1 PROTOCOL DEVELOPMENT Joint Research & Enterprise Office (JREO) St George s University of London Debbie Rolfe Regulatory Assurance Manager Joint Research & Enterprise Office Training
2 What? What is your Research question? What do you want to know? What do you want or need to prove?
3 WHY? Think Purpose - why do you want to know?
4 HOW? How are you proposing to answer the question? How long will it take?
5 WHO? Who is the target? Who do you need?
6 WHERE? Where will you find who/ what you want? Where are all the participants?
8 Your Project, the Protocol A project is a unique series of actions designed to accomplish a unique goal within specific time and cost limitations So first you need to be clear about what it is you want to do OR what question that you want answered
9 There is help. NIHR Research Design Service (RDS) Free support offering support on trial design, appropriate outcome measures and statistical input via It is highly recommended that a qualified statistician is involved in the trial design PRIOR to protocol development
10 Statistical advice at SGUL Biostatistician Irina Chis Ster What exactly do you want to do? Irina could help define OR refine the question How many participants are required to answer the research question(s) or to reach trial objectives? Study design? Blinded/unblinded? How many treatment/intervention arms? Your study could be powered to answer only the primary objectives you could request options to investigate how many more participants would be required to answer further objectives
11 Statistical Input Formulation of trial objectives -suitability of endpoints, their measurement, potential sources of bias, sample size, randomisation and blinding, methods of analysis including interim analysis. Advise on protocol design e.g. sequential, adaptive, cross-over or parallel group Advise on hypotheses e.g. trial may be powered to answer primary objective, however secondary objectives may have to be exploratory
12 Interim Analysis : Possible reason for stopping trial early following Interim analysis- superiority, inferiority, futility Statistical input into trial design and protocol development is recommended; evidence and/or procedures should be in place to accomplish. MHRA GCP inspectors can ask for evidence that this took place
13 Interim Analysis continued: Where the statistician is not editing the protocol directly then the statistician may supply a statistical considerations document version controlled and linked to the protocol on which it is based Where amendments occur during the protocol lifetime statistical review may be required to check impact on design and analysis this review must be documented
14 Number of participants Number and type of interventions Use of service providers Pharmacy, Pathology, Imaging, data collection Data collection tools design and provision Interim analysis Data analysis and reports ALL COST TIME AND MONEY
15 Don t PANIC!!!!!!!
16 Think ahead- COST The JREO team are awaiting your call! /5519 Grant Application MONEY!!!!!! JREO Pre- awards team- will calculate the university staff and resources cost the NHS costing team also in the JREO will cost for time, resource, any tests and procedures above routine care Pre awards team will assist in focusing you on required equipment and publication costs (post trial) Sponsorship costs (if applicable) Regulatory submissions Assist you in making application to the Grant awarding body within deadlines!
17 Project Team Meeting You need to establish your core team Identify required resource and services Contracts? SLAs? Break into elements Define roles and responsibilities of each Project Team member Assign an overall co-ordinator Project Manager Assign tasks and deadlines for each element Ensure appropriate review at each step Regular meetings!
18 JREO Research machine Assist in Co-ordination of service provider input & cost implications E.g. CTIMP trial and the associated costs to be considered..whilst you are sketching your ideas Pharmacy input manufacturing or provision costs Source of IMP- subcontractor identification? Ease of provisionformulary/non-formulary? Delivery mediums? use of aseptic services?
