In Bangladesh, the Ministry of Health and Family Welfare (MOHFW)’s Directorate General of Drug Administration (DGDA) and the Bangladesh Medical Research Council (BMRC) are involved in clinical trial oversight and coordination.

Directorate General of Drug Administration

As per the DrugsCosAct, the BGD-GCP, and the G-IndCTA, the DGDA is the regulatory authority responsible for clinical trial oversight and inspections in Bangladesh. According to the DrugsCosAct, the DGDA also licenses establishments involved with manufacturing, sale, importing, and exporting of drugs; implements pharmacovigilance activities; and inspects and supervises establishments that manufacture and sell drugs.

The BGD-GCP indicates that the DGDA provides the legal framework for clinical trials. The DGDA’s responsibilities include approval and inspection of clinical trial facilities, study protocol approval, and authorizing the import of clinical trial investigational products, with the goal of protecting the safety and rights of trial participants and ensuring that trials are adequately designed to meet scientifically sound objectives. In addition, the DGDA approves and oversees ethics committee (EC) activities (Note: ECs are also referred to as independent ethics committees (IECs)/institutional review boards (IRBs) in Bangladesh).

According to BGD-8 and BGD-13, the DGDA also ensures the quality, safety, efficacy, and usefulness of drugs and medicines which are produced, imported, and marketed in Bangladesh, as well as exported overseas. This includes issuing and renewing licenses for drug manufacturing. Additionally, the DGDA evaluates the proposals of new projects of all systems of medicines and engages in pharmacovigilance activities. See BGD-9 and BGD-12 for the DGDA organogram.

Bangladesh Medical Research Council

The G-BMRC indicates that the BMRC is an autonomous body that operates under the MOHFW. The BMRC’s objectives are to identify problems and issues relating to medical and health sciences and to determine priority areas in research based on healthcare needs, goals, policies, and objectives. The BMRC also provides advice on all health research related matters to government departments and international agencies.

As per the G-BMRC and BGD-36, the BMRC organizes and promotes scientific research in various fields of medicine, public health, reproductive health, and nutrition with specific references to primary health care needs for the application and utilization of health research results. BGD-36 further indicates that the BMRC trains the health research workforce through workshops/training programs, and organizes and disseminates research information through publications, research seminars, workshops, and orientation courses. Additionally, the BMRC initiates, assists, promotes, and coordinates scientific research in the field of health in medical institutions and helps such institutions in developing expertise and facilities for health research.

As stated in the G-BMRC and BGD-16, any health research to be conducted in Bangladesh must be registered with the BMRC. In addition to obtaining the DGDA’s permission to conduct research in Bangladesh, an applicant must obtain ethics approval from the BMRC’s National Research Ethics Committee (NREC). For more information on the NREC, see the Ethics Committee section.

Please note: Bangladesh is party to the Nagoya Protocol on Access and Benefit-sharing (BGD-2), 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 BGD-4.

Contact Information

Directorate General of Drug Administration

According to BGD-13 and BGD-28, the DGDA’s contact information is as follows:

Directorate General of Drug Administration
Aushad Bhavan
Mohakhali, Dhaka-1212, Bangladesh

Phone: +8802-9880803, +8802-9880864, +8802-9880897, +8802-9880924
Fax: +8802-9880854
Email: dgda.gov@gmail.com

Bangladesh Medical Research Council

As per BGD-30, the BMRC’s contact information is as follows:

Bangladesh Medical Research Council
BMRC Bhaban
Mohakhali, Dhaka-1212, Bangladesh

Phone: +8802-222299311, +8802-222298396
Fax: +880-2-222263820
Email: info@bmrcbd.org

Overview

As per the BGD-GCP and the G-IndCTA, the Ministry of Health and Family Welfare (MOHFW)’s Directorate General of Drug Administration (DGDA) is responsible for reviewing, evaluating, and approving clinical trial applications for drugs in Bangladesh. According to the G-BMRC, Phase I-III clinical trials require DGDA clearance, while all phases require ethics committee (EC) (referred to as an independent ethics committee (IEC)/institutional review board (IRB) in Bangladesh) approval.

The BGD-GCP and BGD-22 indicate that a protocol approved by an EC/the Bangladesh Medical Research Council (BMRC) is a required element of a clinical trial application to the DGDA. Therefore, DGDA review and ethics review may not be conducted in parallel. (Note: According to the G-BMRC and BGD-16, the BMRC’s National Research Ethics Committee (NREC) is registered with the US Office for Human Research Protections (OHRP) as an official IRB.)

See the Scope of Review section for detailed information on ethical approval processes.

Clinical Trial Review Process

According to the BGD-GCP, the DGDA must ensure that clinical trial protocols are submitted in advance for review and in accordance with existing national regulations. During its review of clinical trial protocols and/or reports, the DGDA may propose revisions or request additional data on a clinical trial or terminate a trial. The DGDA also evaluates the adequacy of supervision of the trial by reviewing the monitor’s reports to the sponsor. The principal investigator (PI) or contract research organization (CRO) is responsible for submitting the clinical trial application. (Note: Conversely, the G-IndCTA states that the sponsor is responsible for submitting the application.)

As delineated in the DrugsCosAct, the DGDA may obtain a legal opinion or technical analysis/opinion on any matter from one (1) or more persons who are experts or have special knowledge/experience in the matter concerned or may invite them to attend meetings. The BGD-GCP states that the MOHFW’s Clinical Trial Advisory Committee, an expert committee comprised of medical experts of different specialties, supports the DGDA with evaluating/reviewing protocols. In the case of major or critical noncompliance, such as a faulty trial design, the Clinical Trial Advisory Committee will not recommend the protocol for approval. The DGDA’s Clinical Trial Cell will issue a notice to the PI, specifying the reasons for disapproval of the protocol as recommended by the Clinical Trial Advisory Committee/Clinical Trial Cell. See the BGD-GCP for more information on the Clinical Trial Advisory Committee.

Per the DrugsCosAct and the BGD-GCP, the DGDA may accept clinical trial information or approved data received from foreign drug regulatory authorities. Additionally, the DGDA may, subject to the approval of the government, approve fast track clinical trials in case of new drugs for emergency health care or epidemic diseases, or during a public health emergency. The BGD-GCP indicates that protocol amendments and time extensions should be submitted to the DGDA with justification.

As per the BGD-GCP, the DGDA carries out on-site inspections of the clinical trial site. Such inspections may be carried out routinely, randomly, and/or for specific reasons, and should consist of a comparison of the procedures and practices of the investigator with those set out in the protocol and reports submitted to the DGDA by the investigator or the sponsor. The DGDA may also conduct risk-based good clinical practice (GCP) inspections. The inspection should determine whether the investigator has custody of the required records or, if not, who has assumed this responsibility. The data archives should be tested for ease of retrieval. Inspections may include data audit. The DGDA should have easy access to all patient files and raw data used for and generated during the trial. As stated in the G-CTInspect, the aims of the clinical trial inspection program are to verify: GCP compliance to protect the rights, safety, and well-being of trial participants; the credibility and integrity of clinical trial data generated; and compliance with applicable regulatory provisions. For more information, see the G-CTInspect.

The DrugsCosAct and the BGD-GCP indicate that if there is any risk to the participants during the clinical trial, the DGDA Director General may temporarily or permanently stop the trial.

See the G-VacAssess for information on the DGDA’s vaccine authorization process.

(See the Submission Process and Submission Content sections for detailed submission requirements and review processes.)

Directorate General of Drug Administration

As per the BGD-GCP, the Ministry of Health and Family Welfare (MOHFW)’s Directorate General of Drug Administration (DGDA) will charge fees for clinical trial protocol applications and pay reasonable per diem to the members of the Clinical Trial Advisory Committee for attending evaluation meetings. Specific fee amounts are not available at this time.

Payment Instructions

No information is available regarding payment instructions.

Overview

According to the BGD-GCP and BGD-22, a protocol approved by an ethics committee (EC) (referred to as an independent ethics committee (IEC)/institutional review board (IRB) in Bangladesh)/the Bangladesh Medical Research Council (BMRC) is a required element of a clinical trial application to the Ministry of Health and Family Welfare (MOHFW)’s Directorate General of Drug Administration (DGDA). (Note: The BMRC’s National Research Ethics Committee (NREC) is registered with the US Office for Human Research Protections (OHRP) as an official IRB.)

As delineated in the G-BMRC and BGD-16, the applicant must obtain ethics approval from the NREC, which reviews all clinical trials of both non-registered medicinal substances in Bangladesh and new indications of already registered medicinal substances. The NREC also sets standards, advises the MOHFW and other departments on the management of research ethics for Bangladesh, and arbitrates on matters of ethics.

However, per BGD-7, the DGDA requires review and approval by an institution’s/organization’s EC for all clinical trials involving humans. Clinical trials that obtain ethical approval from certain well-established ECs do not require NREC approval.

The IRB-Manual indicates that there are several ECs that review and issue ethical clearance for an institution’s/organization’s students or faculty regarding their research. For more information, see the Scope of Review section.

Ethics Committee Composition

Institutional Ethics Committee

As stated in the BGD-GCP, the EC should consist of a reasonable number of members, who collectively have the qualifications and experience to review and evaluate the science, medical aspects, and ethics of the proposed trial. It is recommended that the EC include at least five (5) members, at least one (1) member whose primary area of interest is in a nonscientific area, and at least one (1) member who is independent of the institutional/trial site.

The IRB-Manual further specifies that there must be adequate experience, knowledge, and variety among the members to make an educated judgment. In addition, the EC:

• Will have a chairman appointed to it
• Must include men and women
• Should be interdisciplinary and cross-sectoral
• Should include both scientific and non-scientific specialists, such as a lawyer, a religious expert, and laypeople
• Must have at least one (1) member (if it is a five (5) member committee) who is not linked with the institution. For bigger committees, at least 40% of the members should be external to the institute/organization

See the BGD-GCP and the IRB-Manual for additional details on EC composition requirements.

National Research Ethics Committee

According to the G-BMRC and BGD-16, the NREC was formed by the BMRC and consists of nine (9) to 13 members. BGD-16 indicates that NREC membership includes a chairman and member secretary. A lawyer, female representative, religious leader, and research methodologist/biostatistician are obligatory members. All relevant new guidelines should be brought to the attention of the members. No information is currently available regarding requirements surrounding NREC renewal or expiration of tenure.

Terms of Reference, Review Procedures, and Meeting Schedule

Institutional Ethics Committee

Per the BGD-GCP, the EC must follow international guidelines on ethical issues and the safety of human subjects exposed to clinical trials, including the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (BGD-29) and the Declaration of Helsinki (BGD-33).

The BGD-GCP indicates that the list of EC members and their qualifications should be maintained. Additionally, the EC should perform its functions according to written operating procedures, maintain written records of its activities and minutes of its meetings, and comply with good clinical practice (GCP) and the applicable regulatory requirement(s). The EC must be independent of the institution/contract research organization (CRO), and all activities must be transparent.

