Overview

Various study forms (logs, templates etc.) are being used at Clinical Trial Sites in order to facilitate the conduct of Clinical Trials and to properly document actions taken. All these documents are a part of Investigator Site File (a binder of trial related documentation) and Pharmacy File (a binder of documentation related to Investigational Medicinal Product; mainly used in Clinical Trials where there are blinded and unblinded Site teams with respect to study treatment received by subjects).

Study forms are carefully designed by clinical research project teams during start-up of the Clinical Trial and modified accordingly throughout the trial on ongoing basis as required.

Data collected on the study forms are subject to ongoing review during regular monitoring visits as well as during Site audits and inspections.

Aim

This article aims to briefly describe the types and purpose of study forms used at Clinical Trial Sites.

Process

All study forms shall be created and maintained respecting Good Documentation and Good Clinical Practices.

Typical essential elements of each study form are:

1. Name of the form
2. Clinical Trial information (protocol name and number etc.)
3. Site related information (fillable or pre-printed information on Site number, address, Principal Investigator name etc.)
4. Properly populated headers and footers (including trial related information, document version and date, pagination)
5. Fields to enter information relevant to the purpose of the form
6. Date and signature fields, as applicable.

Below are the most common study forms used in Clinical Trials.

Delegation of Authority Log

(other names are: Delegation of Responsibility Log, Site Delegation Log)

Purpose & use: to document Principal Investigator’s delegation of trial related responsibilities to Site study team. Its completion starts at Site Initiation Visit and it is handled on ongoing basis during the trial and is finalised at the Close-out Visit. Information collected on this form is an essential part of Site audit/inspection readiness as it allows to check delegated versus actual performed tasks in Clinical Trial.

Typical information to be collected: defined list of all trial responsibilities, composition of Site study team with full names, study roles (e.g., Principal Investigator, Sub-Investigator, Study Coordinator, Study Nurse, Pharmacist etc.) and assigned responsibilities. Start and stop dates of Site team’s involvement are indicated. Each task delegation and any changes are dated/signed by Principal Investigator and each staff member dates/signs the form as well.

Site Training Log

Purpose & use: to document all performed Site staff training.

Typical information to be collected: training dates, training topics (including the description of training materials used), Trainee and Trainer names, their study roles and corresponding signatures confirming performed training.

Site Visit Log

Purpose & use: to identify type of visit to Clinical Trial Site and document visit attendees. Its completion usually starts at Site Initiation Visit (sometimes it is also used to document Site Selection Visits) and it is handled on ongoing basis during the trial and is finalised at the Close-out Visit.

Typical information to be collected: visit dates, purpose (type) of the visit, names, and signatures of Clinical Research Organisation and/or Sponsor attendees, names, and signatures of Clinical Trial Site attendees.

Source Data Location Log

Purpose & use: to document all types of Source Documents and direct location of their storage. Any changes to location of Source Documents should be documented on a properly amended log.

Typical information to be collected: Source Data category (e.g., Informed Consent Process, Medical History, Laboratory Test results etc.), type of source document (e.g., Informed Consent Form, Study Medical Charts/Diaries, Laboratory Reports etc.), physical location (e.g., Subject Paper Binder, Electronical Medical Records etc.).

Informed Consent (Assent) Form Log

Purpose & use: to document Informed Consent (Assent) Forms used in Clinical Trial and to track their signature by subjects. Usually, this form captures information on  Site and Subject levels.

Typical information to be collected:

For Site level: version and date of Informed Consent (Assent) Form, language of ICF, Ethics Committee ICF submission and approval dates, date at which each approved ICF is considered to be implemented at Site.

For Subject level: version and date of Informed Consent (Assent) Form, date of ICF signing by subjects, verification of ICF signature by Clinical Research Associate (date when CRA has checked ICF during monitoring visit).

Subject Pre-Screening Log

Purpose & use: this is an optional log used in the studies where pre-screening (preliminary identification) of subjects is foreseen by the Clinical Trial Protocol. This log is an indicator of Site recruitment efforts even before the first subject is screened in the study.

Typical information to be collected: dates of pre-screening, eligibility of subjects to proceed with selection into the study, reason(s) for pre-screening failure (non-eligibility).

Subject Screening and Enrolment Log

Purpose & use: this is a main form to document subject screening and enrolment.

Typical information to be collected: subject screening dates, subject assigned screening numbers, enrolment (randomisation) dates, eligibility of subjects, reason(s) for screening failure (non-eligibility).

Subject Identification Log

Purpose & use: this form is completed for all subjects that have signed Informed Consent (Assent) Forms and it contains all personal subject information and should never be sent outside the Site nor filed in Trial Master File. This form is exclusively used at Site in order to identify each subject, link them to assigned screening numbers and keep in touch with subjects preventing potential lost to follow-up situations.

Typical information to be collected: subject full name, gender, full date of birth, screening date, screening number, subject’s home address and phone number.

Investigational Medicinal Product (IMP) Accountability Log

Purpose & use: to document the process of assignment, dispensation, and accountability of IMP/Medical Devices, their re-labeling/re-call (if applicable), return and destruction. Concomitant Medications (if provided in the trial) are tracked in the same manner in a separate Concomitant Medication Accountability Log. Usually, this form captures information on  Site and Subject levels.

Typical information to be collected:

For Site level: IMP/Medical Device receipt date, kit number, batch number, expiration date, date dispensed to subject, date returned by subject, date returned or destroyed, corresponding verifications of Site staff and CRA.

For Subject level: IMP/Medical Device kit and batch number, date dispensed to subject and quantity of units dispensed, date returned by subject and quantity of units returned, corresponding verifications of Site staff and CRA.

Site Temperature Monitoring Log

Purpose & use: to document temperature storage monitoring of IMP/Medical Devices/Concomitant Medications/laboratory specimens at Site. These logs are maintained and checked on ongoing basis based on corresponding handling manuals. They contain information critical to the safety of subjects as it is important that allowed temperature storage conditions are kept and any excursions are promptly identified, reviewed, and prevented.

Typical information to be collected: temperature monitoring device ID (serial number), storage location, allowed temperature range, refrigerator/freezer IDs, dates of temperature monitoring, temperature measurements on a particular date and time (including actual temperature reading, minimum and maximum temperatures since the last measurement), verification of entries by Site staff.

Biological Specimen Tracking Log

Purpose & use: to document movements of collected samples from Site to Central Laboratory (if applicable). Usually, this form is used to track frozen samples (e.g., for pharmacokinetics analyses) from the moment of their collection at Site and up till the moment they are shipped to designated Central Laboratory.

Typical information to be collected: visit types at which sample collection was performed, sample types (e.g., primary and back-up), date and time of sample collected, dates of sample shipment from Site, courier airway bill tracking number, verification of entries by Site staff.

Serious Adverse Event (SAE) Report Form

Purpose & use: to document details of SAEs occurred at Site from the moment of Site awareness until their “closure” (no more actions required).

Typical information to be collected: date and time of Site awareness of SAE, SAE details (diagnosis if available, start/end dates and times, classification of SAE type as per Good Clinical Practice, subject information, medical and concomitant medication history, event description, study drug information, actions taken as a result of SAE, relationship of SAE to study drug, outcome of SAE etc.), reporting Site staff’s date, time, and signature.

