How to Analyze and Implement a Research Protocol

How to Analyze and Implement a Research Protocol Phyllis Carelllo, CCRC Bridget Adams, MSHS, CCRA Susan Peterson, RN Oregon Health & Sciences University NIH CA P 30 069533, NCRR UL 1 024120

What is a protocol? § A detailed plan that sets forth the study: – Objectives – Design – Methodology

Why do we need a Protocol? § Why do we need one? – Scientific validity – Subject safety – Replicate the science if necessary – Regulatory requirements

Federal Regulations § 45 CFR 46 – Applies to research involving human subjects conducted, supported or regulated by any federal department or agency – IRB’s are required to review and approve research – IRBs have the authority to suspend or terminate approval of research that puts subjects at risk or is not conducted in accordance with IRB requirements § 21 CFR 50, and 312 or 812 – Applies to FDA regulated studies

Who Writes the Protocol? § Sponsor – Commercial manufacturer ● Pharmaceutical or Biotech company ● Medical Device company § Investigators and study team – Investigator initiated – OHSU Investigator or investigator at another institution

Industry Sponsored Protocols § Protocol generally part of larger investigational plan to get the drug/device approved by FDA – May be large multi-site trials – Changing protocol is difficult – Investigator usually has no input in to study design § Centralized research activities – Data Analysis – FDA reporting – May use a Central Lab § Funding – Sponsor usually pays for all research activities – Contract between sponsor and OHSU

Investigator-Initiated § Independently conceived and developed by scientists - the primary means by which biomedical research is conducted § Range from a small pilot study to large multi-site clinical trials § May study a disease process or an intervention § Investigator responsible for all research activities – Reporting to funding and oversight entities – Data Analysis – Publications § Funding – – – Company (pharmaceutical, biotech, medical device) DHHS (NIH, DOD, DOE, VA, etc. ) Foundations Departmental OCTRI Awards

Who Evaluates the Protocol? § IRB : Subject Protection § Funding agency (NIH, Foundation): $ § Federal Oversight (FDA) if applicable: Protect Public Health § Investigator: Feasibility, Scientific Interest § Study Coordinator: Operational Implementation

IRB Reviewers § § § Is this scientifically valid? Is it safe? Is the risk/benefit ratio appropriate? Is this ethical? Is it compliant with the regulations?

Funding/Oversight Agencies § Is it scientific valid? § Is it feasible? § What it the experience of the Investigator(s)? § What are the facilities and resources available to conduct the study?

Investigator § Industry/Multicenter Studies: PI reads protocol to find out if they are interested in participating – Academic Interest? – Is it scientifically valid? – Does the PI/prospective Coinvestigators have the patients in their clinic? – Does the PI have time to conduct the study?

Coordinator § Learn the protocol requirements – What do I need to do? § May use protocol to develop checklists and data collection forms § Will the proposed budget cover the costs? § Are there unfamiliar procedures? – Specialized expertise – Training § Time – How long is study enrollment open? – Does the PI have time? – Are study personnel over-committed?

Coordinator, cont. § Provide feedback on the feasibility of the study (feasibility checklist http: //www. octri. org/octri/public/index. aspx? pagei d=126&siteid=1&Menu. Selected. Index=7) – Is there adequate space? ● Clinic space ● Storage space ● Coordinator space – Doe we have the subject population? ● In clinic ● Competing studies ● Advertising – Equipment ● Is equipment available for use? ● Do we have to buy equipment? ● Will equipment be provided by the sponsor?

Protocol Review High Lev el o f. S cie ntif ic I nfo rm atio n il f lo e v e ta De L Low Scientific Reviewers: NIH/ Foundation IRB Members Co-Investigators Statistician Auditors Study Coordinators Laboratory Staff

“Protocol” Documents High Lev el o f. S cie ntif ic I nfo rm atio n il f lo e v e ta De L Low Scientific Reviewers: NIH/ Foundation IRB Members Co-Investigators Statistician Auditors Study Coordinators Laboratory Staff

Study Phase Considerations

Clinical Trials § Any research project that prospectively assigns human subjects to intervention and comparison groups to study the cause-and-effect relationship between a medical intervention and a health outcome. § Intervention can be: – – – Drug Device Behavioral Educational Other § Control can be: – Placebo – Standard of Care – Nothing

Study Trial Phases Phase I § Population: – If healthy volunteers – where will you recruit? – If ill population – what is standard of care? § Visit Duration: – What study personnel need to be available and for how long at each study visit? – Where do you have the space to conduct a long visit? § Design – Open label § Aim – Safety