Per the BGD-GCP, only EC members who are independent of the investigator and the sponsor of the trial should vote/provide opinion on a trial-related matter. An EC should make decisions at announced meetings at which at least a quorum, as stipulated in its written operating procedures, is present. The IRB-Manual specifies that quorum is defined as the presence of a majority of members at a meeting. EC members must not vote on their own projects, but all other EC members are eligible to vote. The presence of more than half of the EC members is required to vote on a proposal, and a non-scientist must be present as well.

The BGD-GCP further states that only members who participate in the EC review and discussion should vote/provide their opinion and/or advice. Every member should sign a declaration of conflict of interest. The investigator may provide information on any aspects of the trial, but should not participate in the deliberations or the vote/opinion of the EC. An EC may also invite nonmembers with expertise in special areas for assistance.

As required in the BGD-GCP, the EC should establish and follow written procedures, which should include:

• Determining its composition (names and qualifications of the members) and the authority under which it is established
• Scheduling, notifying its members of, and conducting its meetings
• Conducting an initial and continuing review of trials
• Determining the frequency of continuing review, as appropriate
• Providing, according to the applicable regulatory requirements, expedited review and approval/favorable opinion of minor change(s) in ongoing trials that have the approval/favorable opinion of the EC
• Specifying that no participant should be admitted to a trial before the EC issues its written approval/favorable opinion of the trial
• Specifying that no deviations from, or changes of, the protocol should be initiated without prior written EC approval/favorable opinion of an appropriate amendment, except when necessary to eliminate immediate hazards to the participants or when the change(s) involves only logistical or administrative aspects of the trial (e.g., change of monitor(s), telephone number(s))

In addition, the BGD-GCP indicate that the EC should retain all relevant records (e.g., written procedures, membership lists, lists of occupations/affiliations of members, submitted documents, minutes of meetings, and correspondence) for at least three (3) years after completion of the trial and make them available upon request from the DGDA. The EC may also be asked by investigators, sponsors, or regulatory authorities to provide its written procedures and membership lists.

See the BGD-GCP and the IRB-Manual for additional EC terms of reference and review procedure requirements.

National Research Ethics Committee

BGD-16 indicates that NREC members should be encouraged to attend national and international training programs in research ethics for maintaining quality in ethical review and to be aware of the latest developments in this area.

According to BGD-16, the NREC will conduct a meeting every two (2) months, but the frequency of meetings may increase depending on the number of applications. The agenda should incorporate sufficient time for discussion of the applications. The chairperson will conduct all NREC meetings. In the absence of the chairperson, NREC members will elect a chairperson who will conduct the meeting. The member secretary is responsible for organizing the meetings, maintaining the records, and relevant communication. The notice of a meeting should be issued at least seven (7) days before the meeting.

As per BGD-16, minutes of the previous meeting should be maintained. Proceedings of the meetings should be confidential and maintained in a standard format and should be prepared within three (3) working days after the meeting. Additionally, the NREC should have the following documentation, which should be archived:

• Copy of all study protocols with enclosed documents, progress reports, and serious adverse events (SAEs)
• Minutes of all meetings
• Copy of all existing relevant national and international guidelines on research ethics and laws along with amendments
• Copy of all correspondence with members, researchers, and other regulatory bodies
• Final report of the approved projects

Overview

As per the BGD-GCP, ethics committees (ECs) (referred to as independent ethics committees (IECs)/institutional review boards (IRBs) in Bangladesh) are responsible for ensuring the protection of the rights, safety, and well-being of human participants involved in a clinical trial. It is also an EC’s responsibility to provide public assurance of that protection, by, among other things, reviewing and approving/providing a favorable opinion on the trial protocol, as well as the suitability of the investigator(s), facilities, and the methods and material to be used in obtaining and documenting informed consent of the trial participants. The EC also provides continuing review of the trial protocol and amendments, and of the methods and material to be used.

The BGD-GCP further indicates that special attention should be paid to trials that may include vulnerable participants. An EC should follow the rules, regulations, and ethical guidelines of the Ministry of Health and Family Welfare (MOHFW)’s Directorate General of Drug Administration (DGDA).

According to the G-BMRC, research requires ethical approval as a part of good research governance to:

• Safeguard the dignity, rights, safety, and well-being of all potential research participants
• Protect the rights of a researcher to carry out legitimate investigation, as well as the reputation of the institution
• Minimize potential for claims of negligence made against the researchers, the institution concerned, and any collaborating individual or organization
• Require evidence of ethical approval in refereed journals
• Influence the research design with ethical consideration
• Avoid potential problems later by ensuring that the main ethical issues are addressed before the research starts

As per the G-BMRC, strict guidelines on human genetics research must be followed in order to control and carefully use and disseminate information generated, such that it does not lead to misuse or commercial acquisition. Research protocols should follow established procedures for review and informed consent. The G-BMRC does not specify any particular guidelines or procedures.

The G-BMRC further states that a research proposal involving gene therapy must be evaluated based on medical, scientific, ethical, and safety aspects. The proposal must be first approved by the concerned institutional biosafety committee before submittal to the Bangladesh Medical Research Council (BMRC)’s National Research Ethics Committee (NREC). See the G-BMRC for more specific guidelines involving human genetic and genomic research, including stem cell research.

Role in Clinical Trial Approval Process

The BGD-GCP and BGD-22 state that a protocol approved by an EC/the BMRC is a required element of a clinical trial application to the DGDA. Therefore, DGDA review and ethics review may not be conducted in parallel. (Note: According to the G-BMRC and BGD-16, the BMRC’s NREC is registered with the US Office for Human Research Protections (OHRP) as an official IRB.)

As delineated in the G-BMRC and BGD-16, the applicant must obtain ethics approval from the NREC.

However, per BGD-7, the DGDA requires review and approval by an institution’s/organization’s EC for all clinical trials involving humans. Clinical trials that obtain ethical approval from certain well-established ECs do not require NREC approval.

Institutional Ethics Committee

The IRB-Manual states that simple interventional studies such as health educational interventions, psychological interventions, community interventions, treatment regimens using DGDA approved drugs, and students’ theses/dissertations on small-scale clinical trials can be approved by institutional ECs. There are several ECs that review and issue ethical clearance for the institution’s/organization’s students or faculty regarding their research. An institution’s/organization's EC is only allowed to examine its own research protocols. However, if an institution/organization has no EC, it may obtain ethical approval of its protocols from a nearby EC.

Per the BGD-GCP, the EC should consider the qualifications of the investigator for the proposed trial, as documented by a current curriculum vitae (CV) and/or by any other relevant documentation the EC requests.

The BGD-GCP further states that the EC should review a proposed clinical trial within a reasonable time and document its views in writing, clearly identifying the trial, the documents reviewed, and the dates for the following: approval/favorable opinion; modifications required prior to its approval/favorable opinion; disapproval/negative opinion; and termination/suspension of any prior approval/favorable opinion. Additionally, the EC should conduct a continuing review of each ongoing trial at intervals appropriate to the degree of risk to human participants, but at least once a year.

As indicated in the BGD-GCP, any deviations from, or changes of, the protocol to eliminate immediate hazards to the trial participants, or changes increasing the risk to participants and/or affecting significantly the conduct of the trial, should be promptly reported by the investigator to the EC. Furthermore, the investigator should not implement a deviation from, or a change of, the protocol without prior EC approval/favorable opinion, except where necessary to eliminate an immediate hazard(s) to trial participants, or when the change(s) involves only logistical or administrative aspects of the trial. As soon as possible, the implemented deviation or change, the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be submitted to the EC for review and approval/favorable opinion; to the sponsor for agreement; and, if required, to the DGDA.

According to the BGD-GCP, if the EC terminates or suspends its approval/favorable opinion of a trial, the investigator should inform the institution where applicable and the investigator/institution should promptly notify the sponsor and provide the sponsor with a detailed written explanation of the termination or suspension.

National Research Ethics Committee

According to the G-BMRC and BGD-16, the NREC reviews all clinical trials of both non-registered medicinal substances in Bangladesh and new indications of already registered medicinal substances. Research involving issues of religious or social sensitivity must be approved by the NREC. International collaborative research involving the Bangladeshi population must also receive ethical approval from the NREC, in addition to the government’s administrative approval.

The IRB-Manual further notes that all clinical trials on new drugs or molecules or devices, including bioequivalence and biosimilar studies, should be approved by the NREC. Additionally, only the NREC has the authority to examine a protocol from any institution, whether collaborative or not. As delineated in the G-BMRC and BGD-16, scientific validity should be approved by a valid Scientific Review Committee before submission of a research project to the NREC. As per BGD-16, if a research proposal is not approved by a valid Scientific Review Committee, then it should be approved by the Scientific Review Committee of the BMRC before submission to the NREC. The NREC gives final ethical approval to research proposals, while the Scientific Review Committee analyzes whether the research proposal is of good scientific quality and value. The Scientific Review Committee also reviews the validity and feasibility of the protocol and cited relevant scientific literature (if any) of the proposed research, as well as ethical issues by peer review process. No additional information is available regarding the Scientific Review Committee’s role in review of ethical issues.

BGD-16 further indicates that all decisions will be communicated to the principal investigator (PI) in writing.

As delineated in BGD-16, expedited review may be granted when the research proposal is approved by a valid Scientific Review Committee as methodologically sound without any intervention and risk of distress or injury, physical or psychological, to the participants. The expedited proposal, along with justification, is presented to the NREC at its next meeting.

According to BGD-16, research proposals from university, medical college, or institution undergraduate students that are submitted with a recommendation from the head of the institution or institutional EC approval may be given an exemption from peer review. The exemption may be given if there is no intervention and risk of distress or injury, physical or psychological, to the subjects. The NREC Chairman may give ethical approval of the proposal on the condition that the proposal must be submitted in the next NREC meeting.

The G-BMRC states that in the case of protocol deviation, approval from the NREC must be obtained and the licensing authority must be notified.

The G-BMRC and BGD-16 also indicate that the NREC conducts post-approval monitoring of clinical trials.

Institutional Ethics Committee

Per the BGD-GCP, ethics committees (ECs) (referred to as independent ethics committees (IECs)/institutional review boards (IRBs) in Bangladesh) may charge fees for their services, such as ethical evaluations of protocols and ethical/good clinical practice (GCP) compliance inspections (as required). Fees are fixed by the EC and endorsed by the organization. An annual financial audit system should be in place, and transparency of income and expenditure should be maintained.

Payment Instructions

No information is currently available regarding payment instruction standards for institutional ECs.

National Research Ethics Committee

According to BGD-15 and BGD-16, there is a review and processing fee for Bangladesh Medical Research Council (BMRC) ethical approval via its National Research Ethics Committee (NREC). The fee is based on 2% of the total cost of the approved research project, not exceeding 500,000 Bangladeshi Taka. For clinical trials or drug research, the principal investigator (PI) must pay 50,000 Bangladeshi Taka to the BMRC with the initial submission. However, undergraduate students are required to pay 2,000 Bangladeshi Taka at the time of submission. For amendments and renewals, 50% of the first approval fee will be charged.

No information is currently available regarding BMRC fees for Scientific Review Committee approval.

Payment Instructions

BGD-15 and BGD-16 indicate that the PI must pay the total applicable fee to the BMRC following receipt of ethical approval. The fee is paid by an Account Payee Cheque made out to the “Bangladesh Medical Research Council” at the time the approval letter is received.