Pregnancy Report Form

Purpose & use: to document the occurrence and outcomes of pregnancy in study subjects or partners of study subjects from the moment of Site awareness until their “closure” (no more actions required).

Typical information to be collected: date and time of Site awareness of pregnancy and its details, medications taken at the time of pregnancy awareness (including study drug), medical history, pregnancy outcome etc.

Carpathian Research Group capabilities

CRG as a CRO has supported multiple Sponsors in creation and review of various study forms. We can utilise our profound expertise in order to create/review any specific study form tailored to the Sponsor’s trial related needs.

Information on all other Clinical Trial services that we provide could be found at www.crg.global

You can contact us at info@crg.global

Overview

According to regulations it is required that all Parties conducting particular Clinical Trial are legally bound with contractual arrangements (agreements).

There are various agreements between the Parties involved in Clinical Trials, but one of the most important is a Clinical Trial Agreement (hereinafter referred to as “CTA”).

CTA is a legally binding agreement, approved and signed by all applicable Parties, that manages the relationship between a Sponsor, Investigational Site (hereinafter simply referred to as “Site”), and Investigational Team (e.g., Principal Investigator, Sub-Investigator, Study Coordinator etc.), and outline each Party’s responsibilities and obligations for the Clinical Trial.

CTA should be fully executed the latest at the moment of Site Initiation Visit and not doing so while completing Clinical Trial related activities (especially Subjects’ recruitment) will be a serious violation which could have legal and regulatory consequences.

Aim

This article aims to briefly introduce the process of CTA execution (from the moment of template creation until its signing by all Parties).

Process

In general, the process of CTA execution can be broken down into the following steps which are later described in more detail:

1. Creation and approval of CTA template
2. Review & negotiation of CTA between all applicable Parties
3. Signing the CTA by all applicable Parties.

In the course of Clinical Trial there might be situations requiring changes/modifications to initial fully signed CTA, in such cases a CTA amendment is usually being created and signed in written.

Step I: Creation and approval of CTA template

This step typically includes:

• Creation of CTA template from the scratch (if not available)
• Agreement on the use of either Sponsor’s or Contract Research Organisation’s (CRO) available CTA template (in some cases Site may utilise their own CTA template)
• Adaptation of agreed CTA template to the country-specific and Clinical Trial Protocol requirements, including making it multi-lingual (e.g., English-Ukrainian).

Depending on the signatory Parties CTAs could be of the following types (non-exhaustive list):

• Site – Sponsor and/or CRO
• Investigator (or Sub-Investigator or Study Coordinator) – Sponsor and/or CRO
• Site – Investigator – Sponsor and/or CRO.

Below is a non-exhaustive list of important information/topics that need to be covered in CTA template:

1. Number of CTA, if applicable (for referencing and other purposes)
2. Effective Date of the CTA (explicit information from which date the CTA will be considered as legally binding for all signatory Parties)
3. Information on contracting Party (e.g., name, type of legal entity, legal address, tax ID, etc.)
4. Clinical Trial Protocol title and number
5. If CRO is a signatory to CTA then information on how Sponsor authorised CRO to manage Clinical Trial (e.g., on the basis of corresponding Power of Attorney)
6. Purpose of CTA
7. Functions, rights, and obligations in a particular Clinical Trial of each Party to CTA, including location(s) of Clinical Trial conduct
8. Information on provided Investigational Medicinal Product/Medical Device and its handling up to return or destruction (for “Clinical Trial” purposes only)
9. Information on provided Clinical Trial equipment (if applicable) & materials and their handling up to return or destruction (for “Clinical Trial” purposes only). In case Site uses their own equipment for Clinical Trial then it should be stated that this equipment should be properly maintained, calibrated and that the documentation confirming this should be available
10. Requirements of laws, regulations on Clinical Trial conduct and Data Privacy protection including applicable references
11. Important obligations on direct access to Clinical Trial source documents, handling of protocol deviations, reporting of safety events etc.
12. Obligations on receipt of all necessary Clinical Trial authorisations and ongoing regulatory reporting/notifications
13. Obligations on Clinical Trial related insurance
14. Obligations to allow inspection/auditing of Clinical Trial related activities at Site
15. Obligations on handling of Clinical Trial data (e.g., Case Report Forms), including timelines for data entry and responding to queries, if any
16. Obligations on handling Subject Clinical Trial files (binders) and Investigator Site Files, including Pharmacy Files as applicable
17. Confidentiality provisions, Intellectual Property and Publications requirements
18. Indemnity and limitations of Liability
19. Term of agreement and termination considerations (including due to cancellation/discontinuation of the Clinical Trial)
20. Site budget (including per Subject fees, Site set-up & archiving fees, fees for procedures etc)
21. Payment considerations (currency, frequency, timelines, taxation, commissions & withholding if any) and banking details
22. Contact details for Notices and how they will be transmitted (e.g., via regular mail, e-mail etc)
23. Force majeure provisions
24. Place of jurisdiction and applicable governing law

25.  Statement on prevailing language (if the CTA is multi-lingual)

26.  Statement on how changes/modifications to the text of CTA will be processed

27.  Statement on what provisions will survive the termination of CTA (if any) and for which duration

28.  Signature requirements and applicable Signature fields.

Step II: Review & negotiation of CTA between all applicable Parties

As soon as CTA template is prepared and approved it is being sent to Site for filling of required information (e.g., Site name, addresses, contact persons, banking details), content review and acceptance. Legal Departments of each Party (as applicable) are heavily involved in this process.

Usually, Principal Investigator is a recipient of all applicable CTAs and acts as a facilitator in the process of review and negotiation of CTAs from the Site’s end. On the other hand, CRO is usually acting as a CTA facilitator between Site and Sponsor.

Rounds of review & negotiation last until the moment when CTA text is acceptable for all Parties and could proceed to sign-off.

Step III: Signing the CTA by all applicable Parties

CTAs may be signed wet-ink or electronically (e.g., using DocuSign) depending on what was agreed within the text of CTA.

If wet-ink signed the Parties exchange the original counterparts in an agreed consequent manner until all required Parties will put their signature. In such cases the CTA is executed is several counterparts which are equal to the quantity of signatory Parties, so each of them receives their signed original copy.

The use of electronic signatures greatly facilitates the signing of CTAs and the duration of the period between final CTA text and its full execution.  

Carpathian Research Group capabilities

CRG as a CRO has supported multiple Sponsors in creation, review, negotiation & execution of CTAs for the smooth set-up and initiation of Clinical Trial Sites.

Information on all other Clinical Trial services that we provide could be found at www.crg.global

You can contact us at info@crg.global

Overview

Nowadays the majority of Clinical Trials are multi-national involving various countries, so the main (“master”, typically English) versions of Study Materials should be adapted as per country-specific requirements in order for Sponsor to obtain trial authorisation from Regulatory Authorities and Ethics Committees.

Study Materials are covered in our article Study Materials Development and Review Service

Aim

This article aims to briefly introduce the process of Study Materials’ adaptation to satisfy country-specific requirements.

