D EVELOPING A PRACTICAL PROTOCOL Janet Gallant, Program Manager , - - PowerPoint PPT Presentation

DEVELOPING A PRACTICAL

PROTOCOL

Janet Gallant, Program Manager , Research Education, Capital Health January 21, 2014

OVERVIEW

 Importance of a well-written protocol  First steps  ICH-Good Clinical Practices Content  Common gaps and issues  Recommendations  Resources

DISCLAIMER

 I am not an expert, scientist or methodologist.  I do see /review investigator-initiated research

protocols that do not address all the content

• utlined in ICH-Good Clinical Practices

 These protocols may be judged as ethically sound

by a Research Ethics Board and Health Canada may have reviewed the protocol and issued a “ No Objection Letter”

 Appropriate authorizations do not address the

practical considerations of actually doing the trial

DEFINITION

A research protocol is a document that

describes the background, rationale,

• bjectives, design, methodology, statistical

evaluation of the data, and organization of a clinical research project.

IMPORTANCE OF A WELL-WRITTEN PROTOCOL

Facilitates :  Assessment of scientific, ethical and safety

issues before a trial begins

 Consistency and rigor of trial conduct  Full appraisal of the trial conduct and results

The single most important tool related to the

quality of all aspects of the trial

Recipe for research

POORLY WRITTEN PROTOCOLS….

THE NEED FOR A WELL-WRITTEN PROTOCOL

 Forces the investigators to clarify their thoughts and

to think about all aspects of the study

 A necessary guide for those working on the

research - helps ensure study is performed similarly by different people over time (The study SOP)

 Essential if study involves research on human

subjects

 Component of a research proposal submitted for

funding

 Used to start writing a manuscript when study

completed

FIRST STEPS

 Start with a good question and comprehensive

literature review

 Assess feasibility to develop and run an

investigator-initiated research study

 Is it reasonable?  Do you have the resources?  Is funding required?  Obtain Funding (if applicable)  Learn about the options available to you  Contact the grants office at your institution  Spend considerable time developing a budget-don’t be

• verly optimistic

FIRST STEPS

 Identify the regulations and/or guidelines that apply

to your study

 Does your study involve a drug, biologic,

radiopharmaceutical, natural health product and/or medical device? If so, ICH-GCP Guidelines and certain regulations apply.

 Do you need to submit a Clinical Trial Application (CTA)

to Health Canada?

 Do you understand your ongoing regulatory

responsibilities (if applicable)?

*If you are unsure, contact Health Canada or an expert in your organization

FIRST STEPS

 Create an outline of critical elements  Use your research question to define the study

• bjectives

 Select clinically relevant parameters to define end-

point(s)/outcomes

 Each objective should have a corresponding discussion

in the statistical section

 Define the target population and carefully consider

eligibility restrictions

 Develop a plan for data collection and management  Research design, methodology and procedures  statistical plan  Assess feasibility of the study

WRITING THE RESEARCH PROTOCOL

 Following templates can help guide authors, but do

not always address required content and/or may have sections that do not necessarily apply

 Numerous templates are available but should be

used as formatting guides

 Recommend using ICH-GCP to define protocol

content for trials requiring ICH-GCP compliance

A GRANT PROPOSAL IS NOT A PROTOCOL

REQUIRED CONTENT ICH-GCP: SECTION 6: CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENTS

BACKGROUND

 Background and Significance  Condition to be studied  Description of population to be studied  Current treatments  Treatment to be studied and justification  Preliminary data for study treatment  Purpose of the study  Statement that trial will be conducted in compliance with

protocol, GCP and applicable regulatory requirements

 Appropriate references and citations

OBJECTIVES

 Clearly stated, specific & measureable  After primary objective, several secondary

• bjectives may be listed

 Written statements of what are the expected results

• f the research –hypothesis

 Primary objective should always address a specific

hypothesis

 Secondary objectives may be hypothesis driven or

may include non-experimental objectives(e.g. data registry)

TRIAL DESIGN

 Trial Design  End-points  Methodology & design (e.g. double-blind placebo

controlled)

 How choice of design will address study objectives  Measures to avoid/minimize bias  Description of trial treatments including phase of

development (if applicable)

 Accountability procedures for investigational product  Unblinding procedure (if applicable)  Data to be recorded directly on the case report forms