Overview

The BGD-GCP states that all institutional ethics committees (ECs) must be registered with the Ministry of Health and Family Welfare (MOHFW)’s Directorate General of Drug Administration (DGDA) (Note: ECs are referred to as independent ethics committees (IECs)/institutional review boards (IRBs) in Bangladesh).

Registration, Auditing, and Accreditation

According to the BGD-GCP, an application for registration of the EC must be submitted to the DGDA’s National Advisory Committee on Human Ethics for IRB/IEC Evaluation. The committee will assess the curriculum vitae (CV), experience, and competence of the EC’s members. Additionally, the committee will evaluate the facilities and subsequently make recommendations to the Director General of the DGDA.

Per the BGD-GCP, committee members are required to annually sign a declaration of conflict of interest. If any committee members are affiliated with any EC, they must abstain from participating in access, voting, or inspection activities related to that particular EC. The committee has the authority to co-opt one (1) or more members if necessary. The DGDA also has the authority to cancel or suspend an EC’s approval if it fails to adhere to the BGD-GCP.

The BGD-GCP indicates that the DGDA will approve and oversee the activities of the EC, with renewal required every 2 (two) years. Additionally, the DGDA will charge fees for the EC registration application and pay reasonable per diem to the members of the National Advisory Committee for attending evaluation meetings.

See Annexure 5 of the BGD-GCP for a list of documents required for EC registration approval.

Overview

As per the BGD-GCP and the G-IndCTA, the Ministry of Health and Family Welfare (MOHFW)’s Directorate General of Drug Administration (DGDA) is responsible for reviewing, evaluating, and approving clinical trial applications for drugs in Bangladesh. The BGD-GCP and BGD-22 indicate that a protocol approved by an ethics committee (EC) (referred to as an independent ethics committee (IEC)/institutional review board (IRB) in Bangladesh)/the Bangladesh Medical Research Council (BMRC) is a required element of a clinical trial application to the DGDA. Therefore, DGDA review and ethics review may not be conducted in parallel. (Note: According to the G-BMRC and BGD-16, the BMRC’s National Research Ethics Committee (NREC) is registered with the US Office for Human Research Protections (OHRP) as an official IRB.)

In addition, as delineated in the G-BMRC and BGD-16, any health research to be conducted in Bangladesh must be registered with the BMRC, and scientific validity should be approved by a valid Scientific Review Committee before submission of a research project to the BMRC’s NREC. An applicant must obtain ethics approval from the NREC.

However, per BGD-7, the DGDA requires review and approval by an institution’s/organization’s EC for all clinical trials involving humans. Clinical trials that obtain ethical approval from certain well-established ECs do not require NREC approval.

Regulatory Submission

As per the BGD-GCP, the principal investigator (PI) or contract research organization (CRO) must submit the application for permission to conduct a clinical trial to the DGDA. However, the G-IndCTA states that the sponsor is responsible for submitting the application.

As per BGD-22, the application to conduct a clinical trial must be submitted on the organization’s official letterhead to:

The Director General
Directorate General of Drug Administration
Mohakhali, Dhaka-1212, Bangladesh

The G-IndCTA delineates that two (2) hard copies and two (2) soft copies (i.e., PDF format on CDs) of the application must be submitted to the DGDA. The hard copies must be labeled with the document number, name of the firm, date of submission, etc. The number of volumes must be labeled as “Volume No./Total number of volumes”. The soft copies must also be labeled with the document number, name of the firm, date of submission, etc. Scanned copies of signed documents such as test reports are acceptable, and the rest of the documents should be in PDF format. The table of contents under each heading should be linked to the file(s) or relevant document(s) for easy tracking in the CDs. The table of contents should be hyperlinked to the main document to facilitate the review process. The sponsor/manufacturer should preserve one (1) hard copy and soft copy of the submitted documents for any future reference, if required.

There is no specified language requirement for all the documents to be submitted to the DGDA.

Ethics Review Submission

BGD-16 indicates that all research projects seeking ethical approval should be submitted to the NREC in the prescribed application form (see Annexure A of BGD-15 or BGD-16). All relevant documents should be enclosed with the application form. The proposal, formal application, and relevant documents must be duly signed by the PI and co-investigators/collaborators, and then should be forwarded to the NREC members/secretary.

According to BGD-15 and BGD-16, an application for NREC approval of a clinical trial must be submitted to:

Bangladesh Medical Research Council
Mohakhali, Dhaka-1212, Bangladesh

BGD-15 and BGD-16 further state that four (4) copies of all documents must be submitted to the BMRC. A soft copy on a CD must also be submitted, and all documents should be submitted in an A-4 size data bank file/folder.

There is no specified language requirement for all the documents to be submitted to the BMRC. However, BGD-15 and BGD-16 indicate that the informed consent form, as well as the questionnaire or interview schedule, must be provided in both Bengali and English.

No information is currently available regarding general institutional EC submission process standards or Scientific Review Committee submission process requirements. Each institutional EC has its own required submission procedures, which can differ significantly regarding the application format and number of copies. See BGD-10 and BGD-11 for an example of an institutional EC’s guidelines for students and teachers, respectively.

Regulatory Authority Requirements

As per BGD-22, the following documentation must be submitted to the Ministry of Health and Family Welfare (MOHFW)’s Directorate General of Drug Administration (DGDA) before the commencement of a clinical trial:

• Protocol approved by the Bangladesh Medical Research Council (BMRC)/institutional review board (IRB)/independent ethics committee (IEC) (Note: ethics committees (ECs) are referred to as IRBs/IECs in Bangladesh)
• Investigator’s Brochure (IB)
• Informed consent form (ICF)
• Signed agreements between the sponsor and the contract research organization (CRO), trial center, and/or principal investigator (Pl)
• Curriculum vitae(s) (CV(s)) of PI and associates
• Good manufacturing practice (GMP) certificate of investigational product (IP)
• Certificate of Analysis of IP
• Details on funding of the trials
• Case record form (CRF)
• Standard operating procedures (SOPs) of different activities
• Good clinical practice (GCP) training certificate of PI and team members

The G-IndCTA further states that for clinical trial applications involving biological products, the sponsor is required to submit general information, chemistry manufacturing control information, nonclinical data, and proposed Phase I, II, or III studies (as applicable). See the G-IndCTA for more details.

Ethics Committee Requirements

Institutional Ethics Committee

Per the BGD-GCP, the EC should review the following documents:

• Trial protocol(s)/amendment(s)
• Written ICF(s) and consent form updates that the investigator proposes for use in the trial
• Participant recruitment procedures and written information to be provided to participants
• IB
• Available safety information
• Information about payments and compensation available to participants
• The investigator's current CV and/or other documentation evidencing qualifications, and any other documents that the EC may need to fulfill its responsibilities

For the BMRC’s guidance for institutional ECs regarding submission format, see Annexure C of the IRB-Manual.

National Research Ethics Committee

BGD-15 and BGD-16 indicate that the following documents must be submitted to the BMRC for ethical approval:

• PI cover letter to Director for ethical clearance
• Completed Ethical Clearance Application Form (Annexure A of BGD-15 and BGD-16)
• Signature of PI(s) and co-investigator(s) with detailed addresses (Annexure A of BGD-15 and BGD-16)
• Abstract for National Research Ethics Committee (NREC) (Annexure B of BGD-15 and BGD-16)
• BMRC format for submission of a research proposal for ethical approval (Annexure C of BGD-15 and BGD-16)
• Informed consent form (both Bengali and English) from participant(s) or legal representative/guardian (Annexure D of BGD-15 and BGD-16)
• Questionnaire or interview schedule (both Bengali and English)
• Procedure for maintaining confidentiality
• Budget (Annexure E of BGD-15 and BGD-16)
• Copy of approval from valid scientific review committee (if any)
• Four (4) copies of all documents and a soft copy in CD format to be submitted to the BMRC (all documents should be submitted in an A-4 size data bank file/folder)
• Review and processing fee (RPF) for ethical approval

No information is currently available regarding Scientific Review Committee submission content requirements.

Clinical Protocol

According to the BGD-GCP, the G-IndCTA, and BGD-22, the clinical research protocol should include the following information (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Title page including full title of the clinical study, protocol/study number, protocol version number with date, etc.
• General information (name and address of the sponsor and monitor, etc.)
• Table of contents
• Background information
• Trial rationale, objectives, and purpose
• Trial design and conduct
• Selection and withdrawal of participants, including information on the population and eligibility
• Treatment of participants
• Assessment of efficacy
• Assessment of safety
• Procedures for evaluating an adverse event
• Statistics
• Direct access to source data/documents
• Trial monitoring and supervision
• Quality control and quality assurance
• IP management
• Ethical considerations
• Data handling and record keeping
• Financing and insurance
• Publication policy
• Investigator responsibilities
• Supplements and/or appendices

The BGD-GCP and BGD-22 further state that since the protocol and the clinical trial/study report are closely related, further relevant information can be found in the International Council for Harmonisation’s (ICH) Guideline for Structure and Content of Clinical Study Reports (BGD-31). See the BGD-GCP, the G-IndCTA, BGD-31, and BGD-22 for more detailed requirements.

Overview

The BGD-GCP and BGD-22 indicate that a protocol approved by an ethics committee (EC) (referred to as an independent ethics committee (IEC)/institutional review board (IRB) in Bangladesh)/the Bangladesh Medical Research Council (BMRC) is a required element of a clinical trial application to the Directorate General of Drug Administration (DGDA). Therefore, DGDA review and ethics review may not be conducted in parallel. (Note: According to the G-BMRC and BGD-16, the BMRC’s National Research Ethics Committee (NREC) is registered with the US Office for Human Research Protections (OHRP) as an official IRB.)

In addition, as delineated in the G-BMRC and BGD-16, scientific validity should be approved by a valid Scientific Review Committee before submission of a research project to the NREC.

Regulatory Authority Approval

The BGD-GCP indicates that if there are no issues, the clinical trial protocol should be approved by the DGDA within 60 working days. For fast-track clinical trial protocols, approval should be granted within 15 working days, and for clinical trial protocol amendments, approval should be obtained within 30 working days.

Ethics Committee Approval

The BGD-GCP states that an EC should review a proposed clinical trial within a reasonable time.

As delineated in BGD-16, NREC expedited review may be granted when the research proposal is approved by a valid Scientific Review Committee as methodologically sound without any intervention and risk of distress or injury, physical or psychological, to the participants. The expedited proposal, along with justification for expedition, is presented to the NREC at its next meeting.

According to BGD-16, research proposals submitted to the NREC from university, medical college, or institution undergraduate students with a recommendation from the head of the institution or institutional EC approval may be given an exemption from peer review. The exemption may be given if there is no intervention and risk of distress or injury, physical or psychological, to the subjects. The NREC Chairman may give ethical approval of the proposal on the condition that the proposal must be submitted in the next NREC meeting.

