1.
RESEARCH PROTOCOL
A GUIDE FOR CLINICAL STUDIES, CLINICAL TRIALS AND HEALTH
SERVICES RESEARCH
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A research protocol is the most important document relating to any research study
It describes not only what the study is about and why it is important, but also all the
practical, logistical and ethical issues involved
It should be as detailed as necessary and provide a step-by-step guide to the study (although
there may be some flexibility in the study process)
The purpose of the protocol is not only for review, funding and approval processes, but for
you and your team to develop your ideas, a robust methodology and a clear guide that can be
referred to throughout the study; the protocol also provides a basis for production of any final
reports and publications
Developing a sound research protocol takes time; this is not only because it requires a sound
evidence review, but also ‘thinking out the study’ as though it was taking place in ‘real-time’
and attempting to account for any potential issues and obstacles
Development of the protocol also involves discussion with colleagues and management,
where relevant (e.g. will they support your approach?)
In line with the Research Governance Framework (RGF), it also involves peer-review (where
you will need to address comments and make amendments, as appropriate) followed by
ethical review and final R&D Approval
If this is a clinical trial of an investigational medicinal product (IMP) then approval must be
sought from the MHRA, in addition to approvals under the RGF
See Clinical Trials Regulations
Researchers must ensure they have training in Good Clinical Practice (GCP) before embarking
on a clinical trial
Clinical trial protocols may vary – this is just an example
‘Investigators Brochure’ may also be required for a clinical trial
BACKGROUND INFORMATION
PLEASE INSERT TEXT TO ALL RELEVANT SECTIONS.
1.1.
BACKGROUND
1.2.
INVESTIGATIONAL PRODUCT
1.3.
REGULATORY STATUS
1.4.
PRECLINICAL RESULTS
1.4.1.
IN-VITRO TESTS
1.5.
RISK AND BENEFITS
1.6.
STUDY POPULATION
2. STUDY AIMS AND OBJECTIVES
3. TRIAL DESIGN
3.1.
PRIMARY PERFORMANCE ENDPOINT
3.2.
SECONDARY PERFORMANCE ENDPOINTS
3.3.
SAFETY ENDPOINTS
3.4.
TRIAL DURATION
3.5.
STOPPING RULES
4. PATIENT SELECTION
4.1.
INFORMED CONSENT
4.2.
INCLUSION CRITERIA
4.3.
EXCLUSION CRITERIA
4.4.
SUBJECT WITHDRAWAL
5. STUDY PROCEDURES
Visit 1: Inclusion
Informed consent
Baseline Medical history etc
Visit 2 etc
6. DEVICE
7. ADVERSE EVENT REPORTING
The following definitions are based on ISO 14155: 2011
Where the definition indicates “device”, it refers to any component of the system.
7.1.
ADVERSE EVENT (AE)
Any untoward medical occurrence, unintended disease or injury, or untoward clinical
signs (including abnormal laboratory findings) in subjects, users or other persons,
whether or not related to the investigational medical device
NOTE 1: This definition includes events related to the investigational medical device
or the comparator.
NOTE 2: This definition includes events related to the procedures involved.
NOTE 3: For users or other persons, this definition is restricted to events related to
investigational medical devices.
7.2.
ADVERSE DEVICE EFFECT (ADE)
Any untoward and unintended adverse event related to the use of an investigational
medical device is defined as an Adverse Device Effect.
NOTE 1: This definition includes adverse events resulting from insufficient or
inadequate instructions for use, deployment, implantation, installation, or operation,
or any malfunction of the investigational medical device.
NOTE 2: This definition includes any event resulting from use error or from
intentional misuse of the investigational medical device.
7.3.
SERIOUS ADVERSE EVENT (SAE)
An Adverse Event that:
a) led to death,
b) led to serious deterioration in the health of the subject, that either resulted
in
1. a life-threatening illness or injury, or
2. a permanent impairment of a body structure or a body function, or
3. in-patient or prolonged hospitalization, or
4. medical or surgical intervention to prevent life-threatening illness or
injury or permanent impairment to a body structure or a body function,
c)
led to foetal distress, foetal death or a congenital abnormality or birth defect.
NOTE: Planned hospitalization for a pre-existing condition, or a procedure required
by the Clinical Investigation Plan (CIP), without serious deterioration in health, is not
considered a serious adverse event.