Study Phases cont’d Phase II § Population – Criteria is generally strict – do we have the population? – Do we have conflicting studies? § Duration – Studies generally aren’t long, so when does enrollment end? – If subjects have to go off their meds for a period of time, will you expect a high drop out rate? § Design – Randomized - Who will randomize subjects? – Double blind studies - Who is going to be available to unblind if necessary? § Aim – Continued Safety Evaluations – Initial Efficacy Data

Study Phases Cont. Phase III § Population – Generally large # of subjects, do we have the capacity to see them? – Representative Population (broader inclusion/exclusion criteria), do we have these subjects in our clinic? § Duration – Parallels expected treatment use (several days to years) – do we have the capacity to follow the subjects for a long time? § Design – Generally double bind § Aims – Establish safety and efficacy in the target population

Phase IV § Population – Population prescribed the drug – who will pay for the drug? § Duration – Long Term for chronic diseases – do we have the capacity to see the subjects for years? § Design – Generally open label – Procedures generally same as clinical care – what is research and what is Standard of care? Who pays? § Aim – Economic comparisons – Quality of life – Adherence and compliance

Study Design

Blinding § Single Blind – subject doesn’t know what treatment group they have been assigned § Double Blind – subject and investigator don’t know treatment assignments

Randomization § Selection of treatment/control group by chance § Purpose – Minimize Bias § Several methods – Fixed Allocation Randomization ● Simple (flipping a coin) ● Blocked ● Stratified – Adaptive randomization ● Baseline ● Response randomization

Parallel Design § Subjects are assigned to study arms/groups and stay in that group for the duration of their study Randomization participation Group 1 Group 2 Group 3 Group 4

Cross-over Design § One group is assigned to treatment and one to a control group, at some point in the study they switch assignments Randomization Intervention Placebo Group 1 Group 2

Open Label Extension Study § Investigators and subjects know what intervention they receive Group 1

Observational Study § No Intervention § Draw inferences about the effect of a treatment on subjects, where the assignment of subjects into a treated group versus a control group is outside the control of the investigator – Used when it may be unethical or impractical to conduct a randomized trial – Used for studying public health effects § May involve clinical procedures § May be long term

Break! § Back in 10

Analyze, Analyze If we knew what it was we were doing, it would not be called research, would it? Albert Einstein

Analyzing a Protocol § § § Who? What? Where? When? How? Why?

Protocol Elements § Title § Introduction, background, rational, literature review § Purpose(s), Objective(s) § Research Methods/ Study design ● ● Endpoints Stopping Rules Duration Drug/ Device/ Interventions schedule, modifications, precautions ● Study procedures ● Subjects (#, inclusion/exclusion, withdrawal criteria) ● Safety Assessments § Risks § Statistical Analysis

Protocol Elements, cont. Title page ● Protocol title ● Sponsor ● Spaces for sign-off by investigator (industry sponsor) ● Date and version ● Study Identifier (e-IRB#, OCTRI#, IND#, Sponsor protocol #), as applicable

Protocol Elements, cont. § Introduction with background, rationale, and Literature Review – Provide basis for the research – Summary/Introduction ● Brief description of what is currently known about the drug and/or disease condition to be studied ● Background information (journal articles) ● Justification for dose ● Route of administration

Protocol Elements, cont. § Objectives/Specific Aims – Characterize population – Scope – Duration – Outcomes – Experimental measures

Protocol Elements cont. § Study Population – Total number of subjects (including screen failures/subject withdrawals) – Inclusion/Exclusion criteria ● Age restrictions ● Diagnostic methods (HGB > 12) to determine eligibility ● Pre-existing conditions – Disallowed concomitant medications and/or treatment – Inclusion of vulnerable populations (if applicable) – Individual subject withdrawal criteria – Allowances for temporarily stopping drug/intervention – Dose Modifications

Protocol Elements cont. § Research Design and Methods – Endpoints ● Identifiable change that shows the intervention did what it was supposed to do – Primary Endpoint: measures the specific clinical effect the intervention is preventing/treating (i. e. survival, resolution of desease) – Surrogate endpoints: measures changes in symptom/biological indicator for the success of the intervention (i. e. T-cell count, radiographic imaging, etc. )

Protocol Elements cont. § Research Design and Methods, cont – Endpoints, cont ● Should be Measurable ● Measures should be as objective as possible to avoid bias ● Should be feasible