Overview

The G-BGD-IP states that the sponsor may not start a clinical trial until authorization has been granted for the trial; all conditions of the authorization have been met; an ethics committee (EC) (referred to as an independent ethics committee (IEC)/institutional review board (IRB) in Bangladesh) favorable opinion has been granted; and each trial site has been approved. (Note: According to the G-BMRC and BGD-16, the Bangladesh Medical Research Council (BMRC)’s National Research Ethics Committee (NREC) is registered with the US Office for Human Research Protections (OHRP) as an official IRB.)

As per the BGD-GCP, the principal investigator (PI) or contract research organization (CRO) must submit an application to the Ministry of Health and Family Welfare (MOHFW)’s Directorate General of Drug Administration (DGDA) for permission to conduct a clinical trial in Bangladesh. However, the G-IndCTA states that the sponsor is responsible for submitting the application.

Clinical trials must be conducted in accordance with the good clinical practice (GCP) requirements in the BGD-GCP, which was derived from the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (BGD-29) and other international guidance material.

As delineated in the G-BMRC and BGD-16, in addition to obtaining the DGDA’s permission to conduct research in Bangladesh, an applicant must obtain ethics approval from the NREC. Furthermore, scientific validity should be approved by a valid Scientific Review Committee before submission of a research project to the NREC. However, per BGD-7, the DGDA requires review and approval by an institution’s/organization’s EC for all clinical trials involving humans. Clinical trials that obtain ethical approval from certain well-established ECs do not require NREC approval.

Clinical Trial Agreement

The BGD-GCP states that before the commencement of the clinical trial, an agreement must be signed by the involved parties. This may include an agreement between the investigator/institution, sponsor, and CRO; the sponsor and CRO; and/or the investigator/institution and relevant authority(ies) (where required).

The BGD-GCP further specifies that the sponsor should obtain the investigator's/institution's agreement to:

• Conduct the trial in compliance with GCP, the applicable regulatory requirement(s), and the protocol agreed to by the sponsor and given approval/favorable opinion by the EC
• Comply with procedures for data recording/reporting
• Permit monitoring, auditing, and inspection
• Retain the trial-related essential documents until the sponsor informs the investigator/institution these documents are no longer needed

As per the BGD-GCP, the sponsor and the investigator/institution should sign the protocol, or an alternative document, to confirm this agreement. In addition, the financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution. The sponsor should also ensure that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) provide direct access to source data/documents for trial-related monitoring, audits, EC review, and regulatory inspection.

Clinical Trial Registration

The G-BMRC and BGD-16 indicate that any health research to be conducted in Bangladesh must be registered with the BMRC. The BMRC has developed a form for the registration of research studies and is in the process of developing an electronic submission system for registration. Clinical trials should be registered in the BMRC’s Clinical Trial Registry. According to the G-BMRC, the Clinical Trial Registry will be available through the BMRC website when it is completed. No additional information is available regarding the BMRC's Clinical Trial Registry or its timeline for implementation. Contact the BMRC for more information regarding the registration process. See the Regulatory Authority section for general BMRC contact information.

Safety Reporting Definitions

As per the BGD-GCP, the following definitions provide a basis for a common understanding of Bangladesh’s safety reporting requirements:

• Adverse Event (AE) – Any untoward medical occurrence in a clinical investigation participant who is administered an investigational product (IP) that does not necessarily have a causal relationship with this treatment
• Adverse Drug Reaction (ADR) – All noxious and unintended responses to a medicinal product related to any dose
• Serious Adverse Event (SAE)/Serious Adverse Drug Reaction (SADR) – Any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolonged existing hospitalization, results in persistent or significant disability/incapacity, or results in a congenital anomaly/birth defect
• Unexpected Adverse Drug Reaction – An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator’s Brochure (IB) for an unapproved IP)

Safety Reporting Requirements

Investigator Responsibilities

The BGD-GCP states that the principal investigator (PI) should report all detected SAEs within two (2) working days to the Ministry of Health and Family Welfare (MOHFW)’s Directorate General of Drug Administration (DGDA), the ethics committee (EC) (referred to as an independent ethics committee (IEC)/institutional review board (IRB) in Bangladesh), the data and safety monitoring board (DSMB), and the sponsor. The immediate reports should be followed within seven (7) days by detailed, written reports. The immediate and follow-up reports should identify participants by unique code numbers assigned to the participants rather than by the participants’ names, personal identification numbers, and/or addresses. Additionally, the investigator must report unexpected SADRs to the DGDA and the EC within seven (7) working days.

As per the BGD-GCP, AEs and/or laboratory abnormalities identified in the protocol as critical to safety evaluations should be reported to the sponsor according to the reporting requirements and within the time periods specified by the sponsor in the protocol. For reported deaths, the investigator should supply the sponsor and the EC with any additional requested information (e.g., autopsy reports and terminal medical reports).

However, the G-BMRC delineates that the investigator should report unexpected AEs/ADRs and all SAEs to the sponsor within 24 hours and to the EC that approved the study protocol within seven (7) days. In the event of death, the Bangladesh Medical Research Council (BMRC)’s National Research Ethics Committee (NREC) should also be informed within 24 hours. The G-BMRC and BGD-16 state that the PI should report SAEs and AEs to the NREC.

In addition, BGD-24 states that when an AE is identified, the PI or their designee must document the AE in the case report form (CRF) and the appropriate toxicity grade from the study-assigned toxicity grading scale. An initial report of the SAE must be transmitted through email to the DGDA, as well as to the sponsor and EC, within 24 hours, and AEs should be communicated within 72 hours. The PI must review all AEs, assessing causality and the required course of action in accordance with the protocol and regulations.

Sponsor Responsibilities

According to the BGD-GCP, the sponsor should promptly notify all concerned investigator(s)/institution(s) and the regulatory authority(ies) of findings that could affect adversely the safety of participants, impact the conduct of the trial, or alter the EC’s approval/favorable opinion to continue the trial. The sponsor should expedite the reporting to all concerned investigator(s)/institutions(s), the EC(s) (where required), and the regulatory authority(ies) of all ADRs that are both serious and unexpected. The sponsor should submit to the regulatory authority(ies) all safety updates, as required by applicable regulatory requirement(s).

The G-BMRC indicates that any unexpected SAE that occurs during a clinical trial should be communicated by the sponsor promptly within 14 calendar days to the licensing authority and to the investigator(s) of other trial sites participating in the study. This is so the regulatory authority can immediately stop the clinical trials of unapproved drugs or withdraw from market approved drugs based on a report of Phase IV studies. All other SADRs that are not fatal, or life threatening must be filed as soon as possible but not later than 14 calendar days. At the end of the trial, all AEs, whether related to the trial or not, must be listed, evaluated, and discussed in detail in the final report.

Form Completion & Delivery Requirements

BGD-24 states that the PI or their designee should report to the DGDA through the Adverse Event Reporting Form During Clinical Trial Study, which is available in BGD-24. An initial report of any SAE must be transmitted through email to the DGDA, as well as to the sponsor and EC, within 24 hours, and AEs should be communicated within 72 hours. The PI must also send a casualty assessment report completed by the EC to the DGDA.

According to the BGD-GCP, the sponsor’s expedited reports regarding ADRs that are both serious and unexpected should comply with the applicable regulatory requirement(s) and the International Council for Harmonisation (ICH)’s Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (E2A) (BGD-32).

As per the G-IndCTA, the following data elements are required for reporting SAEs occurring in a clinical trial:

• Participant details (initials and other relevant identifier, gender, etc.)
• Information on suspected drug(s) (dosage form and strength, route of administration, etc.)
• Other treatment(s)
• Details of SAE(s)
• Outcome
• Details about the investigator

For more information on these required elements, see the G-IndCTA.

Interim and Annual Progress Reports

As per the BGD-GCP, the investigator should submit written summaries of the trial status every six (6) months to the Ministry of Health and Family Welfare (MOHFW)’s Directorate General of Drug Administration (DGDA) and the ethics committee (EC) (referred to as an independent ethics committee (IEC)/institutional review board (IRB) in Bangladesh), or more frequently, if requested by the DGDA and the EC. The investigator should promptly provide written reports to the sponsor, the EC, and the institution (where applicable) on any changes significantly affecting the conduct of the trial, and/or increasing the risk to participants.

BGD-16 indicates that reports should be submitted periodically at intervals prescribed by the Bangladesh Medical Research Council (BMRC)’s National Research Ethics Committee (NREC) for review.

Final Report

The BGD-GCP delineates that upon completion of the trial, the investigator, where applicable, should inform the institution. The investigator/institution should provide the EC with a summary of the trial’s outcome, and the DGDA with any required reports. Whether the trial is completed or prematurely terminated, the sponsor should ensure that the clinical trial reports are prepared and provided to the regulatory authority(ies). The G-IndCTA further indicates that in the case of studies prematurely discontinued for any reason including lack of commercial interest in pursuing the new drug application, a summary report should be submitted to the licensing authority within three (3) months. The summary report should provide a brief description of the study, the number of participants exposed to the drug, dose, duration of exposure, details of adverse drug reactions, if any, and the reason for discontinuation of the study or non-pursuit of the new drug application.

According to the BGD-GCP, the sponsor may refer to the International Council for Harmonisation (ICH)’s Harmonised Tripartite Guideline: Structure and Content of Clinical Study Reports (E3) (BGD-31) for further guidance.

As per BGD-16, a report should be submitted to the NREC at the end of the study.

As defined in the BGD-GCP, the sponsor is an individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial. The sponsor is also responsible for the ongoing safety evaluation of the investigational product(s) (IP(s)). According to the G-BMRC, research may be undertaken with assistance from international organizations as sponsors.

The BGD-GCP states that prior to initiating a trial, the sponsor should define, establish, and allocate all trial-related duties and functions. The sponsor may transfer any or all of the sponsor’s trial-related duties and functions to a contract research organization (CRO), but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. The CRO should implement quality assurance and quality control. The CRO must obtain approval from the Ministry of Health and Family Welfare (MOHFW)’s Directorate General of Drug Administration (DGDA) to conduct a clinical trial, with the renewal of approval required every two (2) years. Any trial-related duties and functions that are transferred to and assumed by a CRO should be specified in writing, and any trial-related duties and functions not specifically transferred to and assumed by a CRO are retained by the sponsor.

See BGD-23 for the Requirements for CRO/Clinical Trial Centre form.

Overview

As per the BGD-GCP, the sponsor is responsible for selecting the investigator(s)/institution(s) for a clinical trial in Bangladesh. Each investigator should be qualified by training (including approved good clinical practice (GCP) training) and experience and have adequate resources to properly conduct the trial for which the investigator is selected. The investigator(s) should also meet all the qualifications specified by the applicable regulatory requirement(s) and provide evidence of such qualifications through up-to-date curriculum vitae (CV) and/or other relevant documentation requested by the sponsor, the ethics committee (EC) (referred to as an independent ethics committee (IEC)/institutional review board (IRB) in Bangladesh), and/or the Directorate General of Drug Administration (DGDA).

Additionally, the BGD-GCP indicates that the investigator should be thoroughly familiar with the appropriate use of the investigational product(s) (IP(s)), as described in the protocol, the current Investigator's Brochure (IB), the product information, and other information sources provided by the sponsor. The investigator should be aware of and comply with GCP and applicable regulatory requirements. In addition, the investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties.

