In Uganda, the National Drug Authority (NDA) and the Uganda National Council for Science and Technology (UNCST), in collaboration with the Uganda National Health Research Organisation (UNHRO), are involved in clinical trial oversight.

National Drug Authority

As per the NDPA-CTReg, the G-CTConduct, and the G-TrialsGCP, the NDA is the regulatory authority responsible for clinical trial approval and inspections in Uganda. The NDA grants permission for clinical trials to be conducted in Uganda in accordance with the provisions of the NDPA-Act.

As stated in the NGHRP, the NDA regulates safety, quality, efficacy, handling, and use of drugs or drug related products and devices in research. According to UGA-29, the Clinical Trials Unit in the NDA’s Directorate of Product Safety is responsible for reviewing and approving clinical trial applications, conducting clinical trial site inspections for compliance with good clinical practices, and developing guidance documents.

Please note: Uganda is party to the Nagoya Protocol on Access and Benefit-sharing (UGA-3), 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 UGA-21.

Uganda National Council for Science and Technology

As delineated in the NDPA-CTReg, the NGHRP, and the G-CTConduct, in addition to obtaining the NDA’s permission to conduct research in Uganda, an applicant must obtain approval in the form of a research permit from the UNCST, or from an institution authorized by the UNCST.

As per UGA-30, the UNCST was established by the UNCST-Act as a semi-autonomous government agency under the Ministry of Science, Technology, and Innovation. The mandate of the UNCST is to develop and implement policies and strategies for integrating science and technology into national development policies; to advise the government of Uganda on policy matters necessary for promoting science and technology; and coordinate and guide national research and development in Uganda.

As per the NGHRP, the UNCST registers and, in liaison with the Research Secretariat in the Office of the President of Uganda, clears all research intended to be carried out in the country.

The G-CTConduct and the G-UNCSTreg also state that applicants must register their research proposals, obtain approval, and be issued a research permit from the UNCST prior to initiating a study.

Uganda National Health Research Organisation

The UNHRO-Act authorizes the UNHRO to register and renew research protocols, and to implement and enforce an ethical code of conduct for health research in Uganda. The UNHRO, in collaboration with the UNCST, conducts a scientific and ethical review of all health research protocols for approval. According to the NGHRP, the UNHRO also collaborates with the UNCST to register all health research protocols centrally at the UNCST. No additional information regarding UNHRO’s role is available.

Contact Information

National Drug Authority

According to UGA-23 and UGA-10, the NDA’s contact information is as follows:

National Drug Authority
Head Office
Plot 93, Buganda Road, after St. Catherine Hospital
P.O. Box 23096
Kampala, Uganda

Reception Phone: +256 [0]417 788 100
Directorate of Product Safety Phone: +256 [0]417 788 124
Directorate of Inspectorate Services Phone: +256 [0]417 788 129
WhatsApp: +256 74002080
Innovation & Research Desk: [0]800 101 999 (Toll Free Line), 0791 415555 (WhatsApp)
Email: ndaug@nda.or.ug

Uganda National Council for Science and Technology

As per the G-UNCSTreg and UGA-25, the UNCST’s contact information is as follows:

Uganda National Council for Science and Technology
Plot 6, Kimera Road, Ntinda
P.O. Box 6884
Kampala, Uganda
Phone: +256 414 705500
Fax: +256 414 234579
Email: info@uncst.go.ug

Uganda National Health Research Organisation

Per UGA-26, the UNHRO’s contact information is as follows:

Uganda National Health Research Organisation
Plot 2, Berkeley Lane, Entebbe
P.O. Box 465
Entebbe, Uganda

Tel/Fax: +256 414 321766
Email: unhrodesk4@gmail.com

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

Food & Drug Administration

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

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

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

Office for Human Research Protections and Common Rule Agencies

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

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

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

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

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

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

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

Other Considerations

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

Contact Information

Food & Drug Administration

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

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

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

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

Office for Human Research Protections

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

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

Department of Health & Human Services

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

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

Overview

In accordance with the NDPA-CTReg, the G-CTConduct, and the G-TrialsGCP, the National Drug Authority (NDA) is responsible for reviewing, evaluating, and approving clinical trial applications for registered or unregistered medicines in Uganda. The scope of the NDA’s assessment includes all clinical trials (Phases I-IV).

Per the NDPA-CTReg and UGA-20, the NDA’s review and approval of a clinical trial application are dependent upon the applicant submitting proof in the application of institutional level ethics committee (EC) (research ethics committee (REC) in Uganda) approval and a research permit from the Uganda National Council for Science and Technology (UNCST). UGA-33 further notes that for clinical trials involving human participants, approval must be obtained through the institutional EC portal (the National Research Information Management System (NRIMS) (UGA-33)) before NDA approval. Therefore, the NDA and institutional EC reviews may not be conducted in parallel. However, the G-TrialsGCP indicates that parallel submissions may be made to the NDA and the UNCST. In that instance, the NDA would not make a final decision until after the trial receives UNCST clearance.

Clinical Trial Review Process

National Drug Authority

The NDPA-CTReg, the G-TrialsGCP, and the G-CTConduct indicate that upon receipt of a clinical trial application, the NDA initially screens the application for completeness. If the NDA is not satisfied with the information provided, the applicant will be advised in writing to provide further information or clarification. According to the G-CTConduct, the applicant must submit their responses in writing or in any other format as advised by the NDA, and in the timeframe determined by the NDA. NDA reviews are performed following a first-in first-out principle, except for clinical trials that are to be conducted in public health emergencies such as disease outbreaks, which may be exempted.

The NDPA-CTReg, as amended by the NDPA-CTRegAmdt, indicates that in considering an application for a clinical trial, the NDA must take into account the following:

• Relevance of the clinical trial
• Suitability of the principal investigator (PI)
• Quality of the facilities to be used for the clinical trial
• Adequacy and completeness of the information and procedures to obtain consent of the clinical trial participants
• Provision for indemnity for the PI and insurance for the clinical trial participants
• Terms of the agreement between the sponsor and the PI

Per the G-CTConduct, complete applications are given a Clinical Trial Application code. Applications verified as complete will undergo one (1) of three (3) types of reviews:

• Internal review, which is further subdivided into expedited or routine review
• Expert review, which involves external reviewers co-opted by the NDA following internal procedures
• Joint reviews, which are carried out jointly with other regulatory bodies including the UNCST, Uganda National Health Research Organisation (UNHRO), and the primary EC. These reviews will be coordinated by the UNCST

Expedited review of an application is applicable for:

• Clinical trial applications for investigational drugs to provide treatment where no therapy exists
• Clinical trials conducted in an emergency, such as during a disease outbreak
• Clinical trial applications that do not explicitly meet either above criterion, but are led by the Ministry of Health in the interest of a public health intervention

According to the G-CTConduct, the NDA may decide to a) authorize the clinical trial and issue a clinical trial certificate; b) request additional information to support the application; or c) reject the clinical trial application, providing reasoning. The NDA’s decision is communicated to the applicant in writing. The clinical trial certificate is valid for one (1) year from the date it is awarded (See Form 35 in Schedule 1 of the NDPA-CTReg, as amended by the NDPA-CTRegAmdt). Applicants may apply for renewal of this approval with the Application Form for Renewal of Authorisation of Clinical Trial (UGA-32). See Appendix VI of the G-CTConduct for the Checklist for Application for Authorization of Renewal of Conduct of a Clinical Trial, and UGA-2 for a related clinical trial application screening renewal form.

The G-CTConduct states that any new information that becomes available regarding the product, such as new adverse effects or changes in formulation or the manufacturer, must be submitted to the NDA as soon as possible.

The NDPA-CTReg and the G-CTConduct indicate that the NDA may, on its own initiative, make amendments to the conditions for conducting a clinical trial where it is necessary for the safety or scientific validity of the clinical trial. The NDA will give 15 days’ notice of the intended amendment to the sponsor and the PI with reasons for the amendment, and request a written response to the proposed amendments prior to effecting the amendments. The NDA will, in making amendments to the conditions of conducting a clinical trial, take into consideration the response of the sponsor or PI.

Per the G-CTConduct, applicants may also submit a form to amend the conditions of a clinical trial. The amendment application will be screened for completeness and will essentially be complete in the first instance if it includes all the required documents, appendices, and finished checklist. Applications which are incomplete will not be evaluated, and a letter documenting the deficiencies in the application will be issued to the applicant. The NDA may request supplementary data or documentation where applicable. The NDA will consider the favorable opinion of the EC(s), the UNCST, and other relevant information, and may request that the applicant to submit an interim clinical trial study report to support the decision. Additionally, the NDA may take other regulatory action such as an inspection of the clinical trial site or investigational product manufacturing facility for regulatory and protocol compliance prior to making a decision. The NDA may approve or reject the application and specify the reasons for rejection. The decision will be communicated to the applicant in writing.

See the G-CTConduct for detailed NDA amendment review procedures, and Appendix V of the G-CTConduct or UGA-22 for the clinical trial application amendments screening form.

As per the G-CTConduct, the NDA may at any reasonable time conduct inspections of the trial site prior to or after issuance of a clinical trial certificate. The purpose of the inspections is to assess the staff and facilities to be used or that are being used for the conduct of the clinical trial, and to verify the availability of the necessary resources and feasibility of conducting the study at the proposed site(s). These inspections will assess the compliance of the trial conduct with the conditions of the certificate. The NDA secretariat may contact the PI or sponsor notifying them of the date(s) of inspection. The secretariat will conduct inspections routinely, or as a result of a trigger. In addition, the inspections may be done jointly with the UNCST and/or the EC.

Uganda National Council for Science and Technology

According to the NDPA-CTReg, the NGHRP, and the G-CTConduct, an applicant must also submit a research proposal for review and approval to the UNCST. Per the G-UNCSTreg, the UNCST receives and reviews research protocols for their scientific merit, safety, and ethical appropriateness, and when satisfied, issues permits to conduct the research in Uganda. The research permit is granted at a national level to facilitate access to research resources within the country. The G-UNCSTreg states that as a part of its review, the UNCST liaises with the Research Secretariat in the Office of the President of Uganda to obtain security verification and clearance for the investigator. The investigator must pay a Research Administration and Clearance fee for the entire period of the research project, but such a period must not exceed five (5) years. Investigators interested in continuing a study using an approved protocol beyond the UNCST research permit expiration date should make a written request for an extension or renewal of the permit to the UNCST Executive Secretary. The request should be accompanied by a progress report, the EC approval, and any other institutional approvals, where applicable. See the G-UNCSTreg for detailed extension/renewal request submission information.

The G-UNCSTreg indicates that any changes, amendments, and addenda to the research protocol, research instruments, or the consent form must be submitted to the designated local EC or the lead agency (NDA) for review and approval prior to implementing the changes. The UNCST should be notified of the EC- or lead agency-approved changes within 10 working days.

The UNCST also reserves the right to revoke, suspend, or terminate a research permit, and, if necessary, without giving notice to the investigator, in the event of gross misconduct or violation of the G-UNCSTreg guidelines.

Overview

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

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

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

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

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

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

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

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

• A drug is involved as defined in the FDCAct

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

• The clinical investigation is not otherwise exempt from 21CFR312

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

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

Clinical Trial Review Process

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

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

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

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

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

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

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

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

Expedited Processes

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

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

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

Other Considerations

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

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

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

National Drug Authority

In accordance with the NDPA-CTReg, the G-CTConduct, and the NDPA-FeesReg, applicants are responsible for paying a non-refundable processing fee to submit a clinical trial application for human drugs and vaccines (except for locally manufactured herbal drugs) to the National Drug Authority (NDA). As set forth in the NDPA-FeesReg, the following fees apply:

• Application to undertake a clinical trial for a registered drug – $2,500 USD
• Application to undertake a clinical trial for an unregistered drug – $4,000 USD
• Application to amend a clinical trial application – $200 USD

Payment Instructions

According to the G-CTConduct, the application fee payment details are as follows:

National Drug Authority: TIN 1000054563
Bank: Stanbic Bank Uganda
Account numbers: 9003008068851 (US Dollars) and 903005759829 (Ugandan shillings)
Swift code: SBICUGKX
Acceptable forms of payment: cash in the bank, real time gross settlement (RTGS), electronic funds transfer (EFT), telegraphic transfer (TT), or check

Uganda National Council for Science and Technology

As delineated in the G-UNCSTreg, the Uganda National Council for Science and Technology (UNCST) charges a non-refundable Research Administration and Clearance fee of $300 USD, or its equivalent in Ugandan shillings, to register a research proposal. The UNCST will not register the protocol or issue a research permit until this fee has been paid. Permits are valid for the entire duration specified for a project. However, the fee covers a research period not to exceed five (5) years. Projects that extend beyond the initial five (5) year period are required to pay $300 USD for the extension. All applicants, excluding East African students, are responsible for paying this fee. East African students are only required to pay a fee of $50 USD. However, UGA-20 further indicates that this excludes those pursuing post doctorate studies.

Payment Instructions

The G-UNCSTreg delineates that applicants should make their payments to the UNCST bank accounts and are encouraged to make cash payments to avoid additional bank fees. An official receipt is issued once the UNCST receives a stamped copy of the bank deposit. See Section 6.0 of the G-UNCSTreg for detailed payment information.

