approved protocol. In the event of an interpretation conflict between the SA-GCPs and an international guideline, the SA-GCPs take precedence.

Foreign Sponsor Responsibilities

As required in the SA-GCPs, if South Africa is selected as a clinical trial site but the country of origin or other high-income countries are not, the sponsor must explain the reason(s) why and provide a clear ethical justification. Further, multi-national trials should ensure that a reasonable proportion of project team members are South African researchers, including scientists and health care professionals and those from previously disadvantaged backgrounds.

Data and Safety Monitoring Board

Per the SA-GCPs, the sponsor may establish an independent Data Safety Monitoring Board (DSMB) to assess the progress of a clinical trial, including safety data and critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial. The DSMB must have written standard operating procedures and must maintain written records of all its meetings.

Multicenter Studies

Per the SA-GCPs, if the trial is a multicenter and/or multi-country trial, any differences in trial designs between the South African and other sites must be clearly documented and explained in the trial protocol and/or related documents. In addition, international research groups must comply with South African regulatory requirements, and researchers must adapt the trial design and informed consent procedures to take into account local conditions and characteristics.

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 G-Insurance and the SA-GCPs, all clinical trial sponsors and investigators must obtain adequate insurance and indemnity to cover any liability claims during the conduct of a clinical trial, in accordance with the responsibilities described in the SA-GCPs. As delineated in the SA-GCPs and G-Insurance, a sponsor must follow the principles set forth in the Association of the British Pharmaceutical Industry’s (ABPI) guidelines (ZAF-26 and ZAF-25) to comply with South Africa’s clinical trial insurance requirements. Per the SA-GCPs, research participants should not bear any financial cost to rectify harms that occur as a result of trial participation. The insurer pays the medical costs of necessary treatment to restore the previous position of the participant, if possible, when bodily or other injury is attributable to trial participation. Only bodily injuries of an enduring and disabling character (including exacerbation of an existing condition) and/or death are covered by the insurance. Temporary pain or discomfort or less serious or curable complaints are generally not regarded as trial-related, bodily injury. In the case of an in-utero injury due to the mother’s participation, payment for medical expenses proceeds as though the unborn child is a research participant. For additional details on limitations on liability, dispute resolution, weighting of risk factors, and insurance settlements, see the SA-GCPs.

Per the G-Insurance, the application to conduct a clinical trial must include evidence of comprehensive no fault insurance for serious injury and harm and/or death. In addition, the sponsor must provide indemnification for all investigators and trial sites involved in their clinical studies on compliance with the protocol requirements. In cases where the investigators/site staff were negligent and/or did not comply with the protocol requirements, personal malpractice insurance would apply.

As delineated in the G-Insurance and ZAF-23, an insurance certificate and indemnity must be included in the clinical trial application submitted to the South African Health Products Regulatory Authority (SAHPRA). Per the G-Insurance, the sponsor must include details of the insurance, including the following:

• Name and local address of the insurance company, including contact name and telephone number
• Title and protocol number of the clinical trial
• Date of commencement and termination of coverage
• Liability limit – per occurrence and total per occurrence and total for the study. Note that the limit should be adequate enough to cover extended stay in an intensive care unit or hospital
• Date of issuance of the insurance policy and expiry thereof
• Original or electronic signature of the insurer
• Special conditions if any. It is unacceptable to have special conditions which may invalidate or abate the clinical trial cover
• Any additional coverage
• Declaration of compliance with the SA-GCPs and ABPI guidelines on the certificate and in the patient information leaflet
• Where the insurance is not provided by a local company, a local insurance vendor must be identified with full details
• Insurance policy number
• The amount insured

Compensation

Injury or Death

As set forth in the G-Insurance, all clinical trial sponsors and investigators must have adequate insurance to cover any liability claims during the conduct of a clinical trial, in accordance with the responsibilities as described in the SA-GCPs. As delineated in the SA-GCPs and G-Insurance, a sponsor must follow the principles set forth in the ABPI guidelines (ZAF-26 and ZAF-25) to comply with South Africa’s participant compensation and treatment requirements for trial-related injuries. The guidelines state that the sponsor should furnish written assurance to the investigator that the sponsor will agree to pay compensation to participants and/or their legal heirs in the event of trial-related injuries or death. The investigator, in turn, communicates this information to the relevant ethics committee (EC).

The SA-GCPs, the G-Insurance, and ZAF-26 provide several compensation principles to guide sponsors in fulfilling their obligations (Note: the sources provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

• Compensation should be paid when it can be demonstrated that a causal relationship exists between a participant’s injury and their participation in a trial
• Compensation should be paid when the injury results in permanent injury or disability to the participant
• When there is an adverse reaction to a medicinal product under trial, and injury is caused by a procedure adopted to deal with that adverse reaction
• The sponsor/applicant is under strict liability with respect to injuries caused by the investigational product (IP), and research participants should not bear any financial cost to rectify harms that occur as a result of trial participation
• The insurer should pay the medical costs of necessary treatment to restore the previous position of the participant, if possible
• In the case of an in-utero injury due to the mother’s participation, payment for medical expenses proceeds as though the unborn child is a research participant
• In principle, only bodily injuries of an enduring and disabling character (including exacerbation of an existing condition) and/or death are covered by the insurance; temporary pain or discomfort or less serious or curable complaints are generally not regarded as trial-related, bodily injury
• Where there is an adverse reaction to an IP and the injury is caused by a procedure adopted to deal with that adverse reaction, compensation should be paid for such injury as if it were caused directly by the IP
• Payment for medical expenses is made without acknowledgement of any legal liability and is thus to be understood to be an ex-gratia payment
• The provision of insurance cover and payment of medical expenses does not mean that an injured participant may not pursue legal action against the sponsor for loss or harm not covered by the insurance; however, an argument that pain and suffering, loss of income, and other possible claims should be paid for by the sponsor’s insurer is not sound in South African law and will not succeed
• The likelihood of an adverse reaction, or the fact that the participant has freely consented (whether in writing or otherwise) to participate in the trial should not exclude the participant from being eligible for compensation

According to the SA-GCPs and ZAF-26, the amount of compensation to be paid to the participant should be appropriate to the nature, severity, and persistence of the injury. The compensation should also be generally consistent with the amount of damages commonly awarded for similar injuries. The amount paid in compensation should be abated, or in certain circumstances excluded, in light of the following factors (which will depend on the risk level the participant can reasonably be expected to accept):

• The seriousness of the disease being treated

• The degree of probability that adverse reactions will occur and any warning given

• The risks and benefits of the established treatments relative to those known or suspected of the trial medicines

ZAF-26 provides that in any case where the sponsor agrees to pay the participant, but the two (2) parties differ on what is the appropriate level of compensation, it is recommended that the sponsor agree to seek, at the sponsor’s own cost, the opinion of a mutually acceptable independent expert. This opinion should then be made available to the participant(s), and the expert’s opinion should be given substantial weight by the sponsor in reaching a decision on the payment amount.

Additionally, any participant claims pursuant to ZAF-26 should be made to the sponsor, preferably via the investigator. The participant should include details on the nature and background of the claim, which the sponsor should review expeditiously. The review process may be delayed if the participant requests an authority to examine any medical records relevant to the claim.

Trial Participation

As specified in the G-TIECompensation and the SA-GCPs, the sponsor or the designated representative is responsible for providing compensation to research participants. The SA-GCPs state that before the clinical phase of the trial commences, the EC must approve the documentation on participant compensation. Per the G-EthicsHR-ZAF, the SA-GCPs, and the G-TIECompensation, compensation should be based on time, inconvenience, and expenses. In addition, the G-EthicsHR-ZAF and the SA-GCPs also address researcher requirements to budget for participant travel and other expenses. (See the G-EthicsHR-ZAF for detailed information). See ZAF-5 for an analysis of ethical considerations regarding payment of trial participants in South Africa.

The G-TIECompensation guides sponsors of approved clinical trials and proposes a model for minimum compensation that can be paid. It is not intended as an exclusive approach and the SAHPRA reserves the right to request any additional information. In addition, G-TIECompensation is not applicable to Phase I clinical trials, which pose a higher risk for participants and should be compensated on a different scale.

