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.

Thai Food and Drug Administration

As per the DrugAct, ClinSampleProd, and ClinImprtOrdr, the Thai Food and Drug Administration (Thai FDA) is the regulatory authority responsible for controlling the import of drugs for research purposes, and it also uses this authority to indirectly regulate drug clinical trials in humans. Per ClinSampleProd and DrugProdReqs, the Thai FDA is also responsible for approving requests for permission to produce drug samples for the registration of drug formulas for human research studies. As set forth in the DrugAct, THA-33, and THA-49, the Thai FDA is a regulatory body under the Ministry of Public Health (MOPH)'s Cluster of Public Health Service Support, and is granted control by the MOPH to protect consumer health. The agency is also authorized to ensure the quality, safety, and efficacy of health products including foods, drugs, cosmetics, and medical devices in Thailand.

In addition, per the DrugAct’s 2019 amendments and according to THA-6, the MOPH has the authority to establish and/or amend drug research-related procedures, regulations, and conditions via Government Gazette announcements. The Thai FDA’s Secretary-General is also permitted to control drug research study activities by issuing temporary suspensions, requesting specific improvements, or completely discontinuing a study that fails to comply with the Minister’s published guidelines.

As indicated in the DrugAct, the Thai FDA’s Medicines Regulation Division is a member of the Drug Board (also referred to as the Drug Committee in the English translation of the DrugAct). Per the DrugAct, the board must consist of MOPH departmental directors-general and representatives from related organizations, as well as five (5) to nine (9) drug experts. Every two (2) years, the Minister of Public Health appoints the Committee, which is chaired by the Permanent Secretary of the MOPH. The DrugAct also indicates that the board should appoint a subcommittee to study the drug review and approval process. The subcommittee should include at least the following: an office representative and Office of Consumer Protection Board representatives including association, foundation, and drug industry representatives whose purpose is to produce, sell, import, or order drugs for use in Thailand.

THA-49 further explains that the Medicines Regulation Division is in charge of reviewing licenses to import or order drugs used for clinical research in Thailand that are exempt from drug registration, issuing licenses to produce drug samples for drug formula registration, and issuing licenses to import or order drug samples for research purposes in Thailand. See THA-49 for additional information on the Medicines Regulation Division’s responsibilities. (See also THA-18 and THA-76 for appendices included in ClinSampleProd and ClinImprtOrdr.)

As described in ClinSampleProd and ClinImprtOrdr, the Thai FDA’s Medicines Regulation Division is responsible for application review and recommendation for approval. Per ClinSampleProd, and according to the Thai FDA’s organizational structure depicted in THA-33, the Secretary-General of the Thai FDA then makes the final decision to approve the application.

Division of Innovative Health Products and Services

As explained in THA-91, the Thai FDA’s Division of Innovative Health Products and Services is a service center that provides advice regarding health product authorization and research and development, product classification, and also accepts requests regarding health products. Its responsibilities include reviewing requests for one-stop service, locally researched and produced health products and innovative products. The Division also develops innovative health product authorization processes through electronic channels; conducts research to develop work systems, creates standards for innovative products as well as the locations and processes for production, import, sale, clinical research, and advertising; and develops policies, regulations, criteria, and practices regarding the licensing of health products. Per THA-66, the Division also houses the agency’s One Stop Service & Consultation Center (OSSC) (THA-35) within the Comprehensive Health Products Service Center. OSSC services include providing preliminary consultations, processing product application submissions (e.g., applications submitted to obtain drug import licenses for clinical research purposes), and handling payment services (e.g., permissions and licensing) for various health products including drugs. See the Submission Process section for more details on the import application submission process.

Contact Information

Per THA-72, the Thai FDA’s contact information is as follows:

Medicines Regulation Division
Food and Drug Administration
Ministry of Public Health
88/24 Tiwanon Road
Talat Khwan Subdistrict
Mueang District, Nonthaburi Province 11000

Email: drug@fda.moph.go.th
Email: saraban@fda.moph.go.th (General FDA Correspondence)
Phone: 0 2590 7000
Phone: 0 2590 1556 (FDA Call Center)
Fax: 0 2590 7116

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 DrugAct and ClinImprtOrdr, the Thai Food and Drug Administration (Thai FDA) is responsible for overseeing the import or ordering of drugs for clinical research purposes, and also uses this authority to indirectly regulate drug clinical trials in humans. Per ClinSampleProd and DrugProdReqs, the Thai FDA is also responsible for approving requests for permission to produce drug samples for the registration of drug formulas for human research studies. As per G-ResEthics, the scope of the Thai FDA’s assessment includes Phases I through IV clinical trials for new drugs (also referred to as “modern drugs”), traditional drugs (drugs intended for use in the practice of traditional medicine or to cure animal disease), unregistered drugs, registered drugs being studied in new doses or for indications not previously approved, and locally produced drugs that require efficacy testing.

As indicated in ClinImprtOrdr, ClinSampleProd, and ECRegProc, the Thai FDA’s approvals of a drug import license and of a request for permission to produce sample drugs for human research studies are dependent upon obtaining proof of ethics committee (EC) approval to conduct the clinical trial by a Thai FDA approved EC. ClinSampleProd and ClinImprtOrdr further specify that for both types of approval requests, the application is either submitted to the Thai FDA after the research project and all of the research site(s) have been approved by an EC, or in parallel, pending review by the relevant EC.

Clinical Trial Review Process

As set forth in ClinImprtOrdr, ClinSampleProd, and G-CT-DIPApp, the Thai FDA coordinates the review of applications submitted to obtain drug import licenses for clinical research purposes (N.Y.M.1) and applications submitted to request permission to produce drug samples for human research studies (P.Y.8). Per ClinImprtOrdr and ClinSampleProd, an applicant should submit the application along with supporting documents to the Medicines Regulation Division.

Per G-CT-DIPApp, upon receipt of a drug import license application (N.Y.M.1) package, the Thai FDA’s One Stop Service & Consultation Center (OSSC) (THA-35) sends the application package to an officer in the Thai FDA’s International Affairs and Investigational Drug Section. After administrative processing and troubleshooting, the officer will send the application package to the assigned reviewer to proceed. The reviewer then receives the application package and performs a technical assessment. If the reviewer determines the package is technically correct, then it will be forwarded to the Thai FDA for approval. ClinImprtOrdr specifies that the Secretary-General is responsible for authorizing all drugs to be imported into the country. (See Submission Process and Timeline of Review sections for details on the administrative and technical processing and review timelines.)

According to the DrugAct, the Thai FDA’s approval of a drug import license application for clinical research purposes also serves as an import license that allows the sponsor to import investigational drugs into Thailand. The license will remain valid until December 31^st of the year of issue. The license holder who would like to renew the license must file an application for renewal prior to the license expiration date. (See the Manufacturing & Import section for detailed license renewal instructions).

Per G-CT-DIPApp, after the import license is granted, the applicant must inform or request permission from the Thai FDA prior to initiating the following:

• Changes to clinical trial drug supplies
• Changes to an approved protocol (protocol amendment) or changes related to or affecting participant safety

In cases where the sponsor is required to immediately make one (1) or more amendments because the clinical trial or the use of investigational products in the trial endangers the health of a clinical trial participant or other person, the applicant may immediately make the amendment without prior review by the Thai FDA. A corresponding notification clearly identifying the change and the rationale for immediate implementation of the change must be filed within 15 working days after the amendment implementation date. A corresponding notification letter referring to the related approved import license along with supplemental documents to be provided in the Form for Requesting Corrections/Additional Clarifications are also required (see ClinImprtOrdr (Appendix 12) and THA-18 (Appendix 12)).

Per G-CT-DIPApp, after the import license is granted, the applicant must also notify the Thai FDA of changes to the protocol that do not affect the safety of the trial participants.

No information is currently available on the review process for P.Y.8 application submissions.

Per ClinImprtOrdr and ClinSampleProd, the Ministry of Public Health (MOPH) may also establish an academic committee or subcommittee for certain drugs requiring special supervision (e.g., the Academic Subcommittee on AIDS Vaccine Trials).

As delineated in ClinImprtOrdr and ClinSampleProd, the Thai FDA has procedures to monitor the research project before, during, and after the trial ends or is terminated. ClinImprtOrdr and ClinSampleProd specify that the authorized Thai FDA officer will contact the licensee to schedule an inspection appointment and provide a letter notifying the licensee at least seven (7) days in advance, except in those cases where the Thai FDA has a special request to carry out an inspection immediately and does not notify the licensee in advance. Refer to ClinImprtOrdr and ClinSampleProd for detailed licensee information on preparing for the inspection. See also THA-18 (Appendix 11) and THA-76 (Appendix 7) for the self-examination form containing the Thai officer’s inspection summary).

Refer to the Submission Process section for submission requirements.

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.

Thai Food and Drug Administration

In accordance with ClinDrugFees, the applicant is required to pay a fee to the Thai Food and Drug Administration (Thai FDA) to submit an application to request permission to import or order drugs for research purposes in Thailand. The ClinDrugFees states that the Thai FDA requires an administrative processing fee of 1,000 Baht to review and verify the correctness of certain application requests related to authorization, including:

• Applications to request permission to import or order drugs into the Kingdom for research purposes without registering a drug formula (N.Y.M.1 form) (See ClinImprtOrdr (Appendix 2) and THA-18 (Appendix 2) for N.Y.M.1 form)
• Applications for drug samples produced for research studies (P.Y.8 form) (See ClinSampleProd (Appendix 1) and THA-76 (Appendix 1) for P.Y.8 form)

In addition, per ClinDrugFees and THA-78, the Thai FDA charges the following fees for the technical evaluation of documents of any application request related to authorization:

• Application for permission to import or order drugs for research purposes in the country (N.Y.M.1) or to request permission to register and produce sample drugs for human research studies (P.Y.8): 4,000 Baht
• Application to expand the scope of a license to produce drug samples and register new drugs for human research studies (for drugs in bioequivalence studies): 1,000 Baht
• New research drug application to expand the scope of a license to produce drug samples and register a new drug for human research studies (for drugs other than those in bioequivalence studies): 4,000 Baht
• Application to amend and request specific changes related to the application requests listed in the preceding bullets: 500 Baht
• Requesting a certificate of pharmaceutical product (Certificate of Pharmaceutical Product/Certificate of Free Sale): 500 Baht
• Request for review of accuracy and translation of Good Manufacturing Practice (GMP) assessment report from Thai version to English version: 1,500 Baht

In addition, per ClinImprtOrdr and ClinSampleProd, in the case of the applicant designating a power of attorney to submit a paper application in person or via PDF file, the Stamp Duty fee is 30 Baht per attorney designation.

Payment Instructions

According to the Thai FDA’s One Stop Service & Consultation Center (OSSC) (THA-35) and THA-66, the OSSC’s finance section provides payment services in cases where expenses need to be paid for various submissions, and accepts multiple payment methods including the cash payment counter, cashier’s check, credit cards, and mobile banking applications for the processing of application fees. However, per THA-79, in order to submit an electronic payment using the Thai FDA’s Skynet E-Submission System (THA-54), the applicant must first submit documentation and supporting evidence to request access as required by the OSSC. Once the OSSC approves e-submission system access, the applicant can submit a payment electronically to request a drug importation waiver via THA-54. See Submission Process section for detailed submission instructions and documentation requirements to access THA-54. Refer to THA-57 for the Skynet e-submission user manual and THA-87 for a guide to request a drug importation waiver via THA-54.

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 per ClinImprtOrdr, ClinSampleProd, and ECRegProc, clinical trials require ethics committee (EC) approval for each trial site from an EC recognized by the Thai Food and Drug Administration (Thai FDA). ECRegProc indicates that an EC may function as a committee under a government agency (e.g., the Ethical Review Committee for Research in Human Subjects, Ministry of Public Health (ECMOPH)); as a committee affiliated with a private hospital/institution licensed to comply with the HospitalAct; or, as a committee operating as a part of a non-profit partnership between a government agency and a private organization(s) (e.g., the Central Research Ethics Committee (CREC)). ECRegProc states that the Thai FDA posts a list of the approved/renewed ECs on its website (see THA-90), and as noted in THA-3, this usually occurs every two (2) years. According to THA-4, the ECMOPH and the CREC are both government ECs whose approvals are still active. As discussed in THA-63, the ECMOPH and the CREC are also collaborating on a multi-institutional clinical research project to reduce redundancy during the review process and to develop joint human research ethics guidelines. (See THA-18 and THA-76 for the forms included in the appendices in ClinSampleProd and ClinImprtOrdr.) (Note: The ECMOPH website is not accessible to users residing outside of Thailand.)

Per THA-1, the ECMOPH and the CREC represent the two (2) central ECs recognized by the Thai FDA to review and approve clinical research protocols involving humans. THA-1 further explains that both the ECMOPH and the CREC are categorized as central ECs because they can accept all clinical research studies for review, regardless of the trial sites involved.

Ethical Review Committee for Research in Human Subjects, Ministry of Public Health

Per THA-39, the ECMOPH is responsible for controlling, supervising, and monitoring research in accordance with international ethical principles; developing research policies; suspending unethical research programs; creating a national database of clinical research; establishing a regional/international committee network system; developing personnel capacity to support clinical research in Thailand; and other related or assigned academic projects. See THA-13 for additional details about the ECMOPH, and THA-13 and THA-39 for requirements specifically related to studies approved by the ECMOPH.

Central Research Ethics Committee

Per THA-1, the CREC was formed in 2014 through the cooperative efforts of 26 public and private institutions in Thailand, including the Thai FDA. THA-44 explains that the focus of the CREC is on reviewing multi-center clinical research projects to improve the efficiency of the EC review and to reduce the duplicative review of multi-institutional studies. See THA-44 for additional information on the CREC, and the Submission Process and Submission Content sections for detailed CREC submission requirements.