According to the BGD-GCP, if a coordinating committee and/or coordinating investigator(s) are to be utilized in multicenter trials, their organization and/or selection are the sponsor's responsibilities. Before entering an agreement with an investigator/institution to conduct a trial, the sponsor should provide the investigator(s)/institution(s) with the protocol and an up-to-date IB and provide sufficient time for the investigator/institution to review the protocol and the information provided.

The BGD-GCP further states that the EC should consider the qualifications of the investigator for the proposed trial, as documented by a current CV and/or by any other relevant documentation the EC requests. In addition, the sponsor should designate appropriately qualified medical personnel who will be readily available to advise on trial-related medical questions or problems. If necessary, outside consultant(s) may be appointed for this purpose.

According to BGD-16, a change of investigators and/or place of study must be approved by the Bangladesh Medical Research Council (BMRC)’s National Research Ethics Committee (NREC).

Foreign Sponsor Responsibilities

No information is currently available regarding foreign sponsor regulatory requirements.

Data and Safety Monitoring Board

As per the BGD-GCP, the sponsor should utilize appropriately qualified individuals to supervise the overall conduct of the trial, to handle the data, to verify the data, to conduct the statistical analyses, and to prepare the trial reports. The sponsor may consider establishing a data and safety monitoring board (DSMB) (also referred to as an independent data-monitoring committee (IDMC)) to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial. The DSMB should have written operating procedures and maintain written records of all its meetings.

However, according to the G-BMRC and BGD-16, the formation of a DSMB is mandatory for conducting a clinical trial. Per BGD-16, at least two (2) members must be included from the NREC during the formation of the DSMB.

Per the IRB-Manual, the BMRC’s guidance for institutional ECs, the size of the DSMB is determined by the type of trial and the degree of expertise necessary. A DSMB must be made up of at least three (3) members, with an odd number allowing for a definitive decision in case a vote is required. DSMB members often include individuals with scientific knowledge of the disease/participant population under investigation, as well as practical expertise and skill in current clinical trial conduct and technique, and one (1) or more epidemiologist(s) and statistician(s). Items reviewed by the DSMB include:

• Interim/cumulative data to look for evidence of adverse events related to the study
• If applicable, interim/cumulative data for evidence of efficacy in accordance with preestablished statistical parameters
• Data completeness, accuracy, and timeliness
• Each trial site’s performance
• Factors that could have an impact on the trial's outcome or jeopardize its data confidentiality, such as protocol violations, unmasking, etc.

Multicenter Studies

The BGD-GCP indicates that for multicenter trials, the sponsor should ensure that:

• All investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor and, if required, by the regulatory authority(ies), and given approval/favorable opinion by the EC
• The case report forms (CRFs) are designed to capture the required data at all multicenter trial sites. For investigators collecting additional data, supplemental CRFs should also be provided that are designed to capture the additional data
• The responsibilities of coordinating investigator(s) and the other participating investigators are documented prior to the start of the trial
• All investigators are given instructions on following the protocol, complying with a uniform set of standards for the assessment of clinical and laboratory findings, and completing the CRFs
• Communication between investigators is facilitated

The G-BMRC further states that in a meaningful multicenter trial, all study sites should be conducted in the same way and follow standardized procedures and evaluation criteria. Meetings should be arranged at the initial and intermediary stages of the trial to ensure consistent procedures at all centers. For recruitment, evaluation/monitoring of laboratory procedures, and conduct of trial, standardization of methods should be carried out. If necessary, the protocol should include monitoring of protocol adherence including measures to terminate the participation of some centers. For this purpose, a central monitoring committee could be set up including EC members. In addition, the specific role of coordinators and monitors should be defined, and centralized data management and analysis should be planned.

According to the G-BMRC, a drafting procedure for common final report and publication should be decided at the outset of the trial. No individual center should publish any data until appropriate authorities accept the combined report. It is advisable to establish communication between ECs reviewing multicenter studies in Bangladesh to discuss ethical concerns of the trial, preferably under the guidance of the NREC, which is particularly important if any EC does not grant approval for a study at a site for ethical reasons.

As per the BGD-GCP, efficient communication between sponsors and regulatory authorities is strongly encouraged during the planning stage of multiregional clinical trials (MRCTs). The aim is to secure acceptance of a global approach to study design that spans different regulatory regions. MRCTs should get approved from the national regulatory authority of the country where it could be conducted before starting. All sites participating in MRCTs must adhere to applicable quality, ethical, and regulatory standards. Specifically, MRCTs should be conducted in compliance with the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BGD-29) standards in all regions and sites, and sites should be made available for GCP inspections by regulatory authorities. Monitoring plans and other quality checks should be pre-specified and implemented to address potential risks to participant rights, safety, well-being, and the reliability of study results. Centralized and risk-based monitoring can be particularly useful for MRCTs to monitor and mitigate the impact of emerging regional differences, such as trial participant retention or adverse event reporting (per the BGD-29). A timely and accurate flow of information is crucial between the sponsor, the trial management team, and the participating sites. Additionally, the ICH’s General Principles for Planning and Design of Multi-Regional Clinical Trials (E17) (BGD-6) should be followed.

Insurance

According to the BGD-GCP, the sponsor and investigator/institution may be required to generate and retain an insurance statement to document that compensation to participant(s) for trial-related injury will be available.

The BGD-GCP states that if required by the applicable regulatory requirement(s), the sponsor must provide insurance or must indemnify (legal and financial coverage) the investigator/institution against claims arising from the trial, except for claims that arise from malpractice and/or negligence.

According to the G-BMRC, sponsors are advised to obtain adequate insurance against risk to cover compensation.

Compensation

Injury or Death

According to the BGD-GCP, sponsor's policies and procedures should address the costs of treatment of trial participants in the event of trial-related injuries in accordance with the applicable regulatory requirement(s). In addition, when trial participants receive compensation, the method and manner of compensation should comply with applicable regulatory requirement(s).

As per the G-BMRC, it is the right of the participants included in a research study to have compensation from the investigator in case of injury and/or disability caused by participation in the study. Research participants who suffer physical injury as a result of their participation are entitled to such financial or other assistance as would compensate them equitably for any temporary or permanent impairment or disability. In the case of death, their dependents are entitled to compensation. Procedures and provisions for compensation should be mentioned in the research proposal and be reviewed by the Bangladesh Medical Research Council (BMRC)’s National Research Ethics Committee (NREC). The NREC should give guidelines and/or directions for compensation. In addition, the informed consent form (ICF) should include details about compensation procedures and provisions.

Trial Participation

The G-BMRC states that participants may be paid for inconveniences and time spent. They should be reimbursed for expenses incurred in connection with their participation in the research and may also receive free medical services. However, the payments should not be so large or the medical services so extensive as to induce prospective participants to consent to participate in the research against their better judgment. All payments, reimbursements, and medical services to be provided to research participants should be mentioned in the research proposal and approved by an ethics committee (EC) (referred to as an independent ethics committee (IEC)/institutional review board (IRB) in Bangladesh).

The BGD-GCP delineates that the EC should review both the amount and method of payment to participants to ensure that neither presents problems of coercion or undue influence on the trial participants. Payments to a participant should be prorated and not wholly contingent on the completion of the trial by the participant.

Quality Assurance/Quality Control

As per the BGD-GCP and the G-IndCTA, the sponsor is responsible for implementing and maintaining quality assurance and quality control 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 (GCP), and the applicable regulatory requirement(s), including World Health Organization (WHO) guidance, the BGD-GCP, and the DrugsCosAct.

According to the BGD-GCP, the sponsor is responsible for securing agreement from all involved parties to ensure direct access to all trial-related sites, source data/documents, and reports for monitoring and auditing by the sponsor, and inspection by domestic and foreign regulatory authorities. Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly.

Monitoring Requirements

According to the BGD-GCP, the sponsor should ensure that the trials are adequately monitored, and determine the appropriate extent and nature of monitoring. The determination of the extent and nature of monitoring should be based on considerations such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial. Monitors, which are appointed by the sponsor, should be appropriately trained, and have the scientific and/or clinical knowledge needed to monitor the trial adequately. A monitor’s qualifications should be documented. In addition, if or when sponsors perform audits as part of implementing quality assurance, they should consider the purpose of the audit, the selection and qualification of auditors, and the auditing procedures.

The BGD-GCP delineates that noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory requirement(s) by an investigator/institution or member(s) of the sponsor’s staff should lead to prompt action by the sponsor to secure compliance. If the monitoring and/or auditing identify serious and/or persistent noncompliance on the part of an investigator/institution, the sponsor should terminate the investigator’s/ institution’s participation in the trial. When an investigator’s/institution’s participation is terminated because of noncompliance, the sponsor should notify the regulatory authority(ies) promptly. The Ministry of Health and Family Welfare (MOHFW)’s Directorate General of Drug Administration (DGDA) will enforce the rules and punitive action will be decided by the DGDA.

See the BGD-GCP for more detailed information on monitoring and auditing requirements.

Premature Study Termination/Suspension

As per the BGD-GCP, 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 ethics committee (EC) (referred to as an independent ethics committee (IEC)/institutional review board (IRB) in Bangladesh) should also be informed promptly and provided the reason(s) for the termination or suspension by the sponsor or by the investigator/institution, as specified by the applicable regulatory requirement(s). The G-IndCTA further indicates that in the case of studies prematurely discontinued for any reason including lack of commercial interest in pursuing the new drug application, a summary report should be submitted to the licensing authority within three (3) months. The summary report should provide a brief description of the study, the number of participants exposed to the drug, dose, duration of exposure, details of adverse drug reactions, if any, and the reason for discontinuation of the study or non-pursuit of the new drug application.

In addition, the BGD-GCP indicates that if the trial is prematurely terminated or suspended for any reason, the investigator/institution should promptly inform the trial participants, ensure appropriate therapy and follow-up for the participants, and, where required by the applicable regulatory requirement(s), inform the regulatory authority(ies). If the investigator terminates or suspends a trial without the prior agreement of the sponsor, or if the sponsor terminates or suspends a trial, the investigator should inform the institution where applicable. The investigator/institution should promptly inform the sponsor and the EC and provide a detailed written explanation of the termination or suspension. If the EC terminates or suspends its approval/favorable opinion of a trial, the investigator should inform the institution where applicable and the investigator/institution should promptly notify the sponsor and provide the sponsor with a detailed written explanation of the termination or suspension.

The G-BMRC states that the criteria for termination of a trial must be defined in the trial proposal and a plan of interim analysis must be clearly presented. If the test drug is found more effective or less effective than the standard drug on interim analysis, the trial can be discontinued thereafter, and the better drug should be given to patient(s) receiving the less effective drug.

Electronic Data Processing System

According to the BGD-GCP, the sponsor should utilize appropriately qualified individuals to supervise the overall conduct of the trial, handle the data, verify the data, conduct the statistical analyses, and prepare the trial reports. When using electronic trial data handling or remote electronic trial data systems, the sponsor should:

• Ensure and document that the electronic data processing system(s) conform(s) to the sponsor's established requirements for completeness, accuracy, reliability, and consistent intended performance
• Maintain standard operating procedures (SOPs) for using these systems
• Ensure that the systems are designed to permit data changes in such a way that the data changes are documented and that there is no deletion of entered data
• Maintain a security system that prevents unauthorized access to the data, and a list of the individuals who are authorized to make data changes
• Maintain adequate backup of the data
• Safeguard the blinding, if any

For additional details, see the BGD-GCP.