Post-Trial Access

The G-PostCTAccess guides sponsors on when to consider post-trial or continued access (PTA/CA) to the IP following the trial’s conclusion. Only those participants who derive benefit from the IP will be considered (this excludes participants on standard of care, placebo, and registered medicines). Where appropriate and available, the possibility of PTA/CA should be disclosed to and discussed with potential participants during the initial informed consent process or via a separate consent process. Where appropriate and/or available, details of potential PTA/CA should be included in the clinical trial application form, informed consent form, and patient information leaflet. Additional considerations include the following:

• PTA/CA is not applicable for Phase I and II studies. However, PTA/CA may be necessary for particular diseases (e.g., cancer or rare diseases).
• PTA/CA should be considered for Phase III studies when there is no registered and marketed standard of care in South Africa, provided that data from interim or final analyses shows that access is clinically justifiable.
• PTA/CA is not applicable to Phase IV studies
• A minimum of four (4) years after completion of the study is recommended as the acceptable time period to provide PTA/CA to the participants, unless there are compelling reasons for determining otherwise.
• During the PTA/CA period, the sponsor must ensure monitoring and oversight of participants using the IP.

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

Per the SA-GCPs, the sponsor is responsible for implementing a quality management system to manage quality throughout the design, conduct, recording, evaluation, reporting, and archiving of clinical trials. This quality management system should adopt a risk-based approach for risk identification, evaluation, control, communication, and reporting. The sponsor should focus on trial activities that promote human participant protection and reliability of trial results, which include using qualified individuals, designating qualified medical personnel to respond to trial-related medical questions, and ensuring all aspects of the trial are operationally feasible and avoiding unnecessary complexity, procedures, and data collection. With respect to quality assurance (QA) and quality control (QC), the sponsor is responsible for implementing and maintaining QA and QC systems with written standard operating procedures (SOPs) to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, good clinical practice, and the applicable regulatory requirement(s).

Per the G-Monitor, the responsibility for adequate oversight of the conduct of a clinical trial, including the justification for and selection of monitoring methods, remains that of the sponsor solely.

Per the SA-GCPs, all parties involved in the conduct of a trial should be familiar with guidance in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (ZAF-27) and other international guidelines. Additionally, the investigator must agree to conduct the trial in compliance with the SA-GCPs, ZAF-27, South African Health Products Regulatory Authority (SAHPRA) requirements, and the ethics committee (EC) approved protocol. In the event of an interpretation conflict between the SA-GCPs and an international guideline, the SA-GCPs take precedence.

Monitoring Requirements

In accordance with the SA-GCPs, the sponsor must conduct an independent audit to evaluate trial conduct and compliance with the protocol, procedures, good clinical practice, and the applicable regulatory requirements. The sponsor must appoint individuals who are independent of the clinical trials to conduct the audits and ensure that the auditors are qualified by training and experience to conduct audits properly. The sponsor's audit plan and procedures for a trial audit must be guided by the number of participants in the trial, the type and complexity of the trial, the level of risks to the trial participants, and any identified problem(s). Observations and findings of the auditors must be documented. The sponsor is responsible for obtaining agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, and reports for monitoring and auditing purposes, and inspection by domestic and foreign regulatory authorities.

In addition, per the G-Monitor, the sponsor’s monitoring plan should include planned audits to ensure that monitoring activities are in accordance with the monitoring plan, applicable regulations, guidance, and sponsor’s plans and policies.

Premature Study Termination/Suspension

Per the SA-GCPs, if a trial is prematurely terminated or suspended for any reason, the investigator must promptly inform the trial participants and ensure appropriate therapy and follow-up for them. If the investigator, sponsor, institution, SAHPRA, or the EC terminate or suspend a trial, the investigator must promptly inform the other parties with a detailed written explanation for the termination or suspension. The sponsor is also responsible for ensuring that the South African National Clinical Trials Register (SANCTR) (ZAF-48) is updated as well.

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

Per the SA-GCPs, the sponsor must ensure that the electronic data processing system conforms to the specific documented requirements for completeness, accuracy, reliability, and consistency of intended performance, and that standard operating procedures for using these systems are maintained. In addition, the sponsor must:

• Ensure that the systems are designed to document data changes without deleting previously entered data (i.e., maintain an audit trail)
• Maintain a security system that prevents unauthorized access to the data
• Maintain a register of persons authorized to make data changes
• Maintain adequate data backup
• Ensure that blinding, if any, is maintained during data entry and processing
• Ensure the integrity and confidentiality of data, including any that describe the context, content, and structure of the data – especially when making changes to computerized systems
• If data are transformed during processing, it must be possible to compare the original data and observations with the processed data
• Use an unambiguous participant identification code that allows identification of all data reported for each participant
• Report any transfer of ownership of the data to South African Health Products Regulatory Authority (SAHPRA)

Per the G-Monitor, when developing a study’s monitoring plan, the sponsor should consider how it uses electronic data capture (EDC) systems. EDC systems that are capable of assessing quality metrics in real time will help identify high-risk sites that need more intensive monitoring.

Records Management

As set forth in the SA-GCPs, the sponsor should inform the investigator(s) in writing of the need for record retention, and should notify these parties in writing when the trial related records are no longer needed. The sponsor, or other data owners, must retain all the sponsor-specific essential documents pertaining to the trial for not less than 10 years or until at least two (2) years have elapsed since the formal discontinuation of clinical development of the investigational product (IP).

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, the POPIA provides that the “responsible party” is a public or private body or any other person that, alone or in conjunction with others, determines the purpose of and means for processing personal information.

Data Protection

Per the POPIA, participants have the right to privacy, which includes a right to protection against the unlawful collection, retention, dissemination, and use of personal information by public and private bodies. This right to privacy is subject to justifiable limitations that are aimed at protecting other rights and interests (e.g., the right of access to information). Additional information on the rights of data subjects is provided in the POPIA.

The POPIA states that the responsible party must protect the constitutional right to privacy by safeguarding personal information when it is processed. The law provides conditions under which personal information may be gathered and processed.

• Accountability – The responsible party must ensure that the conditions and all the measures in the POPIA are complied with at the time of the purpose and means of processing is determined
• Processing limitation – Personal information may only be processed in a fair and lawful manner and only with the consent of the data subject
• Purpose specification – Personal information may only be processed for specific, explicitly defined, and legitimate reasons
• Further processing limitation – Personal information may not be processed for a secondary purpose unless that processing is compatible with the original purpose
• Information quality – The responsible party must take reasonable steps to ensure that the personal information collected is complete, accurate, not misleading, and updated where necessary
• Openness – The data subject whose information you are collecting must be aware that you are collecting such personal information and for what purpose the information will be used
• Security safeguards – Personal information must be kept secure against the risk of loss, unlawful access, interference, modification, unauthorized destruction and disclosure
• Data subject participation – Data subjects may request whether their personal information is held, as well as the correction and/or deletion of any personal information held about them

The POPIA establishes a duty requiring a public or private body to register its Information Officer with the Information Regulator (South Africa). Per the POPIA, the Information Officer is responsible for compliance with lawful processing of information and working with and responding to requests by the Regulator. Per the POPIA-Regs, the Information Officer has further responsibilities to:

• Develop, implement, monitor, and maintain a compliance framework
• Conduct a personal information impact assessment to ensure compliance with the conditions for the lawful processing of personal information
• Develop, monitor, and maintain a manual; and make it available upon request by any person, provide copies of the manual to any person upon request and payment of a fee to be determined by the Information Regulator from time to time
• Develop internal measures and systems to process requests for information or access
• Conduct internal awareness sessions on protection of personal information requirements
• Provide reasonable assistance free of charge to the data subject in objecting to processing of personal information (using Form 1 in the POPIA-Regs) and/or correcting or revising a record of personal information (using Form 2 in the POPIA-Regs)

The POPIA provides that records of personal information for research may be retained longer than is necessary for achieving the purpose for which the information was collected or processed if the responsible party has established appropriate safeguards against the records being used for any other purposes.

For additional guidance on processing personal data, including guidance on “special personal information” (e.g., health history) and personal information of children, see the Information Regulator website.

Consent for Processing Personal Data

Per the POPIA and the POPIA-Regs, personal information may only be processed if the data subject and/or the legal representative(s) or guardian(s) consents to the processing. The responsible party bears the burden of proof for the consent. The data subject and/or the legal representative(s) or guardian(s) may withdraw consent at any time if the lawfulness of the processing of personal information will not be affected.

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 South African clinical trials, a freely given, written informed consent is required to be obtained from each participant in accordance with the principles set forth in the NHA, the Declaration of Helsinki (ZAF-44), the SA-GCPs, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (ZAF-27).