According to UGA-20, the payment information is as follows:

Bank: Any Standard Chartered Bank
Account title: Uganda National Council for Science and Technology (UNCST)
Account numbers: 8705611811400 (US Dollars) and 0105610632101 (Ugandan shillings)
Swift code: SCBLUGKA

Food & Drug Administration

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

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

Overview

As per the G-UNCSTreg and the NGHRP, research involving human participants must be reviewed and approved by an institutional ethics committee (EC) (referred to as a research ethics committee (REC) in Uganda), which must be accredited by the Uganda National Council for Science and Technology (UNCST).

Ethics Committee Composition

The NGHRP states that an EC must have at least five (5) members who collectively encompass the qualifications and experience required to review and evaluate the scientific, medical, and ethical aspects of a proposed clinical trial. Specifically, the composition should include:

• Individuals of varying backgrounds, including consideration of gender, cultural backgrounds, and sensitivity to social issues in the community from which research participants are drawn
• At least one (1) individual whose primary concern is scientific, and at least one (1) whose primary concern is non-scientific
• At least one (1) individual who is unaffiliated with the institution
• At least one (1) lay person from the community, whose primary background is not in scientific research involving human participants, and who is capable of sharing insights about the community from which participants are likely to be drawn

Additional criteria for EC membership are available in Sections 4.3 and 4.4 of the NGHRP.

Terms of Reference, Review Procedures, and Meeting Schedule

According to the NGHRP, each EC member must take at least one (1) course in human research protection within one (1) year of appointment to an EC, and thereafter, should undergo continued research ethics education at least once every two (2) years. Membership terms in any EC have a maximum three (3) year duration, after which a member is eligible for reappointment. A person may not serve as a member in more than two (2) ECs concurrently.

As set forth in the NGHRP, each EC must have written procedures, including a process to be followed for conducting reviews. The following minimum requirements must be met:

• Meet at least once every three (3) months
• At least 50% of members, including one (1) member representing community interests, must be present to conduct reviews
• Project approval requires a simple majority of those members present at the meeting
• Respond to any allegations of ethical violations in approved or rejected research projects
• Liaise with other ECs within and outside the country to better carry out its functions
• Submit annual performance reports to the UNCST

The NGHRP further indicates that no EC member may participate in the EC’s initial or continuing review of any project in which the member has a conflict of interest, except to provide information as may be requested by the EC. An EC may also, at its discretion, invite individuals with competence in special areas to assist in the review of protocols which require expertise beyond, or in addition to, that available in the EC. These individuals do not vote at EC meetings. See Sections 4.5.1 and 4.9 of the NGHRP for additional EC review requirements.

As per the NGHRP, an EC must also prepare and maintain the following:

• Detailed written procedures
• Copies of reviewed proposals and corresponding documentation (e.g., scientific evaluations, progress reports, correspondence with investigators)
• Meeting minutes
• Records of continuing review activities

Documents relating to research projects must be retained for at least five (5) years after the research project has been completed. All documents must be accessible for inspection and use by authorized UNCST representatives. See Section 4.6 of the NGHRP for additional EC recordkeeping requirements.

Overview

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

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

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

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

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

Ethics Committee Composition

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

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

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

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

Terms of Reference, Review Procedures, and Meeting Schedule

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

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

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

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

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

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

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

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

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

Overview

In accordance with the NGHRP, the central scope assessed by institutional ethics committees (ECs) (research ethics committees (RECs) in Uganda) relates to safeguarding the rights, safety, and well-being of all trial participants. An EC’s primary functions include:

• Maintaining ethical standards of practice in research
• Protecting participants and investigators from harm or exploitation
• Preserving the participants’ rights and welfare
• Providing assurance to society of the protection of participants’ rights and well-being
• Ensuring adherence to an ethical conduct of research protocol

An EC must also pay special attention to reviewing informed consent and to protecting the welfare of certain classes of participants deemed to be vulnerable (See the Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses, and Neonates; Prisoners; and Mentally Impaired sections for additional information about these populations).

Role in Clinical Trial Approval Process

Per the NDPA-CTReg and UGA-20, proof of institutional EC approval must be submitted in a clinical trial application to the National Drug Authority (NDA). UGA-33 further notes that for clinical trials involving human participants, approval must be obtained through the institutional EC portal (the National Research Information Management System (NRIMS) (UGA-33)) before NDA approval. Therefore, the NDA and institutional EC reviews may not be conducted in parallel.

As stated in the NGHRP, the EC will notify investigators in writing about the outcome of its review. If the EC does not approve a research activity, it will include reasons for its disapproval in the written notification.

As per the NGHRP, ECs may use an expedited review process for research involving no more than minimal risk or for minor changes in previously approved research protocols during a period of one (1) year or less from which approval was given. Minor changes include an addition of a collaborator, a small change in the number of research participants, or spelling corrections. Expedited review processes may also be applied to annual renewal of studies, in which the only outstanding activity is data analysis and report writing. Major changes include, but are not limited to, significant changes in the research methodology or a change in procedures for research participants. Each EC must develop standard operating procedures to define eligibility for expedited review. See the NGHRP for more details on expedited review procedures.

According to the NGHRP, if a multicenter or collaborative trial is being conducted and the same clinical protocol is being used for all the sites, the participating institutions may enter into a joint EC review arrangement. The joint EC review must comply with the requisite ethical standards outlined in the NGHRP.

The NGHRP indicates that ECs must conduct continuing/periodic review of approved trials to ensure compliance with scientific and ethical requirements in accordance with the NGHRP. The EC must conduct the continuing review at intervals appropriate to the degree of risk, but not less than once a year, and have a plan for onsite monitoring of approved studies.

The NGHRP further delineates that changes/amendments in the research protocol cannot be implemented without prior approval from the EC, except when necessary to eliminate an apparent immediate hazard or danger to research participants. Per the NDPA-CTReg, evidence of ethical approval of the amendment to the protocol is a required element of an application to the NDA for deviation from a condition of a clinical trial.

Additionally, the NGHRP states that ECs have the authority to halt, suspend, or terminate approval of research that is not being conducted in accordance with the EC’s requirements, has been associated with unexpected serious harm to research participants, or contravenes the NGHRP. If an EC suspends or terminates its approval, it must provide a written statement for its reasons for doing so, and immediately communicate this decision to the investigator, as well as to the Uganda National Council for Science and Technology (UNCST).

Overview

21CFR56, 21CFR312, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs state that the primary scope of information assessed by the institutional ethics committee (EC) (referred to as an institutional review board (IRB) in the United States (US)) relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial. As delineated in 21CFR56, the Pre2018-ComRule, and the RevComRule, the EC must also pay special attention to reviewing informed consent and to protecting the welfare of certain classes of participants deemed to be vulnerable. (See the Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses, & Neonates; Prisoners; and Mentally Impaired sections for additional information about these populations). The EC is also responsible for ensuring a competent review of the research protocol, evaluating the possible risks and expected benefits to participants, and verifying the adequacy of confidentiality safeguards.

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

Role in Clinical Trial Approval Process

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

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

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

Expedited Review

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

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

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

Continuing Review and Re-approval

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

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

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

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

Exemptions under the Revised Common Rule

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

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

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

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

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

Other Considerations

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

Cooperative Research Studies

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

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

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

No information is currently available.

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

Overview

The Uganda National Council for Science and Technology (UNCST) is the central statutory body responsible for the registration and accreditation of institutional ethics committees (ECs) (research ethics committees (RECs) in Uganda). The UNCST’s NGHRP establishes a national framework for research involving humans to ensure that the rights, interests, values, and welfare of research participants are not compromised.

Registration, Auditing, and Accreditation

As per the NGHRP, the UNCST’s Accreditation Committee for RECs in Uganda (ACREC) must accredit all ECs. An organization that wishes to establish an EC must apply for accreditation of the EC at the UNCST, with assurance that the organization will comply with the requirements set forth in the NGHRP. The assurance must at the minimum include:

• A statement of principles for protecting rights and welfare of human research participants of research conducted at or sponsored by the organization. This may include an appropriate existing code, declaration, or statement of ethical principles, or a statement formulated by the organization itself
• Assurance of availability of staff; office and meeting space for the EC; and sufficient resources to support the EC’s operations
• A list of EC members appointed by the head of the organization or the head’s designee. The members should be identified by name, qualifications, profession, specialty, organization of affiliation, and representative capacity in the EC
• Written standard operating procedures for the EC

The NGHRP indicates that the ACREC will review the organization’s application, and if satisfied, will accredit the EC. An EC is not permitted to commence its activities until ACREC authorization is received.

See UGA-9 for the accreditation application form and the NGHRP for details on EC establishment requirements. A list of UNCST-accredited ECs is also available through UGA-11.

Overview

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

Registration, Auditing, and Accreditation

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

Food & Drug Administration

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

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

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

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

Office for Human Research Protections

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

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

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

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

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

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

Overview

According to the NDPA-CTReg, the G-CTConduct, the NGHRP, the G-UNCSTreg, and the G-TrialsGCP, institutional ethics committee (EC) (research ethics committee (REC) in Uganda) approval, National Drug Authority (NDA) approval, and Uganda National Council for Science and Technology (UNCST) registration are mandatory before a study may commence.

Per the NDPA-CTReg and UGA-20, the NDA’s review and approval of a clinical trial application are dependent upon the applicant submitting proof in the application of institutional EC approval and a research permit from the UNCST. UGA-33 further notes that for clinical trials involving human participants, approval must be obtained through the institutional EC portal (the National Research Information Management System (NRIMS) (UGA-33)) before NDA approval. Therefore, the NDA and institutional EC reviews may not be conducted in parallel. However, the G-TrialsGCP indicates that parallel submissions may be made to the NDA and the UNCST. In that instance, the NDA would not make a final decision until after the trial receives UNCST clearance.

Regulatory Submission

National Drug Authority

According to the NDPA-CTReg, an application to the NDA for authorization to conduct a clinical trial is submitted by a sponsor, who must be one (1) of the following:

• The drug patent holder
• A licensed person (a pharmacist)
• The drug manufacturer
• An agent of the drug patent holder or the drug manufacturer

In those cases where an agent submits the clinical trial application, the agent must also submit a power of attorney verifying their appointment as an agent or a letter of authorization (See Form 30 in Schedule 1 of the NDPA-CTReg or UGA-18). Furthermore, the G-CTConduct indicates that based on the clinical trial agreement between the sponsor and the principal investigator (PI), the NDA will liaise with the in-country PI representing the sponsor regarding the application.

As per the G-CTConduct, the sponsor or authorized person should submit one (1) copy of the completed clinical trial application form for each application. The application must be bound in a single volume (or series of volumes), and the pages numbered sequentially. Appended documents should be bound together with the application, with tabbed sections clearly identifying each appended document. The text and diagrams must be clear and legible in 12 pt Times New Roman font. See Appendix I of the G-CTConduct for the clinical trial application form.

Per C-IncompleteCTA, incomplete submissions will not be received at the NDA registry. All submissions that are deemed incomplete will be returned with a checklist indicating the missing regulatory requirements.

According to the G-CTConduct, an application to conduct a clinical trial must be submitted to:

The Secretary to the Authority
National Drug Authority
P.O. Box 23096
Rumee Towers, Plot 19 Lumumba Avenue
Kampala, Uganda
Phone: (+256) 417 788 100 / 1 0417 799 124 0417 788 129
Fax: (+256) 41 255758 / 343921
Email: ndaug@nda.or.ug; or clinicaltrials@nda.or.ug (per UGA-31)

As per the G-CTConduct, all applications and supporting data submitted to the NDA should be presented in English. Supporting documents that are not in English must be accompanied by an authenticated English translation.

The NDPA-CTReg further indicates that an application for deviation from a condition of a clinical trial must use Form 36, and an application for additional investigators, additional clinical trial sites, or for change of the investigators must use Form 37 (see Schedule 1 of the NDPA-CTReg).

Per the G-CTConduct, the application for amendment of the conditions of a clinical trial can also be found in Appendix III of the G-CTConduct, and on the NDA website at UGA-19. The proposed changes must be listed in a cover letter signed by the applicant. In the cover letter, a clear step-by-step justification for each proposed change(s) must be provided, and the possible consequences with regard to the benefit/risk balance for participants already enrolled in the trial must be summarized. The subject of the cover letter must be “Application to amend CTA XXX” where XXX is the Clinical Trial Application code assigned by the NDA upon authorization of the clinical trial and indicated on the clinical trial certificate. Only one (1) copy of the completed form must be sent to the NDA.

Uganda National Council for Science and Technology

Per the G-UNCSTreg, research protocols submitted to the UNCST for registration and approval must be well written and fully developed. Draft research protocols will not be accepted for registration. In order to register a research protocol, the PI should complete the necessary research application forms. Where a research protocol requires ethical approval by a foreign-based EC, it is advisable that such approval be obtained prior to submitting the protocol to the UNCST.

The online application for UNCST permission to conduct research in Uganda is provided in UGA-28.