Example: Endpoints § Study to determine efficacy of new antibiotic for pneumonia (n=300) – Not objective: patient report of “cure” – More objective: clinical cure evaluation by physician – Most Objective: chest x-ray

Protocol Elements cont. § Methodology and study schedule – Description of recruitment and enrollment procedures – Screening and allocation of subjects to study groups – Subject numbering system to be employed – Preparation of study drug for use – Schedule for administration of test article to subject – Contraindications – Schedule of visits and assessments – Measures to maintain blinding/ unblinding procedures

Protocol Elements cont. § Study measures and assessments – Physical examinations – Measurements of vital signs – Assessment procedures – Clinical Laboratory – Handling of samples – Special safety requirements ● Detailed

Protocol Elements cont. § Research Design and Methods cont. – Description of study procedures/interventions ● Research procedures described in detail so they can be performed consistently ● Common medical procedures may have no detail to allow for appropriate variation among clinicians (if scientifically acceptable) ● Procedures for carrying out physical exams, vital signs, handling samples may be very detailed if it is essential to the data collection

Identification of Unspecified Procedures § Procedures required for safe conduct of a study aren’t always listed in the protocol § Example: the protocol states a Dexa Scan will be completed at Visit 3 § What is a potential unspecified procedure for a Dexa Scan?

Identification of Labs § Example: Protocol states 20 mls of blood – Why? – What tubes to you need to draw? – What is the minimum amount of blood needed? – Does the sample need to be on ice? – Will the sample be processed at OHSU or at a central lab? – Does it need to be shipped that day?

Identification of Standard of Care § PI or MD investigator makes determination § Not always obvious in the protocol § Not always obvious to the MD § Standard of care varies from institution to institution § Be consistent – – don’t bill insurance for one subject and not another without a documented reason.

Protocol Elements cont. § Drug/Device – Drug preparation, administration, storage – Dose modifications – Device Implantation Procedures – Required concomitant medications, if applicable – Drug/Device accountability, retention, final disposition

Protocol Elements cont. – Risks ● Known Risks ● Protection from risks ● Risk/Benefit Analysis – Safety Assessments ● Identify procedures for safety monitoring ● Adverse event recognition, documentation, and reporting requirements – May not be specifically stated in the protocol ● Special precautions for specific side effects, if required

Protocol Elements Cont § Adverse Experiences – – – Recognition and management Documentation Criteria for grading severity Criteria for grading relatedness Follow-up for subjects ● After an adverse event - usually follow until event is resolved ● UPs that occur within 30 days of last study intervention/subject discontinuation must be reported to the OHSU IRB

Protocol Elements Cont § Research Design and Methods (cont. ) – Stopping rules/criteria ● Based on results of interim analysis – Study will be stopped if a certain predetermined proportion of adverse events occur – Study will be stopped if endpoints aren’t being met – Study may be stopped if a clear benefit is shown – May be determined by sponsor, DSMB,

Protocol Elements Cont’d § Research Design and Methods (cont. ) – Duration (individual subjects and study) ● Make sure it is long enough to collect data and accommodate enrollment ● Should be no longer than required to collect enough data to evaluate study endpoints ● Balance Scientific Need with Subject Burden

Protocol Elements Cont’d § Data analyses – Variables to be analyzed – Statistical approaches to employed – Geared toward statisticians – Selection of subjects to be analyzed ● all enrolled subjects (“intent to treat”) ● all eligible subjects (e. g. , 80% compliant)

Other Important Study Documents § OHSU IRB Initial Review Questionnaire (IRQ) § Investigator Drug/Device Brochure § Laboratory/Operations Manual § Standard Operating Procedures (SOPs) § Grant/Contract

Initial Review Questionnaire (IRQ) § Approved by the IRB § Some information that may not be in the protocol – Approved research staff – Funding information – # of subjects at OHSU – Recruiting and consenting procedures

Investigator Drug Brochure/ Device Manual § Reviewed by the IRB § The IB contains information on the drug § Study results to date § All known adverse events and risks § Information for the investigator on dosing § Device Manual will include implant/compatibility/programming requirements

Lab/Operations Manual § Do not require IRB approval § Maybe known by other names § Include minute detail on: – Lab processing – Case Report Form Completion – Patient flow during a visit (e. g. call ahead to see if X-ray is backed up before you head down there with a patient) – Calling and paying for a taxi – Many, many other details

SOPs § Do not require IRB approval § Unit, not protocol, specific § Define the who, what, where, when and how of research activities not outlined in your protocol – Obtaining/verifying informed consent – Drug accountability § Not required of study sites per regulations (required for sponsors) but good to have: – Assure study conduct/data quality – Looked upon favorably by sponsors and regulators § If you have SOPs you will be held to them in an audit