Process

In most of cases the following Study documentation requires country-specific adaptation:

• Informed Consent Forms for subjects to document their agreement to participate in a given Clinical Trial
• Subject Emergency Cards (if used) containing essential Clinical Trial information (Sponsor name, protocol title, general information on the Investigational Medicinal Product etc.) along with contact details of Investigator and Sponsor in case of emergency situations
• Scales and Questionnaires (if used) aiming at collection of information necessary to analyse various aspects of subjects’ participation in a given Clinical Trial
• Subjects’ Recruitment materials, if used (including advertisements)
• Investigational Medicinal Product Labels which will be affixed to the Study Drug in a given Clinical Trial
• Clinical Trial Insurance documentation for participating subjects
• Study Plans (e.g., Project Management Plan, Study Start-up Plan, Clinical Monitoring Plan, Recruitment Plan etc.).

All Study documentation being provided to subjects should always be in language understandable to clinical trial participants , therefore it should be appropriately translated to all official languages in the particular country and included into the submission dossier for Regulatory Authorities and Ethics Committees review before they can grant Clinical Trial Authorisation.

Investigational Medicinal Product Labels are always submitted for Regulatory Authority’s review and used in official language of the country in which a given Clinical Trial is planned to be conducted.

Other documentation mentioned in the above list can be used in English or be bi-lingual (English + official language of the country in which Clinical Trial is to be conducted).

Below is a non-exhaustive list of applicable actions which are performed in order to ensure that Study documentation is compliant with country-specific requirements:

1. Check that documentation is in line with country-specific legislation and regulations governing the conduct of Clinical Trials (both with respect to content and document availability)
2. Check that documentation is accurately identifying the study Sponsor (e.g., name and address, contact details etc.)
3. Check that the Study title is in accordance with the Clinical Study Protocol, and its identification number
4. Check if Investigator’s and Institution’s name and address are accurately specified or there are allocated fields to enter this information (e.g., during Informed Consent Process)
5. Check that Regulatory Authority, Ethics Committee names and approval status are accurately specified
6. Check that Clinical Trial Insurance information (e.g., company name, insurance agreement/policy number, contact details or responsible person) is accurately specified
7. Check that emergency contact details of Clinical Trial Site are specified
8. Check that documentation (e.g., Informed Consent Form) has appropriate signature fields for subject, his/her legally authorised representative (if applicable), impartial witness (if applicable); and for responsible Investigator obtaining Informed Consent Form
9. Check that all document’s headers and footers contain accurate Clinical Trial specific information, type of the document itself, as well as appropriate versioning, dating and pagination
10. Check that country-specific requirements for Data Privacy protection are clearly specified in applicable documentation
11. Check that country-specific requirements for handling of biological samples (e.g., blood, urine, tissue samples etc.), including their exportation abroad with further analysing in Central Laboratory are clearly specified in applicable documentation
12. Check that country-specific requirements for managing subject’s complaints and appeals with regards to Clinical Trial participation are clearly specified in applicable documentation
13. Check that Investigational Medicinal Product Labels clearly specify manufacturer, Clinical Trial specific information, pharmaceutical dosage form, route of administration, quantity of dosage units, strength/potency, batch and/or code number to identify the contents and packaging operation, directions for use, specification “For clinical trial use only” etc.

During the adaptation process the clear and proactive communication between Contract Research Organisation and Sponsor ensures that the process is executed smoothly and reduces the amount of potential deficiency letters received from Regulatory Authorities and Ethics Committees.

Only approved by Sponsor English country-specific versions of Study documentation are sent for corresponding translation for subsequent use in a given Clinical Trial.

Carpathian Research Group capabilities

CRG as a CRO has a proven track record of country-specific adaptations of Study documentation leading to Clinical Trial authorisations and having no documentation-related findings during audits & inspections.

Information on all other Clinical Trial services that we provide could be found at www.crg.global

You can contact us at info@crg.global

Overview

Quality Risk Management (QRM) is an integral part of the corporate Quality Management System. Effective QRM is fundamental to ensuring the protection of human Subjects participating in Clinical Trials and fundamental to reliability of Clinical Trial results.

QRM helps to:

• efficiently manage business operations
• preserve the Resources that would otherwise be consumed on corrective actions and rework
• avoid disruptions to delivering the business objectives.

Aim

This article aims to briefly introduce the risk assessment process as an essential part of successful QRM.

Process

General guidance on risk management exists from multiple sources. As a discipline, risk management is described in academic settings, in other industries, and through standards. Commonly referenced quality standards such as ICH Q9, International Organisation for Standardisation (ISO) 31000, and ICH E6 provide different perspectives and scopes in risk management best practices.

Risk Assessment is a systematic process of organising information to support a risk decision to be made within a risk management process. It consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards

It is commonly understood that risk is defined as the combination of the probability of occurrence of harm and the severity of that harm.

As an aid to clearly defining the risk(s) for risk assessment purposes, four fundamental questions are used at CRG:

1. What might go wrong?
2. What is the probability (likelihood) it will go wrong?
3. What are the consequences (severity or impact)?
4. How easily the issue can be detected (detectability)?

Risk assessment helps to understand risks, their causes, consequences, probabilities, and ability to detect them with enough time for effective mitigation, either with existing controls or with launching contingency plan(s).

The purpose of risk assessment is to provide information and analysis to make informed decisions.

Hazard identification

Hazard identification is a systematic use of information to identify hazards referring to the risk question or problem description. Information can include historical data, theoretical analysis, informed opinions, and the concerns of stakeholders. Hazard identification addresses the “What might go wrong?” question, including identifying the possible consequences.

In Clinical Trials CRG Project Team focuses on participating Subjects’ safety and rights, data quality and reliability, overall study integrity including compliance with applicable laws and regulations, study timelines and costs.

The above-mentioned Subjects’ safety and rights, data quality and reliability are often referred as critical data and processes.

The risk to participating Subjects’ safety is considered as the increased risk arising from the clinical research activity as opposed to the baseline level of risk arising from normal (routine) clinical practice.

The following Risk Sources should be considered in Clinical Trials (non-exhaustive list):

• Therapeutic indication and consequently the type and number of Adverse Events and Serious Adverse Events per Subject, severity of disease and its prognosis, ease, or difficulty to find, enroll and retain Subjects for the duration defined in the study protocol, possible comorbidities that may affect recruitment, incidence and prevalence of the disease, disease seasonal patterns, etc.
• Clinical Trial Protocol, namely, its complexity, fit to the country-specific healthcare environment, number of visits, number of procedures per visit, the length of follow-up, comparators or standard of care requirements, equipment expected to be in place, experience in working with the equipment, central and local lab involvement, etc.
• Subject population, such as recruiting in-patients versus out-patients, vulnerable Subjects’ populations, typical Subjects’ profiles, etc.
• Geography, e.g., countries with a high Clinical Trial experience versus those with a limited experience, distances (thus, travel costs and inconveniences) of participants to get to Clinical Trial Site(s), normal (routine) clinical practice and standard of care in each participating country, logistics of supplies, etc.
• Investigators, namely, their interest, qualifications, location, cooperativeness, time limitations, importance (Key Opinion Leaders), business hours and availability, commitment for the whole study duration, teams, and back-ups, etc.
• Data collection and reliability, e.g., type of the Case Report Forms, monitoring strategy (on-site, remote, centralised, combined), Source Data Verification percentage, data critical for statistical analysis and adequate source data verification decision, etc.
• Investigational Medicinal Product / Medical Device, namely, the phase of development, established safety profile, potential Regulatory limitations to obtain approvals, required study reporting, specific instructions related to study drug / device handling, etc. 
• General study set-up, e.g., the number of Third-Party Vendors, logistics, timelines, agreed and documented delegated roles and responsibilities split between CRG and involved External Parties, collaboration model, clear definition of the scope, agreed risk-acceptance criteria, personnel availability, and qualifications, etc.
• Timelines and budget, e.g., whether the timelines are realistic and supported by available intelligence data, whether the budget is sufficient to cover the study costs, etc.