UGA-20 also provides the following contact information for further information on the UNCST research clearance process:

Beth Mutumba
Phone: 0414 557 025/0755 423 321
Email: b.mutumba@uncst.go.ug

Samuel Barasa
Phone: 0414 557 021/0779 452 441
Email: s.barasa@uncst.go.ug

Ethics Review Submission

UGA-20 indicates that for EC submissions, the applicant should contact the accredited committee at their institution of affiliation or obtain contacts via the UNCST website. After identifying the appropriate EC, the applicant must create an account and fill out the application on UGA-33.

Per UGA-33, NRIMS is an online platform that supports the NDA, the Uganda National Health Research Organisation (UNHRO), the UNCST, and institutional ECs in the regulatory oversight of clinical research. The system provides researchers with an interface with the regulatory agencies in the data capture, data management, data validation, quality control, and overall regulatory compliance related to clinical research management processes. See UGA-33 for more information.

Each EC has its own required submission procedures, which can differ regarding the application format and number of copies.

Overview

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

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

Regulatory Submission

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

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

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

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

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

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

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

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

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

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

Drugs (submitted by Sponsor-Investigators):

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

Therapeutic Biological Product (submitted by Sponsor-Investigators):

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

Center for Biologics Evaluation and Research-Regulated Products:

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

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

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

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

Ethics Review Submission

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

Regulatory Authority Requirements

National Drug Authority

As per the G-CTConduct and UGA-1, the following documentation must be submitted to the National Drug Authority (NDA) in a clinical trial application (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Proof of payment
• Applications for import and/or export of biological materials (if required)
• Clinical Trial Application Form (See Appendix I of the G-CTConduct)
• Trial protocol
• Investigator’s Brochure (See UGA-4 or Schedule 2 of the NDPA-CTReg)
• Participant Information Leaflet and informed consent form
• Certificate of Good Manufacturing Practice (GMP) of the trial medicine or other evidence of manufacturing quality, safety, and consistency
• Package insert(s) for other trial medicines
• Certificate of GMP of the placebo, if appropriate
• Evidence of accreditation of the designated laboratories or other evidence of Good Laboratory Practice (GLP) and assay validation
• Insurance certificate specific for the trial sourced from a local provider or in consultation with the NDA
• Signed and completed declarations by all investigators (See UGA-16 or Form 31 in Schedule 1 of the NDPA-CTReg)
• Approval of ethics committees (ECs) for the protocol
• Uganda National Council for Science and Technology (UNCST) approval
• Full, legible copies of key, peer-reviewed published articles supporting the application
• Sample of the label for the investigational products (IPs)
• Letter of authorization from the manufacturer/product owner (See UGA-18 or Form 30 in Schedule 1 of the NDPA-CTReg)
• Pharmaceutical data on dosage form (See UGA-14 or Form 34 in Schedule 1 of the NDPA-CTReg)
• Duly signed declaration of the monitor (See UGA-17 or Form 32 in Schedule 1 of the NDPA-CTReg)
• Clinical trial agreement between the sponsor and the principal investigator (PI)
• Duly signed declaration by the sponsor and PI of funds of the clinical trial (See UGA-15 or Form 33 in Schedule 1 of the NDPA-CTReg)
• Other supporting documents

The C-InstitutionCert further indicates that clinical trial certificates will not be issued without submission of a valid certificate of suitability of the premises supplying drugs within the respective institutions.

As per the NDPA-CTReg, an application for deviation from a condition of a clinical trial must use Form 36, and an application for additional investigators, additional clinical trial sites, or for change of the investigators must use Form 37 (see Schedule 1 of the NDPA-CTReg).

According to the G-CTConduct, an application for amendment of the conditions of a clinical trial can also be found in Appendix III of the G-CTConduct and on the NDA website at UGA-19. The amendment application must be accompanied by a cover letter signed by the applicant together with required supporting documentation, including a submission of the protocol amendment in tracked changes, a clean copy clearly indicating the protocol version number, valid evidence of payment of amendment fees, and ethical approval of the proposed amendment. See the NDPA-CTReg, G-CTConduct, and UGA-19 for more detailed amendment application content requirements.

Uganda National Council for Science and Technology

As per UGA-20, the PI should have soft copies of the following documents ready before making an online submission through UGA-28 to the UNCST:

• A letter of introduction or recommendation from the affiliated institution in Uganda (for foreign investigators only). The letter should mention the names of the foreign investigators and it should be addressed to the UNCST Executive Secretary
• An administrative clearance letter from the head of the institution where the research is going to be conducted, addressed to the PI and/or the UNCST Executive Secretary
• Admission letter for academic research (applies to only East African students)
• Curriculum vitaes (CVs) for each investigator, dated and signed or initialed on each page
• Proof of payment of research administration and clearance fees for the study

Additionally, a permit must be obtained from the UNCST to export and import plant or animal specimens for further investigations.

See UGA-20 for detailed application requirements.

Ethics Committee Requirements

According to UGA-20 and UGA-28, EC approval is obtained through the National Research Information Management System (NRIMS) (UGA-33).

The NGHRP further indicates that all ECs must develop detailed standard operating procedures for submission of protocols and other requirements. However, at a minimum, the requirements should include:

• Research protocol with version and date
• Informed consent documents
• Study instruments such as questionnaires, case report forms, videos, flip charts, and any other data collection tools or forms
• Samples of trial drugs
• Evidence that the investigator(s) is appropriately qualified, experienced and, where applicable, licensed, and has adequate facilities for the safe and efficient conduct of research
• A plan for disseminating research findings to the community in which the research was carried out, and other authorized agencies in Uganda

Clinical Protocol

As delineated in Schedule 2 of the NDPA-CTReg and UGA-12, the clinical protocol should contain the following information:

• Product name and dosage form
• Trial identification
• Trial objective
• Trial design
• Trial participants
• Treatment profile
• Trial parameters
• Operational aspects
• Adverse event reporting methods
• Evaluation of results
• PI and co-investigator(s) names

For detailed information on these elements, please refer to the NDPA-CTReg and UGA-12.

Regulatory Authority Requirements

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

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

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

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

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

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

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

Ethics Committee Requirements

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

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

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

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

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

Clinical Protocol

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

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

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

Overview

Per the NDPA-CTReg and UGA-20, the National Drug Authority (NDA)’s review and approval of a clinical trial application are dependent upon the applicant submitting proof in the application of institutional ethics committee (EC) (research ethics committee (REC) in Uganda) approval and a research permit from the Uganda National Council for Science and Technology (UNCST). UGA-33 further notes that for clinical trials involving human participants, approval must be obtained through the institutional EC portal (the National Research Information Management System (NRIMS) (UGA-33)) before NDA approval. Therefore, the NDA and institutional EC reviews may not be conducted in parallel. However, the G-TrialsGCP indicates that parallel submissions may be made to the NDA and the UNCST. In that instance, the NDA would not make a final decision until after the trial receives ethical clearance.

Regulatory Authority Approval

National Drug Authority

Per the G-CTConduct, NDA reviews for clinical trials are performed following a first-in first-out principle, except for clinical trials conducted in public health emergencies such as disease outbreaks, which may be exempted.

According to UGA-24, the NDA will screen and acknowledge receipt of a clinical trial application within 10 working days, and reach a decision on the application within 50 working days. (The G-CTConduct further indicates that expedited review, under which a regulatory decision is given to the applicant within 30 working days, is applicable for certain clinical trial applications. See the Scope of Assessment section for more information.)

The G-CTConduct states that the NDA may request supplementary information or documentation when appropriate, which should be submitted within the stated timeline, usually four (4) weeks. The NDA secretariat may grant additional time to provide information upon request by the applicant on a case-by-case basis. If the requested information is not submitted, the application will be archived within 50 working days. The application will need to be resubmitted for review. If the NDA, on its own initiative, makes amendments to the conditions for conducting a clinical trial for safety reasons or the scientific validity of the clinical trial, the NDA will give 15 calendar days’ notice to the sponsor or the principal investigator (PI) and request submittal of a written response to the proposed amendments.

Additionally, according to UGA-24, the NDA conducts annual reviews of ongoing trials within 20 working days and reviews amendments of clinical trial authorization within 20 working days. Per the G-CTConduct, the NDA review timelines published on UGA-24 do not include the time taken by the applicant to respond to any NDA requests for additional information. A stop-clock mechanism is applied each time the NDA requests additional information.

Uganda National Council for Science and Technology

The G-UNCSTreg states that the UNCST provides feedback on the registration status of a protocol within 10 working days from the submission date. According to the NGHRP, the UNCST registration process is normally completed within 14 working days.

Ethics Committee Approval

Per the G-TrialsGCP, an applicant must also submit the clinical trial protocol for review and approval by a UNCST-accredited institutional EC. As indicated in the NGHRP, the EC is required to review a clinical protocol within 60 days from the date of its receipt. In the case of an annual continuing review, the EC should maintain the same anniversary date of approval for any given protocol. Review outcomes must be communicated to the applicant within 14 days of the EC’s review.

Overview

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

Regulatory Authority Approval

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

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

Ethics Committee Approval

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

Overview

According to the NDPA-CTReg, the G-CTConduct, the NGHRP, the G-UNCSTreg, and the G-TrialsGCP, institutional ethics committee (EC) (research ethics committee (REC) in Uganda) approval, National Drug Authority (NDA) approval, and Uganda National Council for Science and Technology (UNCST) registration are mandatory before a study may commence.

As per the NGHRP and the UNHRO-Act, the UNCST also works in collaboration with the Uganda National Health Research Organisation (UNHRO) to register all health research protocols. However, the registration is conducted centrally at the UNCST.

The G-CTConduct and the NDPA-CTReg indicate that following the NDA’s approval of the clinical trial application, the applicant is also required to obtain a permit from the NDA to import investigational products (IPs) approved for the clinical trial. See the Manufacturing & Import topic for more information on IP import permit requirements.

Per the NGCER, community engagement is an opportunity for communities to participate in the design and conduct of research, and enhances the relevance, ownership, and applicability of research findings. See the NGCER for UNCST guidance on how to ensure community engagement, as a way to improve responsiveness to community needs and accountability in research.

Clinical Trial Agreement

As delineated in the NDPA-CTReg and the G-CTConduct, before the trial begins, the sponsor must sign a clinical trial agreement with the principal investigator (PI).

According to the G-TrialsGCP, if the sponsor decides to use a contract research organization (CRO) to conduct the trial, the transferred duties should be specified in writing and evidence of a mutual agreement must be provided. 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 the purpose of monitoring and auditing by the sponsor, and inspection by domestic and foreign regulatory authorities. A signed agreement between involved parties (such as the PI/institution and sponsor; the PI/institution and CRO; and the sponsor and CRO), is considered an essential document before a clinical trial can commence.

Per the G-TrialsGCP, the sponsor should obtain the investigator's agreement to:

• Conduct the trial in compliance with the G-TrialsGCP, the principles of good clinical practice (GCP), the requirements of the NDA, and the protocol agreed upon by the sponsor and given approval by the relevant 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 that these documents are no longer needed

Clinical Trial Registration

The G-CTConduct states that clinical trial registration with a publicly accessible clinical trial registry is a requirement for all industry-funded trials in Uganda. Details of registration should be provided with the clinical trial application.

Overview

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

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

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

Clinical Trial Agreement

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

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

• To conduct the trial in compliance with good clinical practice (GCP), with the applicable regulatory requirement(s), and with the protocol agreed to by the sponsor and given approval/favorable opinion by the EC;
• To comply with procedures for data recording/reporting;
• To permit monitoring, auditing, and inspection; and
• To retain the trial-related essential documents until the sponsor informs the investigator/institution these documents are no longer needed.

The sponsor and the investigator/institution must sign the protocol, or an alternative document, to confirm this agreement.

Clinical Trial Registration

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

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

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

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

Safety Reporting Definitions

In accordance with the NDPA-CTReg, the NDPA-PVReg, the NDPA-PVRegAmdt, the G-CTConduct, the NGHRP, and the G-TrialsGCP, the following definitions provide a basis for a common understanding of Uganda’s safety reporting requirements:

• Adverse Event (AE) – Any untoward medical occurrence in a research participant who is administered an investigational product (IP), and which 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 prolongation of 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 for an unapproved IP)

Safety Reporting Requirements

Investigator Responsibilities

As per the NDPA-CTReg and the G-TrialsGCP, the principal investigator (PI) must report all SAEs/SADRs to the sponsor within 48 hours of first knowledge. The report should identify each participant by an assigned number. When the SAE/SADR results in the participant’s death, the PI should supply the sponsor, the National Drug Authority (NDA), and the institutional ethics committee (EC) (research ethics committee (REC) in Uganda) with any additional information requested.

The NGHRP states that the PI is required to report to the EC no later than seven (7) calendar days upon receiving notice of an SAE/SADR. A detailed report of the SAE/SADR should be submitted within seven (7) calendar days from the date it is reported to the EC. All other AEs should be reported by the PI to the EC as soon as possible, but no later than 14 calendar days.