Records Management

The BGD-GCP states that the sponsor, or other owners of the data, should retain all of the sponsor-specific essential documents pertaining to the trial (see Annexure 2 of the BGD-GCP). The sponsor should retain all sponsor-related essential documents in conformance with the applicable regulatory requirement(s) of the country(ies) where the investigational product (IP) is approved, and/or where the sponsor intends to apply for approval(s). The investigator/institution should also maintain the trial documents as specified in Annexure 2 of the BGD-GCP, and as required by the applicable regulatory requirement(s). The investigator/institution should take measures to prevent accidental or premature destruction of these documents.

As per the BGD-GCP, the essential documents should be retained until at least two (2) years after the last marketing approval or at least two (2) years have elapsed since the formal discontinuation of clinical development of the IP. These documents should be retained for a longer period, however, if required by the applicable regulatory requirement(s) or if needed by the sponsor. The sponsor should inform the investigator(s)/institution(s) in writing of the need for record retention and should notify the investigator(s)/institution(s) in writing when the trial-related records are no longer needed.

For more information, the Ministry of Health and Family Welfare (MOHFW)’s Directorate General of Drug Administration (DGDA) cites the World Health Organization (WHO) Guidance on Good Data and Record Management Practices (BGD-3) as an additional resource.

The G-CROMF states that if applicable, a contract research organization (CRO) master file should be submitted to the DGDA if requested. It should be succinct and, if possible, not exceed 25 A4 pages. An updated CRO master file should be submitted when requested by the DGDA, or if significant changes have been implemented by the CRO. See the G-CROMF for more information on the preparation of a CRO master file.

Responsible Parties

No information is currently available.

Data Protection

No information is currently available.

Consent for Processing Personal Data

According to the G-BMRC, participants must be informed of their rights regarding the storage and destruction of data. The G-BMRC also notes that it is good practice to notify all participants regarding the last approximate date it will be possible to withdraw their data (for example, prior to publication). Researchers should consider whether participants’ data will still be useful if they decide to withdraw. If this is the case, participants will need to consent to its use. They can be given the option to withdraw and also have their data withdrawn, or to withdraw but state that they will allow their data to be used. If a focus group is being carried out, it will not be possible to withdraw one (1) participant’s data following the intervention without removing the data for all the participants, because what one (1) participant says will affect the responses from others. It must be made clear on the participant information sheet that it will not be possible to withdraw data in this case.

Obtaining Consent

In all Bangladeshi clinical trials, a freely given informed consent is required to be obtained from each participant in accordance with the requirements set forth in the BGD-GCP and the G-BMRC.

As per the G-BMRC, BGD-22, BGD-15, and BGD-16, the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by the Bangladesh Medical Research Council (BMRC)’s National Research Ethics Committee (NREC) and provided to the Ministry of Health and Family Welfare (MOHFW)’s Directorate General of Drug Administration (DGDA) with the clinical trial application. The BGD-GCP further indicates that the investigator should have the written approval/favorable opinion from an ethics committee (EC) (referred to as an independent ethics committee (IEC)/institutional review board (IRB) in Bangladesh) of the written informed consent form and any other written information to be provided to participants.

The BGD-GCP states that in obtaining and documenting informed consent, the investigator should comply with good clinical practice (GCP) and to the ethical principles that have their origin in the Declaration of Helsinki (BGD-33). Neither the investigator, nor the trial staff, should coerce or unduly influence a participant to participate or to continue to participate in a trial. Before informed consent may be obtained, the investigator, or a person designated by the investigator, should provide the participant or the legal representative/guardian ample time and opportunity to inquire about details of the trial and to decide whether or not to participate in the trial. All questions about the trial should be answered to the satisfaction of the participant or the legal representative/guardian.

As per the BGD-GCP, the language used in the oral and written information about the trial, including the written ICF, should be as nontechnical as practical and should be understandable to the participant or the legal representative/guardian and the impartial witness, where applicable. Furthermore, none of the oral and written information concerning the trial, including the written ICF, should contain any language that causes the participant or the legal representative/guardian to waive or to appear to waive any legal rights, or that releases or appears to release the investigator, the institution, the sponsor, or their agents from liability for negligence.

The G-BMRC further states that to obtain consent, the investigator must provide the participants with the opportunity and encouragement to ask questions. For studies without any intervention involving a large community, the investigator must also have the consent of the community. For more investigator requirements in obtaining consent, see the G-BMRC.

Re-Consent

According to the BGD-GCP, the ICF and any other written information to be provided to participants should be revised whenever important new information becomes available that may be relevant to the participant’s consent. Any revised written ICF and written information should receive the EC's written approval/favorable opinion in advance of use. The participant or the legal representative/guardian should be informed in a timely manner if new information becomes available that may be relevant to the participant’s willingness to continue participation in the trial. The communication of this information should be documented.

Language Requirements

BGD-15 and BGD-16 indicate that the ICF, as well as the questionnaire or interview schedule, submitted to the BMRC must be provided in both Bengali and English.

As stated in the G-BMRC, the informed consent documentation must be inclusive. If the research involves participants who cannot speak or write English, the documentation needs to be translated (a professional translator needs to be employed unless the investigator is fluent in Bengali). Consideration for people with special needs, for example, dyslexia, will need to be included and the provision for alternative formats of documentation should be made.

Documenting Consent

According to the BGD-GCP, the investigator, or a person designated by the investigator, should fully inform the participant or, if the participant is unable to provide informed consent, the participant’s legal representative/guardian, of all pertinent aspects of the trial including the written information given approval/favorable opinion by the EC. Prior to a participant’s participation in the trial, the written ICF should be signed and personally dated by the participant or the legal representative/guardian, and by the person who conducted the informed consent discussion.

The BGD-GCP further delineates that if a participant is unable to read or if the legal representative/guardian is unable to read, an impartial witness should be present during the entire informed consent discussion. After the written ICF and any other written information to be provided to participants is read and explained to the participant or the legal representative/guardian, and after the participant or the legal representative/guardian has orally consented to the participant’s participation in the trial, and, if capable of doing so, has signed and/or thumb printed and personally dated the ICF, the witness should sign and personally date the consent form. Prior to participation in the trial, the participant or the legal representative/guardian should receive a copy of the signed and dated written ICF and any other written information provided to the participants. During a participant’s participation in the trial, the participant or the legal representative/guardian should receive a copy of the signed and dated consent form updates and a copy of any amendments to the written information provided to participants.

Waiver of Consent

Per the BGD-GCP, where the protocol indicates that prior consent of the trial participants or the legal representative/guardian is not possible, the EC should determine that the proposed protocol and/or other document(s) adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such trials (i.e., in emergency situations).

Per the IRB-Manual, the BMRC’s guidance for institutional ECs, individual consent is not required for a government-wide poll. For a non-intervention form of research or survey including an entire community, the community's consent is not required.

According to the BGD-GCP, the G-BMRC, BGD-15, and BGD-16, the informed consent discussion, the written informed consent form (ICF), and any other written information to be provided to participants should include statements or descriptions of the following (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• The interviewer’s details
• That the trial involves research
• The research method and purpose of the trial
• The trial treatment(s) and the probability for random assignment to each treatment
• The trial procedures to be followed, including all invasive procedures
• The participant’s responsibilities
• Those aspects of the trial that are experimental
• The measures to be taken to minimize risks
• The reasonably foreseeable risks or inconveniences to the participant and, when applicable, to an embryo, fetus, or nursing infant
• The reasonably expected benefits; when there is no intended clinical benefit to the participant, the participant should be made aware of this
• The alternative procedure(s) or course(s) of treatment that may be available to the participant, and their important potential benefits and risks
• The compensation and/or treatment available to the participant in the event of trial-related injury
• The anticipated prorated compensation, if any, to the participant for participating in the trial
• The anticipated expenses, if any, to the participant for participating in the trial
• That the participant’s participation in the trial is voluntary and that the participant may refuse to participate or withdraw from the trial, at any time, without penalty or loss of benefits to which the participant is otherwise entitled
• That the monitor(s), the auditor(s), the ethics committee (EC) (referred to as an independent ethics committee (IEC)/institutional review board (IRB) in Bangladesh), and the regulatory authority(ies) will be granted direct access to the participant’s original medical records for verification of clinical trial procedures and/or data, without violating the confidentiality of the participant, to the extent permitted by the applicable laws and regulations and that, by signing a written ICF, the participant or legal representative/guardian is authorizing such access
• That records identifying the participant will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly available; the participant’s identity will remain confidential if trial results are published
• That the participant or legal representative/guardian will be informed in a timely manner if information becomes available that may be relevant to the participant’s willingness to continue participation in the trial
• The person(s) to contact for further information regarding the trial and the rights of trial participants, and whom to contact in the event of trial-related injury
• The foreseeable circumstances and/or reasons under which the participant’s participation in the trial may be terminated
• The expected duration of the participant’s participation in the trial
• The approximate number of participants involved in the trial and criteria for selection of participants
• The source of the investigational product (IP) that may be culturally unacceptable

See Annexure 1 of the BGD-GCP for an ICF template. See Annexure A of the IRB-Manual, the Bangladesh Medical Research Council (BMRC)’s guidance for institutional ECs, for an example of an ICF in both Bengali and English.

Compensation Disclosure

As set forth in the BGD-GCP, the reviewing EC should ensure that information regarding payment to participants, including the methods, amounts, and schedule of payment to trial participants, is set forth in the written ICF and any other written information to be provided to participants. The method of prorating payment should also be specified.

Overview

The BGD-GCP states that in obtaining and documenting informed consent, the investigator should comply with good clinical practice (GCP) and the ethical principles that have their origin in the Declaration of Helsinki (BGD-33). In accordance with the BGD-GCP, the G-BMRC, BGD-15, and BGD-16, a participant’s rights must be clearly addressed in the informed consent form (ICF) and during the informed consent process.

The Right to Participate, Abstain, or Withdraw

As set forth in the BGD-GCP, a participant should be informed that participation is voluntary and that refusal to participate or withdraw from the trial is allowed, without penalty or loss of benefits to which the participant is otherwise entitled.

According to the G-BMRC, it is also necessary to make it as easy as possible for people to withdraw, bearing in mind that they might not feel comfortable telling the investigator directly that they no longer wish to participate. Options, such as posting a slip, will need to be included.

The Right to Information

According to the BGD-GCP, the G-BMRC, BGD-15, and BGD-16, a potential research participant or the legal representative/guardian has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation for participation or injury/treatment, and any significant new information regarding the research study. (See the Required Elements section for more detailed information regarding participant rights.)

The Right to Privacy and Confidentiality

As per the BGD-GCP, the G-BMRC, BGD-15, and BGD-16, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right.