TRIAL DESIGN

 Maintenance of randomization codes and

procedures for breaking codes

 Discontinuation criteria for participants and/or trial  Stepwise description of all procedures required by

the study-high level of detail

 Initial evaluations  Screening tests  Treatment and modifications  Visit scheduling and windows

* Use table to describe visit procedures-clear and

easy to understand

PROTOCOL GAPS: BLINDING

 Maintenance of blinding  Study staff blinded but the participants were not and the

study staff were conducting assessments on patients

 Unblinded investigator seeing patients when not

supposed to have contact

 Impact of unblinding on data not addressed  Unblinding procedure -who can unblind and how will it

• ccur

PROTOCOL GAPS: RANDOMIZATION

 Randomization  See- through randomization envelopes  Envelopes in sequential order but not numbered  No block randomization to keep numbers in groups

equal

 Stratified randomization not used and baseline

covariates not accounted for (variable expected to influence outcome) –all patients with covariate of diabetes randomized to placebo arm. Keeps group characteristics similar

 What is the procedure for randomization? Random

number tables vs computer generated sequencing

PROTOCOL GAPS: ELIGIBILITY CRITERIA

 Inclusion and exclusion criteria-define and limit the

kinds of patients that can participate in a trial

 Too restrictive  Limit generalizability  Failure to mimic clinical practice  Increased study complexity & cost  Recruitment difficulties  Too open  Too many variables make it difficult to attribute cause

and effect

 Safety concerns (increased risk of side effects in

participants with severe health problems)

 Ambiguity

TIPS FOR ELIGIBILITY CRITERIA

 Keep criteria to a minimum  Include only those necessary to ensure scientific

validity and patient safety

 Clearly defined and verifiable –no room for

interpretation!

 Sample criteria  No history of alcohol abuse  Pregnant women excluded

OR

 No history of alcohol abuse ( more than 3 drinks on any

• ne occasion 3 times per week)

 Women of childbearing potential (define) must have a

negative serum pregnancy test within 24 hours of enrollment

TIPS FOR ELIGIBILITY CRITERIA

 Inclusion criteria  Disease to be studied and documentation of evidence  Clinical indicators of current status  Prior therapy allowed (if any)  Demographics  Exclusion criteria  Specific contraindications (disease, current indicators,

lab values

 Excluded drugs or treatments and time frames  Allergies….

Criteria are for inclusion or exclusion but not both. Write in the affirmative.

PROTOCOL GAPS: WITHDRAWAL OF PARTICIPANTS

 Withdrawal criteria- no description as to :  When and how participants may be withdrawn from the

study and what they will be withdrawn from (study treatment and/or follow-up period)

 Data to be collected  Follow-up (how and for how long)  If participants are to be replaced  No consideration as to which participants and/or data

will be included in analysis

TREATMENT OF PARTICIPANTS

 Treatment (s) to be administered (dose, route,

schedule, treatment period

 Potential side effects (may reference investigator’s

brochure or product monograph)

 Medications : rescue and contraindicated  Procedures for monitoring participant compliance

PROTOCOL GAPS: TREATMENT

 Procedures/treatments defined as standard of care

are not-if they are a direct result from trial participation they are not standard of care even if they in themselves are not experimental

 No procedures for monitoring participant

compliance (e.g. pill counts, adherence questionnaires ) or consideration as to how this information will be incorporated into the analysis

1/29/2014 28

ADVERSE EVENT VS. ADVERSE DRUG REACTION VS. SUADR

 An adverse event (AE) is any untoward event that

• ccurs during the study which does not necessarily

have a causal relationship with the study treatment

 An adverse drug reaction (ADR) is an adverse

event where the possibility of the event being related to study medication cannot be ruled out

 Serious Unexpected ADR (SUADR): a serious

adverse drug reaction, the nature or the severity of which is not consistent with what is known about the product

1/29/2014 29

SERIOUS ADVERSE EVENT (SAE)

 SAE is defined as any untoward medical

• ccurrence (AE) that at any dose:
• Results in death or is life-threatening.
• Requires inpatient hospitalization or

prolongation of existing hospitalization.

• Results in persistent or significant

disability/incapacity.

