220905P - CONDUCT OF SPONSORED CLINICAL TRIALS

Presented at a Webinar on Research Methodology in Health Sciences at Northern Area Armed Forces Hospital (NAAFH) on 5th September 2022. By Professor Omar Hasan Kasule Sr. MB ChB (MUK), MPH (Harvard), DrPH (Harvard) Professor of Epidemiology and Bioethics, King Fahad Medical City R2 Cluster

OBJECTIVES:

• Construct a research protocol and accompanying documents for obtaining regulatory approval.
• Assemble resources needed for a clinical trial: budget, personnel, materials, and medications.
• Organize the enrollment, randomization, medication, and data collection.
• Conclude the study with a close-out, final report, and publication of the results.

KEY STAKEHOLDERS:

• Hospital, the trial site: PI, sub-investigators, research assistants/coordinators, technicians, technicians.
• Participants: patients and healthy volunteers.
• Institutional review board (IRB): internal approval.
• Saudi Food and Drug Authority: external approval and monitoring.
• Sponsor and/or Contract Research Organization (CRO).

THE PROTOCOL - 1: Describes the conduct of the trial:

• Protocol title, protocol number, protocol date, and protocol version (very important).
• Names and addresses of the sponsor, the principal investigator, the laboratory to be used,
• Protocol synopsis,
• Background including the rationale, the population, risks, and benefits
• Trial objectives/outcomes (primary and secondary),
• Trial design such as double-blind, placebo-controlled, open-label, etc. A flow diagram is recommended for clarity, study population, details of randomization, eligibility criteria (inclusion and exclusion)

THE PROTOCOL - 2:

• Construct a research protocol and accompanying documents for obtaining regulatory approval.
• Assemble resources needed for a clinical trial: budget, personnel, materials, and medications.
• Organize the enrollment, randomization, medication, and data collection.
• Conclude the study with a close-out, final report, and publication of the results.

FIGURE:

 

INFORMED CONSENT:

• Informed consent according to GCP guidelines.
• Process of full information disclosure: make sure participant understands procedures, risks, and benefits, and agrees voluntarily and that they can withdraw without giving a reason.
• Signing and dating the informed consent document.
• Reconsenting in case of change of any information disclosed especially protocol amendments and adverse events.

INVESTIGATOR BROCHURE:

• Provides summary information about the investigational product for the benefit of the investigator and regulatory authorities.
• The sponsor prepares and updates the investigator brochure.
• Properties of the investigational product: physical, chemical, pharmacological.
• Details of the drug: doses and frequency, routes of administration.
• Previous studies on the IP: in vitro, in vivo, animal, human.
• Summary and guidance for the investigator.

REQUIREMENTS AT THE SITE:

• Investigational drug room in the pharmacy to store and dispense study drugs.
• Laboratory and other facilities for collecting, analyzing specimens or shipping the for analysis elsewhere.
• Wards, outpatient facilities, examination rooms.
• Offices for research personnel and record storage.
• Research staff: PI, sub-investigators, research coordinators, statisticians, pharmacists.
• Satisfactory site visit report.

APPROVALS:

• Regulatory approval by IRB. Submission of the protocol, investigator brochure, informed consent forms, case record form (CRF), CVs and GCP certificates of principal researchers, insurance, and contracts (as needed).
• Regulatory approval by SFDA: Same submissions as IRB either simultaneously or SFDA after IRB. After SFDA approval the study is registered in the clinical trials register.
• Export license for specimens being sent overseas for analysis. Material Transfer Agreement (MTA) and Data Transfer Agreement (DTA) may be needed.
• Approval by the head of the department where the study will be carried out.

CLINICAL TRIAL AGREEMENT (CTA):

• CTA is signed between the sponsor and the hospital. It covers technical and financial matters. The technical matters must conform to the GCP principles.
• The following are included: timelines, confidentiality, intellectual property, indemnity insurance, and compensation, how to terminate.
• Details of payments to the hospital and the research staff are also specified.

PLANNING:

• Make a list of all events in the form of a calendar and have a pre-trial checklist.
• Construct a trial budget with a detailed costing of costs of study personnel, consumables, site costs, pharmacy, laboratory, training, and management.
• Prepare a staff work schedule.
• List all equipment and supplies needed and plan restocking.

RESEARCH STAFF TRAINING:

• Internal training
• Orientation program for all new staff
• Training on standard operating procedures
• Health and safety training
• External training
• Investigator meeting to train investigators on this study
• Site initiation meeting to go over all trial procedures and documents
• GCP training

PATIENT RECRUITMENT:

• Motivations: medical care, service to society, remuneration? Sensitive.
• How will you access the target population, participant commitment, perceptions, and literacy?
• Recruitment options: hospitals and health centers, referrals, databases, patient support groups, community groups, and advertising.
• Attrition of participants why?

INVESTIGATIONAL PRODUCT MANAGEMENT:

• Importation, storage, and logging.
• Environmental conditions: temperature, humidity, light.
• Randomization, blinding, and dispensing.
• Study close-out and IP destruction.
• IP accountability.

STUDY CONDUCT:

• Screening period
• Recruit and pre-screen,
• Informed consent,
• Protocol specific screening
• Treatment Period
• Confirm eligibility (inclusion/exclusion.
• Perform protocol procedures.
• Perform quality checks (QC and QA).
• Safety follow up
• End visit follow up

SPECIMENS (blood, urine, etc.) COLLECTION, PROCESSING, SHIPMENT, etc.:

• Techniques of collection and laboratory processing.
• Shipment overseas.

STUDY DOCUMENTS (paper or electronic):

• Source data is data in original records or certified copies. ALCOA = Attributable, Legible, Contemporaneous, Original, Accurate.
• Source documents and responsibilities of the Sponsor or PI.

DATA MANAGEMENT:

• Establish and train on quality standards.
• Database designing, building, testing, and implementing, CRF is a key document.
• Database lock: record locking, record signing off.
• Data export for analysis.
• Archiving, sharing, and publishing.

MONITORING, AUDITING, and INSPECTION:

• The sponsor is responsible to monitor to ensure that the trial follows GCP.
• Monitoring checks on the safety and well-being of participants, accuracy, and completeness of the data.
• Records of the monitoring visit are kept and the PI and Sponsor are informed.
• Auditing.
• Inspection.

SUMMARY OF STEP - 1:

1. Define the problem of the research and the hypotheses. Write a synopsis. Type of study phase 1-4?
2. Find a sponsor: trials are expensive and need a lot of money.
3. Select the site: assess its suitability and feasibility.
4. Finalize study documents: protocol, investigator brochure, and informed consent documents.
5. Submit to IRB for internal approval.
6. Finalize contracts with researchers, sponsors, and the hospital.
7. Submit to SFDA for external approval.

SUMMARY OF STEP - 2:

1. Recruit PI, sub-investigators, and other study personnel.
2. Obtain IRB and SFDA approval.
3. Site initiation meeting.
4. Staff training.
5. Receive the investigational product.
6. Conduct the study.
7. Database lock.
8. Close out, archive, destroy extra IP, publish results, and submit to SFDA for drug registration.