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

D EVELOPING A PRACTICAL PROTOCOL Janet Gallant, Program Manager , Research Education, Capital Health January 21, 2014

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

D ISCLAIMER  I am not an expert, scientist or methodologist.  I do see /review investigator-initiated research protocols that do not address all the content outlined 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

D EFINITION  A research protocol is a document that describes the background, rationale, objectives, design, methodology, statistical evaluation of the data, and organization of a clinical research project.

I MPORTANCE OF A W ELL -W RITTEN P ROTOCOL  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

P OORLY W RITTEN P ROTOCOLS ….

T HE N EED FOR A W ELL -W RITTEN P ROTOCOL  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

F IRST S TEPS  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 overly optimistic

F IRST 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

F IRST S TEPS  Create an outline of critical elements  Use your research question to define the study objectives  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

W RITING THE R ESEARCH P ROTOCOL  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 G RANT P ROPOSAL IS NOT A P ROTOCOL

R EQUIRED C ONTENT ICH-GCP: S ECTION 6: C LINICAL T RIAL P ROTOCOL AND P ROTOCOL A MENDMENTS

B ACKGROUND  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

O BJECTIVES  Clearly stated, specific & measureable  After primary objective, several secondary objectives may be listed  Written statements of what are the expected results of 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)

T RIAL D ESIGN  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

T RIAL D ESIGN  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

P ROTOCOL G APS : B LINDING  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 occur

P ROTOCOL G APS : R ANDOMIZATION  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

P ROTOCOL G APS : E LIGIBILITY C RITERIA  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

T IPS FOR E LIGIBILITY C RITERIA  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 one occasion 3 times per week)  Women of childbearing potential (define) must have a negative serum pregnancy test within 24 hours of enrollment

T IPS FOR E LIGIBILITY C RITERIA  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.

P ROTOCOL G APS : W ITHDRAWAL OF P ARTICIPANTS  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

T REATMENT OF P ARTICIPANTS  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

P ROTOCOL G APS : T REATMENT  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

A DVERSE E VENT VS . A DVERSE D RUG R EACTION VS . SUADR 1/29/2014  An adverse event (AE) is any untoward event that occurs during the study which does not necessarily have a causal relationship with the study treatment 28  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