As per the SA-GCPs, the G-EthicsHR-ZAF, and the G-GPHlthCare, the informed consent form (ICF) and patient information sheet(s) are essential documents that must be reviewed and approved by an accredited ethics committee (EC) based in South Africa and provided to the South African Health Products Regulatory Authority (SAHPRA) with the clinical trial application. (See the Required Elements section for details on what should be included in the form.) The principal investigator (PI), or a person designated by the PI, should provide research study information to the participant and/or the legal representative(s), or guardian(s). When drafting and presenting the ICF, special consideration must be taken with regard to the participant’s culture, traditional values, intelligence, and education. The informed consent document should be non-technical and understandable to the participant and in a participant’s preferred written language. The ICF content should be briefly and clearly presented, without coercion or unduly influencing a potential participant to enroll in the clinical trial.

The SA-GCPs directs that none of the oral or written information concerning the study, including the written ICF, should contain any language that causes the participant and/or the legal representative(s) or guardian(s) to waive or to appear to waive their legal rights, or that releases or appears to release the investigator(s), the institution, the sponsor, or the representatives from the sponsor’s liabilities for any negligence.

Re-Consent

The G-GPHlthCare-IC states that the participant must be informed of any relevant new findings over the course of the study, and be given the choice to continue to participate or withdraw from the study. Per the SA-GCPs, written informed consent documentation and other participant-related information should be revised when new information that may be relevant to a participant’s consent or willingness to continue to participate in the trial becomes available. Any revisions must be submitted for ethics review and approval before implementation. Communication of the new information to participants must be documented.

Language Requirements

According to the SA-GCPs and the G-EthicsHR-ZAF, the ICF and any patient information sheet(s) should be written in English and in a vernacular language that the participant is able to understand. The G-GPHlthCare states that the researchers should provide information to the participants in a language that the participant understands and in a manner that takes into account the participant’s level of literacy, understanding, values, and personal belief systems.

Documenting Consent

As stated in the SA-GCPs, the G-EthicsHR-ZAF, and the G-GPHlthCare, the ICF should be signed by the participant and the PI, or the person designated by the PI. If the participant is incapable of giving an informed consent, the legal representative(s) or guardian(s) should sign the ICF. The original signed ICF and patient information sheet(s) should be retained by the investigator and a copy should be given to the participant. The SA-GCPs requires an additional copy of the signed ICF and a source document identifying the study and recording the participation dates should be placed in the participant’s medical records. According to the SA-GCPs, the G-EthicsHR-ZAF, the G-GPHlthCare, and the G-GPHlthCare-IC, in all cases, written informed consent must be obtained. Where the participant is illiterate and/or the legal representative(s) or guardian(s) is illiterate, verbal consent should be obtained in the presence of and countersigned by a literate witness. The participant and/or the participant’s legal representative(s) or guardian(s), the PI or person designated by the PI, and if applicable, a literate witness must personally sign the ICF. Further, the SA-GCPs states that the participant should indicate willingness to participate by making a mark (either a cross or a fingerprint). The witness signs to affirm that the participant willingly consented to participate. The witness dates the mark and signature.

Waiver of Consent

No information is currently available regarding conditions for waiving consent.

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, the Pre2018-ComRule states 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
• 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
• The waiver or alteration will not adversely affect the rights and welfare of the participants
• Whenever appropriate, the participant will be provided with additional pertinent information after participation

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 informed consent essential elements in the SA-GCPs, the G-EthicsHR-ZAF, the G-GPHlthCare, and the NHAParticipants, the informed consent form (ICF) should 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 involves research and an explanation of its nature and purpose
• The procedures to be followed
• Why the potential participant has been approached and their responsibilities
• The aspects of the clinical trial that are experimental
• Any foreseeable risks or discomforts to the participant, and when applicable, to an embryo, fetus, or nursing infant; information should include the probability and magnitude of the foreseeable risks of harm
• Any benefits to the participant or to others that may reasonably be expected from the research; if no benefit is expected, the participant should also be made aware of this
• A disclosure of appropriate alternative procedures or treatments, and their potential benefits and risks
• The probability for random assignment to each treatment
• Participation is voluntary, the participant may withdraw at any time, and refusal to participate will not involve any penalty or loss of benefits, or reduction in the level of care to which the participant is otherwise entitled
• Compensation and/or medical treatment available to the participant in the event of a trial-related injury
• The planned incentives, if any, to attract the participant and the planned reimbursements, if any, for time, inconvenience, and expenses
• The extent to which confidentiality of records identifying the participant will be maintained, the possibility of record access by the sponsor, the ethics committee (EC), or the South African Health Products Regulatory Authority (SAHPRA)
• EC contact details for information and concerns regarding the trial participants’ rights
• The sponsor’s identity
• Potential conflicts of interest of the principal investigator (PI)
• The consequences of a participant's decision to withdraw from the study
• Information about approval from the EC and SAHPRA
• The approximate number of participants in the research study, locally and globally
• The expected duration of participation
• An explanation of whom to contact in the event of research-related injury
• Foreseeable circumstances under which the investigator(s) may remove the participant without consent
• The participant and/or the legal representative(s) or guardian(s) will be notified if significant new findings developed during the study which may affect the participant's willingness to continue

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

South Africa’s ethical standards promote respect for all human beings and safeguard the rights of research study participants. In accordance with the principles held forth in the Declaration of Helsinki (ZAF-44), the SA-GCPs, the G-EthicsHR-ZAF, the G-GPHlthCare, the G-GPHlthCare-IC, the NHAParticipants, and the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (ZAF-27), a participant’s rights must be clearly addressed in the informed consent form (ICF) and during the informed consent process. Below are the basic rights for participants in clinical research studies. (See the Required Elements and Vulnerable Populations sections for additional information regarding requirements for participant rights.)

The Right to Participate, Abstain, or Withdraw

According to the NHA and the NHAParticipants, everyone has the right to participate in any decision affecting their health or treatment, including research. The participant and/or the legal representative(s) or guardian(s) should be informed that participation is voluntary, that the participant may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.

The Right to Information

According to the G-GPHlthCare-IC, a potential research study participant has the right to be fully informed on the nature and purpose of the research study, its anticipated duration, the sponsor and investigator(s), any potential benefits or risks, study procedures, any compensation for participation, injury and/or treatment, and any significant new information regarding the research study. (See the Required Elements section for a more detailed list.)

Per POAIA, a participant may seek access to their clinical trial records, pursuant to their constitutional right of access to any information held by the State or by another person.

The Right to Privacy and Confidentiality

Per the G-GPHlthCare-IC, participants have the right to privacy and confidentiality, and the ICF must provide a statement identifying this right. It is the responsibility of the investigator to safeguard the confidentiality of research data to protect the identity and records of research participants.

The Right of Inquiry/Appeal

Per the G-GPHlthCare-IC, the research participant and/or the legal representative(s) or guardian(s) should be provided with contact information for the investigator(s), and the ethics committee to address clinical trial-related queries, in the event of any injury and/or to appeal against a violation of the participant’s rights. It is also required that the South African Health Products Regulatory Authority (SAHPRA) address and contact information be provided. (See the Required Elements section for more detailed information regarding participant rights.)

The Right to Safety and Welfare

The SA-GCPs and ZAF-44 clearly state that research participants have the right to safety and well-being, which must take precedence over the interest of science and society. The NHA and the NHAParticipants safeguard the rights of all South Africans including vulnerable populations.

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.

The NHA and the G-EthicsHR-ZAF make provisions to protect the rights of a research participant during the informed consent process when the procedure is complicated by medical emergencies. As per the G-EthicsHR-ZAF, the ethics committee (EC) may approve a delay in obtaining informed consent for emergency medical research if:

• Inclusion in the trial is not contrary to the interests of the patient

• The research poses no more risk than is inherent to the participant’s condition, or would be caused by alternative treatments

• The participant, the participant’s next of kin, and/or legal representative(s) or guardian(s) will be informed as soon as is reasonably possible of the participant’s inclusion in the study, and have the option to withdraw from the study at any time

• The research is based on valid scientific hypotheses, and offers a realistic possibility of benefit over standard care

Per the G-CTAPHEmerg, the South African Health Products Regulatory Authority (SAHPRA) states that during a public health emergency, informed consent and the patient information sheet(s) remain essential documents that must be reviewed and approved by an EC and provided to the SAHPRA with the clinical trial application.