Grant/Contract § Grants are reviewed by RGC and the IRB § Contracts are reviewed and negotiated by the Clinical Trials Office, not reviewed by the IRB § Contracts must be signed by the appropriate OHSU institutional signatory (not the PI or Department) before the study can begin

Contract § Industry sponsored trials – – – # of subjects you can enroll # of screen failures Additional procedures Payment terms Invoicing (or not) Term of study § Contracts must be amended if: – – PI changes Budget Changes Want to enroll more subjects The term of the contract is exceeded

Break! § Back in 10

Protocol Implementation § Ready, Set, Go!

Protocol Implementation § Not quite yet … § There a few more hoops…

Training § Research Education Requirements – Responsible Conduct of Research for all – Responsible Conduct of Research Involving Human Subjects – Other RCR as applicable

Training, cont. § Verify study staff have training on Core Competencies – (see OHSU Clinical Research Coordinator Required training Checklist) – Basic Life Support (BLS – initial and every two years) – Phlebotomy (contact Steve Osgood for training) – Point of care testing (contact Jane Culbertson) ● ECG, BP, Vital signs, HCG urine, Urine dipstick § EPIC access/training as required

Training § Staff protocol training – Make sure study staff read and understand the protocol – Have study staff acknowledge their roles in the study – Make sure study staff know how to identify and report deviations – Document that training was completed (sign-in sheet template - see Inservice Documentation Log )

Training, cont. § Research Pharmacy Services (RPS) study initiation visit – PI/ study contact to set up appoint with pharmacy staff per pharmacy policy (see http: //www. ohsu. edu/pharmacy/rps/poli cies. htm)

Training, cont. § OHSU Inservice(s) § If beside nurses will be involved in the study – Complete and submit Clinical Research Study Nursing Summary (link available in the electronic IRQ) – The PI/designee is responsible to provide special training to some or all of bedside nursing staff. Training fees may apply. § Clinical and Translational Research Institute – Inservices required for all studies requesting CTRC nursing services – Complete CTRC nursing services request form – PI/study staff will present protocol and clarify any study specific procedures to be conducted at the

Other considerations § Required Health screening/immunizations – TB test – Hepatitis B immunizations – Ask Employee Health if you have questions 503. 494. 5271

Work-flow planning § Where are prospective subjects to report? § How are subjects routed during the study visit? § Where are study working materials stored? – Template order forms (lab, radiology, RPS) – MD orders – Blank consent documents § How will you communicate changes in procedures/protocols etc to study staff?

Scheduling considerations § Reconcile protocol requirements with practical constraints – Fasting? – Duration of study visit? – Study Personnel availability? – Are you dispensing research medication(s)? – Inpatient studies (who is available to discharge, who is going to see the subject each day of admission) – Lab considerations? – MD orders to ● CTRC -48 hours in advance ● Pharmacy

Scheduling Considerations cont – Does the subject have/need a medical record? – You need a medical number if the subjects are going to have any clinical services at OHSU (e. g. labs, x-rays, MRI) – Medical Record Number Request form at http: //ozone. ohsu. edu/healthsystem/HIS/medr ectrx/reqmrnumhim. pdf

Scheduling Example § Lumbar puncture – Who: MD available – What: LP Tray – are separate needles required? Does the MD have a preference? – When: Time of day? Are subjects NPO? How long is the observation period? – Where: Private room, Bed or gurney? – Why: Endpoint data?

Common Scheduling Problems § Not scheduling enough time § Not scheduling in the appropriate clinical area § Not scheduling with the appropriate personnel (MD available) § Not informing everyone that needs to know § Not formally getting subjects on the clinic/CTRC/or other schedule

EPIC and Research § Consent forms and research documentation must be in Epic if subjects are having clinical services at OHSU per the OHSU Research Documentation in Medical Records Policy (coming soon) and the Informed Consent Forms for Research in Medical Records, Clin 02. 15 http: //ozone. ohsu. edu/healthsystem/POLICYMA NUALS/Clin 02 Med. Rec/Clin 02 -15. pdf § Research Flags – identify a patient as a research subject and provide study- specific information to all personnel involved in their care § Setting research flags in the Integrated Health Record http: //www. ohsu. edu/research/crp/docs/research

Epic and Research Records § To request the ability to set research flags complete the Research Flag Access Request form at http: //www. ohsu. edu/research/crp/docs/research coordinator. xls

Scheduling Cont. § Research Admission - request form available at http: //ozone. ohsu. edu/research/rates/rese archadmission. pdf) § Scheduling at the CTRC instructions available at http: //www. octri. org/octri/public/index. aspx ? pageid=183&menuid=51&siteid=1&Men u. Selected. Index=1

Equipment and Supplies § Do you have everything you need? § Who is responsible for providing supplies § Industry sponsored trials usually provide lab kits(but not always) § Who is responsible for ordering? § Who is responsible for tracking?