Ethics Committee Composition

As per G-ResEthics, institutional ECs should consist of at least five (5) members, both male and female, with the following qualifications:

• At least one (1) member with knowledge and experience in research fields regularly reviewed (e.g., medicine, public health, social science, etc.)
• At least one (1) member who is a lawyer or has legal expertise
• At least one (1) member who is unaffiliated with the institution, and, if possible, that member should be selected from the community where the institution is based
• At least two (2) members who have patient care, counseling, and treatment knowledge and experience
• At least one-third of the total EC should be knowledgeable or trained in human research ethics

ECRegProc, by comparison, also requires institutional ECs to have at least five (5) members who are experts on science, medicine, and ethics. In addition, the committee must include members representing the following qualifications:

• At least three (3) members who are medical professionals
• At least one (1) member must be an expert in a non-scientific category
• At least one (1) member from outside of the institution where the trial is taking place

The International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (THA-28) similarly indicates that ECs should be composed of medical personnel, scientists, and non-scientists, and also notes that while these committees may have differences in legal status, composition, and function, the duties of an EC should be consistent with THA-28. Per an in-country subject matter expert, Thailand is implementing THA-28.

Because each EC has its own requirements, it is recommended that the individual ECs be contacted to confirm their specific requirements.

No information is available on ECMOPH and CREC composition requirements.

Terms of Reference, Review Procedures, and Meeting Schedule

As delineated in G-ResEthics and ECRegProc, ECs must conduct clinical protocol reviews according to THA-28 using written standard operating procedures (SOPs) that are periodically updated, and develop a process for conducting reviews. The SOPs should include information on EC composition, meeting schedules, timeframes for protocol reviews, quorum requirements, decision-making procedures, channels of communicating the decision(s), complaint processes, reviewing fees (if any), protection of protocol confidentiality, and prevention of possible conflicts of interests. The G-ResEthics also states that each EC must establish the composition, member terms of service, and criteria for selecting the committee members, as appropriate. The members must also be appointed officially as evidenced by a written document.

Additionally, per ECRegProc, ECs must meet the following requirements:

• Have the legal qualifications or comply with the government regulations related to providing research or research-related services
• Have a clearly defined structure with proof of appropriately appointed members, including the secretary and secretariat
• Have voting rights and the right to issue independent research opinions without investigator/sponsor involvement, and with no direct or indirect interest or conflict of interest with the investigator or clinical research study
• Have members who are trained in conducting research and clinical trials in human participants, and who participate in ethics training or other related training at least once every two (2) years while serving on the committee
• Have experience in reviewing human research involving experimental drugs for at least 10 studies

For detailed EC requirements and information on other administrative processes, see G-ResEthics and ECRegProc.

Also, refer to THA-47 for a list of CREC forms needed to prepare for initial protocol submission, and THA-37 for a complete list of CREC SOPs.

No information is available on the ECMOPH’s terms of reference, review procedures, and meeting schedule.

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

As delineated in G-ResEthics, ECRegProc, and the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (THA-28), the primary scope of information assessed by Thai Food and Drug Administration (Thai FDA) recognized ethics committees (ECs) relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial. According to THA-10, clinical research and trials (i.e., research studies and experiments on humans) are subject to the medical ethics standards delineated in the Regulations of the Medical Council on Maintaining the Ethics of the Medical Profession (B.E. 2549) (MCEthics), the Declaration of Rights and Code of Conduct for Patients (THA-11), and the Researcher’s Code of Ethics (THA-14).

MCEthics explains that ECs are established to review the ethical aspects of research studies and human trials to protect the rights, safety, and well-being of participants in research studies and human trials. THA-14 further states that researchers should treat all research participants, whether animate or inanimate, with appropriate respect and consideration and should take full responsibility for the impact and consequences of their research. Researchers should also have respect for the dignity and rights of their human participants. THA-11 indicates that every patient has the fundamental right to receive professional medical and health care from health professionals without discrimination as provided for in the Constitution of the Kingdom of Thailand (B.E. 2560). Per G-ResEthics, ECRegProc, and THA-28, ECs must also pay special attention to reviewing informed consent and protecting the welfare of certain classes of participants deemed to be vulnerable. Per an in-country subject matter expert, Thailand is implementing THA-28. (See the Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses, and Neonates; Prisoners; and Mentally Impaired sections for additional information about these populations).

In addition, per G-ResEthics, ECRegProc, and THA-28, ECs are also responsible for ensuring an independent, timely, and competent review of all ethical aspects of the clinical trial protocol. ECs must act in the interests of the potential research participants and the communities involved, evaluating the possible risks and expected benefits to participants; confirming the suitability of the investigator(s), facilities, and methods; and verifying the adequacy of confidentiality and privacy safeguards. G-ResEthics further states that ECs should review the ethical aspects of the protocol in compliance with current international ethical guidelines while taking into account local or national laws, religions, traditions, and cultures. Per G-ResEthics, the appointed EC is also responsible for ensuring that research conducted within the institution adheres to ethical principles including those established in the Declaration of Helsinki (THA-45), the Council for International Organizations of Medical Science (CIOMS)’ International Ethical Guidelines for Biomedical Research Involving Human Subjects (THA-7), and the World Health Organization (WHO)’s Operational Guidelines for Ethics Committees that Review Biomedical Research (THA-64). See G-ResEthics, ECRegProc, and THA-28 for detailed ethical review guidelines. MCEthics further states that the medical practitioner who conducts or participates in the research study on humans must only undertake such study or experiment after it is approved by the EC responsible for the study. The medical practitioner must also conform to G-ResEthics and THA-14 when conducting the research study.

Role in Clinical Trial Approval Process

Pursuant to ClinImprtOrdr and ECRegProc, Thai FDA-recognized ECs are responsible for reviewing and approving protocols for clinical research related to drugs to be imported into Thailand. Per ClinSampleProd and DrugProdReqs, the Thai FDA is also responsible for approving requests for permission to produce drug samples for the registration of drug formulas for human research studies. As stated in ClinImprtOrdr, ClinSampleProd, and ECRegProc, the Thai FDA’s approvals of a drug import license and of a request for permission to produce sample drugs for human research studies are dependent upon obtaining approval by a Thai FDA approved EC. ClinImprtOrdr and ClinSampleProd further specify that for both types of approval requests, the application is either submitted to the Thai FDA after the research project and all the research sites have been approved by an EC, or in parallel, pending review by at least one (1) EC involved in the study. THA-5 further notes that if an approval is obtained from the EC of the research institute or university conducting the trial, an approval from the Ethical Review Committee for Research in Human Subjects, Ministry of Public Health (ECMOPH) is usually optional (unless it is further required by the internal rules and regulations of that research facility).

In the instance of a multicenter clinical trial, G-ResEthics indicates that protocols submitted to each institution’s EC should contain the same content substance and details, and should specify the quality control techniques to ensure that research practices are the same in each institution. Although each institutional EC may independently approve or disapprove an application, G-ResEthics advises the committees from each participating institution to consult with one another to reach a clearly agreed upon decision.

There is no stated expiration date for an EC approval in G-ResEthics, in the ECMOPH guidelines (THA-13), or on the Central Research Ethics Committee (CREC) website (THA-36). Per ECRegProc, ECs must provide continuous supervision and monitoring, and conduct inspections to ensure that clinical trial operations are carried out in compliance with all approved research projects and research sites without any deviations or changes from those approved by the committee, unless otherwise specified according to THA-28. ECs must also supervise and monitor research projects to ensure that participants’ rights, safety, and well-being are protected (e.g., in the case of an adverse event, etc.).

Ethical Review Committee for Research in Human Subjects, Ministry of Public Health

According to THA-13, an application submitted to the ECMOPH is initially reviewed by at least two (2) advisors, followed by a final review by the ECMOPH at its regular meeting. At this meeting, the advisors present a summary of the proposal to the committee along with their recommendations. The committee discusses the proposal and sends a list of comments to the principal investigator (PI) for clarification. Once the PI provides the requested information, the committee makes a final decision, and this is reported to the ECMOPH Chairman and the Permanent Secretary for Public Health respectively. A letter of notification signed by the Permanent Secretary for Public Health is then forwarded to the PI and the responsible organization. As earlier stated, this review and approval process is specific to the ECMOPH. However, it can be used to obtain a better understanding of the EC process within Thailand.

Central Research Ethics Committee

As indicated in THA-44 and THA-24, a research project is eligible to apply for CREC review when it meets one (1) of the following criteria:

• It is a pharmaceutical-sponsored multi-center clinical trial
• It is an investigator-initiated multi-site study granted by a research funding organization (e.g., the National Research Council of Thailand (NRCT), the Thai Health Promotion Foundation, the Health Systems Research Institute (HSRI), etc.)
• It is assigned by the Thai Health Board of Directors for review
• It is a single center, multi-site study of researchers at partner institutions with co-researchers from each site (THA-24)

Per THA-44, when a research proposal is submitted to the CREC for review, the committee will cooperate with all the participating ECs to confirm the researchers are qualified, the institution has adequate facilities, and the proposed research is compliant with institutional regulations, applicable laws, local contexts, and standards of professional conduct and practice. The CREC will also consider the concerns and attitudes of the various communities participating in the project. Once the review process is completed, the decision will be documented in a formal letter. The issued decision letter will be sent to the PI, the contract research organization, and all of the participating ECs. Refer to THA-44 and THA-24 for additional CREC requirements.

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.

As explained in G-ResEthics, Thai Food and Drug Administration (Thai FDA)-recognized ethics committees (ECs) should review their research budgets to ensure that fee information is addressed. In general, the sponsor will pay the investigator based on the number of research participants. The Ethical Review Committee for Research in Human Subjects, Ministry of Public Health (ECMOPH) and the Central Research Ethics Committee (CREC) are both ECs recognized by the Thai FDA to review and approve clinical trial protocols.

G-ResEthics further states that research conducted in public hospitals or public health care facilities involves expenditures such as laboratory tests and lump sum fees determined by the institution. The disclosure of these payments and other budget items enables the EC to evaluate any conflict of interest and helps the investigator to decide whether to conduct the trial.

Ethical Review Committee for Research in Human Subjects, Ministry of Public Health

No information is currently available on ECMOPH fees.

Central Research Ethics Committee

As set forth in CRECFees, the CREC requires investigators to pay a nonrefundable fee to submit a clinical trial research protocol for ethical review and approval.

CRECFees and THA-50 specify the following fees for the ethical review of research projects funded by private capital (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• New research project: 50,000 Baht

· Request for certification renewal of old research project: 20,000 Baht

• Amendments to the research project (research outline amendments/adding a research location): 10,000 Baht
• Report requesting amendments to the research outline: Amendment certified by the local EC of the joint research institute in the CREC-certified research project, followed by a report submitted for CREC consideration (site-specific amendment): No fees charged
• Reporting adverse events, reporting non-compliance, notifying the CREC of a research project closure, and various other reports: No fees charged
• Edit the Certificate of Approval (COA) document: 1,000 Baht
• Edit certification/acknowledgement: 500 Baht
• Edit document with certified seal: 500 Baht

For research projects funded by government agencies, royal colleges, medical professional associations, or personal capital, CRECFees and THA-50 delineates the following fees:

• New research project: 25,000 Baht
• Request for certification renewal of old research project: 10,000 Baht
• Amendments to the research project (research outline amendments/adding a research location): 5,000 Baht
• Report requesting amendments to the research outline: Amendment certified by the local EC of the joint research institute in the CREC-certified research project, followed by a report submitted for CREC consideration (site-specific amendment): No fees charged
• Reporting adverse events, reporting non-compliance, notifying the CREC of a research project closure, and various other reports: No fees charged
• Edit the Certificate of Approval (COA) document: 500 Baht
• Edit the certification/acknowledgement: 250 Baht
• Edit document with certified seal: 250 Baht

Payment Instructions

THA-42 explains that investigators should submit ethics application fee payments to the following bank:

Bank Name: Krungthai Bank
Bank Address: 2/1 SOI Phahonyothin, Phahonyothin Road 40, Sena Nikhom, Jatujak, Bangkok 10900
Swift Code: KRTHTHBK
Branch: Phahonyothin 39
Account Type: Savings Account
Account Name: Foundation for Human Research Promotion in Thailand
Account number: 981-2-84782-0

Per CRECFees and THA-25, the investigators must submit proof of payment with the application submission. CRECFees indicates that the investigators and research sponsor are responsible for paying the fees and preparing the documentation to submit to the research institute. In the case of an investigator having transferred fees for a project that has been cancelled, the investigator may request a refund. The Foundation will deduct 20% of the transferred fee. The investigator should contact the bank for any service fee applied.

THA-50 and THA-25 indicate that any questions regarding the payment submission process may be directed to the following contact:

Miss Netdao Kanseecha
Financial Officer
Phone: 061-089-9966
Email: natdown@crecthailand.org

Per THA-25, if the CREC has no evidence of payment, the application submission will be considered incomplete. See THA-50 for additional information on fee rate based on funding source and fee receipts.

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 indicated in ECRegProc, ClinImprtOrdr, and ClinSampleProd, institutional ethics committees (ECs) and other types of ECs, including the Ethical Review Committee for Research in Human Subjects, Ministry of Public Health (ECMOPH) and the Central Research Ethics Committee (CREC), must be authorized by the Thai Food and Drug Administration (Thai FDA) to conduct ethical reviews of drug clinical trial protocols. ClinImprtOrdr and ECRegProc specify that authorized ECs are responsible for reviewing and approving protocols for clinical research involving drugs to be imported into Thailand. (See also THA-18 and THA-76 for the forms included in the appendices relating to EC authorization in ClinImprtOrdr and ClinSampleProd.)

As per ECRegProc, an acceptance letter issued to the ECs by the Thai FDA is valid for two (2) years and may be obtained by applying to the agency using the Jor Thor Form EC-1 (THA-23). Each EC is also required to submit an annual report (THA-21) to the Thai FDA, and to apply for an acceptance extension no later than 60 days before the expiration date.

ECRegProc states that the Thai FDA posts a list of the approved/renewed ECs on its website (see THA-90) and as noted in THA-3, this usually occurs every two (2) years. These ECs are approved in addition to the centralized ECMOPH and the CREC.

Registration, Auditing, and Accreditation

Pursuant to EC-QualAccredReq, in addition to the ECRegProc approval and renewal of approval documentation requirements, the Thai FDA requires ECs to submit proof of accreditation based on an evaluation by a quality accreditation agency in compliance with international accreditation standards. The following organizations are approved by the Thai FDA to provide quality accreditation reviews:

• National Ethics Committee Accreditation System of Thailand (NECAST)
• The Strategic Initiative for Developing Capacity in Ethical Review (SIDCER)/The Forum for Ethical Review Committees in Asian and Western Pacific Region (FERCAP)
• The Association for the Accreditation of Human Research Protection Programs (AAHRPP)
• Other Thai FDA-approved quality accreditation agencies

Per EC-QualAccredReq, EC submissions will be reviewed and completed within one (1) business day.