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

The NHA, the SA-GCPs, the G-EthicsHR-ZAF, the G-GPHlthCare, and the NHAParticipants require special considerations for vulnerable populations, and characterize them by limited education, limited economic resources, inadequate protection of human rights, discrimination due to health status, limited ability to provide informed consent, limited availability of health care and treatment options, or an inadequate understanding of scientific research. Vulnerable populations include children/minors, mentally and physically disabled, pregnant women, substance abusers, prisoners, armed forces, the homeless, the elderly, members of a group with a hierarchical structure, patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, nomads, refugees, and other vulnerable groups such as persons in dependent relationships.

The SA-GCPs state that ethics committees (ECs) must pay special attention to protecting participants from vulnerable populations. The ECs may impose additional measures such as imposing additional protective measures for the informed consent process or requiring increased monitoring and interim reporting on the participants’ welfare. As per the NHAParticipants, research with vulnerable participants must comply with the following requirements:

• Involve vulnerable persons only when non-vulnerable persons are not appropriate for inclusion

• Not systematically avoid inclusion of vulnerable participants because it is unfairly discriminatory, and would prevent this population from benefiting from relevant research

• Be responsive to health needs and priorities of vulnerable persons, and

• Provide special attention in the ethical review to ensure research-related risks are assessed and minimized, and appropriate consent procedures are followed

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

Persons in Dependent Relationships or Hierarchical Situations

As indicated in the SA-GCPs and the G-EthicsHR-ZAF, participants whose proposed involvement in research arises from dependent or hierarchical relationships need additional attention, and particular attention should be given to ensuring that their consent is both adequately informed and voluntary. In addition, per the NHAParticipants, research is appropriate when research-related risks of harm are minimized. These types of relationships include, but are not limited to, those who are in junior or subordinate positions in hierarchically structured groups, such as prisoners and prison authorities, older persons and their caregivers, and patients and healthcare professionals.

Persons Highly Dependent on Medical Care

Per G-EthicsHR-ZAF, participants who are highly dependent on medical care may have a limited capacity to provide informed consent due to the gravity of their medical condition. In addition, their medical condition may require invasive measures resulting in greater risk. There may also be a perception of coercion if a participant is reluctant to refuse consent for fear that it may compromise the medical treatment. The EC may approve a delay in obtaining informed consent for research participants highly dependent on medical care if the following conditions are met:

• Research is based on valid scientific hypotheses that support a reasonable possibility of more benefit than that offered by standard care
• Participation is not contrary to their medical interests
• Research interventions pose no more risk of harm than that inherent in the participant’s condition or alternative methods of treatment
• As soon as reasonably possible, the participant must be informed and give delayed consent and advised of the right to withdraw from the research without any reduction in quality of care

Persons with Physical Disabilities

As described in the G-EthicsHR-ZAF, recruitment strategies for research participation in general should be sensitive to the possibility that persons with physical disabilities may wish to volunteer and therefore should ensure that there are no unintended barriers to such participation (e.g., the absence of ramps or a lift for wheelchair-bound potential participants). Research involving participants with physical disabilities should anticipate possible barriers and include measures to minimize them.

Elderly Persons

As per the G-GPHlthCare, research involving elderly persons requires consent to be provided by the participant’s legal representative(s) or guardian(s) on that person's behalf. Because of their vulnerability, the elderly should not be included in research unless the research is necessary to promote the health of this population and unless this research cannot instead be performed on legally competent persons.

Research Involving Collectivities

Per the G-EthicsHR-ZAF, a collectivity is a distinct group characterized by common beliefs, values, social structures, and other features identifying them as a separate group. Investigators are required to obtain EC approval for research involving a collectivity when any of the following conditions apply:

• Property or information private to the group as a whole is studied or used

• Research requires the permission of people occupying positions of authority, or involves members acknowledged as representatives to participate

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 SA-GCPs stipulate that minors are younger than 18 years old and are regarded as vulnerable persons due to their lack of legal capacity. The G-GPHlthCare-IC states that a person over the age of 18 years is an adult and is legally competent to decide on all forms of treatment and medical procedures. However, a child who is 12 years of age and older is legally competent to consent to a proposed investigation if the child is of sufficient maturity and is able to understand the benefits, risks, social, and other implications of the research. A minor's/child’s refusal to participate in research must be respected.

Per the SA-GCPs, documented permission from the legal representative(s) or guardian(s) must be obtained in advance prior to approaching the minor to request participation. According to the NHA, the G-EthicsHR-ZAF, the SA-GCPs, the G-GPHlthCare, and the G-GPHlthCare-IC, consent for minors/children to participate in research must be obtained from:

• The legal representative(s) or guardian(s) in all but exceptional circumstances (such as emergencies)

• The minor/child who is competent to make the decision

• Any organization or person required by law (defined in the NHA)

• Where the minor/child is not competent, assent from the minor/child and consent from the legal representative(s) and/or guardian(s)

According to the NHA, where research or experimentation is to be conducted on a minor for therapeutic purposes, the study may only be conducted when:

• It is in the best interests of the minor/child

• It is carried out in such manner and on such conditions as may be prescribed

• The consent of the minor’s parent or guardian is provided

Where research or experimentation is to be conducted on a minor for non-therapeutic purposes, the NHA, the NHAParticipants, the SA-GCPs, and the G-MinisterConsent state that a study may only be conducted when:

• It is carried out in such manner and on such conditions as may be prescribed

• The consent of the Minister of Health is provided, or, where appropriate, consent from a delegated authority

• The consent of the minor’s parent or guardian is provided

• The consent of the minor is provided when the minor is capable of understanding

See the NHAParticipants for detailed application requirements.

In addition, per the G-MinisterConsent, the Minister of Health may not give consent if any of the following circumstances apply:

• The study objective(s) can also be achieved if conducted on an adult

• The research is unlikely to significantly improve scientific understanding of the minor’s/child's condition, disease, or disorder to such an extent that it will result in significant benefit to the minor(s)/child(ren)

• The reasons for the consent to the research by the parent or guardian and, if applicable, the minor/child, are contrary to public policy

• The research poses a significant risk to the health of the minor

• The risk to the health or well-being of the minor is not significantly outweighed by the potential benefit

For more information on ministerial consent for non-therapeutic health research with minors, see the operational guidelines at the G-MinisterConsent.

As delineated in the G-EthicsHR-ZAF and the NHAParticipants, the following additional criteria must be met to conduct clinical trials with minors/children:

• The research study presents minimal risk

• The research study presents more than minimal risk, but potentially direct or anticipated benefit for the participant outweighs the risk

• The research presents more than minimal risk (minor increase), and may not have a direct benefit to the participant, but has a high probability of producing important and relevant information, and that benefit may outweigh the risk

• Adults are not appropriate participants for the research

In all cases, there should be sufficient reasons to justify why minors/children should be included as participants.

Assent Requirements

The SA-GCPs and the G-EthicsHR-ZAF require the ethics committee (EC) to ensure that adequate steps outlined in the clinical protocol are used to obtain a minor’s assent when, in the EC’s judgment, the minor is capable of providing such assent. When the EC determines that assent is required, it must also indicate whether and how such assent should be documented. A minor’s/child’s assent should not be assumed simply because of failure to object during the informed consent process. It is necessary for the minor/child and the legal representative(s) or guardian(s) to be in agreement on participation. The minor’s/child’s refusal to participate is final.

Consent for Processing Personal Data

Per the POPIA, there is a general prohibition on the processing of personal information of children. However, a responsible party may process personal information concerning a child for research purposes to the extent that:

• The purpose serves a public interest, and the processing is necessary for the purpose; or
• It appears to be impossible or would involve a disproportionate effort to ask for consent, and sufficient guarantees are provided to ensure that the processing does not adversely affect the individual privacy of the child to a disproportionate extent.

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.

As per the NHA and the G-EthicsHR-ZAF, any research studies involving pregnant women, women who may become pregnant, or fetuses, require additional safeguards to ensure the research conforms to appropriate ethical standards and upholds societal values. The ethics committee (EC) must provide particular attention to these participants due to the potential for additional health concerns that may arise during pregnancy, and the need to avoid unnecessary risk to the fetus.

The SA-GCPs stipulates that pregnant women, women planning to become pregnant, or breastfeeding women are usually excluded from human clinical trials where a new chemical entity (NCE) or medicines with no information on safety in pregnancy/lactation are investigated for treatment of a particular disease/condition or disorder. However, when safety and other relevant information is available, pregnant or breastfeeding women should be included in clinical trials to ensure that appropriate knowledge about NCEs for this group is developed.