The G-TrialsGCP and the G-CTConduct further indicate that the PI is also required to report to the NDA no later than seven (7) calendar days upon receiving notice of an SAE/SADR. The initial reports to the NDA should be followed promptly by detailed, written follow-up reports after investigations have been completed, no later than 15 calendar days of becoming aware of the event.

Sponsor Responsibilities

According to the G-TrialsGCP, the sponsor is responsible for the ongoing safety evaluation of the IP(s). The sponsor should promptly notify all concerned investigator(s), the NDA, and the EC in writing of findings that could adversely affect the safety of participants, impact the conduct of the trial, or alter the EC's approval to continue the trial. Study participants should also be informed of any new information that could adversely affect their safety.

The NDPA-CTReg and the G-TrialsGCP state that the sponsor should keep detailed records of the trial-related AEs/ADRs reported by the PI.

In addition, according to the G-TrialsGCP, the sponsor should expedite the reporting of all AEs/ADRs that are both serious and unexpected to all concerned investigator(s)/institutions(s), EC(s), and to the NDA. The expedited reporting should occur within the timeframe and format specified by the NDA. Serious and unexpected AEs/ADRs suspected to be related to the IP(s) should be reported to the relevant EC as soon as possible. If the study is multicenter, the sponsor should ensure that all serious and unexpected AEs/ADRs that occur in other study sites are also reported within 15 calendar days of becoming aware of them.

As set forth in the NDPA-CTReg, the sponsor and the PI must also take appropriate safety measures to protect participants against any immediate hazards to their health and safety. When safety measures are taken, the sponsor should provide written notice to the NDA within three (3) working days of this action and the reasons why this action was taken.

Reporting Requirements for SUSARs

As set forth in the NDPA-CTReg, the PI should record and report to the sponsor any suspected unexpected serious adverse reaction (SUSAR) that occurs during the course of trial. In turn, the sponsor should report any SUSARs within seven (7) days of first knowledge to the NDA and the Uganda National Council for Science and Technology (UNCST), or a UNCST-accredited EC.

However, the G-TrialsGCP indicates that the sponsor should report any SUSARs to the NDA within 15 calendar days of becoming aware of the event. The initial reports should be followed promptly by detailed, written follow-up reports after investigations have been completed, no later than 15 calendar days of becoming aware of the event.

According to the NDPA-CTReg and the G-TrialsGCP, the sponsor should also inform the PI of any SUSARs which occur during the course of another trial for which the sponsor is responsible, where the reaction relates to the IP used in the trial. The NDA should maintain a record of all IP-related SUSARs reported to the authority.

Form Completion & Delivery Requirements

Per UGA-31, the NDA has stated that it does not have a template for reporting AEs for clinical trials. The NDA recommends the use of internationally acceptable forms, such as the one provided by the Council for International Organizations of Medical Sciences (CIOMS) (UGA-8).

Safety Reporting Definitions

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

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

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

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

Safety Reporting Requirements

Investigator Responsibilities

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

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

Sponsor Responsibilities

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

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

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

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

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

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

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

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

See 42CFR11 for detailed adverse event reporting requirements.

Form Completion & Delivery Requirements

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

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

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

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

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

Interim and Annual Progress Reports

As per the G-TrialsGCP, the principal investigator (PI) is obliged to submit progress reports as required by the sponsor, the institutional ethics committees (ECs) (research ethics committees (RECs) in Uganda), the Uganda National Council for Science and Technology (UNCST), and the National Drug Authority (NDA). These reports should contain information on:

• How the study is progressing
• The number of participants included in relation to the number screened and the target sample size
• The number of dropouts and withdrawals
• Adverse events
• If the planned time schedule is still appropriate

The format and frequency of reporting is as prescribed by the relevant authorities.

The NDPA-CTReg and the G-CTConduct also state that the NDA may request the sponsor to submit an interim report.

Additionally, per the G-UNCSTreg, although annual renewal of a study is not required, investigators should electronically submit annual progress reports to the UNCST within four (4) weeks following every 12 months of the study for informational purposes only. Failure to do so may result in termination of the research.

See Schedule 2 of the NDPA-CTReg or UGA-6 for the format of the clinical trial report.

Final Report

The NGHRP states that the sponsor is responsible for approving a final study report, regardless of whether the trial has been completed. In addition, the NDPA-CTReg and the G-TrialsGCP require the sponsor to inform the NDA in writing of the conclusion of the trial within 90 days.

However, the G-TrialsGCP further indicates 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 furnish the regulatory authorities with any reports required. All aspects (statistical and clinical) of the protocol should be integrated in order to obtain a final study report that is entirely consistent with the study data generated. Essential elements in the presentation of the results include:

• Baseline comparisons between the treatment groups
• The number of participants actually randomized into the study by treatment group and the number of participants excluded from any of the analyses, by reason and by treatment group
• Major efficacy and safety results by treatment group in the form of tables, graphs, test variables, and statistical parameters, as appropriate
• An assessment of between-group differences with confidence intervals

An account must be made of missing, unused, or spurious data during statistical analyses. All omissions of this type must be documented to enable review.

In accordance with the G-UNCSTreg, it is the investigator’s obligation to submit final reports of the research projects to the UNCST. Investigators are free to adopt any format for writing a final report, but the report should have an abstract, a results section, a discussion of the results, and recommendations. Investigators who are foreign nationals are required to submit a study completion report before returning to their countries.

Interim and Annual Progress Reports

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

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

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

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

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

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

Final Report

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

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

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

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

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

As defined in the NDPA-CTReg, the G-CTConduct, the G-GMPMedicinalAnnexes, and the G-TrialsGCP, a sponsor is the person, company, institution, or organization that takes responsibility for the initiation, management, or financing of a clinical trial. The NGHRP specifically assigns responsibility to the sponsor for providing all the necessary financial support to initiate and complete a research study.

The NDPA-CTReg also specifies that in order to submit a clinical trial application, the sponsor must be one of the following:

• The drug patent holder
• A licensed person (a pharmacist)
• The drug manufacturer
• An agent of the drug patent holder or the drug manufacturer

As stated in the G-TrialsGCP, a 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 rests with the sponsor. The CRO must have the required skills, experience, and competencies to safely conduct clinical trials. Any trial-related duty and function that is transferred to and assumed by a CRO should be specified in writing and evidence of a mutual agreement provided. The sponsor should ensure oversight of any trial-related duties and functions carried out on the sponsor’s behalf, including trial-related duties and functions that are subcontracted to another party by the sponsor's contracted CRO(s). Any trial-related duties and functions not specifically transferred to and assumed by a CRO are retained by the sponsor.

Per the NDPA-CTReg, a local company in Uganda may act as an agent in the clinical trial for a foreign sponsor.

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

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

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

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

Overview

As per the NDPA-CTReg and the G-TrialsGCP, the sponsor oversees the selection of the investigator(s) and the institution(s) for the clinical trial. The G-CTConduct indicates that based on the clinical trial agreement between the sponsor and the principal investigator (PI), the National Drug Authority (NDA) will liaise with the in-country PI representing the sponsor regarding the application. The PI should be a Ugandan resident and licensed by a relevant body in Uganda.

The G-TrialsGCP states that before entering an agreement with an investigator to conduct a trial, the sponsor should provide the investigator with the protocol and an up-to-date Investigator's Brochure (IB). The investigator should also be given sufficient time to review the protocol and the information provided. The PI/investigator(s) should be qualified by education, training, and experience to assume responsibility for the proper conduct of the trial, meet all the qualifications specified by the applicable regulatory requirement(s), and provide evidence of such qualifications through an up-to-date curriculum vitae and/or other relevant documentation requested by the sponsor, the accredited institutional ethics committee (EC) (research ethics committee (REC) in Uganda), and/or the NDA. The PI/investigator(s) should also be thoroughly familiar with the appropriate use of the investigational product(s) (IP(s)), as described in the protocol, current IB, product information, and other information sources provided by the sponsor. Furthermore, the PI/investigator(s) should be aware of, and comply with, good clinical practice (GCP) and the applicable regulatory requirements.

According to the NDPA-CTReg, an application for additional investigators, additional clinical trial sites, or investigator changes must be made using Form 37 in Schedule 1 of the NDPA-CTReg or UGA-13 and must be accompanied by evidence of ethical approval of the clinical trial protocol amendment, where applicable, and the prescribed fees.

In accordance with the G-UNCSTreg, all investigators who are foreign nationals are required to identify and become affiliated with a local organization appropriate for their type of research in Uganda. Investigators arrange the affiliation themselves with the local organization. The investigator should obtain a letter of recommendation from the local organization and submit it to the Uganda National Council for Science and Technology (UNCST).

Foreign Sponsor Responsibilities

The NDPA-CTReg states that in the case of foreign sponsors, a local company in Uganda must submit a letter of authorization from the holder of the patent of the drug, licensed person, or manufacturer of the drug to be the agent in the clinical trial that is responsible for all matters pertaining to the NDA clinical trial certificate. See Form 30 in Schedule 1 of the NDPA-CTReg or UGA-18 for the letter of authorization, and Form 35 in Schedule 1 of the NDPA-CTReg, as amended by the NDPA-CTRegAmdt, for the clinical trial certificate.

Data and Safety Monitoring Board

According to the NGHRP, the G-TrialsGCP, and the NDPA-CTReg, the sponsor is responsible for establishing a Data and Safety Monitoring Board (DSMB) (also referred to as an Independent Data-Monitoring Committee (IDMC)) prior to the trial’s commencement. Per the NGHRP, the DSMB ensures that the study and the data are handled in accordance with the protocol provisions, monitors adverse events/adverse drug reactions and safety data, and preserves the integrity and credibility of the trial. The composition of the DSMB must be provided to the EC. All Phase I, Phase II, and Phase III trials must have a safety monitoring plan and a DSMB. For additional details on DSMB requirements, see 3.6.2 of the NGHRP.

The G-TrialsGCP further indicates that a DSMB should have written operating procedures and maintain written records of all its meetings. A duly signed DSMB charter must be submitted to the NDA prior to recruitment of participants, and any decision not to create a DSMB should be clearly documented and justified in the protocol.

Multicenter Studies

The G-TrialsGCP indicates that multicenter trials must adhere to all national regulatory requirements, ensuring consideration and adaptation of the local context into the general study design. The following should be considered regarding multicenter trials:

• Inclusion and exclusion criteria must be appropriate to consider local realities, as well as trial site-specific differences
• The informed consent procedure must be tailored to local conditions and informed consent forms translated into the local language submitted to the EC for approval
• Study design differences between the Ugandan site(s) and other sites must be fully explained, as well as differences between sites within Uganda. Study extrapolations and conclusions should be relevant to the Ugandan context
• Where necessary, site investigators should develop site-specific standard operating procedures and/or a site implementation plan to guide the respective sites on protocol implementation

Per the G-TrialsGCP, for multicenter trials, the PI is responsible for appointing co-investigators that will be responsible for the various trial sites in Uganda. However, it is the responsibility of the sponsor to ensure all investigators conduct the trial in strict compliance with the approved protocol. In addition, the sponsor should ensure that:

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

Overview

As set forth in 21CFR312 and the US-ICH-GCPs, the sponsor is responsible for selecting the investigator(s) and the institution(s) for the clinical trial and for ensuring that the investigator(s) are qualified by training and experience. Prior to permitting an investigator(s) to conduct a study, the sponsor must obtain the following:

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

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

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

See G-InvstgtrResp for more information on investigator responsibilities.

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

Foreign Sponsor Responsibilities

No information is currently available.

Data and Safety Monitoring Board

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

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

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

Multicenter Studies

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

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

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

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

Insurance

As set forth in the NDPA-CTReg and the G-TrialsGCP, the sponsor is responsible for providing insurance coverage for any unforeseen injury to research participants. The sponsor should provide indemnity for the investigator(s) against claims arising from the clinical trial, except for claims that arise from malpractice or negligence.

According to the NDPA-CTReg, the G-CTConduct, and the G-InsuranceCover, an insurance certificate must be provided to the National Drug Authority (NDA) that is specific to the trial for which the clinical trial application is being submitted. The G-CTConduct also indicates that the clinical trial application must provide evidence that each member of the investigator team is covered by relevant malpractice insurance for the trial.

The G-InsuranceCover further states that the required insurance coverage for research participants in a specific trial at a given site must be obtained from a local insurance company that is registered and operating under law in Uganda. For additional details on the required elements of the insurance policy, see Section 7.0 of the G-InsuranceCover.

According to the G-TrialsGCP, the principal investigator (PI) is responsible for ensuring participants obtain their claim from the local insurance company in the event of any trial-related injury and/or resultant disability.

Compensation

Per the G-TrialsGCP, the sponsor must ensure that information on incentives offered to participants is included in the protocol and informed consent documents. If the study is multicenter, information on the incentives given at all the different trial sites must be provided. If the participating sites are multinational, then the differences in the incentives across the sites must also be explained.

According to the NGHRP, a care package for research participants should be prepared before initiation of a research project. Care and treatment for research participants should be provided with the ideal aim of providing the best proven intervention.