Risk analysis

Risk analysis is the estimation of the risk associated with the identified hazards. It is the qualitative or quantitative process of linking the likelihood of occurrence and severity of harms. The ability to detect the harm (detectability) also factors in the estimation of risk.

Root cause analysis could be used to retrospectively identify the root causes of failure. Primary and secondary causes may be identified using various methodologies (e.g., Five Why’s method). This methodology is recommended to analyse audit findings and issues that have occurred previously.

Failure Modes and Effects Analysis (FMEA), could be used to prospectively analyse potential failures and associated causes, prioritise risks depending on their impact, probability, and detectability, and decide on measures to reduce the risks. The Risk Priority Number (RPN) used in FMEA indicates the attention the QRM team should pay to each risk; the higher RPN, the higher attention and need to treat the risk.

The use of Lessons Learned is important in Risk analysis.

Risk evaluation

Risk evaluation compares the identified and analysed risk against given risk criteria. Risk evaluations consider the strength of evidence for all four of the fundamental questions defined above. In doing an effective risk assessment, the robustness of the data set is important because it determines the quality of the output. Revealing assumptions and reasonable sources of uncertainty will enhance confidence in this output and/or help identify its limitations.

Uncertainty is due to a combination of incomplete knowledge about a process and its expected or unexpected variability. Typical sources of uncertainty include gaps in knowledge, gaps in process understanding, sources of harm (e.g., failure modes of a process, sources of variability), and probability of detection of problems.

The output of a risk assessment is either a quantitative estimate of risk or a qualitative description of a range of risk. When risk is expressed quantitatively, a numerical probability is used. Alternatively, risk can be expressed using qualitative descriptors, such as “high”, “medium”, or “low”, which should be defined in as much detail as possible.

Carpathian Research Group capabilities

CRG as a CRO promotes and encourages all of its staff to exercise ‘‘risk-based thinking” in execution of their job duties, so risks to quality could be proactively identified and prevented. We have extensive experience performing risk assessment in Clinical Trials and can greatly assist Sponsors in proper risk assessments for the benefit of smooth execution of Clinical Trials.

Information on all other Clinical Trial services that we provide could be found at www.crg.global

Overview

Clinical Site Audits are performed by Sponsors as part of quality assurance implementation in the Clinical Study (Trial).

The audit is independent of and separate from routine monitoring or other quality control functions implemented in the Clinical Study. It is performed to evaluate study conduct and compliance with protocol, Controlled Documents (CDs), Good Clinical Practice (GCP), and the applicable regulatory requirements.

Aim

This article aims to briefly introduce the process of Clinical Site Audits which includes preparation, conducting, reporting, and follow up.

Process

Clinical Trial Sites to be audited are determined as a result of Quality Risk Management process based on ICH Q9 on Quality Risk Management, Clinical Study Project, and Sponsor-specific requirements.

Once the Site Audit date is scheduled, the Auditor sends a confirmation e-mail to the PI and other relevant Site staff including the Site Audit agenda; this should include a list of documents to be prepared for review during the Site Audit along with the names of Site staff required during the Site Audit.

On the Audit Day the Auditor should inform the Principal Investigator (PI) of arrival and hold an opening meeting. Depending on site staff availability it might include (or performed later) interview with PI and/or relevant Site Staff to discuss study processes.

The following should be checked during the Site Audit (non-exhaustive list):

• Facilities where study subjects are seen by visiting (touring) them (e.g., exam rooms for subject evaluation and treatment, laboratory and any special testing areas, pharmacy (if applicable), any satellite Sites (if applicable), data entry area etc.
• Storage area and conditions for Investigational Medical Product (IMP) (includes Investigational Medical Device (IMD), ConMeds and/or other study supplies/materials)
• Available equipment to be used in Clinical Study (including validity check for calibration/maintenance documentation).

Auditor performs random and for cause checks of the following (non-exhaustive list):

• Signed Informed Consent Forms
• Source Data Verification of Subjects’ Study Visits and related documentation
• Reported Protocol Deviations
• Reported Safety Events
• IMP/IMD/ConMed accountability records and storage conditions including reported temperature excursions
• Study supplies handling (such as laboratory kits, equipment etc.)
• Investigator Site File completeness.

The Auditor should classify the Audit findings with respect to Clinical Study Protocol, other study documents, regulations, guidelines, or Controlled Documents.

The Auditor should record findings and provide the PI and Site Staff with the opportunity to correct minor problems, where possible. The Auditor should clearly explain all deficiencies found. 

The Auditor should be flexible to a reasonable extent, and re-prioritize activities as needed without compromising the purpose of the Site Audit. Modification of the Site Audit agenda due to organizational reasons is allowed if agreed upon with the PI and Site Staff during the opening meeting.

The Auditor should conduct a closing meeting with the PI and Site Staff to present Site Audit findings, to ensure clear communication of the results. The Site should be informed that their responsible Clinical Research Associate will support Site in resolution of Audit related Action Item(s) and Corrective Action Preventive Action (CAPA) if applicable.

The Auditor should prepare the Site Audit Report.

If during Site Audit any diverging opinions on identified findings were raised – those are to be clearly reflected in Site Audit Report.

The Site Audit Report is a confidential document that is to be distributed only to the recipients specified in the Site Audit Specification.

Clinical Project Manager (PM) is responsible to provide the Auditor with completed Site Audit Follow-up Action Plan containing responses to Site Audit findings as well as a precise description of root causes, Action Items and CAPA (if applicable).

After Site Audit Follow-up Action Plan is agreed, the Auditor should issue the Site Audit Certificate and send it to clinical PM who is responsible for its further distribution to Site.

Follow-up of the implementation of actions documented in Site Audit Follow-up Action Plan is the responsibility of the clinical PM and his/her Project Team.

Carpathian Research Group capabilities

CRG as a CRO has experience in conducting Site Audit(s) to verify Site’s compliance with the Clinical Study Protocol, requirements of International Council on Harmonization Guideline on Good Clinical Practice (ICH-GCP), Food and Drug Administration (FDA) Code of Federal Regulations (CFR), European Union (EU) Directives/Regulations; and other applicable regional and local regulations, and/or any Sponsor/CRG specific requirements and Controlled Documents as applicable.

Information on all other Clinical Trial services that we provide could be found at www.crg.global

Overview

Project Management activities are essentially required to start-up, execute, and complete a particular Clinical Trial (Study) project in compliance with study protocol, other Sponsor’s requirements and GxP guidelines (e.g., Good Clinical Practice, Good Manufacturing Practice, Good Laboratory Practice etc.).

Aim

This article aims to briefly describe Carpathian Research Group (CRG) Project Management activities in Clinical Trials.