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 NHA, the G-EthicsHR-ZAF, and the NHAParticipants, a prisoner may not, even with consent, participate in any scientific experimentation, research study, or clinical trial except under limited conditions. Per the G-EthicsHR-ZAF, prisoners are considered a vulnerable class of persons because of the potential effect of incarceration on the voluntariness of the decision to participate in research. Neither coercion nor undue influence is acceptable in the informed consent process. Researchers should pay attention to whether their intended participants are prisoners who are awaiting trial or are convicted as different ethical issues arise for each group. The recruitment strategy design must pay careful attention to how coercion and undue influence will be avoided. Similarly, persons administering questionnaires or conducting interviews must be conscious of environmental factors that may influence voluntariness. The ethics committee (EC) should include, at least on an ad-hoc basis, a member with experience and knowledge of working with prisoners when deliberating on the protocol.

Per the G-EthicsHR-ZAF, research should be conducted on prisoners only if:

• Their participation is indispensable to the research
• The research cannot be conducted with non-prisoners
• The research concerns a problem of relevance to prisoners
• Sound informed consent processes can be ensured
• Engagement with relevant role players about the proposed research has occurred

Generally, it is unlikely that independent consent by minor prisoners will be justifiable.

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.

According to the NHA, the SA-GCPs, the G-EthicsHR-ZAF, the G-GPHlthCare, and the NHAParticipants, sufficient justification must be provided for any research or treatment involving a participant who has a mental or intellectual impairment or substance abuse related disorder, and the research must be relevant to the mental disability or substance abuse disorder.

Per the G-EthicsHR-ZAF, research involving these populations must conform to the following requirements:

• The research, including observational research, is not contrary to the best interest of the participant
• The research, including observational research, places the incapacitated adult at no more than minimal risk
• The research involves greater than minimal risk but provides the prospect of direct benefit for the incapacitated adult; the degree of risk must be justified by the potential benefit
• The research, including observational research, involves greater than minimal risk, with no prospect of direct benefit to the incapacitated adult, but has a high probability of providing generalizable knowledge
• The legally appropriate person gives permission for the person to participate
• Where appropriate, the person will assent to participation (Note that the incapacitated person’s refusal or resistance to participate, as indicated by words or behavior, takes precedence over permission by a proxy)

The G-EthicsHR-ZAF and the G-GPHlthCare state that research involving unconscious persons requires consent to be provided by the participant’s legal representative(s) or guardian(s) on that person's behalf. Unconscious persons should not be included in research unless the research is necessary to promote the health of the population represented and unless this research cannot instead be performed on legally competent persons.

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 SA-GCPs and the PIC-S-GMP-Guide (which South Africa adopted pursuant to the SA-GMPs), an investigational product is defined as a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial. This includes:

• A product with a marketing authorization when 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 SA-GMPs and the GRMRSA, the South African Health Products Regulatory Authority (SAHPRA) is responsible for authorizing the manufacture of investigational products (IPs) in South Africa. As delineated in the G-ManuImpExp, a manufacturer’s license for IPs is required for both total and partial manufacture, and for the various processes of dividing up, packaging, or presentation, in accordance with the MRSA. To obtain a license, the application form (ZAF-55) should be emailed to SAHPRA at gmplicensing@sahpra.org.za, accompanied by the following information:

• Proof of payment
• Existing SAHPRA license for renewal and amendment applications
• Cover letter
• Site Master File
• Signed declaration
• SAHPRA inspection resolution
• Intellectual property documentation
• Department of Health premises license
• Registration of responsible pharmacist
• South African Pharmacy Council (SAPC) Record of a Pharmacy
• SAPC Record of a Pharmacy Owner
• Municipal Approval/Zoning Certificate

Per ZAF-55, the license is valid for five (5) years and the application to renew the license must be submitted at least 180 days before the expiration of the current license.

In addition, per ZAF-23, a clinical trial application to SAHPRA must include a certificate of good manufacturing practice (GMP) for manufacture of the IP(s). The SA-GCPs also states that the sponsor must ensure that the IP (including active comparator and placebo, if applicable) is manufactured in accordance with applicable GMP standards.

Pursuant to the SA-GMPs, South Africa adopted the PIC-S-GMP-Guide for the manufacturing of therapeutic goods. The PIC-S-GMP-Guide includes requirements for a Certificate of Analysis to be issued by the manufacturer for all IPs to be used in a clinical trial. For GMP agreements with competent international regulatory authorities, the SA-GMPs states that these agreements do not permit automatic acceptance but may be used to enhance regulatory oversight and compliance. SAHPRA may request additional documentation and/or schedule an inspection to ensure GMP compliance. The following conditions demonstrate GMP compliance:

• The site has been approved by a recognized regulatory authority (RA) within the previous three (3) years
• The dosage form of the IP within the application is within the same dosage form grouping as the dosage form approved by the RA
• The product type applied for is the same as the product type approved by the recognized RA
• The activities applied for by the applicant are the same activities that have been approved by the recognized regulator

Import

The SA-GCPs states that IPs may be imported into South Africa only after approval of the protocol by SAHPRA. Samples of the IP to be imported before trial approval require a SAHPRA license under MRSA. The sponsor must ensure that the IP (including active comparator and placebo, if applicable) is manufactured in accordance with any applicable GMP standards. Per G-ManuImpExp to import an IP, the applicant must submit an application form (ZAF-55) to SAHPRA.

Per the G-ImprtPorts, SAHPRA’s Regulatory Compliance Unit is responsible for ensuring that health products at ports of entry meet importation requirements under MRSA, including for IPs. Imported IPs must be accompanied by the certificate of registration that proves authorization under the MRSA.

Please note: South Africa is party to the Nagoya Protocol on Access and Benefit-sharing (ZAF-8), which may have implications for studies of IPs developed using certain non-human genetic resources (e.g., plants, animals, and microbes). For more information, see ZAF-34.

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:

• Thirty (30) days after the FDA receives the IND, or
• FDA provides earlier authorization to ship the IP

The sponsor is responsible for complying with the principles of good manufacturing practice (GMP) as specified in 21CFR210, the G-CGMP-Phase1, and the G-INDPrep. The US-ICH-GCPs also states that the sponsor must ensure that the products are manufactured in accordance with GMPs.

Import

As set forth in 21CFR312, the FDA is also responsible for authorizing the import and export of IPs. An IP may be imported into the US if it is subject to an IND that is in effect for it and complies with one (1) of the following requirements:

• The IP consignee is the IND sponsor, or
• The consignee is a qualified investigator named in the IND, or
• The consignee is the domestic agent of a foreign sponsor, is responsible for the control and distribution of the IP, and the IND identifies the consignee and describes what, if any, actions the consignee will take with respect to the IP

Investigator’s Brochure

In accordance with the SA-GCPs, the sponsor is responsible for ensuring an up-to-date Investigator’s Brochure (IB) is available to the investigator; investigators must provide it to the responsible ethics committee (EC). In the case of an investigator-sponsored trial, the sponsor-investigator must determine whether an IB is available from the commercial manufacturer.

The SA-GCPs states that the IB should contain the following sections, each with literature references where appropriate:

• Table of Contents
• Summary: A brief summary (preferably not exceeding two (2) pages) to highlight the significant physical, chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic, and clinical information available that is relevant to the stage of clinical development of the investigational product (IP)
• A brief introductory statement with the chemical name (and generic and trade name for an approved product) of the IP, all active ingredients in the IP, its pharmacological class and expected position within this class (e.g., advantages), the rationale for conducting research with the IP, and the anticipated prophylactic, therapeutic, and/or diagnostic indications. Also include a description of the general approach to be followed in evaluating the IP.
• Physical, chemical, and pharmaceutical properties and formulation parameters
• Pre-clinical studies (pharmacology, pharmacokinetics, toxicology, and metabolism profiles)
• Effects of IP in humans (pharmacology, pharmacokinetics, metabolism, and pharmacodynamics; safety and efficacy; regulatory and postmarketing experiences)
• Summary of data and guidance for the investigator(s)

Quality Management

As defined in the SA-GCPs, the sponsor must ensure that IPs are manufactured in accordance with good manufacturing practices (GMPs), including the requirements in Annex 13 of the PIC-S-GMP-Guide (which South Africa adopted pursuant to the SA-GMPs). (See Product Management section for additional information on IP supply, storage, and handling requirements). As indicated in ZAF-23, the following information must be furnished in the clinical trial application:

• Whether the IP contains an active substance of chemical origin or of biological/biotechnological origin
• IP name(s) and details (e.g., formulation(s) and strength(s))
• Properties of the IP (e.g., mechanism of action)
• Summary of pre-clinical findings (e.g., laboratory, animal, toxicity, or mutagenicity)
• Summary of clinical findings
• Comparator product(s) name(s) and details
• Concomitant name(s) and details including rescue medications
• Registration status of IP, concomitant, and/or comparator medicine(s); include the IB, South African Health Products Regulatory Authority (SAHPRA)-approved principal investigator (PI), and other international professional information (package inserts) if not approved in South Africa, and a Certificate of Analysis (CoA)
• Whether the IP is modified in relation to its original registration for the purpose of the clinical trial
• Estimated quantity of trial material (each drug detailed separately) for which exemption will be required, including for concomitant medicines to be imported
• Explanation for use of imported drugs when the same product is available in South Africa
• Details of receiving the drugs from supplier including storage, dispensing, and packaging of drugs
• Details of intention to register the IP or explain if registration is not envisioned
• Details of the manufacture, quality control, and stability of the IP (including IP destruction process) and include certificate of good manufacturing practice (GMP)
• Previous studies using this medicine that have been approved by SAHPRA, including the SAHPRA approval number, study title, protocol number, date of approval, national PI/PI, date(s) of progress report(s), and date of final report

See ZAF-23 for detailed instructions on IP submission requirements.

Per the PIC-S-GMP-Guide (which South Africa adopted pursuant to the SA-GMPs), the release of IPs should not occur until after the authorized person has certified that the relevant requirements have been met. CoAs should be issued for each batch of intermediate or active pharmaceutical ingredient, on request. CoAs should be dated and signed by authorized personnel of the quality unit(s) and should show the name, address, and telephone number of the original manufacturer. See the PIC-S-GMP-Guide for certification requirements.

Investigator's Brochure

In accordance with 21CFR312 and the US-ICH-GCPs, the sponsor is responsible for providing investigators with an Investigator’s Brochure (IB). The IB must contain all of the relevant information on the investigational new drug(s)/investigational product(s) (IPs) obtained through the earlier research phases. The sponsor must also update the IB as significant new information becomes available.

As specified in 21CFR312 and the US-ICH-GCPs, the IB must provide coverage of the following areas (Note: The regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

• A brief description of the drug substance and the formulation, including the structural formula, if known
• A summary of the pharmacological and toxicological effects of the drug in animals and, to the extent known, in humans
• A summary of the pharmacokinetics and biological disposition of the drug in animals and, if known, in humans
• A summary of information relating to safety and effectiveness in humans obtained from prior clinical studies
• A description of possible risks and side effects to be anticipated on the basis of prior experience with the drug under investigation or with related drugs, and of precautions or special monitoring to be done as part of the investigational use of the drug
• Summary of data and guidance for the investigator

See 21CFR312 and the US-ICH-GCPs for detailed IB content guidelines.

For investigational new drug applications (INDs) that include clinical data provided from studies conducted outside of the United States (US), 21CFR312 states that the sponsor or applicant must submit a description of the actions taken to ensure that the research conformed to good clinical practices (GCPs). See Section 312.120 of 21CFR312 for detailed requirements.

Quality Management

According to USA-39, submitting a copy of the Certificate of Analysis (CoA) of the clinical batch is suggested, but not required by the Food & Drug Administration (FDA).

The US-ICH-GCPs state that the sponsor must maintain a CoA to document the identity, purity, and strength of the IP(s) to be used in the clinical trial.

Investigational product (IP) labeling in South Africa must comply with the requirements set forth in the SA-GCPs, the GRMRSA, MRSA, and the PIC-S-GMP-Guide (which South Africa adopted pursuant to the SA-GMPs). The GRMRSA states that for an IP to be used in a clinical trial, it must be properly labeled in English and at least one (1) other official language, and should appear in clearly legible and indelible letters. As set forth in the PIC-S-GMP-Guide, the following labeling information must be included on both the outer packaging and the immediate container:

• The name, address, and telephone number of the sponsor, contract research organization (CRO), or investigator

• The pharmaceutical dosage form, route of administration, quantity of dosage units, and in the case of open trials, the name/identifier and strength/potency

• The batch and/or code number to identify the contents and packaging operation

• A trial reference code allowing identification of the trial, site, investigator, and sponsor (if not given elsewhere)

• The trial participant identification number/treatment number and where relevant, the visit number

• The investigator name (if not already included above)

• Directions for use (reference may be made to a leaflet or other explanatory document intended for the trial participant or person administering the product)

• “For clinical trial use only” or similar wording

• The storage conditions

• The period of use (use-by date, expiration date, or re-test date as applicable), in month/year format and in a manner that avoids any ambiguity

• “Keep out of reach of children” except when the product is for use in trials where the product is not taken home by the participant

In addition, precautions against mislabeling should be intensified by trained staff (e.g., label reconciliation, line clearance, and in-process control checks by appropriately trained staff).

The SA-GCPs specify that in blinded trials, the IP should be coded and labeled in a manner that protects the blinding. The IP(s) coding system should include a mechanism that permits rapid IP(s) identification in case of a medical emergency but does not permit undetectable breaks of the blinding.

Investigational new drug/investigational product (IP) labeling in the United States (US) must comply with the requirements set forth in Section 312.6 of 21CFR312, which include the following:

• The immediate package of an IP intended for human use must bear a label with the following statement: “Caution: New Drug-Limited by Federal (or US) law to investigational use”
• The label or labeling of an IP must not bear any false or misleading statements and must not represent that the IP is safe or effective for the purposes for which it is being investigated

The appropriate Food & Drug Administration (FDA) Center Director may grant an exception or alternative to the requirements above for specific lots, batches, or other units of a human drug or biological product that is or will be included in the Strategic National Stockpile.

In addition, the US-ICH-GCPs states that the IP must be coded and labeled in a manner that protects the blinding, if applicable.

Supply, Storage, and Handling Requirements

As defined in the SA-GCPs, the sponsor is responsible for supplying a sufficient quantity of the investigational product (IP) after the sponsor obtains study approvals from the South African Health Products Regulatory Authority (SAHPRA) and the ethics committee (EC). The sponsor must ensure that written procedures include instructions and relevant documents for the investigator to follow for handling and storage of the IP for the trial. The procedures must address adequate and safe receipt, handling, storage, dispensing, retrieval of unused product from participants, and return of unused IP to the sponsor (or alternative disposition if authorized by the sponsor and in compliance with the SAHPRA-approved protocol). In addition, the sponsor must:

• Ensure timely delivery of the IP to the investigator
• Maintain records that document shipment, receipt, disposition, return, and destruction of the IP
• Maintain a system for retrieving the IP and then documenting such retrieval (e.g., for deficient product recall, reclaim after trial completion, and expired product reclaim)
• Maintain a system for disposal of unused IP and for its documentation
• Take steps to ensure that the IP is stable over the period of use
• Maintain sufficient quantities of the IP used in the trials to reconfirm specifications, if necessary, and maintain records of batch sample analyses and characteristics; to the extent that IP stability permits, samples should be retained until analyses of trial data are complete or as required by the applicable regulatory requirement(s), whichever is longer
• Provide and maintain a system for retrieving and disposing of trial-related waste (e.g., syringes and needles)

Per the SA-GCPs, the sponsor should determine acceptable temperatures, conditions, times for IP storage, reconstitution fluids/procedures, and devices for product infusion, if any, that comply with the SA-GPPs. The sponsor must inform all parties involved (e.g., monitors, investigators, pharmacists, storage managers) of these determinations.

The SA-GCPs specify that if significant formulation changes are made in the IP(s) or comparator product(s) during the course of clinical development, the results of any studies of the newly formulated product(s) should be made available prior to its use in the clinical trial. Refer to the SA-GCPs for detailed sponsor-related IP requirements.

Regarding packaging, the PIC-S-GMP-Guide indicates that IPs are normally packed individually for each participant in the clinical trial. The number of units to be packaged should be specified prior to the start of the packaging operations, including units necessary for carrying out quality control and any retention samples to be kept. Sufficient reconciliations should take place to ensure the correct quantity of each product required has been accounted for at each stage of processing. During packaging, the risk of product mix up must be minimized by using appropriate procedures and/or, specialized equipment as appropriate and relevant staff training. The packaging must ensure that the IP remains in good condition during transport and storage at intermediate destinations. Any opening or tampering of the outer packaging during transport should be readily discernible. Similarly, the SA-GCPs state that the IPs must be suitably packaged in a manner that will prevent contamination and unacceptable deterioration during transport and storage.