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

In accordance with ClinImprtOrdr and G-CT-DIPApp, the sponsor or the contract research organization (CRO) is responsible for submitting a drug import license application for clinical research purposes to the Thai Food and Drug Administration (Thai FDA). Per ClinSampleProd and DrugProdReqs, the Thai FDA is also responsible for approving requests for permission to produce drug samples for the registration of drug formulas for human research studies.

As set forth in ClinImprtOrdr, ClinSampleProd, and ECRegProc, the Thai FDA’s approvals of a drug import license and of a request for permission to produce drug samples for human research studies are dependent upon obtaining proof of ethics committee (EC) approval from the Thai FDA to conduct the clinical trial. ClinImprtOrdr and ClinSampleProd further specify that for both types of approval requests, the application is either submitted to the Thai FDA after the research project and all the research sites have been approved by an EC, or in parallel, pending review by at least one (1) EC involved in the study. (Note: Per ClinImprtOrdr, the sponsor is also referred to as the applicant or importer.)

Regulatory Submission

OSSC Pre-Submission Permission

According to THA-77 and THA-75, prior to submitting a drug import license application (N.Y.M.1 form), an applicant must first request permission from the Thai FDA’s One Stop Service & Consultation Center (OSSC) (THA-35) to use the OSSC’s online consultation system (E-Consult) (THA-77). Per THA-65, requesting E-Consult permission is a two-part process that initially requires applicants who are Thai citizens to create a user account and register via Digital ID (THA-89) which enables Thai citizens to access all government agency electronic services using a single user account/password. The user account can then be used to submit applications and supporting documentation to the Thai FDA’s Medicines Regulation Division via the Skynet E-Submission System (THA-54).

Per THA-65 and THA-77, once registered in THA-89, Thai applicants (i.e., the general public, entrepreneurs, or researchers) are subsequently required to provide documentation to E-Consult (THA-77) to confirm that they, or representatives authorized to act on their behalf, are authorized to use the FDA’s Skynet E-Submission System (THA-54). Although non-citizens cannot register directly with THA-89, they can request permission to authorize a juristic person who receives power of attorney (i.e., agency representatives, registration agents, or researchers who submit applications on behalf of an agency). Documentation should be submitted to E-Consult (THA-77) either in person or via email (econsultcenter@fda.moph.go.th) specifying in the subject line: “Request to open the right to use the information system.”

Per THA-77, for Thai applicants, this documentation includes:

• Form for Requesting Permission to Use the Health Product Consultation Information System (E-Consult) (THA-80)
• Copy of identity card

Per THA-77, for juristic applicants with power of attorney, this documentation includes:

• Form Requesting Power of Attorney Permission to Use the Health Product Consultation Information System (E-Consult) (THA-81)
• Copy of juristic person certificate (if any)
• Power of attorney form
• Copy of identity card of grantor (the national identity card issued to Thai citizens)
• Copy of identity card of attorney-in-fact (refers to a passport)

THA-66 indicates that when an applicant completes the process of submitting an in-person request within one (1) day at the service center, a service provider can then forward the request for review and may receive a response within one (1) day. For requests that take more than one (1) day to be reviewed, the service center will forward the application to the Product Division for consideration. See also THA-51 for additional information on services provided by the OSSC’s E-Consult Service.

Import and Export Division Pre-Submission Permission

Per THA-79, the Thai FDA’s Import and Export Inspection Division also requires applicants to request permission to access the Skynet E-Submission System (THA-54) prior to being permitted to submit a drug import waiver application for clinical trial purposes. Applicants requesting access may submit documentation via email to bie.thaifda@gmail.com to open temporary rights first. After reviewing the emailed documentation for correctness/completeness, the officer will reply to the email and request original copies of the documents. A request for permission can also be mailed to the OSSC (THA-35), 4th floor. Also, per THA-87, Thai applicants may register and submit authorization documentation via THA-54 once they have obtained access.

THA-79 states that for Thai applicants, the required authorization documentation includes:

• Copy of the registration certificate of the company or partnership, or a copy of the commercial registration (which has been issued no more than six (6) months and has a grantor to sign)
• Copy of grantor’s identity card (which has not expired on the date of document submission along with a signature to certify the copy)
• Copy of the identity card of the attorney-in-fact (which has not expired on the date of document submission along with a signature to certify the copy)

THA-79 further notes that the applicant has the right to use the Skynet E-Submission System (THA-54) for import/export purposes for no more than one (1) year. The following forms are also provided on the Import and Export Inspection Division webpage (THA-85) to complete these requests: Form Requesting Access to the FDA E-Submission System for Permission to Import Drugs for Other Purposes (THA-83), Form Requesting Power of Attorney Access to the FDA E-Submission System for Permission to Import Drugs for Other Purposes (THA-82), and Application Form for Medicine Importation (THA-84). See also THA-85 for additional related forms that may be useful.

Submissions

N.Y.M.1

As delineated in ClinImprtOrdr, the Thai FDA accepts paper and electronic clinical trial application submission packages for requests to import or order drugs for clinical research. However, paper applications are only to be submitted at the discretion of an agency officer when it is determined that the application process cannot be completed electronically via the Skynet E-Submission System (THA-54) for Medicines Regulation Division review and approval (see Submission Content section for content details).

As per ClinImprtOrdr, for paper submissions, sponsors must submit two (2) original sets with real signatures of the completed N.Y.M.1 form (ClinImprtOrdr (Appendix 2) and THA-18 (Appendix 2)) with the required attachments to the Thai FDA. For paper submissions, the applicant must also submit an MS Word template file for importing the data electronically, so that the file can be connected to the information in the drug importation and clinical research sections in the information system. A copy of all the submitted documents should also be provided in PDF format. G-CT-DIPApp also states that two (2) sets of the application package must be submitted to the Thai FDA. Per ClinImprtOrdr, if the Thai FDA reviewer determines that submitted documents require correction or additional documentation needs to be submitted, the applicant must make corrections/clarifications based on the evaluation results within the specified time by submitting a correction/clarification request form (see ClinImprtOrdr (Appendix 12) and THA-18 (Appendix 12)).

Additionally, per ClinImprtOrdr, the non-local applicant must authorize a qualified person through a power of attorney to submit an application and respond to requests to provide clarification, amend, and/or receive documents related to the submission. The attorney-in-fact should be someone who has knowledge in pharmacy or a related medical field as well as an understanding of requests, permissions, etc. relating to the application submission and associated documentation. The scope and responsibilities of the attorney-in-fact must be specified in the authorization to include filing application submission clarifications and corrections. The authorization documentation should be submitted with the paper application. ClinImprtOrdr further notes that one (1) set of power of attorney submission documentation may only be used for one (1) application submission request.

ClinImprtOrdr also states that the application submission should include documentary evidence for quality control and drug production separated by drug. The identification of the manufacturer of each drug included in the submission must match the one specified in the Microsoft Excel files for the Logistics System (See ClinImprtOrdr (Appendix 7) and THA-18 (Appendix 7) for the manufacturer’s form).

As indicated in ClinImprtOrdr and G-CT-DIPApp, Thai and English are the preferred languages for use in preparing an application package for requests to import or order drugs for clinical research. The following requirements are specified (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Research project name and summary of research project in Thai
• Drug packaging documents for already registered drugs presented in Thai or English (Note: if drug formula documentation from abroad is in a foreign language other than English, then it should be translated into Thai or English and certified that the text matches the Thai/English language version)
• Protocol synopsis in Thai
• Detailed study protocol specification (completed version of study protocol) in Thai or English
• Patient information sheet in Thai or translated to an appropriate language and certified the text matches the Thai version
• Drug labels for every package size in Thai or English
• EC approval document in Thai
• Certificate of Free Sale in English and translated by a trusted certification authority and any other language in which it has been originally issued
• Progress report in Thai

Additionally, as explained in THA-79, once the applicant has obtained permission from the Import and Export Inspection Division to access the Skynet E-Submission System (THA-54), a drug import waiver application (N.Y.M.1) may be submitted electronically. Per THA-87, following official review of the submitted documentation, a response will sent within one (1) business day. THA-87 and THA-79 indicate that once the request is approved, a License Per Invoice (LPI) number will be used in making a goods declaration with the Thai Customs Department. See THA-48, THA-86, and THA-88 for additional information and instructions on submitting an LPI to Customs). Refer to THA-57 and THA-87 for detailed instructions on submitting a drug importation waiver request via the Skynet E-Submission System (THA-54).

P.Y.8

As indicated in ClinSampleProd, the Thai FDA also accepts paper and electronic clinical trial application submission packages for requests for permission to produce sample drugs for human research studies. However, if the electronic system is not available, the application must be submitted in paper form, along with the appropriate supporting documentation (see Submission Content section for content details). In the case of filing via the Skynet E-Submission System (THA-54), information will be filled in the system in a P.Y.8. form, and the research project information will be created automatically. If the Thai FDA reviewer determines that submitted documents require correction or additional documentation needs to be submitted, the applicant must make corrections/clarifications based on the evaluation results within the specified time by submitting a correction/clarification request form (see ClinSampleProd (Appendix 8) and THA-76 (Appendix 8)). The paper documentation should be submitted to the New Drugs and Drug Research Promotion Group within the Medicines Regulation Division or submitted electronically via THA-54. When submitting a paper application, the applicant must also submit a template file for importing the data via THA-54 to serve as a starting point for operators in the electronic process and for use in overseeing the trial. A copy of all the submitted documents should also be provided in PDF format.

Additionally, per ClinSampleProd, the non-local applicant must authorize a qualified person through a power of attorney to submit an application and respond to requests to provide clarification, amend, and/or receive documents related to the submission. The attorney-in-fact should be someone who has knowledge in pharmacy or a related medical field as well as an understanding of requests, permissions, etc. relating to the application submission and associated documentation. The scope and responsibilities of the attorney-in-fact must be specified in the authorization to include filing application submission clarifications and corrections. The authorization documentation should be submitted with the paper application, or via the Skynet E-Submission System (THA-54), if the application is being submitted electronically. ClinSampleProd further notes that one (1) set of power of attorney submission documentation may only be used for one (1) application submission request.

As indicated in ClinSampleProd, Thai and English are the preferred languages for use in preparing an application package to request permission to produce investigational drugs for clinical research. The following requirements are specified:

• Research project name in Thai and English
• Summary of research project in Thai
• Drug labels for every package size in Thai or English
• Patient Information Sheet in Thai
• EC approval document in Thai
• Complete research project details in Thai or English

OSSC Contact Information for Application Submissions

Per THA-74, THA-65, and THA-77, the following is contact information for submitting an application to the OSSC (THA-35) in person or via email, and for requesting permission to access the Skynet E-Submission System (THA-54):

One Stop Service Center (OSSC) 
Building 6, 5^th Floor
Food and Drug Administration Building
Ministry of Public Health
88/24 Tiwanon Road
Talat Khwan Subdistrict
Mueang District, Nonthaburi Province 11000

Email (E-Consult): econsultcenter@fda.moph.go.th
Phone: 02 590 7614 (Consultation E-service for general inquiries, reporting usage problems, and issues related to requesting permissions)

See also THA-52 for the Medicines Regulation Division staff list.

Ethics Review Submission

Per G-ResEthics, each institutional EC should establish its own requirements for protocol submission along with the required documents including the application, number of research protocol copies to be submitted, the patient information sheet, the informed consent form, and the case report form. Each EC should also communicate these requirements to personnel or staff within the institution.

According to THA-4, if a trial site is not affiliated with a Thai FDA-recognized EC, the investigator(s) usually needs to apply to two (2) ECs for approval—the unaffiliated local EC and a central EC approved by the Thai FDA. THA-1 further explains that both the Ethical Review Committee for Research in Human Subjects, Ministry of Public Health (ECMOPH) and the Central Research Ethics Committee (CREC) are categorized as central ECs because they can accept all clinical research studies for review, regardless of the trial sites involved.

Ethical Review Committee for Research in Human Subjects, Ministry of Public Health

According to THA-13, the ECMOPH requires one (1) original and 20 copies of the protocol submitted in Thai, and one (1) copy submitted in English for review purposes.

Per THA-41, investigators can electronically submit applications to the ECMOPH to obtain approval for new research projects or to request other services via the ECMOPH e-submission login page (THA-40).

Central Research Ethics Committee

THA-36 and THA-29 indicate that investigators applying for a new research project should submit an application to the CREC for review via its Online Submission System (THA-43).

THA-29 further explains that in some cases, hard copies may be requested by the CREC officer, with the number of additional hard copies requested subject to the reviewer’s requirements. Per THA-29, one (1) set of hard copy documents, consisting of a project folder and a CD with project information should be submitted. Documents should be placed in a folder indicating the correct number of files in order to avoid processing delays.

THA-29 also states that if a local EC requires a hard copy for the local assessment, the CREC will prepare an introduction letter and local issue assessment form. These documents will be sent to every local EC by email; the researcher/coordinator will be copied on this email. The researcher/coordinator will attach the local CREC introductory letter and assessment form to the hard copy submission package for the local EC.

See also THA-34 for detailed application package documentation submission requirements, and THA-37 for a comprehensive list of all the CREC Standard Operating Procedures (SOPs).

Per THA-34 and THA-38, in the case where the research project is in English, a brief research outline should be provided in Thai as well. In addition, an explanation about the research participants and letter of intent to consent should be provided, if the master version of the informed consent documents are written in English.

