Protocol Adherence

Courtney Duncan
Savita Shashikiran
NIDDK Quality Assurance & Quality Improvement Team
  Define protocol compliance/adherence
 Review compliance standards and importance
 Methods of promoting and demonstrating compliance
Objectives  Discuss when and why the protocol may be changed
 Define non-compliance and deviations
 What to do when things happen?
 • A research protocol is a document that describes the
background, rationale, objectives, design, methodology,
statistical considerations, and organization of a clinical
research project.
• It acts as a ‘manual’ for the research team to ensure
Definitions adherence to research methods.
• Think of it as a “contract” with the IRB.

So how do we define protocol compliance or adherence?

• Compliance is…adherence to all the trial-related
requirements, good clinical practice (GCP) requirements, and
the applicable regulatory requirements
 • Federal Regulations and Guidance (e.g., HHS/OHRP, FDA).
These regulations define:
• [human] subjects
Standards of • Interactions/interventions
Protocol • Sensitive information or materials

Adherence AND provide standards for how all the above must be
treated, enacted, or protected
• ICH Good Clinical Practice (GCP)
• Institutional (NIH) policies & guidance – OHSRP & IRBO
• NIDDK policies and guidance
 • The International Council for Harmonisation’s Good Clinical
Practice (ICH GCP) guidelines serve as a worldwide
Influence of standard for the ethical and scientific quality of designing,
Good Clinical conducting, recording, and reporting trials involving human
subjects.
Practice • Compliance with this standard provides public
assurance that the rights, safety and well-being of trial
subjects are protected, consistent with the principles
that have their origin in the Declaration of Helsinki,
and that the clinical trial data are credible.
 • 4.5.1 The investigator/institution should conduct the trial in compliance with
the protocol agreed to by the sponsor and, if required, by the regulatory
authority(ies) and which was given approval/favourable opinion by the
IRB/IEC. The investigator/institution and the sponsor should sign the protocol,
Good Clinical or an alternative contract, to confirm agreement.
• 4.5.2 The investigator should not implement any deviation from, or changes
Practice – of the protocol without agreement by the sponsor and prior review and
documented approval/favourable opinion from the IRB/IEC of an
amendment, except where necessary to eliminate an immediate hazard(s) to
Compliance trial subjects, or when the change(s) involves only logistical or administrative
aspects of the trial (e.g., change in monitor(s), change of telephone

with Protocol number(s)).

• 4.5.3 The investigator, or person designated by the investigator, should
document and explain any deviation from the approved protocol.
• 4.5.4 The investigator may implement a deviation from, or a change of, the
protocol to eliminate an immediate hazard(s) to trial subjects without prior
IRB/IEC approval/favourable opinion. As soon as possible, the implemented
deviation or change, the reasons for it, and, if appropriate, the proposed
protocol amendment(s) should be submitted: (a) to the IRB/IEC for review and
approval/favourable opinion, (b) to the sponsor for agreement and, if required,
(c) to the regulatory authority(ies).

ICH E6 (R2) Good clinical practice

 Sec. 312.60 General responsibilities of investigators.
• An investigator is responsible for ensuring that an investigation is
FDA - conducted according to the signed investigator statement, the
investigational plan, and applicable regulations; for protecting the

Compliance rights, safety, and welfare of subjects under the investigator's care;
and for the control of drugs under investigation.

with Protocol

Code of Federal Regulations Title 21

 Why is 1- Participant Safety, Rights & Welfare

protocol 2- Data Integrity

adherence
crucial? 3- Regulatory Compliance
 How do we promote protocol adherence?

Protocol
development, Effective Consistent On going review
Training
reviews and Communication Monitoring of the protocol
approvals
Protocol Development, Reviews & Approvals

• Concept Review
• Scientific Review: evaluates the scientific merit and importance of the study, study
design, feasibility, statistical analysis plan and data management plan. The SRC also makes
sure that the study has clearly stated, the aims, the study design and measurable
outcomes.
• Resource Review: Resource review is to identify the available resources to conduct the
research or the study
• Ancillary Reviews: e.g., radiation safety
• IRB Review - Assures, both in advance and by periodic review, that appropriate steps are
taken to protect the rights and welfare of humans participating as subjects in the
research.
• IRB bases its approval on the risk-benefit ratio written in the protocol so any deviation from the
written plan may alter the determination.
 How do we promote protocol adherence
(cont’d)?