Record Requirements

Per the SA-GCPs, the sponsor, or other data owners, must retain all essential documents pertaining to the trial for not less than 10 years or until at least two (2) years have elapsed since the formal discontinuation of clinical development of the IP. In addition, the sponsor should obtain the investigator’s agreement to retain trial-related essential documents until the sponsor informs the investigator/institution that these documents are no longer needed.

Supply, Storage, and Handling Requirements

As defined in the US-ICH-GCPs, the sponsor must supply the investigator(s)/institution(s) with the investigational new drug(s)/investigational product(s) (IP(s)), including the comparator(s) and placebo, if applicable. The IPs must also be suitably packaged in a manner that will prevent contamination and unacceptable deterioration during transport and storage.

Per 21CFR312, the US-ICH-GCPs, the G-CGMP-Phase1, and the G-INDPrep, the sponsor must ensure the following (Note: The regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

• IP product quality and stability over the period of use
• IP manufactured according to any applicable good manufacturing practices (GMPs)
• Proper coding, packaging, and labeling of the IP(s)
• Acceptable storage temperatures, conditions, and times for the IP
• Timely delivery of the IP(s)

Refer to the US-ICH-GCPs, the G-CGMP-Phase1, and the G-INDPrep for detailed sponsor-related IP requirements.

Record Requirements

According to 21CFR312, the sponsor must maintain adequate records showing the receipt, shipment, or other disposition of the IP. These records are required to include, as appropriate, the name of the investigator to whom the drug is shipped, and the date, quantity, and batch or code mark of each such shipment. The sponsor is also required to maintain records showing financial interest paid to investigators. See 21CFR312 for more details.

As per 21CFR312 and the US-ICH-GCPs, the sponsor and the investigator(s) must retain the clinical investigation records and reports for two (2) years after a marketing application (known as a New Drug Application (NDA)) is approved for the IP; or, if an NDA is not approved, until two (2) years after shipment and delivery of the IP is discontinued for investigational use and the Food & Drug Administration (FDA) has been so notified.

In South Africa, the NHARegMicroLabs refers to a specimen as a “diagnostic specimen,” and defines it as any human or animal material, including excreta, secreta, blood and its components, tissue or tissue fluids, that is to be used for the purpose of diagnosis, but does not include live infected animals. The G-EthicsHR-ZAF, in turn, refers to a specimen as a “biological specimen,” and defines it as material from a person including blood and blood products, DNA, RNA, blastomeres, polar bodies, cultured cells, embryos, gametes, progenitor stem cells, small tissue biopsies, and growth factors.

The term “specimen” appears to be used interchangeably with “biological material” in South Africa. The NHABiol and the MTA-Human follow the G-EthicsHR-ZAF definition of biological specimen, defining “biological material” as material from a human being including DNA, RNA, blastomeres, polar bodies, cultured cells, embryos, gametes, progenitor stem cells, small tissue biopsies, and growth factors from the same. The G-EthicsHR-ZAF defines “human biological materials” with the same definition as is used for “biological specimen.”

In addition, the NHABloodCells generally refers to substances of human origin as biological substances.

Please refer to the G-EthicsHR-ZAF, the NHABiol, the NHA, the NHABloodCells, the NHATissue, and the NHAStemCell for more specific definitions of selected terms including blood, cultured cells, embryonic tissue, human tissue, plasma, stem cell, and genetic material.

A specimen, referred to as patient specimen in 49CFR173, is defined as human or animal material collected directly from humans or animals and transported for research, diagnosis, investigational activities, or disease treatment or prevention. Patient specimen includes excreta, secreta, blood and its components, tissue and tissue swabs, body parts, and specimens in transport media (e.g., transwabs, culture media, and blood culture bottles).

In addition, 42CFR73 defines specimen as samples of material from humans, animals, plants, or the environment or isolates or cultures from such samples for diagnosis, verification, or proficiency testing.

The RevComRule defines an identifiable biospecimen as one for which the identity of the participant is or may readily be ascertained by the investigator or associated with the biospecimen. (See 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.)

Import/Export

Per the NHA, the MTA-Human, the NHABloodCells, the NHARegMicroLabs, the NHATissue, and the NHAStemCell, a permit must also be obtained from the National Department of Health (NDOH) Director General to import or export biological substances. Both the South African Health Products Regulatory Authority (SAHPRA) approval letter and the NDOH import/export permit must be included with each biological substance shipment. See also the Submission Content section for information on completing a clinical trial application.

As set forth in the NHA, the NHABloodCells, the NHARegMicroLabs, the NHATissue, and the NHAStemCell, the NDOH Director-General, as delegated by the NDOH Minister, is responsible for establishing regulations related to the import and export of biological substances. In addition, only the Minister can authorize an institution or hospital to import or export biological substances for research purposes.

In accordance with the NHA, the NHABloodCells, the NHARegMicroLabs, the NHATissue, and the NHAStemCell, the NDOH Director-General reviews and approves all import or export requests by an institution or hospital. These requests must be submitted in writing using the application forms that may be obtained by contacting the NDOH Permit Programme at importexportpermit@health.gov.za. The forms also appear as Annexures 1-6 in the NHABloodCells and Form 1 in the NHARegMicroLabs.

Upon review of the application, the Director-General will issue a permit or certificate authorizing the import or export request if the Director-General is satisfied that the submission meets the NHA, the NHABloodCells, the NHARegMicroLabs, the NHATissue, and the NHAStemCell requirements, as applicable. The permit will contain an expiration date for the approved biological substance(s).

General Import/Export Requirements for Biological Substances

The NHABloodCells states that each biological substance to be imported into South Africa must be accompanied by a certificate from the supplier stating that the substance has been exported in terms of the originating country’s applicable laws and regulations.

As per the NHABloodCells and ZAF-7, export permits for biological substances may only be issued by the Director-General to a Southern African Development Community (SADC) member state or to a South African citizen, provided that the country’s market requirements have been met. An applicant must also be registered with the Health Professions Council of South Africa (HPCSA) and operating in South Africa in order to apply for a permit to import or export biological substances. The applicant must also provide the Director-General with written information on stock levels for this substance along with the export application.

Applicants to whom a permit has been issued must keep a record of the import or export and submit this information using the register forms listed in Annexures 4, 5, and 6 of the NHABloodCells. The forms must be submitted to the Director-General annually before the end of February, for the preceding calendar year.

Import/Export Requirements for Specific Biological Substance Categories

The NHABloodCells provides details on unique application requirements for specific types of biological substances as outlined below:

• Import of tissues being used for therapeutic purposes: application must be accompanied by donor health status
• Export of tissues or gametes: application must include written proof that the donated biological substance complies with the NHA requirements
• Import or export of placenta tissue, embryonic or fetal tissue, embryonic, fetal or umbilical stem cells: applications will only be approved with the Minister’s written consent
• Import or export of blood or blood products: applications must be accompanied by a national blood transfusion service certificate and test results. If no documentation is included, the applicant must submit a letter to the Director-General explaining the reason. The Director-General will decide whether tests must be conducted, and the Minister is authorized to determine whether the applicant’s institution can be exempted from these requirements.

Material Transfer Agreement

Per the MTA-Human, all the providers and recipients of human biological material for use in research or clinical trials under the auspices of ethics committees (ECs) must use the “Material Transfer Agreement of Human Biological Materials” in MTA-Human. The agreement must be signed by the research institution’s authorized representative and the EC. The EC’s obligations are to:

• Review and approve research proposals and protocols that require the transfer of human biological materials
• Review and approve the material transfer agreement and ensure it adequately safeguards human biological material and ethical requirements
• Review and approve all secondary use research if the material is to be transferred

The EC must be the last party to sign the agreement after all the provisions of MTA-Human have been satisfied.

Per USA-2, the NIH also requires researchers to use an agreement (e.g., Material Transfer Agreement (MTA) or contract) to transfer materials among academic, nonprofit, and/or industrial organizations. See USA-2 for detailed MTA requirements and Appendix 4 for a sample MTA.

