How to Analyze and Implement a Research Protocol

Transcription

1 How to Analyze and Implement a Research Protocol Phyllis Carelllo, CCRC Bridget Adams, MSHS, CCRA 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 1

2 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 2

3 Investigator-Initiated Independently conceived and developed by scientists Range from a small pilot study to large multi-site clinical trials May study a disease process or an intervention Investigator t responsible for all research activities iti 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 the risk/benefit ratio appropriate? Is this ethical? Is it compliant with the regulations? 3

4 Funding/Oversight Agencies Is it scientifically valid? Is it feasible? What is 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: Academic Interest? Is it scientifically valid? Does the PI/prospective Co-investigators have the patients in their clinic? Does the PI have time to conduct the study? Evaluates the overall feasibility of conducting the study at OHSU 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? 4

5 Coordinator, cont. Provide feedback on the feasibility of the study (see checklist =1&MenuSelectedIndex=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 Low Scientific Reviewers: NIH/ Foundation IRB Members Co-Investigators Statistician Auditors Study Coordinators Laboratory Staff Protocol Documents High Grants Contain: Protocols Contain: Operations Manual: Low Scientific Reviewers: NIH/ Foundation High Level Scientific Concepts May describe several studies Generally have little detail Generally not revised Revisions require funding source approval IRB Members High Level Scientific Concepts Generally describe one study Moderate Level of detail May be revised with IRB approval Co-Investigators Statistician Auditors Little or no scientific information High level of detail for completing tasks May be revised frequently without IRB approval (must be consistent with the IRB approved protocol) Study Coordinators Laboratory Staff 5

6 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 Open Label Study Investigators and subjects know what intervention they receive 6

7 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 participation Randomization 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 7

8 Observational Study No Intervention or Standard of Care 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 Study Phase Considerations Clinical Trials Any research study that prospectively assigns human subjects to an 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 8

9 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 9

10 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 Analyze, 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? 10

11 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) Study Identifier (e-irb#, OCTRI#, IND#, Sponsor protocol #), as applicable Date and version 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 11

12 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 and subject withdrawals Inclusion/Exclusion criteria Age ranges 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 Non-compliance 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.) 12

13 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 Required documentation 13

14 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. 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? 14

15 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 15

16 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 pre-determined 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, or PI depending on the study 16

17 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 dt 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 17

18 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 18

19 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 and some contracts are reviewed by RGC Industry Contracts are reviewed and negotiated by the Clinical Trials Office, not reviewed by the IRB Contracts must be signed dby 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 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 19

20 Break! Back in 10 Where Do I Start? Protocol Implementation General Regulatory Binder Read Protocol List Aims Check IRQ Number of subjects you should request in the IRQ /protocol is study dependent Expected rate of attrition Screen failure rate Numbers need to be reasonable and consistent with the protocol and contract (when applicable) Personnel 20

21 EXAMPLE Need 100 subjects to complete study Expect 20% screen failure rate 15% drop out rate after randomization. 120 subjects (20% of 100) 15 (15% of 100) + 3 (20% of 15) 138 Subjects approximately Protocol Implementation General 2 Groups Hypothyroid 60 participants Age yrs Healthy controls 30 participants Age Inclusion/Exclusion Criteria Interpreter? Package Insert/Drug Brochure /Device Manual Side effects Dosing requirements (taper, modifications) Regulatory Binder Visits Screening Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 (Week 0) (Week 6) (week 12) (week 18) (week 24) Visit 6 (week 30) optional 21

22 Protocol Implementation Questions to ask What What procedures What supplies What equipment Who Who will be performing task, labs Who needs to be contacted in advance (registration, admitting, clinical personnel, CTRC) Where Where will tests be performed Protocol Implementation Questions to ask, cont. When At which visit How much time between visits, time of day How How am I going to accomplish this How am I going to contact Why Why am I doing it safety /study end point SCREENING VISIT What Who Where When How Why To Do Phone Screen C MRN# Medical Record Release C Consent HIPAA C OHSU Notice of Privacy practices C Health Quest. Height/weight CTRC Vital signs RA HRC 10D HRC10 D Pre Sc Before study procedures After consent After NPP After Quest Tele regulation Pre qualify TSH history OHSU policy Inc/exc 1. Phone scr 2. MRN# 3. Research Flag 4. Get blue folders 5. Medical record release form 6. Script 7. Health Q. HCG Urine Pregnancy test CTRC RA HRC10 D Before lab & other procedures Inc/exc 22

23 What EKG (ECG) CBC CMS Triglycerides LDL TSH FreeT4 FreeT3 Urine HCG Ethnicity GDS (older subjects only) MMSE (older Subjects only) WAIS-R Pursuit Rotor (establish Baseline) Wh o RA Where When How Why To Do CTRC 10D Lab Central Lab Central Lab Central Lab Central Lab Central Lab Central Lab Central RA CTRC Lab C CTRC 10D C RC RC RC labs After HQ labs Before Labs & other procedures Blood Draw form. Quest Quest Vocab Equip Inc/exc Inc/safety Inc/safety Reg safety Inc/exc Inc/exc Inc/exc Baseline 8. Urine supplies 9. Scoring PR, GDS, MMSE WAIS-R 10. SCR Insrt. letter 11. Test PR 12. Check list To Do List Medical Record # request forms Research Flag request form Label for urine cup Get some Blue envelopes OP17A scanning Spec sheet for labs Health Questionnaire Order Files for source docs Forms including scoring for each GDS MMSE WAIS-R Pursuit Rotor (Baseline) Test Pursuit Rotor To Do List Screening letter Direction and maps Medical records release forms Medical records release forms Check List Screen failure log UP and protocol deviation log 23

24 Practicum 1. 4 groups 2. Take visit 1 from protocol 3. Put into categories on wall 4. Make a To Do List Protocol Implementation Ready, Set, Go! 24

25 Protocol Implementation Not quite yet There are 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 siteid=1&siteid=1&menuselectedindex=5 ) 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 25

26 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 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 CTRC 26

27 Other considerations Required Health screening/immunizations TB test Hepatitis B immunizations Ask Employee Health if you have questions 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? 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 27

28 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 qmrnumhim.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 28

29 EPIC and Research Consents and research docs must be in Epic if subjects receive clinical services per OHSU Research Documentation in the Integrated Health Record (IHR) Policy ( n02medrec/clin02-15.pdf df ) 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 Scheduling Cont. Research Admission - request form available at n.pdf) Scheduling at the Clinical and Translational Research Center (CTRC) instructions available at 183&menuid=51&siteid=1&MenuSelectedIndex=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? 29

30 Equipment and Supplies Cont. Use of Research Devices and Equipment on/adm html Must be inspected dby Clinical i ltechnology Services if the device/equipment was not purchased by OHSU Computers If the sponsor provides you with a computer for the study (not purchased through OHSU) it must be inspected by ITG 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 ) 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 # 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) 30

31 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 g/adm05-18.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 31

32 Common Protocol Deviations Non-adherence to inclusion/exclusion criteria Failure to comply with dispensing and dosing requirements Incorrect storage of study medications (see Drugs Dispensed to Research Subjects, Clin ANUALS/Clin05Meds/Clin05-11.html) Common Protocol Deviations cont. 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 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 32

33 How to Avoid Deviations cont. Follow OHSU Research and Hospital Policies: IRB Policies: icies/ OHSU Research Policies and Guidance: =123&siteid=1&menuid=1&siteid=1&MenuSelecte dindex=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 33

34 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 i Budget Location/Scheduling Training Feasibility Conducting the Protocol cont. Document, 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 of the results Research Records 34