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

N.Y.M.1

As per ClinImprtOrdr and G-CT-DIPApp, sponsors must submit the following documents to the Thai Food and Drug Administration (Thai FDA) to request a drug import waiver request (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Cover letter
• Application for Permission to Import or Order Drugs for Research Purposes in the Kingdom (N.Y.M.1 form) (see ClinImprtOrdr (Appendix 2) and THA-18 (Appendix 2))
• Checklists and Attached Documents for N.Y.M.1 form (see appendices in ClinImprtOrdr and THA-18)
• Drug labels for every package size in Thai or English
• Package inserts (for registered drugs)
• Prescriptions (for registered drugs)
• Investigator’s Brochure (IB) (for unregistered drugs)
• Informed Consent Form in Thai
• Patient Information Sheet in Thai
• Research project summary in Thai
• Completed version of study protocol in Thai or English
• Chemistry, manufacturing, and control (CMC) information
• Ethics Committee (EC) approval from a Thai FDA-recognized institutionally-based EC and/or an independent EC. If waiting for approval from the relevant EC, instead submit the latest protocol version under consideration.
• Estimates of the amount of study drug, comparators, or other goods to be imported
• Certificate of Analysis
• Certificate of Free Sale in English and other language used
• Drug registration authorization document
• Summary of product characteristics
• Literature review
• Description (name and content) and pictures of lab/materials to be imported
• Power of attorney
• Investigational medicinal product (IMP) information

Per ClinImprtOrdr, when an applicant authorizes a qualified person through a power of attorney to submit an application package, the following documents must also be included with the submission:

• Copy of identity card of the grantor and the attorney-in-fact with signatures to certify that they are true copies
• Stamp duty in the amount of 30 Baht per one (1) power of attorney designation

As delineated in G-CT-DIPApp, applicants are also required to submit the following documents to the Thai FDA regarding EC approval:

• Protocol title
• List of principal investigator(s) (PIs)
• Proposed study site
• List of documents reviewed and approved by the EC, including the document version
• Period of approval and/or date of expired approval

As noted in ClinImprtOrdr, the Ministry of Public Health (MOPH) may also establish an academic committee or subcommittee for certain drugs requiring special supervision (e.g., the Academic Subcommittee on AIDS Vaccine Trials to review AIDS vaccines, etc.). Therefore, when submitting an application to request permission to import or order a specialized drug for clinical research requiring this type of oversight, an additional approval letter from the relevant committee is also required. Additional information on obtaining the approval for the committee is not available.

P.Y.8

Per ClinSampleProd, applicants must submit the following documents to the Thai FDA to request permission to produce drug samples for the registration of drug formulas for human research studies:

• Application for Permission to Produce Drug Samples for Drug Formula Registration (P.Y.8. Form) (see ClinSampleProd (Appendix 1) and THA-76 (Appendix 1))
• Research project summary in Thai
• Certification of compliance with the terms and conditions related to the production of drug samples for use in human research studies
• Certificate of Compliance for Principal Investigators
• Evidence of insurance or compensation
• Power of attorney (for paper submissions)
• A copy of the license to produce modern drugs (for paper submissions)
• Drug labels for every package size in Thai or English
• Copy of Good Manufacturing Practice (GMP) Certificate
• Drug leaflet (for bioequivalence study drugs)
• IB (for research drugs)
• Patient Information Sheet in Thai
• EC approval from a Thai FDA-recognized institutionally-based EC and/or an independent EC, except in the case of waiting for approval from the relevant EC
• Drug quality control and pharmaceutical production documentation
• Documents approved by relevant technical committees (if any)
• Complete research proposal in Thai or English
• Document self-verification form (see ClinSampleProd (Appendix 7) and THA-76 (Appendix 7))

Per ClinSampleProd, when an applicant authorizes a qualified person through a power of attorney to submit an application package, the following documents must also be included with the submission:

• Copy of identity card of the grantor and the attorney-in-fact with signatures to certify that they are true copies
• Stamp duty in the amount of 30 Baht per one (1) power of attorney designation

As noted in ClinSampleProd, the MOPH may also establish an academic committee or subcommittee for certain drugs requiring special supervision (e.g., the Academic Subcommittee on AIDS Vaccine Trials to review AIDS vaccines, etc.). Therefore, when submitting an application to request permission to import or order a specialized drug for clinical research requiring this type of oversight, an additional approval letter from the relevant committee is also required. Additional information on obtaining the approval for the committee is not available.

Ethics Committee Requirements

Per G-ResEthics, each institutional EC should establish its own requirements for protocol submission along with the required documents including the application, number of research protocol copies to be submitted, the patient information sheet, the informed consent form, and the case report form. Each EC should also communicate to personnel or staff within the institution.

Ethical Review Committee for Research in Human Subjects, Ministry of Public Health

Per THA-13, the Ethical Review Committee for Research in Human Subjects, Ministry of Public Health (ECMOPH) requires investigators (applicants) to submit the following documentation for ethics approval:

• One (1) original set and 20 copies of the protocol in Thai and one (1) copy in English for review
• Ethical considerations
• Combined information sheet and informed consent certificate for research participants
• Budget details and funding source
• Curriculum Vitae (CV) for each research team member
• Letter of approval from implementing institution
• Results of ethical review by EC of implementing institution, if available
• Data collection/questionnaire tools
• Letter signed by PI’s supervisor
• For an international project, Thai and foreign PIs required for each side
• Material transfer agreement for transfer of blood or biomedical samples
• References

Refer to THA-13 for detailed ECMOPH submission requirements respectively.

Central Research Ethics Committee

According to THA-34 and THA-38, investigators applying for an initial research project review by the Central Research Ethics Committee (CREC) should submit the following:

• Books/memorandum for research presentation signed by investigator (Word and PDF files required)
• Ethics Consideration Proposal Form for Biomedical Research Projects (CREC form AP 04-S04) signed by investigator (Word and PDF files required)
• Complete research proposal
• Brief research proposal in Thai
• Documents clarifying information about research participants and letter of intent to consent (in the case of a master informed consent form (ICF) version, single document in English is used for all institutions; alternatively, each institution may also use their own documents) (See also THA-46 for ICF template and checklist links)
• Case report form
• IB (including Investigator’s Guide; a certificate that the drug has been approved by the Thai FDA; invoice in the case of a drug that has been registered with the Thai FDA; and a drug leaflet)
• Other documents (including questionnaire or interview form; notebook; documents for invitation to participate in the research, such as brochures, posters, public relations scripts; other documents applicable to volunteers/research participants; documents requiring issuance of a certificate)
• Research injury compensation insurance documents
• Material transfer agreement (MTA) (must be uploaded according to each institution’s form)
• (Draft) Research project budget
• Letter of approval from the junior supervisor (separate documents by institution) (including a list of researchers at all data collection institutes in Thailand)
• Investigator CVs and evidence of good clinical practice (GCP) training or research ethics training
• Conflict of Interest Form completed by PIs/co-investigators (CREC form AP 06-S04) (separate documents by institution)
• Research Outline Completeness Check Form (CREC form AO 01-S04)
• PI for clinical trial phase I/II research projects (CREC form AP02-S04)
• Proof of fee payment

Refer to THA-34 and THA-38 for detailed CREC submission requirements.

Clinical Protocol

As delineated in ClinImprtOrdr, ClinSampleProd, G-ResEthics, and G-CT-DIPApp, the clinical protocol should include the following elements (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Protocol summary/synopsis
• General information (e.g., sponsor and investigator(s) name(s) and address(es))
• Background information (e.g., investigational product name and description)
• Trial objectives and purpose
• Trial design
• Number of trial participants
• Participant selection/withdrawal criteria
• Participant treatment
• Safety and efficacy assessments
• Quality control/quality assurance
• Adverse event reporting requirements (See the Safety Reporting section for additional information)
• Statistics and methods to track trial data
• Sponsor specifications for direct access to source data/documents
• Ethical considerations
• Data management and recordkeeping
• Financing and insurance details
• Publication policy
• Supplements
• Information about each research facility in Thailand
• Number of institutions participating in the research in Thailand
• Other countries where the research project is being conducted
• IMPs to be used

For complete protocol requirements, refer to ClinImprtOrdr and Annex 6 of G-ResEthics, which is directly based upon the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (THA-28) and the ICH guideline Structure and Content of Clinical Study Reports (E3) (THA-27). Per an in-country subject matter expert, Thailand is implementing THA-28. Both of these ICH guidelines are also referenced in G-ResEthics.

G-CT-DIPApp also provides protocol synopsis requirements for submission to the Thai FDA. Please refer to G-CT-DIPApp for detailed information.

In the instance of a multicenter clinical trial, G-ResEthics indicates that protocols submitted to each institutional EC should contain the same content and should specify the quality control techniques to ensure that the research practices are the same in each institution.

Also, see THA-13 for ECMOPH and THA-29 for CREC protocol submission requirements. (See also THA-18 and THA-76 for the forms included in the appendices in ClinSampleProd and ClinImprtOrdr.)

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

ClinImprtOrdr specifies that a drug import license application for clinical research purposes is submitted to the Thai Food and Drug Administration (Thai FDA) after the research project and all the research sites have been approved by the ethics committee (EC), or in parallel, pending review by at least one (1) EC involved in the study. Per ClinSampleProd and DrugProdReqs, the application to produce drug samples for the registration of drug formulas for human research studies must also be submitted to the Thai FDA either after the research project and all the research sites have been approved by an EC, or in parallel, pending review by at least one (1) EC involved in the study.

Regulatory Authority Approval

As specified in THA-78, the Thai FDA has 60 working days to evaluate an application to import or order drugs in the country for clinical research (N.Y.M.1); 60 working days to evaluate an application to produce drug samples to request modern drug registration for human research studies (P.Y.8); 20 working days to review an application to amend a N.Y.M.1 or P.Y.8 submission; one (1) working day to review an application for a certificate of pharmaceutical product (Certificate of Pharmaceutical Product/Certificate of Free Sale); and 30 working days to evaluate the accuracy and translation of a Good Manufacturing Practice (GMP) assessment report from a Thai version to an English version.

Per G-CT-DIPApp, upon receipt of an application package, the Thai FDA’s One Stop Service & Consultation Center (OSSC) (THA-35) sends the application package to an officer in the Thai FDA’s International Affairs and Investigational Drug Section. The officer then screens the package for completeness and informs the eligible sponsor of the results within five (5) working days from the date the application was received. If deemed complete, the officer sends the package to the assigned technical reviewer to proceed. If the officer finds the package to be incomplete, a “Screening Result Notification form” will be sent to the applicant or the applicant’s attorney for correction. If the applicant or the applicant’s attorney fails to fully correct the package within five (5) working days, then the Thai FDA will send a rejection letter and return all the documents to the applicant. However, the applicant may later correct or amend the application package and resubmit it to the OSSC. Once the correction is completed, the officer will send the application package to the assigned reviewer to proceed.

Per G-CT-DIPApp, the reviewer then receives the application package and performs a technical assessment. If the reviewer determines the package is technically correct, then it will be forwarded to the Thai FDA’s Secretary-General for approval. If the reviewer finds the application package technically incorrect, then it will be forwarded to the Thai FDA’s Secretary-General for rejection. If the reviewer finds the technical information to be incomplete, then the applicant or the applicant’s attorney will be asked to clarify and/or submit additional documents/information. If the documentation or amended information is not submitted within five (5) working days, the Thai FDA will issue a rejection letter and return the package to the applicant. However, the applicant may resubmit a corrected package to THA-35 (timeline not specified in G-CT-DIPApp). If the applicant can completely correct the application package, the officer will forward the package to the assigned reviewer for re-assessment.

In addition, ClinImprtOrdr and ClinSampleProd further specify that once the Thai FDA receives the EC approval documentation, the agency will complete its review within 15 days. See also THA-18 (Appendix 13) and THA-76 (Appendix 9) for the form to submit results of EC review to the Thai FDA. Refer to the Submission Process and Submission Content sections for detailed submission requirements.

Ethics Committee Approval

The review and approval process by a Thai FDA recognized EC will vary by institution. However, according to THA-13, which provides the Ethical Review Committee for Research in Human Subjects, Ministry of Public Health (ECMOPH) requirements, and THA-5, which provides more general EC requirements, the EC review and approval process can take between two (2) and three (3) months.

Per G-ResEthics, each EC should establish its own requirements for protocol submission and timeline of review.

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 ClinSampleProd, ClinImprtOrdr, and ECRegProc, a clinical trial can only commence after a sponsor receives approval of a drug import application for clinical research purposes or of a request to produce drug samples for human research studies from the Thai Food and Drug Administration (Thai FDA), as well as approval to conduct the clinical trial from a Thai FDA recognized ethics committee (EC). No waiting period is required following the sponsor’s receipt of these approvals. (See also THA-18 and THA-76 for the forms included in the appendices in ClinImprtOrdr and ClinSampleProd.)

Additionally, the clinical trial should be conducted in compliance with the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (THA-28). Per an in-country subject matter expert, Thailand is now implementing THA-28.

Clinical Trial Agreement

G-ResEthics and THA-28 require the sponsor to sign a letter of agreement with the participating institution(s) before the trial begins. THA-28 also notes that any agreements between the sponsor and the investigator(s)/institution(s) and any other parties involved with the trial should be in writing either as part of the protocol or in a separate agreement.

Per THA-14, researchers should also abide by research obligations and agreements specified by and entered into with fellow researchers, funding agencies, and their affiliates.

Clinical Trial Registration

The ClinImprtOrdr application document checklist (Appendix 3) includes clinical trial registry information as one (1) of the items to be included in the application submission package, specifying that sponsors may register with either the Thai Clinical Trials Registry (TCTR) (THA-31) or a foreign registry. Sponsors may register in more than one (1) location.

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 ClinImprtOrdr, ClinSampleProd, G-AEReptReqs, and the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (THA-28), the following definitions provide a basis for a common understanding of Thailand’s safety reporting requirements:

• Adverse Event (AE) – Any untoward or unfavorable medical occurrence in a research participant to whom a drug product was administered, and which does not necessarily bear a causal relationship to the treatment
• Adverse Drug Reaction (ADR) – All dangerous and adverse reactions resulting from any dose of an investigational drug, for which it is at least reasonably likely that the adverse reaction is attributable to the drug being studied, that is, a relationship cannot be ruled out
• Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (SADR) – Any untoward medical occurrence that at any dose: results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect
• Suspected Unexpected Serious Adverse Reaction (SUSAR) – An unexpected SAE/SADR given the nature of the research procedures and the population being studied
• Unexpected Adverse Event/Adverse Drug Reaction – A reaction where the nature or severity is inconsistent with the applicable product information

Per an in-country subject matter expert, Thailand is implementing THA-28. THA-28 also notes that the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (E2A) (THA-26) should be referenced for additional safety terms not defined in this list.

Safety Reporting Requirements

Investigator Responsibilities

As stated in G-AEReptReqs, the principal investigator (PI) is responsible for reporting all SAEs/SADRs to the sponsor and the ethics committee (EC) no later than 24 hours after the PI becomes aware of the event. The PI must also report all AEs/ADRs to the sponsor and the EC no later than seven (7) calendar days following first knowledge.