Process

Below are relevant definitions for better understanding:

• Project – is a temporary and unique endeavor designed to produce a product, service, or result
• Project Management – the use of specific knowledge, skills, tools, and techniques to deliver the value and achieve goals within the given constraints (of which primary are scope, time, and budget)
• Subject Matter Experts (SMEs) – individuals with specific expertise and responsibility in a particular professional area or field

Project Management Team (Project Director, Clinical Project Manager, and Clinical Project Leader) has full control of a given Clinical Study to ensure participating Subjects’ safety, optimize its resourcing, accelerate its delivery, reduce cost, preserve, and enhance its scientific/medical merit, and ensure highest data quality.

To achieve the above Project Management Team is always uniformly delivering the Clinical Studies within the agreed time, budget, and quality, with support from other Project Team members and other SMEs as per business need.

As Project Management is evidence based and data driven, every decision is made based on scientifically supported facts. The Project Management Team uses all available internal and external systems to collect and analyze all necessary data and performance indicators in order to support and improve project delivery to the highest.

Below are key elements with regards to Project Management:

1. Project Team and Communications

It is main responsibility of Clinical Project Manager to ensure that adequate Resources are available to the Clinical Study project.

Clinical Project Manager is a key contact person for External Parties (Sponsor and applicable Third Party Vendors) and internal Project Team.

Internal Project Team apart from Clinical Project Manager itself, consists of such roles (non-exhaustive list):

• Project Director – usually involved in more complex Clinical Study projects as a support to Clinical Project Manager
• Clinical Project Leader(s) – leading the teams of Clinical Research Associate(s) and Clinical Trial Assistant(s). In Clinical Studies involving blinding of Study Drug there could be blinded and unblinded Clinical Project Leaders leading respective Clinical Research Associate(s) and Clinical Trial Assistant(s)
• Clinical Research Associate(s) and Clinical Trial Assistant(s) – main roles responsible for management of Clinical Study Sites
• Regulatory Manager – as part of Regulatory Affairs supporting all necessary related activities
• Project Coordinator(s) – providing administrative and other support to Clinical Project Manager
• TMF Coordinator(s) – managing the Trial Master File and ensuring its inspection readiness at all times
• Logistic Coordinator(s) – providing logistical support to Clinical Project Manager and the rest of the Project Team as applicable.

Clinical Project Manager develops and maintains a separate standalone list of the Project Team members, their assigned roles and contact details and provides the list upon request.

In addition, Clinical Project Manager develops and maintains a separate standalone Project Communication Plan in order to ensure that Clinical Study project’s communications (including escalations pathways, if applicable) between all involved Parties are effective and consistent.

Careful consideration for Project Team composition and communications should be exercised in the clinical study projects having blinded and unblinded components. In such cases both Project Management and Communication Plans should clearly describe separation of tasks/communication lines between blinded and unblinded clinical study Project Teams and an additional Project Blinding Plan and Site Blinding Plan may need to be created for these purposes.

2. Project Scope of Work and Milestones

After project award a scope of work (responsibility matrix) is being agreed between CRG and Sponsor and is clearly documented in a corresponding Project Management Plan. The above scope of work also includes responsibilities of any project-specific Third Party Vendors.

Every Clinical Study project has project milestones. A milestone anticipates what the Clinical Study project is supposed to achieve at a pre-set date. It should describe a desired future situation.

Clinical Study projects milestones are linked with each other and follow a chronological pattern; therefor careful milestone planning should be considered in order to reach all project deliverables within the scope, budget, and time.

Typical project milestones include, but are not limited to:

• Project start – usually Sponsor defined date
• Dates for First and Last Pre-Study Site Selection Visit
• Site list approved – date at which Sponsor provides initial written list of Clinical Study Sites approved for study participation
• Database Go-Live – date at which Clinical Study database (e.g., Electronic Data Capture system) is live and Subjects’ data can be entered into it
• First Site Initiation Visit – date at which first Clinical Study Site is initiated (opened)
• Recruitment related milestones, such as: First Subject In (date at which first subject in the Clinical Study signs Informed Consent Form), First Subject Randomized (Dosed), Last Subject In (this is an end of study recruitment period), Last Subject Last Visit (date at which last subject in the Clinical Study performs last study visit as per study protocol)
• Database locked – date at which Clinical Study database is locked (“frozen”) and no more information can be entered into it
• Last Close-out Visit – date when the last Clinical Study Site had Close-out Visit
• Project end – date when all project deliverables have been achieved and the project can be considered as closed.

3. Project Documentation

A list of Controlled Documents (SOPs, Policies, Work Instructions, Manuals, Guidelines etc.) applicable to Clinical Study project is agreed between CRG, Sponsor and applicable Third Party Vendor(s) during project start-up phase and is clearly documented in corresponding Project Management Plan.

Clinical study Project Plans are developed to document the process of how the contracted project deliverables will be provided, and who has responsibilities for completing each related activity.

For more information refer to InfoCRG article on Study Materials Development:

https://www.linkedin.com/pulse/infocrgarticle-1study-materials-development-

4. Project Status Reports

Regular updates on the Clinical Project conduct should be reflected in the corresponding Project Status Reports.

The aim of these Reports is to provide (non-exhaustive list):

• Milestones’ achievement status
• Site related information (feasibility, study equipment/materials, initiation, monitoring, recruitment status etc.)
• Regulatory submissions/approval status
• Protocol deviations status
• Third Party Vendor Management status and updates (if any)
• Fulfilment of Key Performance Indicators (if implemented in the Clinical Study project)
• Clinical Study Site payments status
• Project issues, risks, and action items.

Frequency and delivery methods for Project Status Reports submission to Sponsor are documented in the corresponding Project Management Plan.

5. Project Training

Clinical Study project-specific training is provided to the Project Team to improve their level of understanding of the therapeutical (clinical), technical and/or operational aspects of the Clinical Study project. It is the ultimate responsibility of the CRG Clinical Project Manager or designee to ensure that the appropriate Clinical Study project-specific training is timely provided to the Project Team throughout the Clinical Study.

Clinical Study project-specific training may include, but is not limited to Clinical Study Protocol, therapeutic indication (area) of Clinical Study, study Project Plans, various Clinical Study project tools and guidelines, – all of the above is provided to the individual Project Team member according to defined role in Clinical Study project and should be completed prior to starting the associated Clinical Study project tasks.

6. Project Change

All project changes will be logged and evaluated for impact to the Clinical Study project scope, schedule, and cost. The Clinical PM in cooperation with the Project Director (if applicable) will recommend whether to incorporate the changes into a change order request immediately or hold the changes for a future change order release. All suggested changes to the Clinical Study project scope of work, tasks or defined deliverables will be sent to the Sponsor for review. The Clinical PM in cooperation with the Project Director (if applicable) should provide a detailed report of out-of-scope budgetary impact of any changes prior to implementation of the changes. The Sponsor should review and approve any changes prior to their implementation.

7. Project Risk Management

The objectives of the Clinical Study Project Risk Management are to decrease the probability and impact of the negative events in the Clinical Study project.

The evaluation of risks is being performed according to the corresponding severity/likelihood and detectability scales.

