The Principal Investigator (PI) should be qualified by education, training and experience to assume responsibility for the proper conduct of the clinical trial, and should have adequate resources to do so.

Qualifications of a PI

The PI should be trained in Good Clinical Practice (GCP), protocol and trial-specific procedures (e.g., workflows, plans, manuals, SOPs etc.) prior to conducting the clinical trial.

• Training documentation (e.g., training logs, certificates) or supporting documents for waiver of training should be maintained in the Investigator Site File accordingly. Refer to your relevant Institutional Review Board (IRB) for their minimum training requirements for the PI.

For clinical trials conducted in Singapore, the PI should be a qualified practitioner or qualified pharmacist.

• A qualified practitioner is a locally registered medical practitioner under the Medical Registration Act or a registered dentist under the Dental Registration Act.
• A qualified pharmacist is a locally registered pharmacist under the Pharmacists Registration Act, who holds a valid practising certificate and is in active practice as defined in the Pharmacists Registration (Practising Certificates) Regulations. Please refer to the Ministry of Health's Guidance on Pharmacists as Principal Investigators for further details.

For clinical trials assessing investigational products in specialised therapeutic areas, the PI should be at least an Associate Consultant (AC) in the same therapeutic area.

• Such clinical trials often involve complex diagnostic evaluation or trial procedures that require specialised skills. A suitably qualified AC and above would have sufficient training and experience to conduct such clinical trials properly, as well as to handle unforeseen adverse events or difficulties during the conduct of the clinical trial.

For clinical trials assessing locally registered therapeutic products routinely used by a general practitioner during clinical practice, it may be acceptable for the PI to be a general practitioner.

For clinical trials where the PI holds a conditional registration with the Singapore Medical Council (SMC) requiring the PI to “work under supervision”, a statement from the PI’s supervisor supporting the PI's involvement in the trial must be included the clinical trial application submitted to HSA.

• Refer to SMC's website on conditional registration for more details

Responsibilities of a PI

The PI is responsible to ensure that clinical trials are conducted in compliance with the protocol, standard operating procedures, GCP and applicable regulatory requirements.

The regulatory obligations of a PI conducting a clinical trial are as follows:

• Conduct clinical trials in compliance with the protocol, applicable regulations, the principles of GCP and the standard operating procedures relevant to the clinical trial
• Conduct clinical trials at location(s) specified in the clinical trial application
• Ensure that all medical/dental care and decisions relating to the participants are the responsibility of an investigator who is a qualified practitioner
• Ensure that any individual to whom a trial-related activity is delegated is qualified by education, training, and experience to perform the delegated trial-related activity
• Maintain a list of appropriately qualified persons to whom significant trial-related activities have been delegated
• Ensure that informed consent requirements are complied with
• Keep adequate essential records for the specified period
• Declare every financial interest, including that of any person assisting the PI, to the IRB
• Report serious adverse events within stipulated timelines to sponsor, and IRB if required
• Ensure that there is a system of traceability established and maintained at the trial site, if the trial involves a Class 2 CTGTP

Investigator Oversight

The investigator may delegate trial-related activities to other persons or parties. In situations where the investigator is supported by the sponsor in identification of a suitable service provider to undertake any activities under the responsibility of the investigator (e.g., for implementing decentralised elements in clinical trials like engaging nurses to conduct home visits, or courier to deliver the IP to the participants’ homes), the investigator retains the final decision on whether the service provider intended to support the investigator is appropriate based on information provided by the sponsor. In such a situation, the investigator should ensure that the clinical trial agreement made with the sponsor specifies the involvement of the service provider.

The PI retains the ultimate responsibility and should maintain appropriate oversight of the persons or parties to whom the PI has delegated trial-related activities (including those undertaken by service providers supported by the sponsor) to ensure the rights, safety and well-being of the trial participants and the reliability of data.

The level of investigator oversight of the delegated activities should depend on the nature of the delegated activities and be proportionate to the importance of the data being collected and the risks to trial participant safety and data reliability. For example, a greater level of investigator oversight would be required for trial-related activities that are not performed as part of clinical practice, or collection of trial data for primary and secondary efficacy and safety endpoints.

Some examples of investigator oversight include:

• Ensuring that delegated investigator site staff and service providers are appropriately qualified and adequately informed about relevant aspects of the protocol, the investigational product(s) and their assigned trial activities
• Maintaining oversight of investigator site staff and service providers delegated to perform trial-related activities, including establishing agreements, delegation, training, collection and review of source records, measures to safeguard the privacy of participants, data integrity and confidentiality etc., where applicable
• Ensuring that informed consent is obtained from participants prior to trial participation
• Ensuring eligible participants are enrolled into a clinical trial
• Ensuring adequate medical care is provided to participants
• Ensuring that the clinical trial is conducted in compliance with the protocol, applicable regulations, the principles of GCP and the standard operating procedures relevant to the clinical trial
• Permitting monitoring and audits by the sponsor, GCP inspections by regulatory authorities, and reviews by IRBs
• Maintaining essential records

Adequate Resources

The investigator should have sufficient time, an adequate number of available and qualified staff, and adequate facilities for the foreseen duration of the trial to conduct the trial properly and safely.

