ICTMC & SCT 2017 Conference, Liverpool REGISTRY-BASED RANDOMISED CONTROLLED TRIALS – THE FUTURE FOR CLINICAL TRIALS? David Beard GDPhys, MCSP, MA, MSc, DPhil, FRCS (hon) Professor of Musculoskeletal Sciences Co-Director Royal College Surgical Trials Unit (SITU, Oxford) & Extended Scope Practitioner (NHS Knee), Swansea

Disclosures Institutional Research Grants – Zimmer Biomet Committees - Arthritis Research UK, Finnish Academy Various Journal Review Institutional support - ZB PRO-MAPP Ltd – Non Exec Director – Oxford Uni Spin Out

Outline General advantages of registry use for trials (focus on orthopaedic) Challenges Design Response Outcome measures Validity of the data Practicalities

General advantages Efficiency of effort Available infra-structure Funding Patient perspective (repetition)

Orthopaedic Registries – not just longitudinal data collection….. 1975

Purpose

Purpose Survival ! (re-operation/revision)

Purpose

Orthopaedic Registry - Advantages Mandated data collection – govt. Response rate – usually v good Ownership by many parties Not onerous Not cost prohibited Level of standardisation Third party evaluation - bias

Embedding RCT’s - Challenges Design Response rate Outcome measures Validity Structure and pragmatics

IDEAL http://www.ideal-collaboration.net

IDEAL-D Obvious need to evaluate using existing infra-structure or coherent methods

Design - comparison Same confounders Which Rx is best? Device V Device : TKR1 v TKR2 (assumes standardised surgical technique) V V Procedure V Procedure: P1 v P2

X Design - limitations V Surgery V No Rx : P1 v 0 Surgery V Conservative Rx: P1 v C1 V Surgery V Placebo Rx: P1 v Plc

Design

Design – CSAW. Can Shoulder Arthroscopy Work? Group AMSR: No Surg. Active Monitoring with Specialist Reassessment (natural Hx) Group ASAD: bone removed, active surgical Rx Group AO: Arthroscopy only (“placebo” ASAD) No Rx control V Active Rx Active Rx V “placebo ASAD”

Design (and response rate) Non Acute Population: No data for non operative group Response rate Existing registry IT database Patients with ACL rupture A. ACL Reconstruction (with post op rehab) B. Non operative Rx Rehabilitation Questionnaires at 6/12 and 1 year - + 50%? No ACLR ACLR Follow up at 18 months KOOS 4 Follow up at 18 months

98% down to 55% for same implant Outcome Most registries limited – SAFETY BASED failure by survival (re-operation) Few with PROMs Endpoint? revision inadequate poor function, pain failing implants not revised 98% down to 55% for same implant

TOPKAT - Re-operations n=13 Complication PKR TKR Major revision (single stage) 1 - Minor revision (exchange of poly insert) 2 Manipulation under anaesthetic 6 Aspiration Injection under anaesthetic Sub Total (re-operations) 7

Primary Outcome - OKS 1.8 point diff 1.5 point diff p=0.03 p=0.09

Outcome measures – Marion Campbell/Rumana Newlands Mapping exercise England and Scotland Various trials outcome listing, ease of extraction, cost Assessing clinical importance of missing outcomes Core outcomes OK – secondary?

Outcomes Inserting new trial specific outcomes without compromising registry data…… Hybrid outcome measures…

Validity Data collected with “registry” mindset? Prospective OK – Retrospective?? Selection bias +++

Validity - research UTMOST – NIHR HTA Efficient Study Designs Risk-benefit and costs of unicompartmental (compared to total) knee replacement for patients with multiple co-morbidities: a non-randomised study, and different novel approaches to minimise confounding. Professor Daniel Prieto-Alhambra Validate registry findings with RCT Hawthorne type effects – RCT v cohort ?

Integrated process Simple? Registry Profile 10 yrs Embedded RCT

Complexity of process and data input L Davies

IT - Integrated Data Collection Clinicians Providers Commissioners Manufacturers Patients Unified platform, different applications clinical pathway software clinical PROMS software longitudinal surveillance software dedicated trials software

Summary – Trials in Registries in Ortho Several advantages ..and is possible Not all trial designs – A V B only - no proof of efficacy Response rate needs monitoring Need to insert appropriate outcomes Validity – potential…work in progress Data collection system – work in progress

Thank You Encaenia, Oxford Three Cliffs, Gower