The G-BMRC indicates that participants should be told of the limits to the investigators' ability to safeguard confidentiality and of the anticipated consequences of breaches of confidentiality. Degree of importance of confidentiality depends on the nature of the research study. If the research study involves collection of data on sensitive issues, protections of confidentiality become prominent and essential. Limitations of the investigator related to breach of confidentiality and anticipated consequences of breaches of confidentiality should be told to participants.

The G-BMRC further states that it is the duty of the investigator to maintain appropriate confidentiality of research data. The investigator should handle the data in such a way that an individual remains unidentified. The investigator should adopt the following measures to maintain confidentiality:

• Code numbers for data
• Remove core sheets (containing names and addresses of the participants)
• Omitting identifications
• Prevent unlimited access to data
• Train related manpower in confidentiality
• Keep research records in locked cabinets
• Provide security codes for computerized records

The Right of Inquiry/Appeal

The BGD-GCP state that the ICF should include information on the person(s) to contact for further information regarding the trial and the rights of trial participants, and whom to contact in the event of trial-related injury. As per the G-BMRC, the address of the contact person must also be provided in case of queries.

The Right to Safety and Welfare

The G-BMRC indicates that during development of a research proposal, the investigator should consider respect for human dignity and protection of the rights and welfare of participants. The investigators should also be competent enough to safeguard the welfare of the research participants, and the researcher should oversee whether prevailing legal provisions and administrative arrangements ensure that the human rights and welfare of participants involved in health research are adequately considered and protected in conformity with ethical principles.

The BGD-GCP states that in emergency situations, when prior consent of the participant is not possible, the consent of the legal representative/guardian, if present, should be requested. When prior consent of the participant is not possible, and the legal representative/guardian is not available, the ethics committee (EC) (referred to as an independent ethics committee (IEC)/institutional review board (IRB) in Bangladesh) should determine that the proposed protocol and/or other document(s) adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such trials. In such instances, enrollment of the participant should require measures described in the protocol and/or elsewhere, with documented approval/favorable opinion by the EC, to protect the rights, safety, and well-being of the participant and to ensure compliance with applicable regulatory requirements. The participant or the legal representative/guardian should be informed about the trial as soon as possible. Consent to continue and other consent, as appropriate, should be requested.

Overview

According to the BGD-GCP and the G-BMRC, research participants from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process.

As per the BGD-GCP, vulnerable participants include individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure, such as medical, pharmacy, dental and nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable participants include patients with incurable diseases, persons in nursing homes, unemployed, illiterate or impoverished persons, and patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.

The G-BMRC indicates that efforts should be made to ensure that individuals or communities invited for research be selected in such a way that the burdens and benefits of the research are equally distributed. Racial equalities should be maintained on genetic research, and economically or socially disadvantaged persons should not be used when there are persons better off than them. Involvement of those who have reduced autonomy as research participants, such as prisoners, students, subordinates, employees, and service personnel, requires adequate justification since the consent provided may be under duress or various other compelling reasons.

The BGD-GCP states that when a non-therapeutic trial is to be carried out with the consent of the participant’s legal representative/guardian, the ethics committee (EC) (referred to as an independent ethics committee (IEC)/institutional review board (IRB) in Bangladesh) should determine that the proposed protocol and/or other document(s) adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such trials.

See the IRB-Manual for the Bangladesh Medical Research Council (BMRC)’s guidance for institutional ECs regarding vulnerable populations.

The G-BMRC defines a child as a person below the age of 18. Consideration should be taken before involving children as study participants. Children should not be involved as participants in research that might be equally carried out in adults, and they should only participate in research to obtain knowledge regarding their health needs.

According to the G-BMRC, participation of children in a clinical evaluation of a new drug trial is permitted only after Phase III clinical trials in adults. If testing the therapeutic value of a drug in a primary disease of children, the study can be carried out earlier. Study design of interventions applied to a child participant for the benefit of diagnostic, preventive, or therapeutic purposes should be justified in relation to anticipated risks involved in the study and anticipated benefits to society. Such interventions should be at least as advantageous as any available alternative interventions. The benefit and risk to the child participant should be determined before intervention, otherwise the benefit will be low when compared to the knowledge that is to be gained. In addition, the study should be well designed to ensure adequate medical and psychological support to the parent and children.

The G-BMRC further indicates that consent should be obtained from the parent/legal guardian of each child before inclusion in the study. The parent/legal guardian is given the opportunity to observe the research as it proceeds to be able to withdraw the child if they decide that it is in the child’s best interest to do so.

Assent Requirements

As per the BGD-GCP, when a clinical trial includes minors, the participant should be informed about the trial to the extent compatible with the participant’s understanding and, if capable, the participant should sign and personally date the written informed consent.

The G-BMRC delineates that consent from each child should be taken to the extent of the child’s intelligence and capabilities, such as in the case of mature minors from the age of seven (7) years up to the age of 18 years. Any child at any moment that wants to withdraw and/or refuse to participate in the study, even if the parent/legal guardian has given consent, should be respected unless there is no acceptable alternative medically recognized therapy.

See Annexure B of the IRB-Manual, the Bangladesh Medical Research Council (BMRC)’s guidance for institutional ECs, for an example of an assent form in both Bengali and English.

The G-BMRC states that it is always best to avoid involvement of pregnant or nursing mothers in research except for trials which gather new knowledge on pregnancy, fetuses, and lactation where non-pregnant or non-nursing women are not suitable participants. The research should be well designed in such a way that protects or advances the health of pregnant or nursing women, fetuses, or nursing infants with no more than minimal risk.

According to the G-BMRC, it is mandatory to describe the opportunity and benefits to the women as a participant in a study, and deprivation from any opportunity or benefit is unethical. Women should not be encouraged to discontinue nursing without proper assessment where breastfeeding is harmful to the infant, and compensation of supplementary food should be considered. At any time or while participating in research, women who desire to undergo medical termination of pregnancy should follow the applicable laws.

The G-BMRC further indicates that research involving prenatal diagnostic techniques to detect fetal genetic disorders or any abnormalities should follow the relevant World Health Organization (WHO) guideline.

The G-BMRC indicates that efforts should be made to ensure that individuals or communities invited for research be selected in such a way that the burdens and benefits of the research are equally distributed. Involvement of those who have reduced autonomy as research participants, such as prisoners, requires adequate justification since the consent provided may be under duress or various other compelling reasons.

According to the BGD-GCP, when a clinical trial includes participants who can only be enrolled in the trial with the consent of the legal representative/guardian (e.g., patients with severe dementia), the participant should be informed about the trial to the extent compatible with the participant’s understanding and, if capable, the participant should sign and personally date the written informed consent. In addition, when a non-therapeutic trial is to be carried out with the consent of the participant’s legal representative/guardian, the ethics committee (EC) (referred to as an independent ethics committee (IEC)/institutional review board (IRB) in Bangladesh) should determine that the proposed protocol and/or other document(s) adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such trials.

The G-BMRC states that the rights and welfare of mentally challenged and mentally differently able persons who are incapable of giving informed consent or those with behavioral disorders must be protected. Appropriate proxy consent from the legal representative/guardian should be taken after the person is well informed about the study, need for participation, risks and benefits involved, and the privacy and confidentiality procedures. The entire consent process should be properly documented.

According to the BGD-GCP and the G-BGD-IP, an investigational product (IP) (also referred to as an investigational medicinal product (IMP) in Bangladesh) is any medicinal product which is being tested within a trial or any product, including placebo, that is being used as a reference in a clinical trial. This includes products with marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, when used for an unapproved indication (off-label use), or when used to gain further information about an approved use.

Manufacturing

According to the DrugPolicy, the G-IndCTA, the G-BGD-IP, BGD-8, and BGD-13, the Ministry of Health and Family Welfare (MOHFW)’s Directorate General of Drug Administration (DGDA) is responsible for authorizing the manufacture of drugs, including investigational products (IPs) (also referred to as investigational medicinal products (IMPs)), in Bangladesh. The G-IndCTA indicates that the clinical trial applicant must obtain a license for manufacturing for testing and analysis, as issued by the DGDA.

The DrugRules states that if the entity proposing to manufacture a drug for the purpose of examination, test, or analysis does not hold an existing license to manufacture drugs in Bangladesh, a Form 17 license (BGD-21) must be obtained before commencing such manufacture. The application for a Form 17 license (BGD-21) must be submitted to the DGDA using Form 18 (BGD-34), and must be made or countersigned by the head of the institution in which, or a director of the firm or company by which, the substance will be manufactured. A Form 17 license (BGD-21) will, unless sooner cancelled, be in force for one (1) year from the date of issue, and may thereafter be renewed one (1) year at a time.

According to the BGD-GCP, the IP(s) must be manufactured in good manufacturing practice (GMP)-compliant facilities. For investigational new drugs (INDs), the sponsor must submit the IND certificate from the national regulatory authority of the country of origin to the DGDA. In this case, the DGDA may consider the IND certificate from country of origin if the country is a World Health Organization (WHO) Listed Authority (WLA) or a stringent regulatory authority. As per the BGD-GCP, the sponsor should ensure that the IP(s) (including active comparator(s) and placebo, if applicable) is characterized as appropriate to the stage of development of the product(s), is manufactured in accordance with any applicable GMP, and is coded and labeled in a manner that protects the blinding, if applicable. If required, the DGDA may conduct a GMP inspection of the IP manufacturing site. The DrugsCosAct indicates that if the manufacturer’s pharmacovigilance program is not conducted effectively, the DGDA’s Director General may temporarily suspend or cancel the license of the concerned establishment to manufacture drugs.

The G-BGD-IP further indicates that release of a product is contingent upon providing the GMP certificate, the Certificate of Analysis (CoA), and a data log (See Annexure 2 of the G-BGD-IP). Additionally, IPs manufactured for clinical trials must comply with GMP guidelines from the WHO, the European Union (EU), the Pharmaceutical Inspection Co-operation Scheme (PIC/S), or the United States (US). As per the G-GMPBioProd, the DGDA has adopted the WHO guideline on Good Manufacturing Practices for Biological Products (BGD-5) for the purpose of GMP.

Import

According to the G-BGD-IP and the BGD-GCP, the DGDA is responsible for authorizing the import of IPs into Bangladesh. Permission for importing IPs is issued by the DGDA as a no objection certificate (NOC). The G-BGD-IP specifies that in the application for an NOC to import/locally collect IPs, the sponsor/principal investigator (PI) should mention the amount they want to import/collect with the justification (See Annexure 6 of the G-BGD-IP for the Application Form of Import of IMPs/Placebo and Annexure 7 of the G-BGD-IP for the Checklist of NOC for IMPs). The DGDA will verify the amount according to the protocol and issue the NOC. The manufacturer providing the IP(s) must also obtain a relevant license/permission from the DGDA. The DGDA has a legal responsibility to ensure that the IP has been manufactured in accordance with GMP and meets the conditions of the clinical trial authorization and the product specification file (PSF) (See Annexure 1 of the G-BGD-IP).

The DrugsCosAct indicates that as with the manufacture license, an import license may be temporarily suspended or canceled by the DGDA Director General if the manufacturer’s pharmacovigilance program is not conducted effectively.