7.4.
SERIOUS ADVERSE DEVICE EFFECT (SADE)
Adverse device effect that has resulted in any of the consequences characteristic of a
serious adverse event
Note: This definition includes incidents and near incidents.
An ADE that has resulted in any of the consequences characteristic of a SAE or that
might have led to any of these consequences if suitable action had not been taken or
intervention had not been made or if circumstances had been less opportune, is
defined as a SADE.
Note: This definition includes incidents and near incidents.
7.5.
SERIOUS PROCEDURE RELATED ADVERSE EVENT
(SPRAE)
A SAE that occurs due to any procedure specific to the clinical investigation, including
the implantation or modification of the system, is defined as a SPRAE.
7.6.
UNEXPECTED SERIOUS ADVERSE DEVICE EFFECT
(USADE)
A SADE that is unexpected in nature is defined as an unexpected serious device
effect.
Serious adverse device effect which by its nature, incidence, severity or outcome has
not been identified in the current version of the risk analysis report
NOTE: Anticipated serious adverse device effect (ASADE) is an effect which by its
nature, incidence, severity or outcome has been identified in the risk analysis report.
7.7.
RECORDING AND REPORTING OF ADVERSE EVENTS
AEs will be documented from the point of enrollment until the patient is exited from
the study. …….All AEs, regardless of relatedness or outcome, must be reported.
Information reported on the AE Form shall include a description of the event, the
date of event onset, the relatedness of the event to the procedure, the relatedness
of the event to the device, the expectedness of a SADE and a serious procedure
related AE, actions taken as a result of the event, the outcome of the event, and the
date the event was first noticed by, or reported to the investigator.
For AEs which require immediate reporting, initial reporting may be done by
telephone or e-mail, followed by the completed electronic AE Form. Contact
information is given on each AE Form and is available in the investigator site file.
All other AEs will be reported on the adverse event form in a timely manner after the
investigator first learns of the event.
All ongoing AEs will be followed-up until the last study visit. Following study exit,
there will be a one month follow-up period for safety. During this period, if any AEs
are reported as device or procedure related, they will be included in the study.
7.8.
EMERGENCY CONTACT DETAILS IN CASE OF
SAE/SADE
In case of an immediately reportable AE the investigators can contact ……by phone.
Contact details are available in the Investigator Site File.
8. DATA HANDLING
8.1.
SOURCE DATA DOCUMENTATION
The investigator must ensure accuracy, completeness and timeliness of the data
reported in CRFs and in all other required reports. Data reported on CRFs, which are
derived from source documents, must be consistent with the source documents or
the discrepancies need to be justified in a documented rationale, signed and dated
by the (principal) investigator, to be filed in the patient file. Only authorized persons
may complete CRFs. CRFs shall be signed by investigators as specified on the
Delegated Tasks List included in the Investigator Site File.
The investigator must retain the Investigator Site File, patient data sources and CRFs
in accordance with local law and regulations or for at least two years after closure of
the study, whichever is longer. The investigator should take measures to prevent
accidental or early destruction of the study related materials.
8.2.
PATIENT CONFIDENTIALITY
The investigators and institutions involved in this study will provide direct access to
source data and documents only to the sponsor and appropriate authorities for the
purposes of monitoring, audit, Ethics Committee review or regulatory inspection.
Each subject taking part in the study will have agreed explicitly to such access by
signing the informed consent.
The sponsor will ensure that no subject will be identifiable either from the final
report or published results.
9. ETHICS
This clinical study was designed and shall be implemented and reported in
accordance with the ISO 14155 (2011), with applicable local regulations, and with
the ethical principles laid down in the Declaration of Helsinki.
9.1.
QUALITY CONTROL AND QUALITY ASSURANCE
10. STATISTICS
10.1.
ANALYSIS PATIENT SETS
10.2.
SAMPLE SIZE CALCULATION
10.3.
DEMOGRAPHIC AND BASELINE CHARACTERISTICS
10.4.
ANALYSIS OF PERFORMANCE
10.5.
ANALYSIS OF SAFETY
11. FINANCING AND INSURANCE
12. SPONSORSHIP AND INDEMNITY
13. PUBLICATION POLICY
14. REFERENCES
15. APPENDIX
APPENDIX A - Schedule of Study Assessments