On going
Comprehensive Effective Consistent
review of the
Training Communication Monitoring
protocol
 How to • Document participant eligibility
• Document consent
demonstrate • Document data
protocol • Document contacts (calls, study visits, etc.)
• Document training of staff
adherence • Seek approval and document protocol changes
What happens when we do not follow the
protocol?

Non-
Deviations
Compliance
 Any change, divergence, or departure from the
IRB-approved research protocol.
• Major deviation: Deviations that could affect
the subject safety or integrity of the data
• Minor deviation: Deviations that are not
major
Deviations
All deviations are reportable to the IRB and
Sponsor (if applicable). However, timing of when
to report depends on the classification of the
deviation.
 Deviations from the IRB-approved protocol that
have, or may have the potential to, negatively
impact, the rights, welfare or safety of the subject,
or to substantially negatively impact the scientific
integrity or validity of the study. Such as:
Major • Failure to obtain legally effective consent prior to
Deviations initiating research procedures
• Enrollment of a participant who did not meet all
inclusion/exclusion criteria
• Performing a study procedure that has not been
approved by the IRB
 • Deviations that do not have the potential to
negatively impact the rights, safety, or welfare of
subjects or others, or the scientific integrity or
validity of the study. Such as:
• Completing a study visit outside of the required
timeframe when, in the opinion of the investigator,
Minor there are no safety implications, and it is not
detrimental to the validity of the study.
Deviations • Use of an expired consent form in which the
information contained is not substantively different
than the currently approved consent unless the
deviation occurs repeatedly.
• A signed copy of the consent form was not given to the
participant.
 Failure of an investigator to follow the applicable laws,
regulations, or institutional policies governing the protection
of human subjects in research, or the requirements or
determinations of the Institutional Review Board (IRB),
whether the failure is intentional or not.
• Which includes not adhering to the IRB approved protocol.
Definition of
Non- 1. Continuing non-compliance - A pattern of recurring non-compliance that
either has resulted, or, if continued, may result in harm to subjects or
otherwise materially compromise the rights, welfare and/or safety of subjects,
Compliance affect the scientific integrity of the study or validity of the results. The pattern
may comprise repetition of the same non-compliant action(s), or different
non-compliant events. Such non-compliance may be unintentional (e.g. due to
lack of understanding, knowledge, or commitment), or intentional (e.g. due to
deliberate choice to ignore or compromise the requirements of any applicable
regulation, organizational policy, or determination of the IRB).
2. Serious non-compliance - Non-compliance, whether intentional or not, that
results in harm or otherwise materially compromises the rights, welfare
and/or safety of the subject. Non-compliance that materially affects the
scientific integrity or validity of the research may be considered serious non-
compliance, even if it does not result in direct harm to research subjects.
 It is the responsibility of the PI to determine whether a
deviation is major or minor and to ensure proper reporting.
When making the determination of whether the unapproved
Points to deviation is major or minor, the PI should consider whether
the deviation may have or negatively affected any of the
Remember following:
• The rights, safety, or welfare of the subject
• The scientific validity of the study (the ability to draw
conclusions from the study data)
 Assess the situation and define the “event”
• What happened? Get a full understanding.
When things
• Has this occurred before?
happen
• Categorize the event
• Is this a deviation and/or non-compliance?
o Is this a major or minor deviation?

• Why? Keep asking why until you get to the root.

• Even minor events need to be assessed as trends
in minor deviations may indicate systemic issues in
how the study is being conducted.
• Examples - Is the protocol unclear or inaccurate?
Was the participant unaware of expectations? Is
there an error in the order set? Were instructions
clear to nursing staff?
 When Correct it
things • Address the issue immediately.

happen
Prevention
• How to prevent it from recurring?
• Examples – Amend the protocol, provide training,
utilize checklists/calendars, develop quality control
systems

Document & Track the event accordingly

• CRIS
• REDCap (Events Reporting Form)
 When
things
happen
When you are unsure:
• Review the protocol
• Review Policies 801 and 802
• Check with your PI, navigator or QA/QI
 • Protocol adherence forms the backbone
of successful, safe, ethical, and credible
CONCLUSIO clinical trials.
N