For safety reporting requirements specific to the Ethical Review Committee for Research in Human Subjects, Ministry of Public Health (ECMOPH) and the Central Research Ethics Committee (CREC), please see THA-13 and THA-37 respectively.

Sponsor Responsibilities

As delineated in THA-28, sponsors who are permitted to import or order drugs for research in Thailand and those who are licensed to produce drug samples for human research studies, must comply with the Thai Food and Drug Administration (Thai FDA)’s safety monitoring and reporting requirements. ClinImprtOrdr and ClinSampleProd state that the following information is viewed as urgent and is required to be reported:

• SAEs/SADRs that never occurred before because the research team used safety reporting information from other countries to substantiate investigational product (IP) use
• Other safety and security information useful to evaluating IP risk-benefit assessment, IP changes to the method of administration, or changes required to the overall research process
• Unexpected SAE/SADR incidents that never occurred before, with an increased incidence or severity and considered to be of clinical importance
• Significant harm to the participant, such as the ineffectiveness of an IP used to treat a life-threatening disease
• Significant new information about experimental animal safety studies, such as carcinogenicity

Per ClinImprtOrdr and ClinSampleProd, an ADR report must be filed in the following specified timelines:

• Unexpected SAEs/SADRs that are fatal or life-threatening must be reported to the Thai FDA within seven (7) days from the first knowledge of the incident’s occurrence. Any additional relevant information should be sent within eight (8) days of the initial report
• Unexpected SAEs/SADRs that are not fatal or life-threatening must be reported to the Thai FDA within 15 days from the date of SAE/SADR notification. A report must also be submitted periodically with any additional information.
• AEs/ADRs that occur following the research participant’s participation in the study or after the study has been completed must be reported within 15 days from first knowledge of the event

According to G-AEReptReqs and G-ResEthics, the sponsor is also required to report all SUSARs to the EC as soon as possible, but no later than seven (7) calendar days for all fatal or life-threatening events, and no later than 15 calendar days for any non-fatal or non-life-threatening events. The sponsor must include the main points of concern. In addition, the sponsor must report to the EC any other non-local adverse reactions that may increase risks to participants within 15 days. Additionally, the sponsor must report any non-local SAEs/SADRs including SUSARs at least every six (6) months to the EC.

G-ResEthics and THA-28 state that the sponsor is responsible for expediting the reporting of all SUSARs to the investigator(s)/institution(s) participating in the trial, the EC(s), and to the Thai FDA. These reports should comply with G-AEReptReqs and the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (E2A) (THA-26). See G-AEReptReqs for detailed reporting requirements for the investigator and sponsor.

Other Safety Reports

THA-28 indicates that the sponsor should submit to the Thai FDA all safety updates and periodic reports as required by applicable regulatory requirements. The sponsor is also responsible for the ongoing safety evaluation of investigational drug(s) and should promptly notify all concerned parties of findings that could adversely impact the safety of research participants, the conduct of the trial, or alter the EC’s approval or favorable opinion to continue the trial.

Per ClinImprtOrdr and ClinSampleProd, annual and end of study safety reports must be provided to the New Drugs and Drug Research Promotion Group within the Thai FDA’s Medicines Regulation Division. The annual report must be submitted as a document within three (3) months of the one (1) year anniversary of the study, and the final safety report must be submitted as a document within six (6) months after the study has concluded. In addition, a list of all SAE/SADR incidents involving research participant(s) should be included in the annual report. A detailed summary table with the number of SAEs/SADRs organized by terminology (symptoms and diagnosis) should be provided. See Appendix 21 in ClinImprtOrdr (Appendix 21 in THA-18) and Appendix 17 in ClinSampleProd (Appendix 17 in THA-76) for an example of the reporting form.

ClinImprtOrdr and ClinSampleProd further notes that other reports must be made in writing with information such as summary of risk assessment issues and related details for submission to the New Drugs and Drug Research Promotion Group.

Form Completion & Delivery Requirements

As per G-AEReptReqs, all SAEs/SADRs and SUSARs must be reported on the Thai FDA’s Health Product Vigilance Center (HPVC) (THA-30) SAE reporting form (THA-22) or the Council for International Organizations of Medical Sciences (CIOMS)’ form (THA-20). According to THA-37 and THA-20, AEs/ADRs and SAEs/SADRs must be reported to the Thai FDA. THA-22 indicates that the SAE form should be sent to the HPVC via mail, fax, or email at:

Health Product Vigilance Center
Food and Drug Administration
Ministry of Public Health
88/24 Tiwanon Road
Nonthaburi 11000
Thailand

Fax: 02 590 7253 or 02 591 8457
Email: adr@fda.moph.go.th

Pursuant to ClinImprtOrdr and ClinSampleProd, individual reports should be submitted electronically via the Thai FDA’s HPVC (THA-30), unless the system is unavailable. The report may also be submitted as a document to the New Drugs and Drug Research Promotion Group within the Thai FDA’s Medicines Regulation Division.

Individual report data should include at minimum the following information:

• Research participant information for those that can be identified (e.g., participant codes)
• Investigational drugs used in research study
• AE/ADR symptoms or results suspected of being connected to the drugs
• Source of follow-up reports
• Research project code or name
• Reporting numbers (e.g., report number specified by sponsor)

Per ClinImprtOrdr and ClinSampleProd, for research studies involving participants whose identities are disclosed, submitted AE/ADR reports should include the participant codes unless the Thai FDA’s Office of the Board of Directors deems it necessary to reveal the code immediately.

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 delineated in G-ResEthics, the investigator(s) must submit progress reports on the status of the trial to the ethics committee (EC) at the designated interval (not specified). For high-risk research protocols, investigator(s) should report the progress more frequently than for a low-risk protocol. The investigator should also provide a proposed schedule to submit a progress report to the EC from the date of protocol submission for ethical review, which should be at least once a year.

The International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (THA-28) further notes that investigator(s) should submit a research summary report in writing to the EC once a year, or more often, as required by the EC. Investigator(s) should send a written report to the EC and the institution, if applicable, regarding any changes that may impact the research process and/or cause increased risk to the research participants. Per an in-country subject matter expert, Thailand is implementing THA-28.

In addition, according to ClinImprtOrdr and ClinSampleProd, the sponsor must submit a study progress report annually to the Director of the Thai Food and Drug Administration (Thai FDA)'s Medicines Regulation Division between October 1 and 31 every year until the study ends. Per ClinImprtOrdr, for N.Y.M.1/investigational product (IP) import applications, this report should be submitted using the progress report form in Appendix 15 in THA-18, and accompanied by a delivery letter to the Thai FDA’s Director of the Bureau of Medicine using the format in Appendix 14 in THA-18. Per ClinSampleProd, for P.Y.8/IP sample production applications, the report should be submitted using the progress report form in Appendix 11 in THA-76, and accompanied by a delivery letter to the Thai FDA’s Director of the Bureau of Medicine using the format in Appendix 10 in THA-76.

Requests that already have information in the FDA’s Skynet E-Submission System (THA-54) must submit documents according to the system’s procedures. See Submission Process section for detailed information on submitting information via the FDA’s Skynet E-Submission System (THA-54).

Final Report

As specified in ClinImprtOrdr, in the event of early termination of the research study, the sponsor must submit a summary report (Appendix 19 of ClinImprtOrdr) to the Thai FDA within 60 days after the closeout of the last study site.

G-ResEthics also requires investigator(s) to submit a final report to the EC upon the trial’s termination.

For reporting requirements specific to the Ethical Review Committee for Research in Human Subjects, Ministry of Public Health (ECMOPH), please see THA-13. Also, refer to THA-37 for Central Research Ethics Committee (CREC) reporting requirements. The ECMOPH and the CREC are both ECs recognized by the Thai FDA to review and approve clinical trial protocols.

Individual ECs should be contacted to confirm their specific requirements.

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.

In accordance with G-ResEthics, and the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (THA-28), a sponsor is defined as an individual, company, institution, or organization that takes responsibility for the initiation, management, and/or financing of a clinical trial. Per an in-country subject matter expert, Thailand is implementing THA-28.

Per G-ResEthics and THA-28, the Thai government also permits a sponsor to authorize a contract research organization (CRO) to perform one (1) or more of a sponsor’s trial-related duties and functions. However, the ultimate responsibility for the trial data’s quality and integrity always resides with the sponsor. Any trial-related responsibilities to be transferred and assumed by a CRO should be specified in a written agreement or contract. A sponsor may be domestic or foreign.

Per THA-65 and THA-77, although applicants residing outside Thailand cannot register directly with Digital ID (THA-89), they can request permission to authorize a juristic person who receives power of attorney to use the OSSC’s online consultation system (E-Consult) (THA-77) and to submit applications to the FDA’s Skynet E-Submission System (THA-54).

THA-28 also states that the sponsor may be a sponsor-investigator if the individual both initiates and conducts, alone or with others, a clinical trial, and under whose immediate direction the investigational product is administered or dispensed. The sponsor-investigator’s obligations include both those of a sponsor and those of an investigator.

According to THA-13, the Ethical Review Committee for Research in Human Subjects, Ministry of Public Health (ECMOPH) requires the sponsor and/or CRO to be legally registered in Thailand. The ECMOPH is one (1) of the ethics committees approved by the Thai Food and Drug Administration (Thai FDA) to approve clinical research protocols. See THA-13 for additional ECMOPH sponsor requirements.

Per ClinImprtOrdr, the sponsor is also referred to as the applicant or importer, and in ClinSampleProd, the sponsor is also referred to as applicant.

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

In accordance with G-ResEthics and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (THA-28), 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. Per an in-country subject matter expert, Thailand is implementing THA-28. THA-14 also states that researchers must have basic knowledge in the field of research.

Additionally, per THA-28 and G-ResEthics, the sponsor must define and allocate all study related duties and responsibilities to the relevant parties participating in the study. Prior to entering into an agreement with the investigator(s) and the institution(s) to conduct a study, the sponsor should provide the investigator(s) with the protocol and an investigator’s brochure.

Foreign Sponsor Responsibilities

No information is available regarding foreign sponsor regulatory requirements.

Data Safety Monitoring Board

Although not specified as a sponsor requirement, G-ResEthics, G-AEReptReqs, and THA-28 encourage the establishment of a Data Safety Monitoring Board.

Multicenter Studies

As delineated in G-ResEthics and THA-28, in the event of a multicenter clinical trial, the sponsor must ensure that:

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

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

ClinImprtOrdr and ClinSampleProd specify that financing and insurance information should be included in the study protocol and protocol summary. If not included in the protocol and research project summary, a financial/insurance agreement should be attached separately in the application package as one (1) of the documents that the ethics committee (EC) considers approved or certified (e.g., Patient Information Sheets, etc.). G-ResEthics also states that the sponsor should provide insurance or indemnify the investigator/institution against claims arising from the trial, except for claims that arise from malpractice and/or negligence, if required by applicable regulatory requirements.

Compensation

Injury or Death

As specified in ClinImprtOrdr, ClinSampleProd, G-ResEthics, G-CT-DIPApp, and the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (THA-28), the sponsor or the designated contract research organization (CRO) is responsible for providing information related to compensation in the event of trial-related injuries or death to research participants and/or their legal heirs. ClinImprtOrdr further states that payment of compensation (if any) will be determined on a monthly basis to participants involved in the research. (See THA-18 and THA-76 for the forms included in the appendices in ClinSampleProd and ClinImprtOrdr.)

Per an in-country subject matter expert, Thailand is implementing THA-28. The sponsor must also inform the participants of any available medical treatment in the event of trial-related injuries. MCEthics further indicates that medical practitioners are responsible for harm or damage because the research studies involving the participant were not the fault of the participant.

Trial Participation

As per G-ResEthics, Phase I trial participants should be compensated for travel, loss of work, or other expenses incurred while participating in the trial.

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

As stated in ClinImprtOrdr, ClinSampleProd, and G-ResEthics, 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 are generated, recorded, and reported in compliance with the protocol and the International Council for Harmonisation (ICH)'s Guideline for Good Clinical Practice E6(R2) (THA-28). Per an in-country subject matter expert, Thailand is implementing THA-28.

G-ResEthics and THA-28 explain that the sponsor is required to obtain 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.

G-ResEthics and THA-28 further specify that the sponsor must also obtain the investigator(s) and the institution(s) agreement to:

• Conduct the trial in compliance with THA-28, applicable regulatory requirement(s), and the protocol agreed to by the sponsor and approved by the ethics committee (EC)
• Comply with data recording and reporting procedures
• License monitoring, auditing, and inspection
• Retain essential documents until the sponsor informs them that they are no longer needed

Any agreements should be made in writing and the sponsor should sign the protocol, or a separate agreement.

Pursuant to G-ResEthics and THA-28, QC should be applied to each stage of data handling to ensure that all data are reliable and have been correctly processed. In addition, per THA-28, the sponsor should focus on trial activities essential to ensuring participant protection and the reliability of trial results. The quality management system should also 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 (Critical Process and Data Identification)
• Identify risks to critical trial processes and data (Risk Identification)
• Evaluate the identified risks against existing risk controls (Risk Evaluation)
• Decide which risks to reduce and/or which risks to accept (Risk Control)
• Document quality management activities and communicate to those involved in or affected by these activities (Risk Communication)
• Periodically review risk control measures to ascertain whether the implemented quality management activities are effective and relevant (Risk Review)
• 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 (Risk Reporting)

ClinImprtOrdr states that the trial must be conducted in accordance with the Good Clinical Practice (GCP) and Good Laboratory Practice (GLP) principles.

Monitoring Requirements

G-ResEthics and THA-28 note that the sponsor may choose to perform a clinical trial audit as part of its QA system. The purpose of the audit should be to evaluate trial conduct and compliance with the protocol, SOPs, and other applicable regulatory requirements. 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 SOPs, the auditor observations are documented, and data are available as needed for the Thai Food and Drug Administration (Thai FDA). No specific timeframe is provided for the audit process.

Per ClinImprtOrdr, the sponsor and investigator must facilitate the Thai FDA’s monitoring of the clinical trial to ensure compliance with GCP and GLP, safety reporting, and progress reporting requirements.

In addition, per THA-28, 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 onsite monitoring, a combination of onsite 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). See THA-28 for detailed information on the sponsor’s role in developing monitoring systems.