Injury or Death

In accordance with the NGHRP, the sponsor is responsible for providing compensation to research participants and/or their legal heirs in the event of trial-related injuries, disability, or death. The sponsor must ensure that participants who suffer any trial-related injuries receive free medical treatment for such injuries, and financial or other assistance that would compensate them equitably for any resulting impairment, disability, or handicap. The sponsor should provide care until complete cure or stabilization of a trial-related injury. The investigator and/or study sponsor must pay the cost of referral and management of the condition when a referral has been made for a trial-related injury or a serious adverse event related to the study. Furthermore, the sponsor is required to ensure that research participants are not asked to waive their legal rights to seek compensation.

Per the NGHRP, a trial-related injury may be physical, social, economic, or psychological, and may be classified as follows:

• Definitely: When injury is directly caused by participation in a research project

• Probably: When injury is most likely explained by participation in a research project but when no definite proof of causality is evident

• Possibly: When explanation for injury is equally due to participation in a research project or other cause

• Unlikely: When injury is more likely explained by another cause other than participation in a research project

Subject to applicable laws in Uganda, research participants will be entitled to compensation when injury related to their participation in a research project is classified as “Probably” or “Definitely.”

According to the NGHRP, the sponsor and investigator must put in place a mechanism for compensating trial-related injury at the commencement of a study. The mechanism, which may include, inter alia, insurance, and medical care, should be acceptable to the institutional ethics committee (EC) (research ethics committee (REC) in Uganda). The EC, research participant, and/or investigator may initiate the compensation process. The EC, sponsor, and investigator must agree on an appropriate mechanism for arbitration.

Trial Participation

In the clinical trial application made to the NDA, the applicant must explain how the participant(s) will be compensated for their time and other inconveniences, in accordance with the G-CTConduct.

In addition, per the NGHRP, participants must be fairly compensated for inconveniences, time spent, and expenses incurred while taking part in a study such as travel costs, refreshments, meals, and any other compensation deemed appropriate by the EC. Research participants may also receive free medical services. The compensation or medical services must not be so out of proportion as to induce prospective research participants to consent to participate in the trial against their better judgment.

According to the G-TrialsGCP, the sponsor must ensure that participants are reimbursed for all reasonable costs incurred by their participation in the trial.

Post-Trial Access

In accordance with the NGHRP, the duration and sustainability of care and treatment for the participant after the study should be negotiated before initiation of the study. Sponsors are encouraged, but not obliged, to provide care for concurrent illnesses not associated with the research project. However, investigators and sponsors are obliged to manage serious adverse events related to the study (including paying for associated costs thereof) until they are fully resolved or stabilized. Investigators should provide relevant follow up procedures for participants for an appropriate period of time after the trial.

Insurance

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

Compensation

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

Injury or Death

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

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

Trial Participation

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

Quality Assurance/Quality Control

The NDPA-CTReg states that the sponsor should maintain quality assurance and quality control systems for the conduct of clinical trials and for the generation of documentation, recording, and reporting of data. The G-TrialsGCP indicates that the sponsor is also responsible for implementing the 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). Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly.

According to the G-TrialsGCP, the sponsor should implement a quality management system throughout all stages of the trial process, and should focus on the trial activities essential to ensuring participant protection and the reliability of trial results. The quality management system should use a risk-based approach including: critical process and data identification, risk identification, risk evaluation, risk control, risk communication, risk review, and risk reporting. For additional details, see the G-TrialsGCP.

Monitoring Requirements

As per the G-TrialsGCP, the sponsor should ensure that the auditing of clinical trials/systems is conducted in accordance with the sponsor's written procedures on what to audit, how to audit, the frequency of audits, and the form and content of audit reports. The observations and findings of the auditor(s) should be documented and accessible to the institutional ethics committee (EC) (research ethics committees (RECs) in Uganda) and the National Drug Authority (NDA). The audit report should be submitted to the NDA if evidence of GCP or protocol non-compliance is found.

The G-TrialsGCP further states that in accordance with the NDPA-CTReg, the sponsor should appoint a monitor tasked with trial oversight and reporting on the progress of a study. The monitor should ideally have adequate medical, pharmaceutical, and scientific qualifications. The investigator(s) should accept the possibility of an audit or monitoring visit by an independent auditor appointed by the sponsor, and/or an inspection by the NDA, EC, or relevant local and international regulatory authorities.

Premature Study Termination/Suspension

Per the NDPA-CTReg, in the case of a sponsor-initiated clinical trial termination, the sponsor must notify the NDA within 15 days using the format specified in Schedule 2 of the NDPA-CTReg or UGA-5. The notification must give reasons for the termination, indicate the disposal process for the unused investigational product, and give the effective date of the termination. The G-CTConduct further requires that evidence of the NDA notification be provided to the EC and the Uganda National Council for Science and Technology (UNCST).

In addition, the G-TrialsGCP requires that if a trial is prematurely terminated or suspended for any reason, the investigator should inform the participants, assure appropriate therapy and follow-up for the participants, and inform the NDA. Furthermore, if the investigator terminates or suspends a trial without prior agreement of the sponsor, the investigator should inform the institution where applicable, and the investigator/institution should inform the sponsor and the EC. The investigator should provide the sponsor and the EC with a detailed written explanation of the termination or suspension.

Quality Assurance/Quality Control

Per the US-ICH-GCPs, the sponsor should implement a system to manage quality throughout all stages of the trial process, focusing on trial activities essential to ensuring participant protection and the reliability of trial results. The quality management system should use a risk-based approach that includes:

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

As stated in the US-ICH-GCPs, the sponsor is responsible for implementing and maintaining quality assurance (QA) and quality control (QC) systems with written standard operating procedures (SOPs) to ensure that trials are conducted and data generated, recorded, and reported in compliance with the protocol, the US-ICH-GCPs, and the applicable regulatory requirements. The sponsor is responsible for obtaining agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, reports for monitoring and auditing purposes, and inspection by domestic and foreign regulatory authorities. QC should be applied to each stage of data handling to ensure that all data are reliable and have been correctly processed. A written agreement must be signed by both the sponsor and the investigator or any other parties involved with the clinical trial, verifying that all parties agree to the trial protocol, the monitoring and auditing practices, the SOPs, and their respective duties.

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

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

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

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

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

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

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

Monitoring Requirements

As part of its QA system, the US-ICH-GCPs notes that the sponsor should ensure the trial is monitored and audited. The purpose of the audit should be to evaluate trial conduct and compliance with the protocol, SOPs, the US-ICH-GCPs, and other applicable regulatory requirements. The sponsor should appoint auditors to review the clinical trial. The sponsor should ensure that the auditors are qualified by training and experience, and the auditor’s qualifications should be documented. The sponsor must also ensure that the audit is conducted in accordance with the sponsor’s own SOPs and the auditor observations are documented. The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. The extent and nature of monitoring is flexible and permits varied approaches that improve effectiveness and efficiency. The sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or where justified, centralized monitoring. The sponsor should document the rationale for the chosen monitoring strategy (e.g., in the monitoring plan).

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

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

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

Premature Study Termination/Suspension

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

According to the US-ICH-GCPs, if it is discovered that noncompliance significantly affects or has the potential to significantly affect participant protection or reliability of trial results, the sponsor should perform a root cause analysis and implement appropriate corrective and preventive actions. Further, the EC should also be informed promptly and provided the reason(s) for the termination or suspension by the sponsor.

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

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

Electronic Data Processing System

According to the G-TrialsGCP, 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
• Ensure the integrity of the data, including any data that describes the context, content, and structure

For additional details, see Section 4.8 of the G-TrialsGCP.

The G-TrialsGCP states that quality control should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly. The sponsor should base their approach to validation of electronic data processing systems on a risk assessment that takes into consideration the intended use of the system and the potential of the system to affect human participant protection and reliability of trial results. The sponsor should maintain a documented record of SOPs that guide step-by-step retrospective assessment of data quality and study performance. These SOPs should cover system setup, installation, and use. The SOPs should also describe system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning, and decommissioning. The responsibilities of the sponsor, investigator, and other parties with respect to the use of these computerized systems should be clear, and the users should be provided with training in their use.

According to the G-TrialsGCP, satisfactory maintenance and back-up procedures for computer databases must be provided. Case report forms (CRFs) should be designed to meet the specific data requirements set out in the study protocol. The effects of missing and inaccurate data should be minimized to maintain data quality. The system for routinely checking the data collection and entry throughout the course of the trial should be documented. Checks for validity and consistency of the database should be on separate items as well as on predetermined combinations of items in the CRFs. The SOP for data editing should ensure that any queries about data validation are brought to the attention of the investigators. Database lock should be done after completion of the validation and editing processes are documented.

Records Management

The G-TrialsGCP and the G-CTConduct state that the sponsor and the PI are responsible for archiving and ensuring the safety of all trial-related documentation. Per the NDPA-CTReg, documents and information provided to the National Drug Authority (NDA) along with a clinical trial application for unregistered investigational products (IPs) should be kept for 20 years following the trial's completion. Documentation for trials involving IPs to be registered should be kept for two (2) years after the registration of the IP. The NDPA-CTReg and the G-CTConduct further state that the holder of the clinical trial certificate should inform the NDA in writing prior to destroying the documents. Per the G-CTConduct, documents may be stored in electronic (soft and scanned) or hard copies.

In addition, the G-TrialsGCP requires that if the sponsor discontinues the clinical development of an IP, the sponsor should maintain all sponsor-specific essential documents for at least two (2) years after formal discontinuation. 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.

According to the NGHRP, collaborating research partners must agree on appropriate data access and use rights before commencement of the study. Investigators must have in place mechanisms for maintaining the confidentiality of research participants and their communities. Furthermore, a collaborating research partner must not transfer data to a third party without the written consent of the other partner. Local investigators must have unrestricted access rights to data sets collected through a collaborative research project. Lastly, investigators must ensure that research records from which the data has been obtained are available at the research site for at least five (5) years after completion of the research project. Electronic records are acceptable.

Electronic Data Processing System

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

Records Management

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

In addition, the US-ICH-GCPs states that the sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents including source documents. The storage system used during the trial and for archiving (irrespective of the type of media used) should allow for document identification, version history, search, and retrieval. The sponsor should ensure that the investigator has control of and continuous access to the data reported to the sponsor. The investigator/institution should have control of all essential documents and records generated by the investigator/institution before, during, and after the trial.

Responsible Parties

For the purposes of data protection requirements, the sponsor may act as a “data controller” in relation to research data. As per the NITA-U-PrivAct, the data controller determines the purposes for and the manner in which personal data is processed or is to be processed. The “data processor” processes personal data on behalf of the data controller. Data controllers and processors must be registered with the National Information Technology Authority - Uganda (NITA-U). See the NITA-U-PrivAct, the NITA-U-PrivReg, and the PDPO-Note for detailed registration requirements.

Data Protection

As per the NITA-U-PrivAct, a data controller or processor must:

• Be accountable to the data subject for data collected, processed, held, or used
• Collect and process data fairly and lawfully
• Collect, process, use, or hold adequate, relevant, and not excessive or unnecessary personal data
• Retain personal data for the period authorized by law or for which the data is required
• Ensure quality of information collected, processed, used, or held
• Ensure transparency and participation of the data subject in the collection, processing, use, and holding of the personal data
• Observe security safeguards in respect of the data

See Part III of the NITA-U-PrivAct and NITA-U-PrivReg for detailed requirements on data processing, record retention, and processing of personal data outside Uganda.

Consent for Processing Personal Data

As delineated in the NITA-U-PrivAct, for the purposes of processing personal data, consent means any freely given, specific, informed, and unambiguous indication of the data subject’s wish which, by a statement or by a clear affirmative action, signifies agreement to the collection or processing of the data subject’s personal data.

According to the NITA-U-PrivAct, a data controller or data processor must obtain the consent of the data subject before collecting or processing personal data, and the data must be collected for a lawful, specific purpose. Unless otherwise provided under the NITA-U-PrivAct, a data subject has the right to object to the collection or processing of personal data at any time. See the NITA-U-PrivAct and NITA-U-PrivReg for detailed requirements on consent to data collection or processing, record retention, and processing of personal data outside Uganda.

The NITA-U-PrivAct and NITA-U-PrivReg further state that data subjects have a right to (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Request a data controller to give a description of the personal data held by the controller
• Prevent processing of personal data
• Appeal a decision to continue processing personal data
• Request a data controller to correct or delete personal data about the data subject that is inaccurate, irrelevant, excessive, out of date, incomplete, misleading, or obtained unlawfully

See the NITA-U-PrivAct and NITA-U-PrivReg for more information on data subject rights.

Children

According to the NITA-U-PrivAct, personal data relating to children must not be collected or processed unless it is carried out with the prior consent of the legal representative/guardian; is necessary to comply with the law; or is for research or statistical purposes. The NITA-U-PrivReg further requires that every data collector, data processor, and data controller establish a system to determine the age of participants whose personal data is to be collected, processed, or stored, and where the data relates to a child, describe the manner of obtaining consent of a legal representative/guardian, where necessary.

Responsible Parties

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

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

Data Protection

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

NIH Privacy Requirements

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

Consent for Processing Personal Data

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

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

See USA-86 for more information on these circumstances.