Clinical Study Project Risk Management (including risk identification, assessment, and review) should be documented in the corresponding Project Risk Management Plan (or any other Clinical Study Project Plan as per agreement with the Sponsor).

8. Project Quality

Maintaining consistent Clinical Study project quality is a key factor to a successful Clinical Study project delivery.

Depending on the agreed Clinical Study project scope of work the Quality Assurance for a particular Clinical Study could be CRG’s or Sponsor’s responsibility. All quality related responsibilities and activities should be clearly documented in the corresponding Clinical Study Project Plans.

In any case CRG QA is responsible for Quality Assurance of all CRG internal processes (e.g., Controlled Documents management, training, internal audit program and corrective and preventive action implementation, archiving etc.).

All inspections and audits of Clinical Study Sites should be handled as per applicable CRG’s and/or Sponsor’s Controlled Documentation.

9. Project Governance

Project governance is an “oversight function that is aligned with the organization’s governance model and encompasses the project life cycle” (according to Project Management Institute definition).

As per particular Sponsor’s requirement some Clinical Study projects may have an established project governance procedure and CRG should follow it as much as practically possible.

Typically, a project governance charter is being created and agreed between CRG and Sponsor. The aim of this charter is to specify the responsibilities of each participating Party with respect to the objectives of the Clinical Study, the achievement of Clinical Study project milestones, any financial issues, escalation of issues, key performance indicators, risk review etc.

Carpathian Research Group capabilities

CRG as a CRO has a high Project Management expertise tailored to specific participating Country requirements. With CRG support Sponsors can be sure that their projects will be delivered on time, within scope and agreed budget.

Information on all other Clinical Trial services that we provide could be found at www.crg.global

Overview

The vital part of each Clinical Trial conduct is management of Essential Documents.

According to established Good Clinical Practice (GCP) guidelines “Essential Documents are those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. These documents serve to demonstrate the compliance of the Investigator, Sponsor and Monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements.”.

The various Essential Documents are grouped in three sections according to the stage of the Clinical Trial during which they will normally be generated:

1. before the clinical phase of the trial commences,
2. during the clinical conduct of the trial, and
3. after completion or termination of the trial.

GCP provides descriptions of the purpose of each Essential Document, and whether it should be filed in either the Investigator/Institution or Sponsor files, or both.

Trial Master Files (either paper or electronic, hereinafter referred to as “(e)TMF”) should be established at the beginning of the trial, both at the Investigator/Institution’s Site (usually referred to as “Investigator Site File”) and at the Sponsor’s office. A final close-out of a trial can only be done when both Investigator/Institution and Sponsor files are reviewed and it is confirmed that all necessary documents are filed appropriately.

Aim

This article aims to briefly describe the management of Trial Master File in Clinical Trials.

Process

Essential Documents should be collected and filed in the (e)TMF according to:

• GCP
• Drug Information Association (DIA) TMF Reference Model
• Sponsor’s requirements
• Approved TMF Management Plan
• Regulatory requirements.

Essential Documents must be provided to the Sponsor and/or Regulatory Authorities representatives at first request. These documents must be always audit ready and available for review during the Clinical Trial conduct and within the defined by Sponsor/local Regulatory timelines archiving period.

The essential role in (e)TMF management of Clinical Trials lies within “TMF Coordinator” job role (at CRG it is a separate role, but in different companies it could be embedded into other clinical trial roles).

Typical responsibilities of TMF Coordinator are:

• Collection of Essential Documents for (e)TMF from Project Team members
• Renaming of Essential Documents according to TMF Naming Conventions specified in corresponding TMF Management Plan
• Timely submission of collected Essential Documents to (e)TMF:

1. by directly uploading them to electronic TMF or filing them to paper TMF
2. by separately sending them to the Sponsor/TPV’s TMF Specialist via previously approved TMF distribution list of e-mails/mailing addresses along with the corresponding completed transmittal forms.

In execution of the above responsibilities TMF Coordinator (blinded or unblinded, if applicable) closely cooperates with the rest of CRG Project Team.

(e)TMF Structure

Usually, the (e)TMF consists of the Trial File, Country File and Site Files:

• Trial File – documentation applicable to the trial level
• Country File – documentation applicable to the country level (in case more than one country participate in the Clinical Trial)
• Site File – documentation applicable to the site level, including Pharmacy File, if applicable.

The TMF Index is usually based on the DIA TMF Reference Model (version is agreed on a project-by-project basis). It is used to transmit final documents to their appropriate filing location and contains relevant information about TMF expectations for the Clinical Trial.

TMF Index according to the DIA TMF Reference Model is broken into several sections: Trial Management, Central Trial Documents, Regulatory, Investigational Review Board/Independent Ethics Committee and other Approvals, Site Management, Investigational Medicinal Product and Trial Supplies, Safety Reporting, Centralized Testing, Third Parties, Data Management, Statistics.

Depending on the activities being carried out, many Clinical Trials require additional documents not specifically mentioned, therefore the additional sections as part of the TMF Index might be included that will facilitate reconstructing and evaluating of the clinical trial conduct.

Filing of documents into (e)TMF

All responsible Clinical Trial Project Team members are required to ensure that the Essential Documents are submitted/uploaded to (e)TMF in a timely manner.

Essential Documents filed into (e)TMF should be checked prior to submission/uploading by applicable Project Team members, so they satisfy Good Documentation Practices.

Essential Documents should be checked against the next parameters (non-exhaustive list):

• Documents titled in compliance with the requirements of approved TMF Naming Conventions
• Version of document in line with the related SOPs/Work Instructions/Clinical Study Project Plans/applicable templates
• Document format – PDF is preferred document format for electronic TMF upload
• Document included in the correct section in a Transmittal Form for electronic TMF upload (if applicable)
• Originals or Certified Copies
• Translations if required and availability of corresponding Certificate of Translation Accuracy.

When a certain document is missing or is incomplete a “Note to File” Form should be completed, dated, and signed by the responsible Project Team member. Its purpose is to explain clearly and explicitly the reason of why the document is missing or is incomplete. It should be filed in (e)TMF replacing the missing document or clarifying any document-related issue(s).

Unblinded (e)TMF management

In case the Clinical Trial consists of blinded and unblinded components, at the beginning of the Clinical Trial unblinded Project Team is assigned. Unblinded Project Team is responsible to manage unblinded Essential Documents (these are usually related to Investigational Medicinal Products) and their filing to unblinded (e)TMF. Unblinded Essential Documents are located in corresponding Pharmacy File at Clinical Trial Sites. 

Unblinded Essential Documents are managed only by unblinded Project and Site Teams similarly to blinded Essential Documents and this should be clearly reflected in TMF Management Plan.

(e)TMF retention and archiving

The retention and/or destruction procedures will be agreed with the Sponsor or applicable Third Party Vendor and described in corresponding TMF Management Plan. The retention period is to be adhered to and in accordance with the current country laws and regulations.

Carpathian Research Group capabilities

CRG as a CRO has extensive experience in management of (e)TMF and with our expertise Sponsors could be confident on (e)TMF inspection/audit readiness at any moment of Clinical Trial lifecycle.