Equipment and Supplies Cont. § Use of Research Devices and Equipment – http: //ozone. ohsu. edu/Health. Systems/ Adm 10 Environ/Adm 10 -04 -10. html – Must be inspected by Clinical Technology Services if the device/equipment was not purchased by OHSU § Computers – If the sponsor provides you with a computer for the study (not purchased

Administrative Set-up § Prior to enrollment – OGA #/ FAID – Industrial Accounts/ Research Rates (see Research Study Rate Request, Account(s) Setup, and Billing of Clinical Services, Adm 05. 17 ) – Send account #s to Research pharmacy

Administrative Set-up § Clinical Trials Registration – Guidance Regarding the International Committee of Medical Journal Editors (ICJME) Requirement for Clinical Trial Registration – OHSU does not have an institutional account # , so make sure to register for an individual account # – Takes up to two weeks – Need to submit IRB approval memo and keep study status up to date (minimum updates every 6 months) – Not Required if: ● Study doesn’t meet definition of clinical trial ● Industry-sponsored multicenter (Sponsor registers) ● Multicenter trials where OHSU is not the coordinating center (Coordinating center registers)

Administrative Set-up § Investigational Devices – Prior to enrolling Medicare beneficiaries you Must submit to OHSU’s Medicare Fiscal Intermediary in advance for review and approval – http: //ozone. ohsu. edu/Health. Systems/ Adm 05 Billing/Adm 05 -18. html

Administrative Set -up § Off campus activities – If OHSU employees will be working where they are directly contacting human subjects in facilities that are not owned or leased by OHSU you need to complete the Off Campus Clinical Activities Authorization Request

Incomplete Protocol Analysis and Implementation § Leads to protocol non-compliance § Leads to poor decision making – Subject Safety – Study Conclusions § Leads to protocols that go nowhere § Leads to budget deficits – More involved in the study than you thought § Regulatory Headaches

Common Protocol Deviations § Non-adherence to inclusion/exclusion criteria § Failure to comply with dispensing and dosing requirements § Incorrect storage of study medications § Use of prohibited concomitant medications § Visits outside of study windows § Protocol requirements not followed – tests not done – incorrect tests – safety labs not done

Common Protocol Deviations cont. § Failure to follow subject termination plan § Failure to report adverse events § Over-enrolling study § Failure to follow statistical plan § Failure to amend protocol and obtain IRB approval prior to implementing changes § Failure to document and report deviations

How to Avoid Deviations cont. § Follow OHSU Research and Hospital Policies: – IRB Policies: http: //www. ohsu. edu/xd/about/services/ integrity/policies/ – OHSU Research Policies: http: //www. octri. org/octri/public/index. a spx? pageid=123&siteid=1&menuid=1& siteid=1&Menu. Selected. Index=6

How to Avoid Deviations cont. § PI needs to supervise the conduct of the study § Delegate study tasks to qualified individuals (e. g. physical exams delegated to MD, FNP, PA)

Conducting the Protocol for Compliance § Once the study has IRB approval the study team is expected to adhere to the protocol without deviations – unless it is for the safety of the subject Research Protocol

Conducting the Protocol cont. § Protocol Modifications – An amendment/modification can be submitted for IRB approval to address new information/difficulties – Should analyze new procedures prior to implementation – Strive to minimize modifications so that data remains “poolable” ● Don’t want to compare apples and oranges – Maintain consistency within and between the protocol, consent, and procedure manuals

Conducting Protocol cont. § Modifications – Re-evaluate before submitting modification to the IRB, when appropriate, but always before implementation ● Budget ● Location/Scheduling ● Training ● Feasibility

Conducting the Protocol cont. § Document, Document – If it wasn’t documented it wasn’t done – If the procedure documentation is questionable so is the data – Document all special circumstances that might affect the interpretation Research of the results Records

References § Drugs Dispensed to Research Subjects, Clin 05. 11 http: //ozone. ohsu. edu/healthsyste m/POLICYMANUALS/Clin 05 Meds/ Clin 05 -11. html