• Is a congenital anomaly or birth defect

EFFICACY AND SAFETY

 ICH-GCP Section 6 provides little guidance  Most safety parameters address adverse event

reporting

 Refer to investigator and sponsor obligations (ICH-

GCP Section 4.11and 5.16-5.17) for additional guidance on safety procedures

 Sponsor must expedite reporting of all adverse drug

reactions which are serious and unexpected

 Sponsor should submit to the regulatory authorities

safety and/or periodic reports as specified in the regulations

ADVERSE EVENT REPORTING

 Investigator must report all SAEs immediately to the

sponsor except those SAEs that the protocol or

• ther document (e.g. investigator’s brochure)

identifies as not needing immediate reporting

 Adverse events identified in the protocol as critical

to safety evaluations should be reported to the sponsor according to the requirements and timelines specified in the protocol

ADVERSE EVENT REPORTING

 Should all adverse events be collected ? Reported?  Challenge with investigator-sponsored protocols is

cost to review all events as opposed to those which are most critical.

 Also, majority of this type of research involves a

marketed drug being used outside of the conditions specified in the product monograph so considerable information is already known about drug .

CONSIDERATIONS

 Sponsor is responsible for ongoing safety

evaluation and promptly notifying investigator(s) and regulatory authorities of findings related to safety-what is critical to monitor safety?

 There are differences between the sponsor and

investigator obligations around adverse event reporting –REB requires reporting of all SAEs

 It’s also important to consider what is known about

the study drug and what information needs to be captured to ensure sufficient safety monitoring and to capture any and all SUADR.

CONSIDERATIONS

 How will SUADR be captured and reported? Who

will assess expectedness ?

 Sponsor may stipulate in protocol to immediately

report at minimum SAEs thought to be related to study drug and those that are critical to safety evaluation

 Protocol may define expected disease related

SAEs that they do not want immediately reported unless they are thought to be related to study drug

CONSIDERATIONS

 Doesn’t mean that the investigator does not monitor

• r collect adverse events –investigator still

responsible for medical management of patient and sponsor should still be evaluating and monitoring events that do not require immediate reporting

 Should you report SUADR’s to holder of the

marketing authorization?

 Phase 4 trials report via pharmacovigilance  All other phases define process before trial starts

PROTOCOL GAP : QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES

 ICH-GCP Section 6 offers no guidance other than

there must be content in the protocol to address this

 Refer to ICH-GCP Section 5.1 for Sponsor’s

• bligations for Quality Assurance and Control

 Frequently no monitoring plan for such trials  Suggest keeping monitoring plan separate from

protocol or otherwise all changes will require REB approval

 The content of a monitoring plan is in itself a

challenge to develop

PROTOCOL GAP: MONITORING PLAN

 What should be monitored and how often?  100% source data verification likely not feasible  At minimum monitoring should occur before, during

and after a trial

 Statistical sampling may be used to define the

amount and type of data monitored

 Suggest implementing a risk-based monitoring

plan- consider what could go wrong, the likelihood

• f it happening and what the impact would be on

participant safety and data integrity

OTHER REQUIRED CONTENT

 Data handling and record keeping  Statement regarding direct access to source

documents

 Ethical concerns  Statistical Plan and Considerations  Publication

FORMATTING ESSENTIALS

 Version number and/or date to track current version  Page numbers and total number of pages  If appendices included they are referenced in main

body and if they are referenced they are included

 If using tools and templates carefully consider what

does and doesn’t apply to your study

PROPER PLANNING PREVENTS POOR PERFORMANCE!

REMEMBER

 Poorly written protocols :  Ineligible participants enrolled  Ambiguity results in various interpretations –study not

reproducible

 May result in numerous protocol amendments and/or

protocol violations

 Scientific integrity compromised  Waste resources  The protocol should be easy to understand -Keep

your audience in mind.

 Can be viewed as an official agreement between

investigators or organizations, as well as a guideline for study coordinators and staff.

IN CLOSING

 Find a good template or use what is required at

your institution

 Ensure all content as per ICH-GCP is addressed  Engage the experts  Make no assumptions-ask questions if unclear  Resources:  Research Methods Unit (Halifax)  Research Services Consultations for Investigator-

Initiated Research (Capital Health)

 Standard Protocol Items : Recommendations for

Interventional Trials (SPIRIT) Checklist

 National Institute of Neurological Disorders and Stroke

(NINDS) Template

CONTACT

janet.gallant@cdha.nshealth.ca