Obtaining Consent

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

As per the NGHRP, the NDPA-CTReg, the G-CTConduct, and the G-TrialsGCP, the informed consent form (ICF) and the participant information leaflet are viewed as essential documents that must be reviewed and approved by an accredited institutional ethics committee (EC) (research ethics committee (REC) in Uganda) and provided to the National Drug Authority (NDA) with the clinical trial application. (See the Required Elements section for details on what should be included in the ICF.)

The G-TrialsGCP states that before informed consent may be obtained, the principal investigator (PI), or a person designated by the PI, should provide the participant or 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 legal representative/guardian.

As stated in the NGHRP, an investigator must seek informed consent only after ascertaining that the prospective research participant has adequate understanding of the relevant facts and of the consequences of participation. For certain types of research, the EC may require the investigator to administer a comprehension test (or test of understanding) to ensure that prospective research participants have acquired adequate understanding of the relevant facts and of the consequences of participation.

Per the G-TrialsGCP, 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. The written ICF and any other written information to be provided to participants should be read and explained to the participant or legal representative/guardian. According to the NGHRP, verbal consent may be obtained in studies that present no more than minimal risk or in studies where for justifiable reasons written consent may not be feasible. ECs reserve the right to determine when verbal informed consent may be appropriate and acceptable.

Additionally, as stated in the G-TrialsGCP, the language used in the oral and written information about the trial, including the written ICF, should be as non-technical as practical and should be understandable to the participant or legal representative/guardian and the impartial witness, where applicable. Neither the PI, nor the trial staff, should coerce or unduly influence a participant to participate or to continue to participate in a trial. None of the oral and written information concerning the trial, including the written ICF, should contain any language that causes the participant or 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 and/or malpractice.

See the NGHRP and the G-TrialsGCP for detailed requirements for obtaining consent.

Re-Consent

According to the G-TrialsGCP, the written 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 approval/favorable opinion in advance of use. The participant or 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.

The NGHRP specifies that re-consent from participants must be obtained if there are changes in the conditions or procedures of the research or if new information becomes available that could affect the participant’s willingness to continue in the research.

Language Requirements

As per the NGHRP and the G-CTConduct, the ICF should be written in English and in a vernacular language that the participant is able to understand. The G-TrialsGCP further indicates that for multicenter trials, the informed consent procedure must be tailored to local conditions, and ICFs must be translated into the local language and submitted to the EC for approval.

Documenting Consent

The G-TrialsGCP and the NGHRP state that prior to participation in the trial, the written ICF should be signed and personally dated by the participant or legal representative/guardian, and by the person who conducted the informed consent discussion.

The G-TrialsGCP delineates that the impartial witness for participants unable to read should sign and personally date the ICF, after the participant or legal representative/guardian has orally consented to the participation in the trial. If capable of doing so, the participant or legal representative/guardian should sign and personally date the ICF. By signing the ICF, the impartial witness attests that the information in the ICF and any other written information was accurately explained to, and apparently understood by, the participant or legal representative/guardian, and that informed consent was freely given.

According to the NGHRP, a thumbprint on the ICF is also acceptable in lieu of a signature. Where the use of signed consent forms is not feasible, alternative viable methods should be employed.

The G-TrialsGCP and the NGHRP indicate that a copy of the signed ICF must be offered to the participant or legal representative/guardian prior to participation in the trial. The G-TrialsGCP further specifies that during the course of the trial, the participant or 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 the participant.

Waiver of Consent

According to the NGHRP, an EC may waive some or all of the requirements for the investigator to obtain informed consent and/or a signed/thumb-printed consent form for some or all of the research participants of a particular study if the EC determines that:

• The research project carries no more than minimal risk (risk that is no more than the risks encountered in normal daily life in a stable society)
• The research project could not practicably be carried out without the waiver or alteration (whenever appropriate the research participants will be provided with additional pertinent information after participation)
• Deception needs to be applied to achieve the objectives of the study
• The only record linking the research participant and the research project would be the ICF and the risk to the research participant would be potential harm resulting from a breach of confidentiality
• The research participant is involved in an emergency situation and informed consent cannot be reasonably obtained from the individual or the representative

Obtaining Consent

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

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

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

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

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

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

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

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

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

Re-Consent

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

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

Language Requirements

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

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

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

Documenting Consent

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

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

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

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

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

Waiver of Consent

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

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

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

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

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

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

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

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

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

Based on the NGHRP, the NDPA-CTReg, and the G-TrialsGCP, the informed consent form (ICF) should include the following statements or descriptions, as applicable (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• The study involves research and an explanation of its nature and purpose
• The procedures to be followed
• The expected duration of the trial
• The trial treatment(s) and the probability for random assignment to each treatment (where appropriate)
• The participant's responsibilities
• Those aspects of the trial that are experimental
• Any reasonably foreseeable risks or discomforts to the participant, and whether the project involves more than minimal risk
• Any benefits to the participant or to others that may be reasonably expected from the research; if no benefit is expected, the participant should also be made aware of this
• The disclosure of specific appropriate alternative procedures or therapies available to the participant
• The extent to which confidentiality of records identifying the participant will be maintained and who will have access to the participant’s medical records
• For research involving more than minimal risk, the policy on compensation and/or medical treatment(s) available to the participant in the event of a trial-related injury
• The extent of the investigator’s responsibility, where applicable, to provide medical services to the participant
• The nature, form, and extent of compensation for participation
• The identity of a sponsor and any potential conflict of interests
• The sponsors’ and the investigators’ institutional affiliation(s)
• A contact name and number of the principal investigator and/or site investigator
• Participation is voluntary, the participant can withdraw from the study at any time, and refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled
• The participant or legal representative/guardian will be notified in a timely manner if significant new findings develop during the study which may affect the participant's willingness to continue
• A witness may represent vulnerable populations during the informed consent process, if applicable
• The study has been approved by an accredited Ugandan-based institutional ethics committee (EC) (research ethics committee (REC) in Uganda)
• The particular treatment or procedure may involve risks to the participant (or to the embryo or fetus, if the participant is or may become pregnant), which are currently unforeseeable
• Foreseeable circumstances under which the investigator(s) may remove the participant without consent
• Additional costs to the participant that may result from participation in the study
• The consequences of a participant’s decision to withdraw from the research and procedures for orderly withdrawal by the participant
• The approximate number of participants in the research study
• If the research involves collecting biological or genetic materials, participants must be provided with an explanation on how specimens will be managed at the end of the study. If samples will be stored for future use, separate consent should be obtained
• Whether, when, and how any of the products or interventions proven by the study to be safe and effective will be made available to participants at the end of the study, and if the participants will be expected to pay for them

Compensation Disclosure

According to the G-TrialsGCP, the sponsor must ensure that information on incentives offered to participants is included in the informed consent documents. If the study is multicenter, information on the incentives given at all the different trial sites must be provided. If the participating sites are multinational, then the differences in the incentives across the sites must also be explained.

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

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

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

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

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

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

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

Compensation Disclosure

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

Overview

The G-TrialsGCP states that in obtaining and documenting informed consent, the principal investigator (PI) or delegate should comply with the ethical principles that have their origin in the Declaration of Helsinki (UGA-27), the NGHRP, and the G-TrialsGCP. Additionally, in accordance with the NGHRP, the NDPA-CTReg, and the G-TrialsGCP, a participant’s rights must be clearly addressed in the informed consent form (ICF) and during the informed consent process.

See the Required Elements; Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired sections for additional information regarding requirements for participant rights.

The Right to Participate, Abstain, or Withdraw

As set forth in the NGHRP and the G-TrialsGCP, the participant or legal representative/guardian should be informed that participation is voluntary, that the participant may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.

The Right to Information

According to the NGHRP and the G-TrialsGCP, a potential research participant or legal representative/guardian has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation for participation or injury/treatment, and any significant new information regarding the research study.

The Right to Privacy and Confidentiality

The NGHRP and the G-TrialsGCP indicate that all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right. It is the responsibility of the investigator(s) to safeguard the confidentiality of research data to protect the identity and records of research participants.

The Right of Inquiry/Appeal

As per the NGHRP and the G-TrialsGCP, the research participant or legal representative/guardian should be provided with contact information for the investigator(s) and the institutional ethics committee (EC) (research ethics committee (REC) in Uganda) to address trial-related inquiries in the event of any injury and/or to appeal against a violation of the participants’ rights.

The Right to Safety and Welfare

The NGHRP and the NDPA-CTReg state that a research participant’s right to safety and the protection of the participant’s health and welfare must take precedence over the objectives of biomedical research.

Overview

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

The Right to Participate, Abstain, or Withdraw

As set forth in 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, a potential participant and/or a legal representative(s) or guardian(s) must be informed that participation is voluntary, that the participant may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.

The Right to Information

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

The Right to Privacy and Confidentiality

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

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

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

The Right of Inquiry/Appeal

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

The Right to Safety and Welfare

The US-ICH-GCPs clearly states that a research participant’s right to safety and the protection of the participant’s health and welfare must take precedence over the interests of science and society.

The NGHRP allows the institutional ethics committee (EC) (research ethics committee (REC) in Uganda) to waive some or all of the informed consent requirements in instances of emergency situations where consent cannot be reasonably obtained from the participant or legal representative/guardian.

The G-TrialsGCP further states that in emergency situations, when prior consent of the participant is not possible, the consent of the legal representative/guardian, if present, should be requested. When prior consent of the participant is not possible and the legal representative/guardian is not available, enrollment of the participant should require measures that are described in the protocol and/or elsewhere, with documented approval 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 legal representative/guardian should be informed about the trial as soon as possible and provide consent to continue or other consent as appropriate, should this be requested.

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

Medical Emergencies

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

Emergency Use Situation

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

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

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

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

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

Emergency Research

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

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

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

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

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

Military Operations

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

Overview

According to the NGHRP, additional safeguards must be included in a study to protect vulnerable populations. Vulnerable populations are characterized as research participants who are incapable of protecting their own interests due to insufficient power, intelligence, education, resources, strength, or other requisite attributes. These participants are also considered to be vulnerable due to their limited capacity or freedom to provide or decline consent. Vulnerable populations include children/minors, prisoners, the homeless, substance abusers, mentally and physically handicapped, armed forces, terminally ill, and pregnant women. Characteristics that constitute vulnerability in such populations include one (1) or more of the following:

• Limited economic empowerment
• Conflict and post-conflict situations
• Inadequate protection of human rights
• Discrimination on the basis of health status
• Limited availability of health care and treatment options
• Communities in acute disaster and disease epidemics

As per the G-TrialsGCP, vulnerable participants also 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.

The NGHRP states that where appropriate, there should be a provision for involvement of a community in the research process right from inception to post research period. Additionally, the institutional ethics committee (EC) (research ethics committee (REC) in Uganda) must carefully consider and approve the mode of consent for participants from vulnerable populations. In order to protect vulnerable communities, ECs must ensure that selection of the particular community is justified by the research goals, and the research is relevant to the needs and priorities of the community in which it is to be conducted.

Per the NGHRP, for all vulnerable populations and individuals:

• Research can only be conducted in the population and with individuals if the objectives of the research cannot be addressed using non-vulnerable populations and individuals
• Risk of participating in research is justified by anticipated benefits
• The intervention or procedure presents experiences that are commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations
• The intervention or procedure is likely to yield generalizable knowledge about the population or individual’s disorder or condition that is of vital importance for the understanding or amelioration of that disorder or condition
• ECs may co-opt a person knowledgeable about and has experience working with the vulnerable group and individuals

The G-TrialsGCP further indicates that special protections for vulnerable populations can include:

• Allowing no more than minimal risks for procedures that offer no potential individual/direct benefits for participants
• Supplementing the participant’s agreement by the permission of family members, legal guardians, or other appropriate representatives
• Requiring that the research be carried out only when it is targeting conditions that affect these populations
• Safeguards can be designed to promote voluntary decision-making, limit the potential for confidentiality breaches, and otherwise work to protect the interests of those at increased risk of harm
• Appointment of advocates to the EC when such proposals for clinical trials on institutionalized individuals are under review

See the Children/Minors and Pregnant Women, Fetuses & Neonates sections for additional information about these vulnerable populations. See the NGHRP and the G-TrialsGCP for more examples of and details on vulnerable populations.

Persons in Hierarchical Relationships

As per the G-TrialsGCP, there is a possibility of diminished voluntariness of consent from potential participants who are in a subordinate relationship. Their agreement to volunteer may be unduly influenced, whether justified or not, by the expectation of preferential treatment if they agree to participate in the study or by fear of disapproval or retaliation if they refuse. Examples include medical and nursing students; subordinate hospital and laboratory personnel; workers in settings where research studies are conducted; and members of the armed forces or police.

Overview

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

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

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

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

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

The NGHRP and the G-CTChldrnWmn define a child as a person below the age of 18.