In accordance with the NHA, the NHASpecAmend, the NHABiol, and the MTA-Human, prior to removing or withdrawing any biological material from the body of a living person for research purposes, consent must be obtained from that person in writing, before a competent witness. In the event that the person is a minor, the parents or guardians of that person must provide consent. Furthermore, when withdrawing blood, the NHASpecAmend requires written consent from persons older than 16 years. Per the MTA-Human, the sponsor must obtain the completed informed consent form (ICF) from the donors of human biological materials and data, and submit it with the project protocol to the ethics committee (EC) for approval. Further, the sponsor must submit the ICF for secondary uses of the material to the EC should the need arise. Secondary use is defined as the use of the materials for health research purposes other than the uses determined in the approved protocol.

The NHABiol specifically states that when taking biological samples from a child, where the person is younger than 18 years, Part 3, Section 129 of the ChildrensAct must be followed.

Additionally, the NHABiol requires the following consent for the removal or withdrawal of biological samples to treat a person with mental illness:

• The mentally ill person’s consent, if capable;
• A court appointed curator, spouse, next of kin, parent or guardian, major child, brother, or sister, partner or associate, if the mentally ill person is incapable of giving consent; and
• The head of the health institution in the case of an emergency

Similarly, the NHA and the NHABiol include consent provisions for the donation of human bodies and the tissue of deceased persons. These documents state that any person who is competent to make a will may donate their body or any specified tissue to be used after death for medical and dental purposes, as long as the person signs the will in the presence of at least two (2) competent witnesses. The person may also give consent to a post-mortem examination of their body for research purposes, and may select an institution or person as the recipient. In the absence of a donation as described above, the individual’s spouse, child over 18 years, parent, guardian, or brother/sister over 18 years may donate the person’s body or any specific tissue to an institution or person for research purposes. Please refer to the NHA and the NHABiol for detailed requirements. (See the Required Elements and Participant Rights sections for additional information on informed consent).

The SA-GCPs observe that many biological samples are collected during clinical interventions for diagnostic purposes, which means the potential for future use of these samples may be presented. Use of human biological materials and their associated data facilitates research in new technologies, which include genetic and genomic research, and cell and gene therapy (CGT). Sponsors and researchers should, therefore, follow the fundamental ethical principles that underpin all research involving human biological materials and their associated data. Research proposals must address specifically the social value of the research especially in the local context; how consent, privacy, confidentiality will be managed; and the potential effect on families, communities, and other groups. Specific concerns include protection of privacy and whether and how incidental findings are to be communicated to the person from whom the sample originates.

Human Tissue Sample Consent Requirements

The G-EthicsHR-ZAF presents separate consent provisions for the use of human tissue samples. With reference to human tissue samples, donor consent should be obtained where it is proposed to use tissue samples that have been held:

• in storage following, or in association with, clinical investigations
• in archives or banks, or removed during a clinical study, or used in research that may lead to harm, benefit, or injustice to a donor of such tissue

In addition, consent must be voluntary and specific to the purpose for which the tissue is to be used. The participant must be given full information about the study, be advised on storage and future use of samples, and be assured of data related confidentiality and privacy.

In addition, per the NHATissue, tissue banks are required to develop donor record management systems in which the tissue donor register contains the full identity and relationship of the consenting person. The system will also document tissue banking processes, including the process of obtaining informed written consent.

Human Stem Cell Consent Requirements

The NHAStemCell similarly states that authorized stem cell banks must retain a record of the donor’s written informed consent. Further, no person shall use stem cells or its therapeutic research products for educational purposes unless authorized by the National Department of Health (NDOH) and is compliant with the following requirements:

• Has obtained the donor’s informed written consent even in the case of residual tissue, blood, or blood products; and
• Is certain the donor has donated voluntarily, and it is properly documented

The NHA also indicates that the NDOH Minister may permit research on stem cells and zygotes that are not more than 14 days old on a written application, and if the applicant documents the research for record purposes, and prior consent is obtained from the donor.

See ZAF-3 for an analysis of human tissue legislation and stem cell therapy in South Africa.

Human Genetic Research Consent Requirements

The G-EthicsHR-ZAF states that the investigator or institution must obtain consent for human genetic research. Investigators and institutions must comply with numerous requirements to ensure participant consent, protection, and privacy rights are upheld with regard to the storage of genetic materials. See the G-EthicsHR-ZAF for consent requirement details.

Waiver of Consent

In reference to both human tissue sample and genetic research consent, the G-EthicsHR-ZAF indicates that an EC may sometimes waive the consent requirement in cases where there is minimal risk of commercial exploitation or privacy violations. For additional details, see section 3.3 of the G-EthicsHR-ZAF.

As delineated in the G-IC-IVDs, the Food & Drug Administration (FDA) only provides informed consent guidance with respect to its regulations governing the informed consent requirement when human specimens are used for FDA-regulated in vitro diagnostic device investigations.

Informed consent requirements guiding Department of Health & Human Services (HHS)-conducted or -supported research on human research participants is regulated by the Pre2018-ComRule and 45CFR46-B-E.

Per the Pre2018-ComRule and the G-SpecimensResrch, the HHS views research involving human subject specimens as research involving human participants and subject to informed consent requirements, if the specimens obtained may be classified as identifiable private information. Identifiable private information or identifiable specimens are those that can be linked to specific individuals by the investigator(s) either directly or indirectly through coding systems. The RevComRule further defines an identifiable biospecimen as one for which the identity of the participant is or may readily be ascertained by the investigator. See the Pre2018-ComRule, RevComRule, the G-SpecimensResrch, USA-2, USA-9, and USA-1 for additional information. See also the G-SpecimensResrch for exemptions to this definition.

Additionally, as defined by the HHS’ National Institutes of Health (NIH) in USA-72, research with specimens, cells, cell lines, or data involves human subjects when:

• The specimens, cells, or data must be or must have been obtained from individuals who are alive, and must be or must have been obtained by an investigator conducting research; and
• The investigator either must be obtaining or must have obtained specimens, cells, or data through interaction or intervention with living individuals, or must be obtaining or have obtained individually identifiable private information.

See USA-72 for detailed frequently asked questions (FAQs) on this topic.

Per the Pre2018-ComRule, the RevComRule, and USA-2, prior to collecting, storing, or using a research participant’s biological specimen(s), consent must be obtained from the participant and/or a legal representative(s). 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.

The RevComRule requires the informed consent form to provide one (1) of the following statements about any research that involves the collection of identifiable private information or identifiable biospecimens:

• A statement that identifiers might be removed from the identifiable private information or identifiable biospecimens and that, after such removal, the information or biospecimens could be used for future research studies or distributed to another investigator for future research studies without additional informed consent from the subject or the legally authorized representative, if this might be a possibility
• A statement that the subject's information or biospecimens collected as part of the research, even if identifiers are removed, will not be used or distributed for future research studies
• A statement that the subject's biospecimens (even if identifiers are removed) may be used for commercial profit and whether the subject will or will not share in this commercial profit
• Whether the research will (if known) or might include whole genome sequencing (i.e., sequencing of a human germline or somatic specimen with the intent to generate the genome or exome sequence of that specimen)

Furthermore, the RevComRule delineates the requirements of broad consent—an alternative consent process—for the storage, maintenance, and secondary research use of private information or identifiable biospecimens. Broad consent requires that the following information be provided to the participant and/or the legal representative(s) or guardian(s):

• Certain basic elements from the normal consent process related to risks, benefits, confidentiality, voluntary statement, commercial profit, contact information, and whole genome sequencing elements
• Types of research that may be conducted
• A description of the information or biospecimens that might be used in future research, whether sharing might occur; and the types of institutions or researchers that might conduct research
• A description of the length of time that the information or biospecimens may be stored, maintained, and used
• A statement that participants will or will not be informed of the details of any specific research studies that might be subsequently conducted
• A statement that research results either will or will not be disclosed to participants
• An explanation of whom to contact for answers to questions about the subject's rights and about storage and use of the subject's identifiable private information or identifiable biospecimens, and whom to contact in the event of a research-related harm.

The RevComRule does allow the use of identifiable information or biospecimens in instances where the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) determines the research could not practicably be carried out without the information in that form. 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 more information on broad consent and informed consent waivers.

The HHS’ G-StoredData-Tissues and USA-2 recommend that the following be included in informed consent documents for biospecimen collection:

• A clear description of the operation of the biospecimen resource including details such as whether identifiable information will be maintained by the biospecimen resource and/or whether research results will be linked to the biospecimen
• Conditions under which samples and data will be released to recipient investigators
• Procedures for protecting the privacy of human research participants and confidentiality of data
• Specific descriptions of the nature and purpose of the research
• Information about the consequences of DNA typing if human genetic research is anticipated

(See the Required Elements and Participant Rights sections for additional information on informed consent).