Change from LM 1.4 v 1.0: added Principal Investigator (PI) Site Risk Evaluation Checklist Prior to Study Initiation.

List of roles: Sponsor, EPCTU Manager, Principal Investigator, Co-Investigator, Site Project Manager/Study Nurses.

Sponsor

Sponsor is responsible for writing the protocol according to the standards for FIH-studies/EPCTs and implement a system to manage quality throughout the design, conduct, recording, evaluation, reporting and archiving of clinical trials. This includes doing a risk assessment for the totality of the trial.

EPCTU Manager

Ensure that the study team is appropriately qualified, experienced and trained for conduction of FIH studies/EPCTs and handling of emergency situations. See to that education/training is up to date, such as annual life support training - CPR (Cardiopulmonary resuscitation; S-CPR for nurses and A-CPR for physicians). A documented list of life support training must be kept at the EPCTU.

Moreover, the EPCTU Manager shall:

1. Secure that the unit is appropriately staffed at any time of study conduct.
2. Take responsibility for facilities and basic structure of the unit.
3. See to that fire evacuation procedures are established.
4. See to that back-up power supply is available.
5. Take responsibility for the security of the facility with respect to unauthorized or limited access.
6. See to that provisions are in place for insurance and indemnity.

Principal Investigator (PI)

In addition to the comprehensive requirements pertaining to being a PI, additional and more specific requirements for PI in FIH studies/EPCTs comprise:  

1. Being thoroughly familiar with the European Medicines Agency, EMA, Guideline on strategies to identify and mitigate risks for FIH and ECTs with IMPs.
2. Having relevant knowledge in pharmacology to secure an appropriate review of pre-clinical data, assess the pharmacology and subsequent aspects, such as the proposed starting dose, dose escalation proposal/stopping criteria etc for IMP. For FIH in particular, consulting clinical pharmacology expertise may be advisable.
3. Obtaining sufficient information and knowledge regarding the study procedures and IMPs (such as targets, mechanism of action and potential adverse events) to be able to assess the risk for possible harm, perform Informed Consent process and make clinical judgments during the study.
4. Performing a risk analysis based on the protocol and the IB, for each study, together with the study team. The risk evaluation should have a quality at least comparable to SOP Quality and Risk Management and clearly conclude that anticipated risks and risk mitigation are adequately balanced (See the "Risk Analysis" section under Procedures Before Study Start.
5. Creating/reviewing the application for the Ethics Committee (EC) and Informed Consent documents (ICD), so that they cover specifically important information regarding drug characteristics (pharmacological and toxicological) to support start and maximum dose and explain and justify risks for the specific study.
6. When relevant, seeing to that the ICU is informed about the specific study before study start and dosing of patients.
7. Supervising dosing procedures on site during and after dosing. This could also be delegated to a Co-Investigator.
8. Being aware of and follow the specific stopping rules for the study.
9. Writing drug requisitions for the study.
10. Nominating a co-investigator.

Sub-Investigator

The Sub-Investigator should perform the study specific tasks that have been delegated by the PI.

Site Project Manager/Study Nurses

Site Project Manager and/or Study Nurse shall see to that such as vital function monitoring devices are operative, including control of alarms, and emergency equipment, emergency cart, emergency medication and temperature control for IMPs is performed before study start. Moreover, they shall:

1. Set up and maintain the Trial Master File (TMF) or Investigator Site File (ISF) as applicable.
2. For each study suject, follow the study flow chart. 
3. Prepare IMP if this is not done by the pharmacy. Only simple processes of dissolving/dispersing or diluting/mixing of IMPs should be made by the study staff. More complicated processes of dissolving/dispersing or diluting/mixing must be made by units with adequate facilities, knowledge and qualifications, e.g. a pharmacy.
4. Connect study subjects to appropriate vital sign monitoring.
5. Administer lifesaving adrenalin, when needed.

Qualified staff

It is important that the unit has trained and experienced staff available to undertake the trials they are conducting. Minimum staffing during the dosing phase must be two study nurses and medical supervision of PI or co-investigator during and after dosing. Time frames for the dosing phase will be set depending on the specific study.

Risk analysis

When performing the risk assessement, the FIH/EPCTU shall ensure that all relevant safety aspects of the trial are considered. The sponsor’s risk evaluation should be reviewed. The FIH/EPCTU shall make their own assessment and retain any discussions with the sponsor (whether sponsor is a hospital or pharmaceutical/biotechnology company). Upon a possible disagreement with the sponsor; the PI should seek review by a professional with relevant expertise at the hospital.