According to the G-CTChldrnWmn, data supporting the conduct of a clinical trial involving children should demonstrate that the benefit to the population outweighs the risk. For interventions or procedures that have no potential individual benefits for children:

• The risks must be minimized and no more than minimal;
• The purpose of the research must be to obtain knowledge relevant to the particular health needs of the population;
• The social value of the research for the children is compelling, and the research cannot be conducted in any other population; and
• Any research-related risk is the least possible for achieving the objectives of the research

While consent from the child’s parent or guardian is required in most cases, the NGHRP does allow for mature and emancipated minors, as described below, to provide consent. As per the NGHRP, mature minors are defined as individuals 14-17 years of age who have drug or alcohol dependency or a sexually transmitted infection. Emancipated minors are defined as individuals below the age of majority (18 years) who are pregnant, married, have a child, or are self-sufficient. Mature and emancipated minors are permitted to independently provide informed consent to participate in research if the following conditions exist:

• The institutional ethics committee (EC) (research ethics committee (REC) in Uganda) approves the research study as acceptable to the parents/legal guardians based on evidence from the community
• The protocol provides clear justification for targeting mature and emancipated minors as participants, and for not involving parents/legal guardians in the consent process

Assent Requirements

The NGHRP requires a child’s affirmative agreement to participate in research when the child is eight (8) years of age and older. A child's assent is obtained after the parent’s/legal guardian’s consent is obtained. The child’s assent or dissent takes precedence over the parent’s/legal guardian’s consent.

The G-CTChldrnWmn further indicates that for pediatric studies, adequate provisions should be made for soliciting the assent of the children and permission of their parents/legal guardians. Investigators should provide an understandable age-specific informed assent and information sheet for children.

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

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

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

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

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

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

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

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

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

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

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

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

Assent Requirements

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

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

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

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

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

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

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

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

The G-CTChldrnWmn states that data supporting the conduct of a clinical trial involving pregnant/lactating women should demonstrate that the benefit to the population outweighs the risk. For interventions or procedures that have no potential individual benefits for pregnant/lactating women:

• The risks must be minimized and no more than minimal;
• The purpose of the research must be to obtain knowledge relevant to the particular health needs of the population;
• The social value of the research for the pregnant/lactating women is compelling, and the research cannot be conducted in any other population; and
• Any research-related risk is the least possible for achieving the objectives of the research

According to the G-CTChldrnWmn, legally valid consent should be obtained from the participant or spouse as appropriate and in line with the NGHRP. As per the NGHRP, any Ugandan clinical studies involving pregnant women and fetuses require additional safeguards to ensure that the research conforms to appropriate ethical standards and upholds societal values. Informed consent should be obtained from both the mother and father of the embryos and fetuses. However, the father's consent is not required if: (i) the purpose of the study is primarily to meet the mother's health needs; (ii) the father's identity and/or whereabouts are unknown; (iii) the father is not reasonably available; or (iv) the pregnancy resulted from rape or incest and (v) the father is incompetent to give consent.

The G-CTChldrnWmn further indicates that for clinical trials involving pregnant women that have the potential for harm to the fetus, the participant should be informed about the potential risks, and research should be conducted only after assessing that the benefits (to the mother or fetus, as appropriate) outweigh the risk involved, and with informed consent of the participants.

(See the Required Elements section for general informed consent form requirements.)

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

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

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

Pregnant Women and Fetuses

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

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

Neonates

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

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

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

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

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

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

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

The G-TrialsGCP states that residents of prisons are often considered vulnerable because in a confined setting, they have few options and are denied certain freedoms that non-institutionalized persons enjoy. Some individuals with this characteristic may also have diminished capacity to consent, and therefore require the additional protections for participants who lack decisional capacity.

Institutional ethics committees (ECs) (research ethics committees (RECs) in Uganda) must review the need for special protection of the rights and welfare of these vulnerable populations and include protections when necessary.

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

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

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

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

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

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

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

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

The G-TrialsGCP states that residents of mental institutions are often considered vulnerable because in a confined setting, they have few options and are denied certain freedoms that non-institutionalized persons enjoy. Some individuals with this characteristic may also have diminished capacity to consent, and therefore require the additional protections for participants who lack decisional capacity.

Institutional ethics committees (ECs) (research ethics committees (RECs) in Uganda) must review the need for special protection of the rights and welfare of these vulnerable populations and include protections when necessary.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

As delineated in the NGHRP, the NDPA-CTReg, the G-CTConduct, the G-GMPMedicinalAnnexes, and the G-TrialsGCP, an investigational product (IP) is defined as a pharmaceutical form of an active ingredient or a placebo being tested or used as a reference in a clinical trial. Per the G-GMPMedicinalAnnexes, the G-CTConduct, and the G-TrialsGCP, an IP is also referred to as an investigational medicinal product (IMP) in Uganda and includes:

• A product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form
• When used for an unapproved indication
• When used to gain further information about an approved use

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

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

Manufacturing

According to the NDPA-CTReg, the G-CTConduct, and the G-TrialsGCP, the National Drug Authority (NDA) is responsible for authorizing the manufacture of investigational products (IPs) in Uganda. The NDA will only approve the manufacture of an IP after approval of the clinical trial application. The NDPA-CTReg indicates that if the IP is to be manufactured in Uganda, the holder of the clinical trial certificate must apply to the NDA for a manufacturing license.

Uganda follows the G-GMPMedicinal, the G-GMPMedicinalAPIs, and the G-GMPMedicinalAnnexes for good manufacturing practice (GMP), which were adopted from Pharmaceutical Inspection Co-operation Scheme (PIC/S) guidance. Per the G-GMPMedicinal, the holder of the NDA’s manufacturing authorization must manufacture IPs to ensure that they are fit for their intended use, comply with the requirements of the clinical trial authorization, and do not place participants at risk due to inadequate safety, quality, or efficacy. The G-GMPMedicinalAnnexes further states that for manufacturers to be able to apply, and comply with, GMP for IPs, cooperation between manufacturers and sponsors of clinical trials is required. This cooperation should be described in a technical agreement between the sponsor and manufacturer.

The G-GMPMedicinalAPIs indicates that when manufacturing active pharmaceutical ingredients (APIs) for use in clinical trials, process and test procedures should be flexible to provide for changes as knowledge of the process increases and clinical testing of a drug product progresses from pre-clinical stages through clinical stages. Once drug development reaches the stage where the API is produced for use in IPs, manufacturers should ensure that APIs are manufactured in suitable facilities using appropriate production and control procedures to ensure the quality of the API. Additionally, the manufacture of APIs for use in clinical trials should be documented in laboratory notebooks, batch records, or by other appropriate means.

See the G-GMPMedicinal, the G-GMPMedicinalAPIs, and the G-GMPMedicinalAnnexes for more detailed manufacturing requirements.

Import

The NDA is responsible for authorizing the import of IPs. The NDPA-CTReg and the G-CTConduct state that prior to IP import or manufacture, the sponsor or principal investigator (PI) must be granted a clinical trial certificate by the NDA. According to the NDPA-CTReg, the holder of the clinical trial certificate must then apply for a permit to import the IP approved for the trial.

According to the G-VerImprtExprt, an application for an import verification certificate under extraordinary circumstances (which include clinical trials approved by the NDA) must be submitted electronically through the National Drug Authority Management Information System (NDAMIS) (UGA-34) by a person duly authorized to import drugs into Uganda (an import license holder). The G-VerImprtExprt includes clinical trials approved by the NDA in its definition of “extraordinary circumstances.” The application should be accompanied by:

• A clinical trial certificate for drugs for use in clinical trials
• A copy of the proforma invoice from the supplier
• A donation certificate, if applicable
• Authorization for drugs to be used in a medical camp, if applicable
• Evidence of current GMP compliance of the manufacturer. The manufacturer should have GMP certification issued by the NDA, or the national medicines regulatory authorities of the following countries/regions: the United States of America (USA), the European Union (EU), the United Kingdom (UK), Switzerland, Canada, Australia, Iceland, Liechtenstein, Norway, or prequalified by the World Health Organization
• Documented evidence/justification describing the emergency or extraordinary circumstance
• A filled application form for the authorization for importation of narcotic drugs and psychotropic substances and precursors, if applicable
• Evidence of registration of the drug(s) in the country of origin or emergency use approval of the drug by the competent authority in the country of origin, by a supranational body and any other regulatory authority if not registered

As stated in the G-VerImprtExprt, the application is screened for completion and correctness, then the applicant is billed the prescribed fees (see the NDPA-FeesReg for more information). The NDA will issue a verification certificate upon receipt of a successful application. The verification certificate is valid for 12 months from the date of issue.

See the G-VerImprtExprt for detailed import permit application submission requirements and review procedures. Additionally, see the Submission Process, Submission Content, and Regulatory Fees sections for detailed clinical trial application requirements.

Please note: Uganda is party to the Nagoya Protocol on Access and Benefit-sharing (UGA-3), which may have implications for studies of IPs developed using certain non-human genetic resources (e.g., plants, animals, and microbes). For more information, see UGA-21.

Manufacturing

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

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

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

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

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

Import

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

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

Investigator's Brochure

In accordance with the NDPA-CTReg, the sponsor is responsible for updating the Investigator’s Brochure (IB), which is a compilation of the clinical and non-clinical data on the investigational product(s) (IPs). The G-TrialsGCP further indicates that the IB should be reviewed at least annually and revised as necessary in compliance with a sponsor's written procedures. Relevant new information may be so important that it should be communicated to the investigator(s), and possibly to the institutional ethics committee(s) (ECs) (research ethics committees (RECs) in Uganda) and/or regulatory authorities, before it is included in a revised IB.

According to the G-TrialsGCP, the sponsor is generally responsible for ensuring that an up-to-date IB is made available to the investigator(s), and the investigators are responsible for providing the up-to-date IB to the responsible ECs and the National Drug Authority (NDA). In the case of an investigator sponsored trial, the sponsor-investigator should determine whether a brochure is available from the commercial manufacturer. If the IP 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 this guideline.

The G-TrialsGCP, the NDPA-CTReg, and UGA-4 require the IB to provide coverage for the following areas:

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

See Section 7.3 of the G-TrialsGCP for detailed content descriptions, and UGA-4 or Schedule 2 of the NDPA-CTReg for the format of the IB.

Quality Management

Uganda follows the G-GMPMedicinal, the G-GMPMedicinalAPIs, and the G-GMPMedicinalAnnexes for good manufacturing practice (GMP), which were adopted from Pharmaceutical Inspection Co-operation Scheme (PIC/S) guidance. Per the G-GMPMedicinal, GMP ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the clinical trial authorization. The forementioned documents must be used for periodic GMP inspection of all manufacturers of medicinal products within and outside Uganda whose products are registered or subjected to registration in the country. Manufacturers that are GMP compliant will be issued GMP compliance certificates.

According to the G-CTConduct and the G-TrialsGCP, the sponsor must ensure that the IP(s) is manufactured in accordance with GMP. The G-CTConduct further indicates that evidence of manufacture under GMP standards must be submitted with the clinical trial application to the NDA. In cases where the sponsor or the PI is not the manufacturer, and where confidentiality considerations prevent disclosure of certain information to the sponsor or the PI, any relevant IP/application information should be submitted to the NDA through the sponsor or the PI in a sealed envelope marked “CONFIDENTIAL.” Alternatively, the information may be sent to the Clinical Trials Unit with the necessary password protection at clinicaltrials@nda.or.ug.

The G-TrialsGCP states that if significant formulation changes are made in the investigational or comparator product(s) during the course of clinical development, the results of any additional studies of the formulated product(s) (e.g., stability, dissolution rate, bioavailability) needed to assess whether these changes would significantly alter the pharmacokinetic profile of the product should be available prior to the use of the new formulation in clinical trials and submitted to the NDA for review and authorization.

According to the G-GMPMedicinalAnnexes, the manufacturer should establish and maintain a quality control system placed under the authority of a person who has the requisite qualifications and is independent of production. Quality control of the IP, including that of the comparator product, should be performed in accordance with the information submitted in the application for the clinical trial. See the G-GMPMedicinal and the G-GMPMedicinalAnnexes for more information on quality control requirements.

Additionally, the G-GMPMedicinalAnnexes indicates that a pharmaceutical quality system which is designed, set up, and verified by the manufacturer should be described in written procedures, taking into account the guidance in the G-GMPMedicinal that is applicable to IPs. The product specifications and manufacturing instructions may be changed during development, but full control and traceability of the changes should be documented and maintained. The selection, qualification, approval, and maintenance of suppliers of starting materials, together with their purchase and acceptance, should be documented as part of the pharmaceutical quality system to ensure the integrity of the supply chain and protect against falsified products. The product specification file should be continually updated as development of the product proceeds, ensuring appropriate traceability to the previous versions. It should include, or refer to, at least the following documents:

• Specifications and analytical methods for starting materials, packaging materials, intermediate product, bulk product, and finished product
• Manufacturing methods
• In-process testing and methods
• Approved label copy
• Relevant clinical trial authorizations and amendments thereof, clinical trial protocol, and randomisation codes, as appropriate
• Relevant technical agreements with contract givers and acceptors, as appropriate
• Stability plan and reports
• Details of plans and arrangements for reference and retention samples
• Storage and transport conditions
• Details of the supply chain including manufacturing, packaging, labeling, and testing sites for the IPs

For more information on pharmaceutical quality system requirements, see the G-GMPMedicinal and the G-GMPMedicinalAnnexes.