Premature Study Termination/Suspension

G-ResEthics and THA-28 state that if a trial is prematurely terminated or suspended, the sponsor should promptly inform the investigators/institutions and the regulatory authority(ies) of the termination or suspension and the reason(s) for the termination or suspension. The sponsor or the investigator/institution should also promptly inform the EC and provide the reasons for the study’s termination or suspension.

G-CT-DIPApp also specifies that in the event of the premature discontinuance of a trial, the Thai FDA must be notified no later than 30 working days after the date of discontinuance. G-CT-DIPApp further notes that a corresponding notification letter referring to the related approved import license along with supplemental documents as indicated in Appendix 13 is needed, and a corresponding notification letter along with supplement documents as indicated in Appendix 14 is needed. (Note: Appendices 13 and 14 as referenced in G-CT-DIPApp are only available in the ClinImprtOrdr.) As stated in ClinImprtOrdr and ClinSampleProd, at the conclusion or termination of a clinical trial, a summary report must also be submitted within 60 days after the closeout of the last study site. ClinImprtOrdr and ClinSampleProd further explain that details of remaining medicines to be destroyed and evidence supporting the destruction or return of the study drugs should also be included (Appendix 20 in ClinImprtOrdr and Appendix 16 in ClinSampleProd each contain a sample notification form required to be completed when terminating a research project). (See also THA-18 and THA-76 for the forms included in the appendices in ClinSampleProd and ClinImprtOrdr.)

Per G-CT-DIPApp, after the import license is granted, the applicant must also notify the Thai FDA when the clinical trial has been discontinued in its entirety or at any clinical trial site for reasons not related to the safety of clinical trial, or if the trial has been discontinued prematurely.

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 G-ResEthics and THA-28, when using electronic trial data processing systems, the sponsor must ensure that the electronic data processing system conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistency of intended performance, and that standard operating procedures are maintained for using these systems. Per THA-28, the sponsor’s approach to validate such systems should be based on a risk assessment that takes into consideration the intended use and the potential of the system to affect participant protection and reliability of trial results. Refer to G-ResEthics and THA-28 for detailed information on electronic trial data systems. ClinImprtOrdr and ClinSampleProd also note that sponsors should ensure that research facilities are prepared for inspections by the Thai Food and Drug Administration (Thai FDA) by ensuring that research participant source data and case report forms are stored in electronically based data collection systems.

Records Management

As set forth in G-ResEthics and THA-28, sponsor-specific essential documents should be retained until at least two (2) years after the last approval of a marketing application in an International Council for Harmonisation (ICH) region, until there are no pending or contemplated marketing applications, or at least two (2) years have elapsed since the formal discontinuation of an investigational product’s clinical development. The sponsor should inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed.

In addition, THA-28 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

The PDPA defines the “data controller” as the person or juristic person having the power and duties to make decisions regarding the collection, use, or disclosure of the personal data.

Data Protection

Per the PDPA, the data controller must ensure that collected personal data remains accurate, up-to-date, complete, and not misleading. Personal data collection must be limited to the extent necessary in relation to the lawful purpose of the data controller. The data controller’s purpose for collecting data must meet one (1) of the purposes specified in the PDPA in order to be permitted to collect personal data, with the data subject’s explicit consent (see Section 23 of PDPA for details).

PDPA further specifies that personal data includes health and genetic data and requires the data subject’s explicit consent. Permissible personal data collection includes data collected in the interest of public health, such as protecting against cross-border dangerous contagious diseases or epidemics which may be contagious or pestilent, or ensuring standards or quality of medicines, medicinal products, or medical devices, provided there are measures to safeguard the rights and freedom of the data subject, including the confidentiality of personal data. Additionally, in the event that the data controller sends or transfers personal data to a foreign country, the destination country or international organization that receives such personal data must have an adequate data protection standard, and must be carried out in accordance with the rules for personal data protection as prescribed by the Personal Data Protection Commission (PDPC). See PDPC-Estab and THA-62 for additional information on the PDPC. Refer to the PDPA for a detailed list of permissible data collection purposes.

As set forth in the PDPA, the data controller is responsible for the following duties:

• To provide appropriate security measures for preventing the unauthorized or unlawful loss, access to, use, alteration, correction, or disclosure of personal data; such measures must be reviewed when necessary, or when technology has changed in order to efficiently maintain proper security and safety, and also comply with the minimum standard specified by the PDPC
• In the case of personal data being provided to other persons or legal persons other than the data controller, the data controller must take action to prevent such person(s) from using or disclosing the personal data unlawfully or without authorization
• Establish an examination system for personal data erasure or destruction when the retention period ends, when the personal data is irrelevant or beyond the purpose necessary for which it has been collected, when the data subject has requested to do so, or when the data subject withdraws consent, except where the retention of such personal data is for the purpose of freedom of expression
• Notify the PDPC of any personal data breach without delay and, where feasible, within 72 hours after having become aware of it, unless such breach is unlikely to result in a risk to the rights and freedoms of the persons whose data have been breached

Refer to the PDPA for additional information on data controller responsibilities. See also PDPC-Breach, G-PDPBreaches, THA-15, THA-10, and THA-17 for data controller guidelines on assessing data breach risks and applicable PDPC reporting requirements.

As described in the PDPA, with regard to personal data record management, the data controller must maintain, at least, the following records in order to enable the data subject and the PDPC to monitor in either written or electronic form the following: the collected personal data; the purpose of the collection of personal data; data controller details; personal data retention period; rights and methods for access to the personal data, including the conditions regarding the person’s right to access their personal data and the conditions to access such data; personal data use or disclosure; rejection of or objection to a request for personal data; and details of the appropriate personal data security measures.

Per the PDPA, the data protection legislation states that a data protection officer must be designated in the event the data controller/data processor is deemed a public authority per the PDPC; if the activities of the data controller/data processor in the collection, use, or disclosure of personal data, or the system itself, requires regular monitoring, due to the large quantity of personal data; or, if the core activity of the data controller/data processor is the collection, use, or disclosure of personal data for which the explicit consent of the data subject has not been obtained. See the PDPA for guidance related to data protection officers. See also THA-61 for a detailed guidance on the PDPA.

Consent for Processing Personal Data

The PDPA states that the data controller must not collect, use, or disclose personal data, unless the data subject has given consent prior to or at the time of such collection, use, or disclosure, except in the case where the data controller is permitted to do so by the provisions of the PDPA or any other laws. These cases may include the preparation of historical documents or public interest archives, research, or statistics, or preventing or suppressing a danger to a person’s life, body, or health.

The PDPA specifies that a request for consent must be made explicitly in a written statement or via electronic means unless consent cannot be done by those means. In addition, the data controller must inform the data subject of the purpose for collecting, using, or disclosing the subject’s personal data. The request for consent must be presented in an easily accessible and intelligible form and with statements using clear and plain language that is neither deceptive nor misleading to the data subject. The data controller must also ensure that the data subject’s consent is freely given.

The PDPA further explains that the data subject may withdraw consent at any time. The withdrawal of consent must be as easy as giving consent, unless there is a restriction of the withdrawal of consent by law, or the contract which gives benefits to the data subject. However, the withdrawal of consent must not affect the collection, use, or disclosure of personal data that the data subject has already legally consented to. If the withdrawal of consent will affect the data subject in any manner, the data controller must inform the data subject of the consequences of withdrawal.

In the event that the data subject is a minor who is not sui juris by marriage or has no capacity as a sui juris person under the PDPA, the request for consent from such a data subject must be made as follows:

• In the event that giving consent is not an action that the minor is entitled to exercise independently, the consent of the holder of parental responsibility over the child must be obtained
• Where the minor is below the age of 10 years, the consent must be obtained from the holder of parental responsibility over the child
• In the event that the data subject is incompetent, the consent must be obtained from the custodian who has the power to act on behalf of the incompetent person
• In the event that the data subject is quasi-incompetent, the consent must be obtained from the curator who has the power to act on behalf of the quasi-incompetent person

The above stated provisions also apply to the withdrawal of data consent of the data subject, the notice given to the data subject, the exercise of rights of the data subject, the complaint of the data subject, and any other acts under the PDPA for the data subject who is a minor, an incompetent person, or a quasi-incompetent person.

Refer to the G-PDPConsent for detailed data controller guidance on obtaining consent, and the G-PDPNotif for data controller guidelines on the conditions to be assessed when notifying a data subject of the purpose and details related to collecting their personal data. THA-16 also provides useful information on these guidelines.

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 Thai clinical trials, a freely given informed consent must be obtained from each participant in accordance with the requirements set forth in ClinImprtOrdr, ClinSampleProd, G-ResEthics, G-CT-DIPApp, and the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (THA-28). Per an in-country subject matter expert, Thailand is implementing THA-28. MCEthics further states that a medical practitioner who conducts research studies and human experiments must obtain the consent of the participant and must be ready to protect the participant from harm arising from that experiment.

As per ClinImprtOrdr, ClinSampleProd, G-ResEthics, and THA-28, the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by an institutional ethics committee (EC) recognized by the Thai Food and Drug Administration (Thai FDA), and provided to the Thai FDA with the drug import license application to conduct a clinical trial. (See the Required Elements section for details on what should be included in the form.) (Note: The ICF is referred to as the Patient Information Sheet in G-CT-DIPApp.) (See also THA-18 and THA-76 for the forms included in the appendices in ClinSampleProd and ClinImprtOrdr.)

G-ResEthics and THA-28 state that the investigator(s) or the representative(s) must provide detailed research study information to the participant or legal representative/guardian. G-ResEthics and THA-28 also specify that the oral and written information concerning the trial, including the ICF, should be easy to understand and presented without coercion or unduly influencing a potential participant to enroll in the clinical trial. The participant and legal representative/guardian, should also be given adequate time to consider whether to participate. THA-11 also explains that patients who seek medical treatment have the right to receive truthful and adequate information about their illness, examination, treatment, advantages and disadvantages from the examination, and treatment from health professionals, in a language that patients can easily understand. Patients can then choose to make decisions about consenting or not consenting to the health professionals treating them, except in cases of urgent and life-threatening emergencies. THA-14 further states that researchers should take pains to explain the objectives and scope of their research to the human participants without deceiving or coercing them and they should not violate their participants’ rights as private individuals. Researchers should respect the rights and dignity of their human participants and enlist their consent prior to any research experiments involving human participants.

As per G-ResEthics and THA-28, none of the oral and written information concerning the research study, including the written ICF, should contain any language that causes the participant or legal representative/guardian to waive or to appear to waive legal rights, or that releases or appears to release the investigator(s), the institution, the sponsor, or their representatives from their liabilities for any negligence.

THA-13 provides informed consent documentation guidelines required by the Ethical Review Committee for Research in Human Subjects, Ministry of Public Health (ECMOPH), which is one (1) of the institutional ECs approved by the Thai FDA.

As noted in THA-34, the Central Research Ethics Committee (CREC) does not have its own informed consent documentation guidelines and directs investigators to the ICF template and checklist provided by the Forum for Ethical Review Committees in Thailand (FERCIT) (see THA-46 for document links).

Re-Consent

No information is currently available regarding re-consent requirements.

Language Requirements

As stated in ClinImprtOrdr and ClinSampleProd, the ICF content and accompanying information (Patient Information Sheet) should be presented in the participant’s language, must be submitted in Thai and translated to English, and certify that the text in other languages aligns with the Thai translation. G-CT-DIPApp also indicates that the Patient Information Sheet should be presented in Thai.

Documenting Consent

G-ResEthics and THA-28 state that the participant or legal representative/guardian, and the investigator(s) must sign and date the ICF. Where the participant is illiterate, or the legal representative/guardian is illiterate, verbal consent should be obtained in the presence of and countersigned by an impartial witness. The NatHlthAct also indicates that the participant’s consent must be obtained in writing prior to conducting the trial.

Waiver of Consent

As per G-ResEthics, the EC should establish the conditions under which an informed consent discussion and/or signing the ICF can be waived. In these cases, the investigator must explore other means to protect the participant’s confidentiality. For example, if the investigator uses information from a participant’s medical records, the investigator must also ensure that the ICF is kept in the medical record by having the participant sign the form in advance and keep it in the records, or by having the participant sign the ICF later. The EC will then consider waiving the informed consent as long as the investigator provides proof that the participant is informed about the method for collecting the data, and that the participant’s privacy is protected.

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 ClinImprtOrdr, ClinSampleProd, the G-ResEthics, and the G-CT-DIPApp, the informed consent form (ICF) (also referred to as the Patient Information Sheet in G-CT-DIPApp) should include the following statements or descriptions, as applicable (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• The study purpose and objectives
• The expected duration of research participant’s involvement in the trial
• Experimental aspects of the study
• The participant’s responsibilities in participating in the trial
• Any expected risks or discomforts to the participant, and when applicable, to an embryo, fetus, or nursing infant
• Disclosure of alternate procedures or treatments available to participants, including the benefits and risks
• The trial treatment(s) and the probability for random assignment to each treatment
• The research procedures to be followed, including all invasive procedures
• The expected benefits that can be obtained from the study; if no benefit is expected, the participant should be made aware of this
• Compensation and/or treatment available for the participant in the case of trial-related injury
• Payment of compensation (if any) determined on a monthly basis to research participants
• Various expenses (if any) for research participants
• That participation is voluntary, and that the participant may refuse to participate or withdraw from the study at any time without guilt or loss of benefits to which the participant is otherwise entitled
• That the Thai Food and Drug Administration (Thai FDA), research investigators, the ethics committee (EC), and regulatory agencies are permitted to directly inspect participant’s original medical records to validate the accuracy of clinical research procedures and/or other information without violating the participant's right to maintain confidentiality beyond the limits allowed by laws and regulations, and that, by signing a written ICF, the participant or legal representative/guardian is authorizing such access.
• The extent to which confidentiality of records identifying the participant will be maintained
• That the participant or legal representative/guardian will be notified in a timely manner if significant new findings develop during the course of the study which may affect the participant's willingness to continue
• Individuals to contact for further information regarding the trial, the rights of trial participants, and whom to contact in the event of trial-related injury
• Foreseeable circumstances under which the investigator(s) may remove the participant without consent
• Estimated number of participants participating in research for the entire project, and the number of participants at each institution in Thailand

THA-13 provides information sheet guidelines required by the Ethical Review Committee for Research in Human Subjects, Ministry of Public Health (ECMOPH), which is one (1) of the institutional ethics committees approved by the Thai FDA.