19 Review Who else Select appropriate reviewers in relation to type of CT being conducted Core team - Trial Manager, Regulatory Affairs, data management, medical safety, Chief Investigator, Clinical Supplies/pharmacy, R&D office, Specialist review may ALSO be required for example pharmacologist for a pharmacokinetic Trial PEER REVIEW! Especially for grant applications! Recommendations can be provided per funding body based on prior experience
20 What exactly is a Protocol? The most common dictionary meaning of a protocol is a system of rules and formal steps that explains the correct conduct and procedures to be followed in formal situations. A protocol according to SI is A document that describes the objectives, design, methodology, statistical considerations, and organisation of a clinical trial
21 OK (roughly) what it will INCLUDE Background and rationale behind the research question(s)! Study plan! Description of type of participants Description of interventions giving detail to tests, procedures, medications and dosages with a string of built in safety elements to protect those participants. Duration of individual participant study inclusion AND overall study length (approval to close) Clearly defined the End of Trial
22 So the idea is beginning to take shape Review process of draft protocol is continual and alongside your grant application until ALL parties agreed on final document version for regulatory submission
23 Why use Templates? Ensures key sections or wording are included Ensures consistency between documents across organisation Certain elements MUST be included Schedule 1, Part 2 (5) of SI 2004/1031 Will also force you into considering elements that may have otherwise not have been considered
24 Guidance on basic content ICH Guideline for Good Clinical Practice E6 (R1) section 6 MHRA website SPIRIT 2013 guidelines : Standard Protocol Items: Recommendations for Interventional Trials
25 JREO have 3 protocol templates currently (with a view to grow the protocol template suite) CTIMP Non-CTIMP (Pharmacy involvement) Device (generic) Templates still to be developed generic Questionnaire/ data collection protocol Non-CTIMP (no pharmacy involvement) Medical Device templates (???) to cover range of options
26 Drum rollllllllll
27 The Protocol
28 Key headings/elements Why? Background Information and rationale Describe the research question and justify ethically and scientifically why study needed Describe interventions required with risk/benefit analysis for each intervention Choice of comparator/dose selection Important references (published/unpublished) to support your theory/ hypothesis
29 Key headings/elements How? Objectives and Trial design study objectives reflect the scientific questions answered by the trial and will define its purpose and scope Closely tied in with trial design and analysis methods Describe trial type and design Specify and explain choice of study design because of it close relationship to trial objectives and its influence on study method, conduct, costs, results and interpretation
30 Key headings/elements Who and Where? Participants, interventions and outcomes Who are they- eligibility criteria How many and where from (this should be vague) What are you going to do with them IMP dose and schedule/ clinical interventions- tests and procedures/visit schedules Safety- management through modifications, rescue therapies, concomitant therapy and any restrictions
31 Key headings/elements How? Treatment assignment detail How stratification factors? By whom How is allocation sequence generated/ who generates Level of blinding if relevant Who knows? How would treatment be revealed in case of emergency?
32 Key headings/elements How? Data collection, management and analysis Description of study instruments e.g. questionnaires, laboratory tests, assessment tools Where data collected, stored and retention period- in relation to archiving Statistical methods for analysing primary and secondary outcomes and justification Statistical plan or where it can be found if not in the protocol
33 Key headings/elements How? Data monitoring - Who will be overseeing the data? Data Monitoring Committee? Role and function Interim analysis? Access to this data? Stopping rules? Safety reporting for participants What needs reporting- expected Vs unexpected How assessed and by whom How reported and in what format Who to and within what timelines
34 Key Elements Good housekeeping Consent/assent procedures Data collection, use, storage and maintenance inclusive of biological specimens Statement of compliance with GCP, relevant EU directive according to type of research, any other applicable laws Insurance/ indemnity arrangements Reference to relevant Sponsor SOPs Publication/authorship policy
35 Elements of Success Version control!!! Keeping everyone in the loop Review circle kept complete Grant awarded yay!!!!!!!!!!!! add the funder to the protocol work towards finalising your draft protocol in preparation for regulatory submission
36 UNFORTUNATELY It does not stop there!
37 Amendments! But why worry?
38 Substantial vs Non-substantial You must involve your statistician! Who will review for implications i.e. check still statistically powered to answer research question? may have cost implications. Contingency line in grant???
39 JREO Plans OUR evolving Protocol templates. Inclusion of tabulated Synopsis which should contain key field required to upload onto publicly accessible trial registration sites e.g. Clinicaltrials.gov Smart document auto population of information fields within synopsis to main document Protected fields to ensure uniformity Need your feedback
40 So.. What do you need to do?
41 JREO Team will help guide you all the way Phone our Office coordinator Jay ex 4986
42 JREO Workshops * Talk will last approximately 1 hour* o June Code Breaking in Clinical Trials 12.30pm 18 June Board room H2.7 July Medical Devices legislative updates 12.30pm 23 rd July Teaching room basement JW **Training programme will start again in September!! please visit the portal for further details** All presentations will be available on the portal for your reference We are always contactable to answer queries and help you through the process We can also help you with Grant applications and costing!! Both NHS and University Joint Research & Enterprise Office Training