Investigator's Brochure

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

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

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

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

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

Quality Management

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

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

Labeling for investigational products (IPs) (known as investigational medicinal products (IMPs) in Uganda) must comply with the requirements set forth in the G-GMPMedicinalAnnexes, the NDPA-CTReg, the G-CTConduct, the NGHRP, and the G-TrialsGCP. As specified in the G-GMPMedicinalAnnexes, the labeling operation should be performed at an authorized manufacturing site.

As per the NGHRP and the G-TrialsGCP, the sponsor is responsible for ensuring the proper labeling of the IPs. The IPs and comparator products must be labeled in conformity with the clinical protocol.

According to the NDPA-CTReg and the G-CTConduct, the IP must be labelled as specified in UGA-7 or Form 38 of the NDPA-CTReg. The NDPA-CTReg, the G-GMPMedicinalAnnexes, and UGA-7 require the following labeling information to be included on both the outer packaging and the immediate container (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• The name, address, and telephone number of the sponsor or manufacturer; the G-GMPMedicinalAnnexes specifies the investigator or contract research organization could also be the main contact for IP information, clinical trial, and emergency unblinding
• The name/identifier and strength/potency, and in the case of blinded trials, all product labeling should indicate “placebo/comparator or [name/identifier] + [strength/potency]”
• The pharmaceutical dosage form, route of administration, and quantity of dosage units
• 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 storage conditions
• Pack sizes (unit or volume)
• The instructions for use
• The period of use (use-by date, expiration date, manufacturing date, or re-test date), in month/year format
• “For clinical trial use only” or similar wording
• “Keep out of reach of children” except when the IP is for use in trials where it is not taken home by participants

The G-GMPMedicinalAnnexes further states that where products are blinded, systems should be in place to ensure that the blind is achieved and maintained while allowing for identification of “blinded” products, when necessary, including batch numbers of the products before the blinding operation. Rapid identification of the product should also be possible in an emergency. Where the manufacturer has been delegated the responsibility for generation of randomization codes, the manufacturer should ensure that unblinding information is available to the appropriate responsible investigator site personnel before the IPs are supplied. The expiry date assigned to all products for use in the trial should be the expiry of the shortest dated product so that the blinding is maintained.

For additional detailed labeling information and exceptions, see the G-GMPMedicinalAnnexes.

The G-TrialsGCP requires that in blinded trials, the coding system for IPs should include a mechanism that permits rapid identification of the products in case of a medical emergency, but does not permit undetectable breaks of the blinding. The G-CTConduct further indicates that a sample of the label for imported products must be included with the clinical trial application to the National Drug Authority (NDA).

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

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

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

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

Supply, Storage, and Handling Requirements

As delineated in the G-TrialsGCP and the G-CTConduct, the sponsor must ensure timely delivery of the investigational product(s) (IP(s)) to the principal investigator (PI)/investigator(s). Additionally, the sponsor must maintain sufficient quantities of the IP(s) used in the trial to reconfirm specifications, should this become necessary. The G-TrialsGCP further states that the sponsor should not supply the investigator(s)/institution(s) with the IP(s) until the sponsor obtains National Drug Authority (NDA) and institutional ethics committee (EC) (research ethics committee (REC) in Uganda) approvals. However, according to the NDPA-CTReg, the PI is responsible and accountable for the IP.

Furthermore, per the G-TrialsGCP, the sponsor should 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, 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 NDA approved protocol and/or where available, applicable regulatory requirement(s)).

As delineated in the G-GMPMedicinalAnnexes, IPs are normally packed individually for each participant included in the clinical trial. The number of units to be packaged should be specified prior to the start of the packaging operations, including units necessary for carrying out quality control and for any retention samples to be kept. Sufficient reconciliations should take place to ensure that the correct quantity of each product required has been accounted for at each stage of processing. Procedures should describe the specification, generation, testing, security, distribution, handling, and retention of any randomization code used for packaging IPs, as well as code-break mechanism. Appropriate records should be maintained.

Per the G-GMPMedicinalAnnexes, packaging must ensure that the IP remains in good condition during transport and storage at intermediate destinations. Any opening or tampering of the outer packaging during transport should be readily discernible. Where the manufacturer is delegated by the sponsor to perform the regulatory release of the IP, the arrangements should be defined in an agreement between the sponsor and the manufacturer. Relevant clinical trial authorization and amendment information should be available for reference in the product specification file, and the manufacturer should ensure the necessary clinical trial authorizations are in place prior to shipping the product for use in the trial.

Per the G-TrialsGCP and the G-CTConduct, the sponsor must also maintain a system for retrieving IP(s), as well as for the disposal of unused IP(s). The G-GMPMedicinalAnnexes further delineates that returned IPs should be clearly identified and stored in an appropriately controlled, dedicated area. The manufacturer or sponsor’s representative should destroy IPs only with prior written authorization by the sponsor. The arrangements for destruction of IPs must be described in the protocol. Any arrangement between sponsor and manufacturer regarding IP destruction should be defined in their technical agreement. Destruction of unused IPs should be carried out only after reconciliation of delivered, used, and recovered products and after investigation and satisfactory explanation of any discrepancies upon which the reconciliation has been accepted.

See the G-GMPMedicinalAnnexes, the G-TrialsGCP, and the G-CTConduct for detailed sponsor-related IP requirements.

Record Requirements

As per the G-CTConduct and the G-TrialsGCP, the sponsor must maintain records that document shipment, receipt, disposition, return, and destruction of the IP(s). The sponsor must also maintain a system for documenting the retrieval of IP(s) and the disposal of unused IP(s), as well as records of batch sample analyses and characteristics.

Per the G-GMPMedicinalAnnexes, there must be sufficient documentation to demonstrate that appropriate segregation has been maintained during any IP packaging operations. To facilitate a recall of the IP, a detailed inventory of the shipments made by the manufacturer should be maintained. Inventory records of returned IPs should be kept. Additionally, records of destruction operations should be retained, including a dated certificate of destruction or a receipt for destruction to the sponsor. These documents should clearly identify or allow traceability to the batches and/or participant numbers involved, and the actual quantities destroyed.

The G-CTConduct indicates that the pharmacist of record must maintain instructions for the handling of IP(s) and trial related materials, if not indicated in the protocol or Investigator’s Brochure (IB). The pharmacist must also maintain shipping records for the IP(s) and trial related material, as well as for receipt date(s) of product delivery and quantity.

According to the G-GMPMedicinalAnnexes, product specification file documents must be retained for at least five (5) years, and the sponsor should retain the clinical trial master file for at least 25 years after the end of the trial, unless otherwise specified in relevant national laws. If the sponsor and the manufacturer are not the same entity, the sponsor must make appropriate arrangements with the manufacturer to fulfil the clinical trial master file retention requirement. Arrangement for retention of such documents and the type of documents to be retained should be defined in an agreement between the sponsor and manufacturer. Per the G-GMPMedicinal to the G-GMPMedicinalAnnexes,, batch documentation/manufacturing records must be retained by the manufacturer for at least five (5) years after the completion or formal discontinuation of the last clinical trial in which the batch was used.

Supply, Storage, and Handling Requirements

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

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

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

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

Record Requirements

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

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

In Uganda, a specimen is also referred to as human material. As delineated in the NGHRP, human biological materials consist of any substance obtained from a human research participant. This material includes, but is not limited to: blood, urine, stool, saliva, hair, nail clippings, skin, microorganisms, and other associated bio-products.

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

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

The RevComRule defines an identifiable biospecimen as one for which the identity of the participant is or may readily be ascertained by the investigator or associated with the biospecimen. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the RevComRule applies to research.)

Import/Export

The G-CTConduct state that applications for import and/or export of biological materials, if applicable, must be included in the clinical trial application to the National Drug Authority (NDA).

Additionally, the NGHRP delineates that all exchanges and transfers, including importation and exportation of human materials for research purposes, require Uganda National Council for Science and Technology (UNCST) clearance, except for the exchange of human materials between organizations within Uganda. In order to justify transfer of human materials abroad, investigators, sponsors, and collaborators should demonstrate that in-country capacity to perform certain types of investigations/testing does not exist or is inadequate. Per the G-UNCSTreg, where it is proven that no capacity for a given investigation exists in Uganda, or where exchange of research material is needed for quality assurance purposes or other justifiable reasons, research materials may be transferred to, exported to, or exchanged with more advanced facilities abroad.

Per the NGHRP and the G-UNCSTreg, the following are the necessary steps for the exchange or transfer of human materials for research purposes abroad or from abroad:

• The research project that involves the exchange or transfer of human material must first be registered by the UNCST
• The applicant must be a legal resident of Uganda and be affiliated with a locally registered and recognized organization in Uganda
• A request for exchange or transfer of human material must be made in writing to the Executive Secretary of the UNCST
• A Material Transfer Agreement (MTA) and any other document related to the exchange or transfer of human material must accompany the request for the exchange or transfer of the material

According to the NGHRP, the UNCST is required to provide feedback within 14 calendar days from the submission date. However, the G-UNCSTreg states that the UNCST must provide feedback within 10 working days from the submission date. The feedback may be an approval or clearance, a rejection or disapproval, or comments to improve the quality of the application. Once the UNCST approval is obtained, the investigator can proceed to facilitate the transfer, export, or exchange of the research specimen.

Material Transfer Agreement

As set forth in the NGHRP and the G-UNCSTreg, the UNCST application for permission to transfer, export, or exchange samples for research purposes from one (1) organization to another, within the country and abroad, must be accompanied by an MTA between the provider organization and the recipient organization. Per the NGHRP, the MTA should include the following details:

• A list of the parties and their addresses; the MTA is signed only by authorized party representatives and the effective date of the MTA must be indicated
• A detailed description of the materials to be exchanged
• The purpose for transfer or export of the human biological substance
• A list of authorized users of the materials
• The location where the material is to be transferred
• Period of use and disposal plans for the material
• Clear arrangements for benefit sharing of any accruing or anticipated future benefit at the point of termination
• The provider organization should state whether the recipient organization is permitted to own any of the derivatives or products discovered through the use of the material
• Directions for handling product commercial rights
• Publication requirements/restrictions, including citation requirements if information about the material is published
• The governing law(s) of the provider’s and recipient’s countries
• Recipient organization’s responsibilities for the proper handling and use of the material
• Recipient and provider agreement on liability for any misuse of the material
• Description of specific restrictions for the recipient organization
• A statement indicating what technologies would be transferred to the provider organization or country, if applicable
• A warranty stating that the material is being provided “as is”
• A clause stating that the MTA may be amended at any time by written mutual consent of the parties

See Section 10.4 of the NGHRP for detailed MTA requirements. Per the UNCST-RevTemp, data ownership and associated intellectual property rights in both the Data Sharing Agreements and MTAs must be discussed and agreed upon by collaborating partners at the inception of a research study within the context of the investigator's institutional regulations/provisions. Templates of Data Sharing Agreements and MTAs, as applicable, must be presented as part of the research protocol to be reviewed by the institutional ethics committee (EC) (research ethics committee (REC) in Uganda).

See the G-Biobank for more information on the collection, receipt, storage, processing, and dissemination of biological specimens by biobanks in Uganda.

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

In accordance with the NGHRP, investigators must comply with several informed consent requirements for the acquisition, storage, and future use of human biological samples from research participants in Uganda.

For any research involving the collection of human biological or genetic materials, the investigator must provide an explanation to the research participant in the informed consent form (ICF) regarding how the specimens will be managed at the end of the study.

For samples to be stored for future use, the investigator is also required to obtain a separate informed consent from the participant. This process includes the use of a separate ICF that states the following:

• The purpose of the sample storage
• The quantities of samples to be stored
• The location of the stored samples
• Measures the investigator will take to protect participant confidentiality
• The policies that will govern the use of the samples in future research
• The potential risks and benefits of storing samples for future research
• Any other information deemed necessary by the investigators, the institutional ethics committee (EC) (research ethics committee (REC) in Uganda), and the Uganda National Council for Science and Technology (UNCST)

As per the NGHRP, the investigator must also give the research participant the right to choose whether the samples should or should not be stored for future studies. A Ugandan scientist must be included as co-investigator in all future studies using the human materials collected from Uganda. Participants must not be penalized for their refusal to store the samples and reserve the right to withdraw their samples from storage if the samples are linked. Any future research study on such samples is subject to review by an EC. Where identifiable samples have been collected, for example, as part of routine surveillance, emergency procedures, laboratory quality control, notifiable diseases, routine counseling and testing, etc., without the prior intention of conducting research on the samples, the samples’ sources must be traced to provide consent for use of the samples in research.

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

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

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

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

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

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

Per the Pre2018-ComRule, the RevComRule, and USA-2, prior to collecting, storing, or using a research participant’s biological specimen(s), consent must be obtained from the participant and/or a legal representative(s). See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.

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

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

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

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

The RevComRule does allow the use of identifiable information or biospecimens in instances where the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) determines the research could not practicably be carried out without the information in that form. Furthermore, it removes the requirement for the investigator to seek a waiver of informed consent to obtain information or biospecimens to screen, recruit, or determine eligibility of prospective participants. See USA-54 for more information on broad consent and informed consent waivers.

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

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

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