As noted in THA-34, the Central Research Ethics Committee (CREC) does not have its own informed consent documentation guidelines and directs investigators to the ICF template and checklist provided by the Forum for Ethical Review Committees in Thailand (FERCIT) (see THA-46 for document links).

See the Vulnerable Populations and Consent for Specimen sections for further information. See also Appendix 11 (Part 4) in THA-18 and Appendix 7 (Part 4) in THA-76 for a checklist of items to be included in the ICF.

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 G-ResEthics and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (THA-28), Thailand’s ethical standards promote respect for all human beings and safeguard the rights of research participants. The Declaration of Rights and Code of Conduct for Patients (THA-11) also states that every patient has the fundamental right to receive professional medical care and health care from health professionals without discrimination as provided for in the Constitution of the Kingdom of Thailand (B.E. 2560). Per an in-country subject matter expert, Thailand is implementing THA-28. ClinImprtOrdr, ClinSampleProd, G-ResEthics, THA-28, the NatHlthAct, and G-CT-DIPApp, state that a participant’s rights must also be clearly addressed in the informed consent form (ICF) (also referred to as the Patient Information Sheet) and during the informed consent process.

The Right to Participate, Abstain, or Withdraw

As set forth in ClinImprtOrdr, ClinSampleProd, G-ResEthics, G-CT-DIPApp, and THA-28, the participant or legal representative/guardian should be informed that participation is voluntary, that the participant may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled. NatHlthAct also states that the participant may withdraw consent at any time. THA-11 similarly states that the patient has the right to be fully informed in order to make a decision to participate or withdraw from being a participant in a health practitioner’s research.

The Right to Information

As delineated in ClinImprtOrdr, ClinSampleProd, G-ResEthics, the NatHlthAct, G-CT-DIPApp, and THA-28, a potential research participant or legal representative/guardian has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation for participation or injury/treatment, and any significant new information regarding the research study. THA-11 states that patients who seek medical treatment have the right to receive truthful and adequate information about their illness, examination, treatment, advantages and disadvantages from the examination, and treatment from health professionals, in a language that patients can easily understand. Patients can then choose to make decisions about consenting or not consenting to the health professionals treating them, except in cases of urgent and life-threatening emergency.

The Right to Privacy and Confidentiality

As per ClinImprtOrdr, ClinSampleProd, G-ResEthics, G-CT-DIPApp, and THA-28, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right. In addition, per G-ResEthics, which incorporates the principles of the Declaration of Helsinki (THA-45), every precaution should be taken to respect the privacy of the participant, the confidentiality of the participant’s information, and to minimize the impacts of the study on the participant. THA-11 further states that unless the patient’s permission or approved legal authorization is obtained, healthcare personnel cannot disclose the patient’s information.

The Right of Inquiry/Appeal

ClinImprtOrdr, ClinSampleProd, G-ResEthics, G-CT-DIPApp, and THA-28 state that the research participant or the legal representative/guardian should be provided with contact information for the sponsor and the investigator(s) to address trial-related inquiries. THA-11 similarly indicates that every patient has the right to know the name, surname, and profession of the healthcare personnel in charge.

The Right to Safety and Welfare

G-ResEthics 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. THA-14 explains that researchers should take full responsibility for the impact and consequences of their research regarding themselves, their research participants, and society at large.

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

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.

Per the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (THA-28), research participants involved in clinical research under emergency circumstances are viewed as vulnerable and should be provided additional protections to ensure their safety and well-being. Per an in-country subject matter expert, Thailand is implementing THA-28. In addition, per the Declaration of Rights and Code of Conduct for Patients (THA-11), patients who are in a life-threatening condition are entitled to immediate, urgent assistance from a healthcare practitioner as required, regardless of whether the patient requests assistance.

THA-28 explains that in an emergency, if the signed informed consent form (ICF) cannot be obtained from the research participant, the consent of the legal representative/guardian should be obtained. If prior consent cannot be obtained from the legal representative/guardian, the participant’s enrollment should follow measures specified in the protocol, and/or elsewhere, to ensure compliance with ethics committee (EC) and other applicable regulatory requirements. Documented EC approval to protect the participant’s rights, safety, and well-being must also be obtained. The participant or the legal representative/guardian should be informed about the trial as soon as possible and provide consent. Consent should also continue to be obtained throughout the trial as appropriate per THA-28. However, THA-11 further notes that except in an emergency, every patient has the right to obtain sufficient information regarding their illness from healthcare personnel prior to deciding to allow any treatment.

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 G-ResEthics and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (THA-28), in all Thai clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process. Per an in-country subject matter expert, Thailand is implementing THA-28.

G-ResEthics characterizes vulnerable populations as those who are dependent on others and are unable to express their opinion freely or make their own decisions. THA-28 adds that, whether reasonable or not, the participant may also consent to participate out of fear that they will be penalized for not participating. This may apply, for example, to members of a hierarchical organization such as medical, pharmacy, dental, or nursing students and lower-level hospital personnel and staff rooms. THA-28 also notes that participants in this study population may be persuaded to enter a trial with the hope of obtaining benefits from their participation in the research. Per G-ResEthics, these participants may include hospitalized patients, prisoners, children, the mentally impaired, critically ill and psychotic patients, pregnant women, and the disadvantaged. Per THA-28, other vulnerable participants may include drug company employees, soldiers, prisoners, patients with incurable diseases, emergency patients, unemployed or poor people, members of minority groups, the homeless, immigrants, and young people who are unable to give consent on their own.

The G-ResEthics specifies that trials involving vulnerable persons must meet the following requirements:

• Irrefutable rationale for conducting research clearly explained in the protocol
• Precautions against possible physical and mental harms exercised
• Appropriate research procedures used
• Ensure that, as applicable, the participant’s parents or legal representative/guardian are fully informed about the study
• Proof that the participants are voluntarily participating in the study
• Ensure that the possible risks should not be greater than minimal when a study will not have a direct health benefit to the vulnerable group, unless the ethics committee permits a greater than minimal risk study to be conducted

See the Children/Minors; Pregnant Women, Fetuses & Neonates; 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.

According to the ThaiCode, a minor is someone under 20 years of age or unmarried. The Ethical Review Committee for Research in Human Subjects, Ministry of Public Health (ECMOPH) guidelines (THA-13) specifies that the age suitable to give consent is 18 years or older. Per THA-37, according to the Central Research Ethics Committee (CREC), a minor is someone under 18 years of age. The ECMOPH and the CREC are both ethics committees (ECs) recognized by the Thai Food and Drug Administration (Thai FDA). The Declaration of Rights and Code of Conduct for Patients (THA-11) also indicates that a child is someone under 18 years of age.

As set forth in G-ResEthics, when the research participant is a minor, informed consent should be obtained from the parents, guardians, or legal representatives. Additionally, precautions against possible physical and mental harms should be exercised. Furthermore, the rights of the minors should be respected for their voluntary decision to participate in a clinical study. THA-11 similarly indicates that parents or legal guardians may exercise their rights on behalf of a child patient who is not over 18 years of age.

The International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (THA-28) states that when a clinical trial includes minors, the minor should be informed about the trial to the extent compatible with the minor’s understanding and, if capable, the minor should sign and personally date the written informed consent. Per an in-country subject matter expert, Thailand is implementing THA-28.

Assent Requirements

THA-13 specifies that assent is required for minors seven (7) through 18 years of age. Different assent forms should be created for the following age groups: seven (7) to 13 and over 13 until 18. Per THA-37, the CREC requires children 13 years of age and older to sign an assent form.

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 G-ResEthics, any Thai clinical studies involving pregnant women and fetuses require additional safeguards to ensure that the research conforms to appropriate ethical standards and upholds societal values. Adequate information on the safety and impacts to the fetus should also be made available.

In addition, the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (THA-28) indicates that the informed consent form should include a statement on the reasonably foreseeable risks or inconveniences to the participant, and when applicable, to an embryo, fetus, or nursing infant. Per an in-country subject matter expert, Thailand is implementing THA-28.

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.

According to G-ResEthics, prisoners are considered vulnerable because incarceration could affect their ability to make a voluntary decision regarding participation in research. A research study involving prisoners should ensure that these prospective participants are informed and are given the opportunity to make their own decisions without any interference from a higher authority.

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.

Per G-ResEthics, informed consent should be obtained from the legal representatives or guardians of participants for studies involving psychiatric or mentally incapacitated patients. The Declaration of Rights and Code of Conduct for Patients (THA-11) also states that parents or legal representatives may exercise their rights on behalf of a physically or mentally handicapped child patient who cannot exercise their rights on their own.

As further explained in MentalHlthAct, any research to be conducted with patients who are mentally impaired have the right to:

• Receive treatment according to medical standards that protect human dignity
• Have information about their illness and treatment kept confidential other than what is required to be disclosed by law
• Sign an ethics committee (EC) approved consent form prior to participation
• Receive equal access to state health insurance and social security systems

In addition, MentalHlthAct prohibits disclosure of health information of mentally impaired participants in a manner that may damage the individual, except in the event that the patient or others may be in danger, for public safety, or specific laws require this information to be disclosed.

MentalHlthAct also states that any research involving patients who are mentally impaired can only be performed after obtaining their consent as well as EC approval and approval from other relevant authorities to conduct the study. The patient’s approval may be revoked at any time. Treatment may only be administered once the patient has been informed as to why the treatment is necessary and provided with the details and benefits prior to giving consent. In the case of a patient under 18 years old, or one who lacks the ability to make decisions, the patient’s parent or legal guardian should provide consent. If the patient is to be admitted to a public hospital or treatment facility, signed consent is necessary. Research is permitted in the case of patients with mental impairments who are either facing dangerous conditions or compulsory treatment is required.

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

In accordance with G-ResEthics and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (THA-28), 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 it is used or assembled (formulated or packaged) in a different way from the approved form, when used for an unapproved indication, or when used to gain further information about an approved use. Per an in-country subject matter expert, Thailand is implementing THA-28.

G-ResEthics states that an investigational drug used in a clinical trial falls into one (1) of four (4) categories:

• New drugs
• Unregistered drugs in Thailand
• Drugs registered by the national drug authority, but being studied in new doses or indications not previously approved
• Locally produced drugs that require efficacy testing

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 the DrugAct, ClinSampleProd, and ClinImprtOrdr, the Thai Food and Drug Administration (Thai FDA) is responsible for authorizing the manufacture of investigational products (IPs) in Thailand. The Thai FDA will approve the manufacture of an IP after the clinical trial application has been approved.

As explained in ClinSampleProd, the Thai FDA’s approval of a request to manufacture drug samples for investigational purposes is obtained using the P.Y.8 form (ClinSampleProd (Appendix 1) or THA-76 (Appendix 1)).

ClinSampleProd specifies that the following information must be included with the P.Y.8 form (Appendix 1):

• Detailed list of manufactured drugs
• Appearance and color of medicine
• Number or quantity to be produced
• Quantity of drug ingredients (must be reported in metric units or in a percentage)
• Packaging size (packaging details)
• Specifying if drug samples are for human research studies or cases other than human research studies
• Drug label (two (2) copies)
• Medicine package document (two (2) copies)
• Other documents in the case of producing drug samples for human research studies

See also the Appendix 6 (Evidence of Drug Quality Information) in ClinSampleProd and (THA-76 (Appendix 6)) for additional requirements included on this form.

ClinSampleProd and ClinImprtOrdr, also state that the IP must be manufactured in accordance with good manufacturing practice (GMP) guidelines.

In addition, per ClinSampleProd, following the Thai FDA’s approval to manufacture IP samples, the applicant must also obtain approval prior to implementing changes in the following categories:

• Changes that must be notified
• Changes that require a change request to be submitted before proceeding, and
• Changes that require a new production permit request to be submitted

ClinSampleProd indicates that when the change complies with one (1) of the listed categories, the applicant should:

• Prepare documents and evidence according to the document self-check form for requesting changes using the Appendix 13 form or (THA-76 (Appendix 13))
• Submit a request to amend the details regarding permission using the Appendix 14 form or (THA-76 (Appendix 14)) (1 set)

Per ClinSampleProd, along with the Appendix 14 form, the applicant should attach relevant documents showing the revised section(s) and one (1) set of power of attorney documentation for each paper submission. ClinSampleProd notes that one (1) request can only change one (1) main issue. For example, in the case of requesting to extend the validity of medicines, this is a change in quality and results in a new expiration date label) to be submitted in one (1) request. Additionally, for amendment requests that refer to information already submitted via the FDA’s Skynet E-Submission System (THA-54), the applicant must submit documents according to the system's procedures.

For changes that require the Thai FDA’s Medicines Regulation Division to be notified, ClinSampleProd states that the applicant should submit a letter of explanation, refer to the sample drug production license for human research studies that has been received, and attach related documents showing the revised sections or other information that needs to be notified as detailed in the Appendix 15 form or (THA-76 (Appendix 15)).

Import

As delineated in ClinImprtOrdr, the Thai FDA is also responsible for authorizing the import of IPs. The Thai FDA’s approval of a drug import license application for clinical research purposes serves as the import license using the N.Y.M.1 form (ClinImprtOrdr (Appendix 2) and THA-18 (Appendix 2)). Per DrugImprtRules-1989 and DrugImprtRules-2009, all requests approved by the Thai FDA to order or import drugs into the country for research purposes are exempt from registration.

According to ClinImprtOrdr and THA-18, the following documents are also required to be submitted to the Thai FDA:

• Import license application/N.Y.M.1 (ClinImprtOrdr (Appendix 2) and THA-18 (Appendix 2))
• Summary of research project (Thai)
• Ethics committee (EC) approval letter
• Patient Information Sheet (in Thai)
• Complete research project details (in Thai or English)
• Drug labels for every package size (in Thai or English)
• Drug documentation (for drug formulas that have already been registered)
• Investigator’s brochure (IB) (for drugs not yet registered)
• Pharmaceutical quality control and production documents
• Drug name(s) (including dosage form, quantity, and details of every packaging size)

ClinImprtOrdr also states that the quantity of the IP must be calculated based on the number of study participants of each institute for the whole study duration in accordance with the information in the study protocol. The amount of the IP cannot exceed 20% to cover drug damage. Please refer to ClinImprtOrdr for more detailed IP supply requirements.