Information on all other Clinical Trial services that we provide could be found at www.crg.global

You can contact us at info@crg.global

A Clinical Trial can have multiple Third Party Vendors requiring effective oversight which can be challenging for Sponsors. The proper documentation proving continuous oversight must be available on Sponsor’s side which will ensure participating Subjects’ protection and Clinical Trial’s data integrity.

Challenges of oversight can be overcome through the effective implementation of vendor management plans, key performance indicators, master service agreements, and constant communications.

Aim

This article aims to briefly introduce the process of management of Third Party Vendors (TPVs) which includes their selection, qualification/re-qualification, contracting and oversight.

Process

Selection of proper TPV is essential for successful Clinical Trial conduct. All interactions with TPVs should follow the highest legal, professional, and ethical standards.

Proactive approach in identification of issues and the risk mitigation strategies should be developed in cooperation with TPVs.

TPV selection and the type of their qualification/re-qualification should be considered based on the conducted risk assessment, industry background check, previous experience of cooperation with this TPV (if applicable), etc.

Competitive bidding (sending the same request for proposal to several selected TPVs) is preferred during TPV selection process in a particular Clinical Trial, but the final decision about TPV selection remains with the Sponsor. 

Each TPV qualification/re-qualification is conducted under close supervision of Quality Assurance Department which can involve different Subject Matter Experts in the process of risk assessment, qualification, and evaluation of its results.

Quality Assurance Department is responsible for timely follow-up of all identified Action Items/Corrective and Preventive Actions (CAPA) detected during TPV qualification/re-qualification.

When included in the contracted scope of work for a particular Clinical Trial, the Project Management team should oversee the TPV activity and promptly report any issues to Quality Assurance Department.

At a Clinical Trial Project level, the Project Manager or designees should review key TPV documentation (e.g., operational manuals, quick reference guides, templates, and forms) for consistency with Clinical Trial Protocol requirements and Project-specific needs. Any inconsistencies should be clarified, appropriately documented, and timely resolved.

Project Manager or designees will create the appropriate TPV management plan for each particular TPV. The above plan will include at a minimum the TPV’s scope of work, oversight responsibility, specific Key Performance Indicators if applicable (including frequency of assessments), communication pathways.

Escalation pathways during business cooperation with TPVs should be clearly defined and agreed between all Parties within appropriate TPV management plan to allow the smooth execution of contracted services.

Carpathian Research Group capabilities

CRG as a CRO has extensive experience in management of different Third Party Vendors and selecting the most suitable ones for successful Clinical Trial execution.

Information on all other Clinical Trial services that we provide can be found at www.crg.global

You can contact us at info@crg.global

Overview

As per Good Clinical Practice (GCP) guideline “the purposes of trial monitoring are to verify that:

• a) The rights and well-being of human subjects are protected.
• b) The reported trial data are accurate, complete, and verifiable from source documents.
• c) The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).”.

Clinical Trial monitoring is achieved via conducting the monitoring visits to Clinical Trial Sites (hereinafter referred to as “Sites”) either face-to-face or remotely.

The visits are performed by monitors (Clinical Research Associates, CRAs).

According to GCP guideline:

• “a) Monitors should be appointed by the sponsor.
• b) Monitors should be appropriately trained and should have the scientific and/or clinical knowledge needed to monitor the trial adequately. A monitor’s qualifications should be documented.
• c) Monitors should be thoroughly familiar with the investigational product(s), the protocol, written informed consent form and any other written information to be provided to subjects, the sponsor’s SOPs, GCP, and the applicable regulatory requirement(s).”.

The Sponsor of each Clinical Trial is responsible to develop a systematic, prioritized, risk-based approach to monitoring Clinical Trials. 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).

Centralized monitoring is a remote evaluation of accumulating data, performed in a timely manner, supported by appropriately qualified and trained persons (e.g., data managers, biostatisticians). Centralized monitoring processes provide additional monitoring capabilities that can complement and reduce the extent and/or frequency of on-site monitoring and help distinguish between reliable data and potentially unreliable data.

Aim

This article aims to briefly introduce the monitoring, describe the types of monitoring visits of Sites in Clinical Trials, and focus on a Pre-Study Site Selection Visit as a starting point in the monitoring process.

Process

Depending on the timeframe (phase) in which each particular Clinical Trial Project is the following visits types are identified:

• Pre-Study Site Selection Visit (also known as Pre-Study Visit, Site Selection Visit, Site Qualification Visit)
• Site Initiation Visit
• Interim Monitoring Visit (also known as Routine Monitoring Visit)
• Close-out Visit.

Additionally, Co-Monitoring Visit(s) may be performed with the aim of either supporting the CRAs in their visit activities or assessing Site’s/CRAs’ adherence to Clinical Trial Protocol, GCP and other clinical research regulations. Co-Monitoring Visits are out of scope of this article.

Monitoring visits have typically one business day in duration, but depending on Clinical Trial complexity, amount of data to be reviewed and other factors their duration can be increased.

The main written documentation of each monitoring visit (irrespectively of its type) includes:

• Confirmation letter – a letter/e-mail sent to Site well in advance of planned monitoring visit and which includes the details and activities to be done during the visit
• Visit report – detailed description of all activities performed during the visit as well as all identified deficiencies, deviations, and action item(s)
• Follow-up letter – a letter/e-mail sent to Site after the visit has been conducted and which includes the details of all activities performed during the visit as well as all identified deficiencies, deviations, and action item(s).

All confirmation, follow-up letters and Site Initiation Visit Report (per GCP requirements) are to be properly stored in Investigator Site File located at Sites.

Pre-Study Site Selection Visit (PSSV)

This is the starting point of interactions between Sponsor/CRO and Clinical Trial Site. It is performed after the Site Identification & Feasibility process has been completed.

The PSSV is performed to ensure that:

1. A potential Principal Investigator (PI) is qualified and interested in conducting the clinical study
2. The PI’s Site has adequate facilities, and resources to properly complete all required study activities
3. Site has required pool of patients to complete enrollment.

Items to be reviewed/discussed may include, but are not limited to:

• Feasibility Questionnaire completed by Site
• Clinical Study Protocol/Synopsis and Clinical Study timelines
• Enrollment (recruitment) target, strategy, expectations, and availability of subject population
• Qualifications/ training, experience, interest and availability of the PI and Site Staff performing study related duties
• PI and Site Staff obligations, ICH-GCP / ISO 14155 guidelines (if applicable) and regulatory requirements
• Therapeutic area being investigated (including applicable standard of care)
• The PI’s/Site Staff’s regulatory inspection/audit experience, if any, and the outcome of the inspection/audit(s)
• IRB/IEC requirements, documentation, and approval timelines
• Site budget and execution of Clinical Trial Agreements
• Informed Consent Process and documentation requirements
• Source document and study record requirements, as well as Source Data definitions and Good Documentation Practice
• Monitoring visit process/schedule, PI and Site Staff availability, other competitive clinical trials with the same pathology run by Site
• The monitoring strategy including remote monitoring and remote Source Data Verification capacity and acceptance (if applicable)
• Electronic Data Capture (EDC) requirements, including vendor-specific experience, internet connectivity, and computer availability, if applicable
• Turn-around time for data entry and data query resolution
• Local country / Site-specific requirements for clinical study conduct (e.g., Site SOPs)
• Reporting and documenting safety events (e.g., Adverse Events, Serious Adverse Events, Adverse Events of Special Interest, SUSARs, pregnancy, study drug overdose etc.)
• Medical management of study subjects remotely, if appropriate
• Assessment of storage area and conditions for Investigational Medical Product (IMP) (includes Investigational Medical Device (IMD) and/or other study supplies/materials)
• IMP/IMD Accountability procedures (receipt, storage, dispensing, and record keeping)
• Laboratory sample handling procedures, including supplies, collection, and shipment.