The BGD-GCP states that all importation of clinical trial drugs should go through customs even though a clinical trial import license has been obtained or a NOC has been received from the DGDA. In addition, the G-BGD-IP indicates that shipping of IPs should be conducted according to instructions given by or on behalf of the sponsor in the shipping order.

As per the G-BGD-IP, DGDA officer(s) may inspect the premises of the trial site/sponsor/contract research organization (CRO) facilities to evaluate the following documents:

• The CoA of each batch of the IP(s) as well as comparator(s), if relevant
• A copy of the letter of approval of clinical trial
• A copy of a valid GMP certificate for the IP issued by the competent regulatory authority in the country of origin
• The cover sheet should be completed by the sponsor and accompany each consignment of IPs (See Annexure 4 of the G-BGD-IP)

For more information, the DGDA cites the WHO Guidelines on Import Procedures for Medical Products (BGD-1) as an additional resource.

Please note: Bangladesh is party to the Nagoya Protocol on Access and Benefit-sharing (BGD-2), 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 BGD-4.

Investigator’s Brochure

As per the BGD-GCP, the sponsor is generally responsible for ensuring that an up-to date Investigator’s Brochure (IB) is made available to the investigator(s), and the investigators are responsible for providing the up-to date IB to the responsible ethics committees (ECs) (referred to as independent ethics committees (IECs)/institutional review boards (IRBs) in Bangladesh). The sponsor should provide the investigator(s)/institution(s) with the protocol and an up-to-date IB before entering an agreement with an investigator/institution to conduct a trial. In the case of an investigator sponsored trial, the sponsor-investigator should determine whether a brochure is available from the commercial manufacturer. If the investigational product (IP) (also referred to as an investigational medicinal product (IMP) in Bangladesh) is provided by the sponsor-investigator, then the sponsor-investigator should provide the necessary information to the trial personnel. In cases where preparation of a formal IB is impractical, the sponsor-investigator should provide, as a substitute, an expanded background information section in the trial protocol that contains the minimum current information described in the BGD-GCP.

The BGD-GCP indicates that when planning trials, the sponsor should ensure that sufficient safety and efficacy data from nonclinical studies and/or clinical trials are available to support human exposure by the route, at the dosages, for the duration, and in the trial population to be studied. According to the BGD-GCP and the G-BGD-IP, the sponsor should update the IB as significant new information becomes available.

As per the BGD-GCP, the IB is a compilation of the clinical and nonclinical data on the IP(s) that are relevant to the study of the product(s) in human participants. Its purpose is to provide the investigators and others involved in the trial with the information to facilitate their understanding of the rationale for, and their compliance with, many key features of the protocol, such as the dose, dose frequency/interval, methods of administration, and safety monitoring procedures. The IB should include:

• Title page
• Confidentiality statement
• Table of contents
• Summary
• Introduction
• Physical, chemical, and pharmaceutical properties and formulation
• Information on nonclinical studies (pharmacology, pharmacokinetics and product metabolism in animals, toxicology)
• Information on effects in humans (pharmacokinetics and product metabolism; safety and efficacy; marketing experience)
• Summary of data and guidance for the investigator

See the BGD-GCP for detailed content guidelines.

Quality Management

The G-BGD-IP states that the sponsor or principal investigator (PI) should submit to the Ministry of Health and Family Welfare (MOHFW)’s Directorate General of Drug Administration (DGDA) the good manufacturing practice (GMP) certificate of the manufacturing plant from the national regulatory authority of the country of origin. IPs should be produced in accordance with the principles and guidelines of GMP for medical products. Production processes for IPs are not expected to be validated to the extent necessary for routine production, but premises and equipment are expected to be qualified.

The G-BGD-IP further indicates that release of a product is contingent upon providing the GMP certificate, the Certificate of Analysis (CoA), and a data log (See Annexure 2 of the G-BGD-IP). IPs manufactured for clinical trials must comply with GMP guidelines from the World Health Organization (WHO), the European Union (EU), the Pharmaceutical Inspection Co-operation Scheme (PIC/S), or the United States (US). As per the G-GMPBioProd, the DGDA has adopted the WHO guideline on Good Manufacturing Practices for Biological Products (BGD-5) for the purpose of GMP.

Labeling for investigational products (IPs) (also referred to as investigational medicinal products (IMPs) in Bangladesh) must comply with the requirements set forth in the BGD-GCP and the G-BGD-IP. The BGD-GCP indicates that the sponsor should ensure that the IP(s) (including active comparator(s) and placebo, if applicable) is coded and labeled in a manner that protects the blinding, if applicable. In blinded trials, the coding system for the IP(s) should include a mechanism that permits rapid identification of the product(s) in case of a medical emergency but does not permit undetectable breaks of the blinding.

According to the G-BGD-IP, labeling should comply with the requirements of the Ministry of Health and Family Welfare (MOHFW)’s Directorate General of Drug Administration (DGDA). The following information should be included on labels, unless its absence can be justified:

• The name, address, and telephone number of the sponsor, contract research organization (CRO), or investigator (the main contact for information on the IP, clinical trial, and emergency unblinding)
• The pharmaceutical dosage form, route of administration, quantity of dosage units, and in the case of open trials, 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 or treatment number and, where relevant, the visit number
• The investigator’s name (if not already provided on the label)
• The directions for use (reference may be made to a leaflet or other explanatory document intended for the trial subject 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 participants

For additional detailed labelling information, see the G-BGD-IP.

Supply, Storage, and Handling Requirements

The BGD-GCP indicates that the sponsor should not supply an investigator/institution with the investigational products(s) (IP(s)) (also referred to as investigational medicinal products (IMPs) in Bangladesh) until the sponsor obtains all required documentation, such as a favorable opinion from an ethics committee (EC) (referred to as independent ethics committee (IEC)/institutional review board (IRB) in Bangladesh) and the Ministry of Health and Family Welfare (MOHFW)’s Directorate General of Drug Administration (DGDA). The G-BGD-IP further states that the IPs should remain under the control of the sponsor.

According to the BGD-GCP and the G-BGD-IP, the sponsor is responsible for supplying the investigator(s)/institution(s) with the IP(s) and should ensure timely delivery of IP(s) to the investigator(s). Per the BGD-GCP, the sponsor should:

• Take steps to ensure that the IP(s) are stable over the period of use
• Maintain sufficient quantities of the IP(s) used in the trials to reconfirm specifications, should this become necessary, and maintain records of batch sample analyses and characteristics. To the extent stability permits, samples should be retained either until the analyses of the trial data are complete or as required by the applicable regulatory requirement(s), whichever represents the longer retention period

The G-BGD-IP indicates that the packaging must ensure 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. The BGD-GCP further states that the IP(s) should be packaged to prevent contamination and unacceptable deterioration during transport and storage.

The BGD-GCP further indicates that the sponsor should determine, for the IP(s), acceptable storage temperatures, storage conditions (e.g., protection from light), storage times, reconstitution fluids and procedures, and devices for product infusion, if any. The sponsor should inform all involved parties (e.g., monitors, investigators, pharmacists, storage managers) of these determinations. As per the BGD-GCP and the G-BGD-IP, the sponsor should also ensure that written procedures include instructions that the investigator/institution should follow for the handling and storage of IP(s) for the trial and documentation thereof. The procedures should address adequate and safe receipt, handling, storage, dispensing, and retrieval of unused product from participants, and return of unused IP(s) to the sponsor (or alternative disposition if authorized by the sponsor and in compliance with the applicable regulatory requirement(s)).

The G-BGD-IP states that all IPs used and unused must be accounted for by the study monitor/sponsor. Disposal of used or unused IPs must be initiated only after the written instruction from the sponsor/study monitor has been obtained. After finishing the trial, the sponsor/principal investigator must inform the DGDA about the remaining and used amount of IPs using the form in Annexure 5 of the G-BGD-IP.

For more information on the destruction of IPs or the return of IPs to the sponsor, see the G-BGD-IP.

Record Requirements

Per the BGD-GCP, the sponsor should:

• Maintain records that document shipment, receipt, disposition, return, and destruction of the IP(s)
• Maintain a system for retrieving IPs and documenting this retrieval (e.g., for deficient product recall, reclaim after trial completion, expired product reclaim)
• Maintain a system for the disposition of unused IP(s) and for the documentation of this disposition.

The G-BGD-IP delineates that IP records must be maintained to demonstrate adherence to the trial protocol and credibility and integrity of the data. The BGD-GCP further indicates that the investigator/institution and/or a pharmacist, or other appropriate individual who is designated by the investigator/institution, should maintain records of the IP's delivery to the trial site, the inventory at the site, the use by each participant, and the return to the sponsor or alternative disposition of unused product(s). These records should include dates, quantities, batch/serial numbers, expiration dates (if applicable), and the unique code numbers assigned to the IP(s) and trial participants. Investigators should maintain records that document adequately that the participants were provided the doses specified by the protocol and reconcile all IP(s) received from the sponsor.

As per the G-BMRC, human biological samples include whole or part of organs, tissues, cells (somatic and gonadal), bodily fluids or samples like serum, buffy coat, DNA, hair, nails, excreta, sweat, buccal scrapings, etc.

The G-BMRC also defines identified specimens as those linked to personal information in such a way that the person from whom the material was obtained could be identified by name, patient number, or clear pedigree location (e.g., the person’s relationship to a family member whose identity is known). Unidentified specimens are those for which identifiable personal information was not collected or, if collected, was not maintained and cannot be retrieved by the repository.

Import

The G-BMRC indicates that the import of biological materials for research and development should be regulated by the Government of Bangladesh. Clinical trials using cells after major manipulation or those sponsored by multinational entities involving stem cell products imported from abroad require prior approval of the Bangladesh Medical Research Council (BMRC) and the Ministry of Health and Family Welfare (MOHFW).

Export

According to the G-BMRC, ethical issues exist pertaining to consent requirements for the banking and further uses of tissue and DNA samples, their control and ownership, and the benefit sharing to the individual or community. Permission must be obtained for shipping repository samples abroad.

Material Transfer Agreement

The G-BMRC states that when using repository research samples, there should be appropriate material transfer agreements (MTAs) with the repository for depositing samples as well as for taking them out with clear reasons. Third parties must be allowed to take samples only after approval from the BMRC’s repository ethics committee.

According to the G-BMRC, the sample collector must obtain informed consent from the donor for DNA banking or for cell-line transformation and banking. The process of seeking informed consent for purposes of banking must clearly be stated in addition to possible risks and benefits, the conditions under which samples from the repository will be provided to other researchers, how long and in what condition the samples will be preserved in the repository, and what the costs to individual researchers will be in obtaining samples from the repository. The sample collector must also clearly inform all donors that they reserve the right to order destruction of their samples from the repository at any time. To prevent any exploitation and protect the rights of participants, the main requirements at collection level are:

• Individual informed consent
• Approval of the ethics committee (EC) (referred to as independent ethics committee (IEC)/institutional review board (IRB) in Bangladesh)
• Approval of the Repository Ethics Committee (which may be formed by the Bangladesh Medical Research Council (BMRC))

For more information on using repository samples, see the G-BMRC.