Additionally, the PI should be able to demonstrate (e.g., based on retrospective or currently available data) a potential for recruiting the proposed number of eligible participants within the recruitment period as agreed with the sponsor.

Medical or dental decisions to be made by qualified practitioners

The PI must ensure that an investigator, who is a qualified practitioner, is responsible for the medical or dental care given to the participants and for all trial-related medical or dental decisions made on behalf of the participants. Examples of these decisions include:

• Confirming participant eligibility
• Assessing clinical response to an investigational therapy
• Providing medical care to participants during the clinical trial
• Reviewing safety assessments (e.g. physical examinations, vital signs, safety laboratory test results)
• Assessing and reporting adverse events

Note: Participant eligibility should be reviewed based on the protocol. The practice of enrolling participants into a clinical trial based on "protocol waiver" is discouraged, as there may be implications to the credibility of the trial results, if participants who have not fulfilled the eligibility criteria were enrolled.

Delegation and training of investigator site staff

Investigator site staff are persons who assist the PI in the conduct of the clinical trial. Examples of investigator site staff may include sub-investigators, clinical research coordinators, nurses, pharmacists etc.

Every person or party conducting a clinical trial must do so in accordance with the protocol, applicable regulations, principles of GCP and SOPs relevant to the clinical trial. They should be delegated by the PI and adequately qualified (by education, training and experience).

The PI should maintain a record of the persons and parties to whom the PI has delegated trial-related activities. Such records (e.g., Delegation Log) should capture the roles, tasks and signatures of the delegated investigator site staff.

Documentation of delegation should be proportionate to the significance of the trial-related activities.

• Delegation documentation (e.g., Delegation Log) would be required for significant trial-related activities (e.g., informed consent, eligibility assessment, investigational product (IP) management, key efficacy and safety assessments etc).
• Delegation documentation (i.e. Delegation Log) may not be required for trial-related activities that are performed as part of clinical practice. For example, delegation documentation may not be required for phlebotomists collecting blood for routine safety laboratory tests, but would be required for phlebotomists collecting blood for pharmacokinetic (PK) blood sampling as they would not be familiar with PK schedule in the protocol. However, there should be documentation on file (e.g., email to relevant Head of Department or Note to File) to indicate the involvement of the relevant departments and staff, with the authorisation of the PI.

The investigator should ensure that persons or parties to whom the investigator has delegated trial-related activities are appropriately qualified and are adequately informed about relevant aspects of the protocol, the investigational product(s) and their assigned trial activities (including activities conducted by staff provided by other parties in accordance with local regulatory requirements). Trial-related training may include relevant aspects of GCP, protocol or trial-specific procedures (e.g., workflows, plans, manuals, SOPs etc.). Refer to your relevant Institutional Review Board (IRB) for the minimum training requirements for the investigator site staff. Training documentation (e.g., training logs, certificates) should be maintained in the Investigator Site File accordingly.

• Trial-related training to persons assisting in the trial should correspond to what is necessary to enable them to fulfil their delegated trial activities that go beyond their usual training and experience. For example, pharmacists involved in IP management of an unregistered product should be trained on IP management, but may not require trial-related training if they are involved in IP management of a registered product used as part of clinical practice
• In situations where large teams (e.g., radiologists, nurses, pharmacy technicians) are involved in conducting significant trial-related activities, a proportionate, risk-based approach may be considered for delegation and training. For example, if the trial-related activity is performed in accordance with the protocol, the PI may delegate a staff of supervisory position (e.g., head of department, nurse manager or pharmacist) to be part of the investigator site team. The PI should ensure that the investigator site staff in the supervisory position completes the required trial-related training and the investigator site staff under their care are similarly trained. Training documentation should be maintained accordingly.

Change of PI

For ongoing or suspended trials, an amendment application for change of PI must be submitted to us and the IRB prior to implementing the change.

As the PI should have sufficient time to properly conduct and maintain oversight of the clinical trial, we recommend a change of PI if the PI is away on extended leave for more than four months.

It would be recommended to specify an end date for all investigator site staff on the current Delegation Log, and complete a new Delegation Log for all investigator site staff to be delegated by the new PI. The superseded Delegation Log should be retained on file.