During PSSV CRA ensures the adequacy of facilities where study subjects will be seen by visiting (touring) them (e.g., exam rooms for subject evaluation and treatment, laboratory and any special testing area, pharmacy (if applicable), any satellite sites (if applicable), working area for Site staff, data entry area etc.) CRA also ensures the adequacy of available equipment to be used in clinical study (including validity check for calibration/maintenance documentation).

As part of PSSV CRA requests/collects any required Site documentation which may include, but is not limited to:

• Confidentiality (Non-Disclosure) Agreement, if applicable
• Medical licenses (Institution and Site staff) and dated/signed Curriculum Vitae (CVs)
• Current GCP and ISO 14155 (if applicable) training certificates or certificates of relevant training(s) as listed on the corresponding CVs
• IRB/IEC membership list (roster), SOPs (if applicable) and statement of compliance
• Electronic Health Records related documentation, if used
• Completed dated/signed Project-specific forms and questionnaires required to qualify the Site, as applicable
• Local laboratory reference ranges, accreditation certificates and CV of Head of local laboratory if it will be used
• Dated/signed attendees log, Clinical Study Protocol, and Investigator Brochure acceptance pages.

The above documents may be collected as originals or copies, depending on Sponsor’s/country specific requirements.

On the basis of conducted PSSV and the review of all applicable documentation the Sponsor either approves Site’s participation in the given Clinical Trial or declines it.

If Site is approved CRA sends an appropriate Site Selection Letter and in case of disapproval – the appropriate Site Non-Selection Letter.

The above letters will thank PI and Site Staff for completion of Selection activities and will state the further actions to be completed (if Site is approved) or will explain the reason(s) for non-selection decision.

Carpathian Research Group capabilities

CRG as a CRO has extensive experience in conducting Pre-Study Site Selection Visits and choosing the most suitable Sites for successful Clinical Trial execution.

Information on all other Clinical Trial services that we provide could be found at www.crg.global

You can contact us at info@crg.global

Overview

Feasibility and Site identification are fundamental critical aspects of planning and executing successful Clinical Trials.

Feasibility and Site identification involves identifying potential Sites that meet the study’s eligibility criteria, based on factors such as patient population, Site capabilities, access to the required clinical infrastructure and personnel, regulatory requirements, logistical considerations, and appropriate locations where the Clinical Trial can be conducted.

Feasibility can be performed at 3 levels: Clinical Program Level (assesses the overall strategy of the set of Clinical Trials of a particular study drug/device), Clinical Study Level (assesses the strategy in a given Clinical Trial) and Site/Investigator Level.

Aim

This article aims to briefly describe the processes of Feasibility and Site identification at a Site/Investigator Level.

Process

To identify suitable Sites, Clinical Trial Sponsors and/or assigned Clinical Research Organizations (CROs) often use various tools and resources, including databases of potential Sites, previous experience with similar Clinical Trials, and recommendations from Investigators or Key Opinion Leaders (KOLs) in the relevant therapeutic area.

Once potential Sites have been identified, Sponsors/CROs utilize their agreed and documented procedures of contacting them and making necessary assessments. Usually, the starting point of further communication is the execution of Confidentiality (Non-Disclosure Agreement) between Sponsors/CROs and potential Sites, so that confidential Trial-related information & documents can be shared.  

Feasibility assessments are usually conducted in a form of distribution of corresponding feasibility questionnaire/survey with further Site interviewing and discussion of provided Site’s feedback.

Feasibility assessments aim to identify if Sites have the necessary capabilities and resources to conduct the Clinical Trial successfully according to the proposed design, timeline, and budget. Feasibility process also helps to determine the potential risks, challenges, and opportunities associated with Clinical Trial conduct and among other considers the Site infrastructure, patient recruitment potential, regulatory and ethical aspects, logistical setup etc. This information can be used to refine the study design and identify potential strategies for addressing any barriers that may arise during the Clinical Trial.

Below is the non-exhaustive list of aspects which are being assessed during Feasibility and Site Identification process:

1)    Clinical aspects: overall interest of Investigator in the research field, study population and actual number of patients seen by the Investigator per given time period (e.g., month/quarter/year); standard of care and readiness to accept background and comparative therapy, as well as level of training/knowledge for specific treatment tools and technology

2)    Site “demographics”: geographic location of the Site since it may influence patient’s access and availability of Sponsor/CRO to control Clinical Trial conduct. Evaluation of Site Staff’s experience, such as Primary Investigator, Sub-Investigator(s), Pharmacist(s), Nurse(s), Study Coordinator(s) and their proficiency in terms of Protocol related knowledge; assessing Site staff availability to conduct the Clinical Trial

3)    Recruitment and retention: evaluation of recruitment potential of Site (usually per month or per year) throughout the duration Clinical Trial. Identification of any conflicting studies that may influence patient recruitment. By gathering this information, a “less Sites – more patients” approach can be introduced for cost saving and quicker enrollment purposes by choosing the most prospective Sites  

4)    Regulatory & Ethical aspects: gathering of information on local requirements for obtaining Regulatory Authority’s and Ethics Committee’s Clinical Trial approvals, requirements for Trial documentation and translations (if any)

5)    Site infrastructure: adequate facilities that meet Protocol requirements and Good Clinical Practice standards. Clinical Trials have specific requirements related to study drug/device storage, processing of biological samples (e.g., refrigerated centrifuge etc.), necessary equipment to conduct trial-related procedures etc. It is important to assess Site’s capabilities related to such requirements, whether everything required is available at the Site or needs to be procured, whether there are Site staff members who have the relevant expertise to conduct these activities and use such equipment/tools. Most of Clinical Trials utilize electronic Case Report Forms (e-CRFs) and other electronic Trial systems and it is important to assess whether Sites have capabilities to use electronic data capture and their familiarity with such tools. It will also be assessed if Site has capabilities to provide enough working space for Clinical Trial Monitoring procedures as well as for hosting Regulatory Inspection(s) and Site Audit(s)

6)    Quality: one more aspect which also needs to be evaluated is whether Sites have undergone Sponsor/ independent Site Audit(s) in the past. It may be advisable to check whether the Site had undergone any FDA/EMEA audits and if so, were any concerns/findings raised.

Based on the findings of the feasibility assessments, the Clinical Trial Project Team can then make informed decisions about which Sites should proceed to Pre-Study Site Selection Visits (can be performed on-site or remotely) and eventually be approved for participation in the Clinical Trial (mandatory subject to approval of applicable Regulatory Authorities and Ethics Committees).

Carpathian Research Group capabilities

CRG as a CRO considers Clinical Trial Feasibility & Site Identification service among our key strengths as we effectively utilize our strong in-house medical expertise and connections with Key Opinion Leader(s) in numerous therapeutic fields.  

Information on all other Clinical Trial services that we provide could be found at www.crg.global