Special considerations should be brought to:

1. Confirmation/re-calculation of the starting dose and dose increments. In order to determine a safe starting dose, the methods used for determination of the strength and/or the potency of the product need to be relevant for the intended mechanism of action, reliable and qualified.
2.  Any dose escalation procedures.
3. Relevance of study design (i.e. population, administration, assessments etc.).
4. IMP (i.e. relevance of safety/toxicology information, mode of action, the nature of the target, pharmacokinetic (PK) and pharmacodynamic (PD) information, a description of potential polymorphisms etc.).
5. Any specific rescue medications/antidotes, supportive emergency facilities and staff, specific emergency scenarios etc.
6. Extra staffing/resources (i.e. identifying specific training, expertise, facilities or specific location/wards in unit for conduct of certain trials etc.).

A written document in which identified risks and risk mitigation measures are adequately balanced should always be available.

Pre-study clinic meeting

A follow up of the risk analysis and actions performed will be done by the PI and study team at a pre-study clinic meeting.

Dry run

A study rehearsal, “dry run procedure”, will be performed before the study starts. During this rehearsal, all members of the study team will be present. A flow chart with all the procedures for the specific study will be set up and reviewed step-by-step from the time point when the study subject enters the EPCTU until their study treatment is completed.

Intensive Care Unit (ICU)

The EPCTUs must have immediate access to equipment and staff for resuscitating and stabilizing individuals in an acute emergency (such as cardiac emergencies, anaphylaxis, cytokine release syndrome, convulsions, hypotension), and ready availability of Intensive Care Unit facilities (ICU). Procedures must be established between the EPCTU and its nearby ICU regarding the responsibilities and undertakings by each unit in the handling and care of patients.

The PI or designee will inform the ICU about the specific study before study start. Documentation regarding the given information shall be kept in the Investigator’s Site File.

It is recommended that a general agreement is in place between the departments involved, well before start of the study.

Checklist before study start

The Site Project Manager or Study Nurse will review the Principal Investigator (PI) Site Risk Evaluation Checklist prior to study initiation - Template  so that all tasks/items are performed or checked, such as temperature control for IMP, emergency chart check, alarms etc.

PI

The PI shall supervise dosing procedures on site during and after dosing. This can also be delegated to a Sub-Investigator.

IMP and dosing

A temperature control of the refrigerator/room where the IMP is stored will be performed before any IMP is given to any study subjects. Preferably a pharmacy will handle this up to the time of administration.

Before dispensing the IMP to a subject, the staff will verify the subject’s identity to ensure that IMP is dispensed/administered to the correct individual. IMP will be dispensed/administered in accordance with the protocol and/or any other study specific requirements.

Before the IMP is dispensed/administered to the subject, a second member of the study team will check that the correct quantity/batch/dose etc. has been prepared, and that the IMP is administered to the right subject. This will be documented on the IMP source documents for the specific study.

When relevant, dose increases will proceed with caution, and there must be an adequate period of observation between the administration of the IMP to the first, second and subsequent subjects in a cohort to observe and interpret reactions and adverse events. The duration of the interval of observation must be justified and will depend on the properties of the product and the data available, including non-clinical PK and PD.

Administration in the next dose cohort must not occur before participants in the previous dose cohort have been treated and data/results from those participants are reviewed in accordance with the protocol. The decision to proceed to the next cohort will be discussed with sponsor when relevant, and should be documented.

Study population

The study team must ensure that study subjects are correctly identified and that their medical history is thrustworthy (checked with their primary doctor, “fastlege”). The financial compensation to study subjects entering a trial must be reasonable and is not expected to match a day’s salary at work. It should be approved by the Ethics Committee.

The study protocol will define the inclusion/exclusion criteria for the study.

Monitoring of adverse events/reactions

The trial protocol shall provide a specific plan for monitoring of adverse events or adverse reactions. The mode of action of the IMP, findings in the non-clinical toxicity studies and, particularly for FIH, any anticipated responses, will be used to identify likely adverse events. Minimum safety and tolerability measurements shall comprise physical examination, cardiac-pulmonarymonitoring including vital signs, clinical laboratory parameters at pre-dose and relevant post-dose time points. The data should be compared with screening data.

All clinical staff must be trained to identify adverse reactions and how to respond to those or any other adverse events. A rationale for the length of the monitoring period and the nature of monitoring within, and if deemed appropriate outside, the EPCTU must be provided in the protocol.

Participation in the specific trial must for each study subject be recorded in the medical journal (and in the subject’s “kjernejournal”, in which it is to be deleted after the study follow up period). In addition, they must all be provided with a contact telephone number to call if there should be questions related to their study participation.

The protocol or referenced document should include a plan for prompt communication of serious adverse events (SAEs) and suspected unexpected serious adverse reactions (SUSARs), between trial subjects, staff and the sponsor.

In the case of emerging safety issues, i.e. an SAE, the investigators must inform the sponsor and participants as soon as possible, and at least prior to any planned next dosing.

Stopping rules

The protocol must define stopping rules for the cohort and study, such as processes and responsibilities for making decisions about dosing of subjects, dose escalation and stopping the cohort or study.

The general study procedures in NorCRIN for close-out must be followed.

• Principal Investigator (PI) Site Risk Evaluation Checklist prior to study initiation - Template