In addition, per G-CT-DIPApp, after the import license is granted, the applicant must inform or request permission from the Thai FDA prior to initiating the following:

• Changes to clinical trial drug supplies
• Changes to an approved protocol (protocol amendment) or changes related to or affecting participant safety
• In cases where the sponsor is required to immediately make one (1) or more amendments because the clinical trial or the use of IP in the trial endangers the health of a clinical trial participant or other person, the applicant may immediately make the amendment without prior review by the Thai FDA. A corresponding notification clearly identifying the change and the rationale for immediate implementation of the change must be filed within 15 working days after the amendment implementation date. A corresponding notification letter referring to the related approved import license (see ClinImprtOrdr (Appendix 2) and THA-18 (Appendix 2) for N.Y.M.1 form), along with supplemental documents as stated in Appendix 12, are also required. (Note: The Additional Amendment/Clarification Request Form referenced in G-CT-DIPApp as Appendix 12 is only available in ClinImprtOrdr and THA-18 (Appendix 12))

Furthermore, per G-CT-DIPApp, after the import license is granted, the applicant must also notify the Thai FDA in the following cases:

• Changes to the protocol that do not affect the safety of the trial participants
• When the clinical trial has been discontinued in its entirety or at any clinical trial site for reasons not related to the safety of clinical trial participants
• IB changes
• Chemistry and manufacturing or quality changes that do not affect drug quality or safety
• Premature discontinuation of a trial (See the Risk & Quality Management section for detailed notification requirements)

Per THA-19, a request for an expedited license to order or import IPs may also be submitted to the Thai FDA for the following:

• Clinical research purposes
• To produce sample IPs for human research
• To expand the scope of drug results for human research to include a new research project
• To address a public health emergency
• To address an urgent clinical research need, in the event a facility runs out of an IP (an EC waiver may be required)

See the Regulatory Fees section for information on IP import fees. See also the Submission Process section for instructions on submitting a drug import waiver request to the Thai FDA.

The DrugAct states that a license will remain valid until December 31st of the year of issue. The license holder who would like to renew the license must file an application for renewal prior to the license expiration date. Once the renewal application has been filed, the license holder may continue to conduct business unless the renewal request is denied. A license holder whose license has expired for not more than one (1) month may file an exemption indicating the reason for obtaining a license extension. However, an application renewal request submitted after one (1) month from the date of license expiration is not permitted. In the event that the Thai FDA does not issue or grant a license renewal request, the applicant may appeal in writing to the Minister within 30 days from the date of receiving the notice rejecting the request. The applicant may obtain a temporary license to operate the business until a final decision is issued by the Minister.

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 ClinImprtOrdr, ClinSampleProd, G-ResEthics, G-CT-DIPApp, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (THA-28), the sponsor or the designated contract research organization (CRO) is responsible for providing the investigators with an Investigator’s Brochure (IB). The IB must contain all of the relevant information on the investigational product(s) (IPs) obtained through the earlier research phases, including preclinical, toxicological, safety, efficacy, and adverse events data. The sponsor should also update the IB as significant new information becomes available. Per an in-country subject matter expert, Thailand is implementing THA-28. ClinImprtOrdr and ClinSampleProd further state that the IB should comply with the current version of THA-28. Per ClinImprtOrdr, the sponsor is also referred to as the applicant or importer.

As specified in G-ResEthics, ClinImprtOrdr, and ClinSampleProd, and in accordance with THA-28, the IB must provide coverage of the following areas:

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

See Section 7 of THA-28 for detailed content guidelines.

ClinImprtOrdr and ClinSampleProd also indicate that evidence must be provided that the IB has been submitted to the ethics committee. In addition, per G-CT-DIPApp, the applicant must notify the Thai Food and Drug Administration (Thai FDA) of changes to the IB after the import license is granted.

Quality Management

ClinImprtOrdr and ClinSampleProd also state that the IP must be manufactured in accordance with Good Manufacturing Practice (GMP) guidelines.

As stated in ClinImprtOrdr, ClinSampleProd, and the DrugAct, the Thai FDA requires the manufacturer to provide the following (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Evidence of manufacture under conditions compliant with current GMPs
• A Certificate of Analysis for each batch of IPs (must be in Thai if the manufacturer is foreign)
• A drug registered in a foreign country is required to have a Certificate of Product (CPP)/Certificate of Free Sale (CFS)/evidence of registration from the Drug Control Department from that country and certified by a qualified translator
• A Certificate of Free Sale
• In the case that the product is approved for marketing authorization in Thailand, provide a copy of certificate of drug registration and evidence that the imported drug and the registered drug are produced by the same manufacturer

Per G-CT-DIPApp, the chemistry, manufacturing and control (CMC) information for an IP submission to the Thai FDA must comply with specific requirements for a new chemical entity. Depending on the phase of the clinical trial, the completed CMC template, as well as the following additional quality information as outlined in the template, must be submitted (Note: The appendices referenced in G-CT-DIPApp are only available as Appendices 7 and 8 in the ClinImprtOrdr and Appendices 7 and 8 in THA-18.)

Additionally, per ClinImprtOrdr, in cases where an applicant submits “Drug quality control and production documents” for drug formulas registered in Thailand, the drug documentation approved by the Thai FDA must be used. When the “Drug quality control and production documents” are for drug formulas registered in other countries, the drug documentation of the specific country should be used. If the documentation is in a language other than English, it should be translated to Thai or English, and certified that the text in other languages matches the Thai/English language. See Appendix 7 of ClinImprtOrdr or THA-18 (Appendix 7) for additional information.

Per G-CT-DIPApp, after the import license is granted, the applicant must also notify the Thai FDA of chemistry and manufacturing or quality changes that do not affect drug quality or safety.

See also THA-18 and THA-76 for the forms included in the appendices in ClinImprtOrdr and ClinSampleProd.

Refer to the Product Management section for additional information on IP supply, storage, and handling requirements, and the Submission Process and Submission Content sections for detailed application requirements.

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 product (IP) labeling in Thailand must comply with the requirements set forth in ClinImprtOrdr, ClinSampleProd, G-ResEthics, G-CT-DIPApp, the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (THA-28). Per an in-country subject matter expert, Thailand is implementing THA-28. G-ResEthics and THA-28 state that the IP must be coded and labeled in a manner that protects blinding, if applicable. In addition, per G-CT-DIPApp, if a drug product is registered in Thailand, a certified copy of a certificate(s) of drug registration by the Thai Food and Drug Administration (Thai FDA) must be submitted.

ClinImprtOrdr, ClinSampleProd, and G-CT-DIPApp specify that in general, primary and secondary labels must contain (at least) the following requirements (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• All containers and packaging of all sizes are to use the same format as the actual label
• Thai language should be used, except for the drug name/drug code and research project sponsor information, where Thai or English language may be used; in the case of drugs administered by medical study personnel, the label information may be submitted in Thai or English
• Drug name/drug code, strength, pharmaceutical form, drug delivery system, unit quantity; in the case of a blind treatment study, the label must specify: “Placebo or [Drug Name/Drug Code] + [Strength]”
• Research project code or name
• Production model and/or code number to identify components and packaging process
• Participant number or treatment number and appointment number (if applicable)
• Methods of drug use may refer to documentation specifically describing participants (such as drug use records) or to communicate how medical study personnel can correctly administer the drug product
• Name, address, and telephone of the sponsor, contract research organization (CRO), or the investigator (main point of contact for clinical research product information and emergency treatment disclosure), unless the participant receives an identification card displaying this information (with attached documents) and is advised to keep this document in their possession at all times
• Statement indicating “for clinical research purposes only” or in other words with the same meaning in the Thai language
• Drug storage conditions
• Period of use (use as appropriate within the expiration date or retest date) in months/years and in a manner that avoids ambiguity
• Statement indicating “keep out of the reach of children” in Thai or in other words meaning the same in Thai, unless the participant is not going to take home the medicine

As described in ClinImprtOrdr and ClinSampleProd, primary labels where the primary packaging is always combined with the secondary packaging, should consist of (at least) the following:

• Drug name/drug code, strength, pharmaceutical form, drug delivery system (the dosing route may not be established for the oral solid dosage form), unit quantity, in the case of blind treatment study, specify: “placebo or [drug name/drug code] + [strength]"
• Research project code or name
• Production model and/or code number to identify the components and packaging procedure
• Participant number or treatment number and appointment number (if applicable)
• Sponsor/CRO/investigator name

Refer to ClinImprtOrdr and ClinSampleProd for additional primary label requirements.

Per ClinImprtOrdr and ClinSampleProd, drug labeling must be carried out in a facility licensed to manufacture drugs and in accordance with the DrugProdReqs (see Appendix 12). As indicated in ClinImprtOrdr and ClinSampleProd, in the case of drug preparation for administration at the research site, new labels must be attached to the drug package to be used (e.g., injectable drug preparations, preparing to dispense drugs to be taken immediately, etc.). The applicant must ensure that the principal investigator (PI) or designee:

• Prepare label(s) or label image(s) with appropriate and accurate information for the purposes of the research project
• Prepare a standard operating procedure (SOP) manual or a standardized method for preparing drugs and labeling drugs in accordance with the rules and methods for producing modern drugs
• Ensure the SOPs are administered by a pharmacist or other health professional at the research site who has received appropriate training
• Provide evidence to document that practices have been inspected by a second party under strict labeling control
• Preserve evidence and record various related documents to support inspection by the authorized person or the Medicines Regulation Division

The applicant does not need to submit a label in this case along with the request, but must ensure that the PI or designee complies with these requirements and is always available for inspection or inspection of the research.

Per ClinImprtOrdr, for labels on drugs authorized for importation or ordering into Thailand for research purposes and that have been submitted to the Medicines Regulation Division, the applicant may refer to the original application document if there is no change from the original submission. As described in ClinImprtOrdr, in the case of a request to change the information on the duration of drug use, an additional label indicating the new date and using the original production version should be added. The new label(s) or label image(s) should be submitted in the same format as the original label used, which may cover the original date. However, the new label must not cover the original production version for quality control reasons, and the labeling must be performed at a facility licensed to manufacture the drugs. If necessary, the on-site labeling requirement may be waived. In such cases, the drug must be labeled by a pharmacist or other health professional at the site, or an appropriately trained research supervisor.

Similarly, per ClinSampleProd, for drug labels previously submitted to the Medicines Regulation Division to produce drug samples for human research studies, the applicant may refer to the original document, if it has not been amended. Additionally, the requirements for requesting a change to the period of use on the drug label also follow the same requirements as those delineated for ClinImprtOrdr.

Per ClinImprtOrdr and ClinSampleProd, if necessary, the applicant may request that the Medicines Regulation Division consider a waiver of drug label requirements in the following cases:

• Information on drug labels for clinical drug research projects that are conducted in many countries and cannot be changed in a timely manner upon submission of the first authorization request (passing the application review and entry into the system)
• Information on the label that may refer to other documents (e.g., reference method of dosage administration, record of drug use, etc.) should be attached to the reference document with an explanation
• Additional labeling after the drug is brought into Thailand in order to comply with the requirements for research drug labels: a label(s) or label image(s) must appear in the same format as the actual label; information on the label that may refer to other documents, such as how to give medicine, reference to medication records, etc., by attaching the reference document with an explanation; the place of labeling is a licensed facility to produce the correct drug, or, if necessary, a waiver may be requested for the labeling operation to be in a controlled location instead. In such cases, labeling procedures must be performed by a pharmacist or other research site health professional, or by an appropriately trained research supervisor. Operational procedures and a record of practices should be prepared, and these documents should be checked by a second person. The labeling should be strictly controlled, and operations must be consistent with modern drug production manufacturing guidelines and procedures.

In addition to completing the Request for Drug Waiver in Specific Cases Form (see Appendix 6 of ClinImprtOrdr, Appendix 6 of THA-18, Appendix 5 of ClinSampleProd, or Appendix 5 of THA-76), the reasons should be stated, and the SOPs should be attached.

ClinImprtOrdr and ClinSampleProd state that recommendations for how the drug is to be used should be identified in the protocol for use in accordance with the established indications. If the drug is registered in Thailand as a drug procured from the market in Thailand, there is no need to obtain approval for another production process or packing process. The following should be added to the original container, but not over the original label:

• Sponsor, CRO, or investigator name
• Research project code
• Statements "for clinical research purposes only" or other words synonymous with the Thai language

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 G-ResEthics and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (THA-28), the sponsor or the designated contract research organization (CRO) must supply the investigator(s)/institution(s) with the investigational products (IPs), including the comparator(s) and placebo, if applicable. The sponsor or the designated CRO should not supply either party with the IP(s) until approval is obtained from the Thai Food and Drug Administration (Thai FDA) and the Ethical Review Committee for Research in Human Subjects, Ministry of Public Health (ECMOPH), another ethics committee (EC) (e.g., the Central Research Ethics Committee (CREC)), and/or the local EC. The ECMOPH and the CREC are both ECs recognized by the Thai FDA. Per an in-country subject matter expert, Thailand is implementing THA-28.

G-ResEthics and THA-28 specify that the sponsor or the designated CRO must ensure the following:

• Timely delivery of the IP(s)
• Records maintained for document shipment of the IP(s)
• Written procedures including instructions for handling and storage of the IP(s), adequate and safe receipt of the IP(s), dispensing of the IP(s), retrieval of unused IP(s), return of unused IP(s) to the sponsor, and disposal of unused IP(s) by the sponsor
• 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 IP handling and storage conditions and shelf life

Refer to the G-ResEthics and THA-28 for detailed, sponsor-related IP requirements. As defined in G-ResEthics and THA-28, the sponsor is also accountable for supplying the IP, including the comparator(s) and placebo, if applicable.

Record Requirements

As per G-ResEthics and THA-28, the sponsor should inform the investigator(s) and institution(s) in writing of the need for record retention and should notify the investigator(s) and institution(s) in writing when the trial related records are no longer needed. Additionally, the sponsor must ensure sufficient quantities of the IP(s) used in the trial to reconfirm specifications, should this become necessary, and should maintain records of batch sample analyses and characteristics. All sponsor-specific essential documents should be retained for at least two (2) years after formal discontinuation of the trial or in conformance with applicable regulatory requirements.