Site-Less CRO Model and esource: Framework for Action

Site-Less CRO Model and esource: Framework for Action Joe Martinez, RPh, PDE, PPC Princeton, NJ

In-home and site-less clinical trials: changing the landscape How to test drugs, devices and procedures better How to get therapies to patients sooner and at less cost

In-home and site-less clinical trials: changing the landscape How to test drugs, devices and procedures better How to get therapies to patients sooner and at less cost Topics Current model overview Siteless CRO model overview esource Considerations

Drug Development Model 1970 s forward

Refuse-to-file @ FDA There has been a sharp increase in Refuse-to-File (RTFs) issued by the FDA from 2009 onwards 1 Main reasons include 2 Clinical data deficiencies and Data Presentation (~39%) CMC issues (~28%) ectd issues (25%) Other (8%) 1 June 2011 issue of Nature Reviews: Drug Discovery, Volume 10, page 403 2 Based on publically-available RFTs.

esource Business Case Scenario Legacy Model Set Up & SPA Recruitment Up to 1 year Trial Duration 30 days to 1.5 years DB Lock 0.3 years Analysis Site-less CRO Model with CTRP Up to 1+ year 4-8 wks 30 Days to 1.5 years 0.1 years Up to 6 mos Validate & lock data faster 6 days vs. 60 days Decrease patient burden and increase retention Time savings of 1+ years

Site-less CRO and Legacy Model Comparison Legacy CRO and Sites Sponsor Site-less CRO Sponsor Legacy CRO and Research Sites $$$$ Site-less CRO with CTRP Sites Sites Sites $ $ $ Sites $ Site-less CRO Unbundles services Increases quality Decreases costs Decreases response time Allows proactive and realtime analysis and action $$

Site-less CRO and CTRP Hybrid Model Legacy CRO and Sites Sponso r Site-less CRO Legacy CRO and Research Sites Site-less CRO with CTRP Sites Sites * Works extremely well as hybrid model with existing or future clinical trials

Site-less Clinical Research Organization (CRO) Pharmacists facilitate recruitment, informed consent, enrollment, protocol understanding, and regulatory compliance: Enhances patient adherence to protocol Reduces patient withdrawal Reduces trial costs and time Patient Recruitment and Enrollment Contact Order Form Modular Approach CTRP w/ Patient-Centric Coordination: Remote visits In-home nurse visits Medical monitoring AE reporting and follow-up Direct-to-patient clinical supplies Blood labs and other ancillary services CTRP Pharmacist Coordination: Technology/Phone/Video Conferencing Legacy Model and Patient Office Visits: Site/Physical Office visit at baseline and end of study according to protocol CTRP - clinical trial research pharmacist

Technology Platform: Web and Mobile etraining and econsent Clinical Supply/Direct Shipping Patients are recruited Patient data are collected by technology program Additional trial processes include: etraining, econsent, Online Conferencing, Clinical Supplies Distribution, EDC, Safety/AE Online Conferencing EDC and Safety

Patient Enrollment/Screening and Patient Waiting Room Patient Enrollment functionality - will offer general patient management services in order to process site resupply calculations correctly but can be expanded to include additional. Patient Waiting Room - to provide needed resources with a complete overview of the trial and where each patient is currently at in process. The material contained in this presentation is proprietary and confidential. It is provided it to clients for their sole use. Access to this presentation should be restricted to authorized individuals. This document contain proprietary and confidential information.

Patient Visit Management and Site Supply Patient Visit Management - to correctly manage clinical supplies throughout the trial. initial Site Supply and dynamic Site Resupply - allows the ability to adjust site resupply requests in-trial and automatically send requests to the clinical supply vendor

Reports Reporting and system integration - includes a Dashboard with Key Risk Indicators

In-home and Nursing Services

Streaming Health Wearable Data WA MT ND MN OR ID SD WY NE NV UT CA CO KS OK AZ NM TX ProRA Proactive Risk Assessment Engine HI IA MO AR LA WI IL MS MI IN KY TN AL OH GA WV SC FL NC PA VA DC NY MD NJ DE VT NH ME MA CT RI Streaming Health Data for Predictive Alerts: Geo-fencing Metabolic Physical Activity Specific factors

Smarter Trials and Easier for Patients Data Input Clinical Data Cloud Data: - Integration - Aggregation - Analysis Data Swamp Data Lake Data warehouse rebuild cannot ask? s fast enough to address real-time Operational analytics to address issues in real-time

esource Business Case Scenario Legacy Model Set Up & SPA Recruitment Up to 1 year Trial Duration 30 days to 1.5 years DB Lock 0.3 years Analysis Site-less CRO Model with CTRP Up to 1+ year 4-8 wks 30 Days to 1.5 years 0.1 years Up to 6 mos Validate & lock data faster 6 days vs. 60 days Decrease patient burden and increase retention Time savings of 1+ years

Site-less CRO with esource Technology Flow esource of data More effective monitoring No paper forms All entries up to date, no bolus of queries One source verification Regulatory esubmission Compliant EDC, CDISC and Domains More cost effective

Clinical Data Management and EDC CRF Design, Database build & validation Edit checks programming and testing Data Management Plan (DMP) development Clinical data review and query management External data transfer and reconciliation AE, concomitant medication, and medical history coding SAE reconciliation Development of custom status reports Database lock procedures

Clinical Programming and Biostats Randomization Plan & sample size determination Development of Statistical Analysis Plan (SAP) CDISC data conversion Statistical analysis Programming of tables, listings and figures (TLFs) Clinical programming for integrated safety and efficacy summaries (e.g., ISS/ISE) Statistical representation, programming of TLFs (data monitoring) and safety meetings (DMC/DSMB/DSMC) Clinical programming support for periodical reports (e.g. DSUR) Statistical reports

CDISC and its Standards CDISC The Clinical Data Interchange Consortium, non-profitable organization that defines the world-wide standards for representing clinical & non clinical data, required by the regulatory authorities as part of submissions. SDTM Study Data Tabulation Model, representing the collected clinical data in standardized structure and controlled terminology. ADaM Analysis Data Model, representing study analysis data in defined datasets structure. CDASH Clinicat Data Acquisition Standards Harmonisation, describes the basic recommended data collection fields SEND - Defining the structure and format of standard nonclinical tabulation datasets

Submission-ready Data Flow TLFs ADaM

Submission-Ready Clinical Data CDISC mandatory requirement Submission-Ready goes beyond CDISC Requirements are new - If you expect it, verify your CRO(S) will deliver Submission-Ready package

Features of Site-less CRO / esource trials Are conducted in participants homes via a central virtual coordinating center Use videoconferencing and other telehealth technologies to conduct trial activities such as recruitment, screening, informed consent, education, and data collection Allow direct communication and relationships between participants and a trusted study health professional (e.g., clinical trial research pharmacist [CTRP]) Maximize resources, study time, and return on investment via: Site-less CRO with CTRP services for recruiting, enrollment, and trial with in-country support In-home nursing services and Direct-to-Patient clinical medicines distribution Technology for data aggregation and ProRA (proactive risk assessment) Available from http://www.centerpointclinicalservices.com.

Studies suited to site-less CROs Site-less CROs are ideally used when: No office visits/assessments are required or remote assessments are appropriate Participants live in disparate or remote geographical areas Participants have complex diseases or other issues that make site visits difficult (e.g., those with disabilities or who need to be accompanied) Cold-chain medicines must be transported Study duration is long Site-less trials large or small can complement highly monitored phase 3 trials and reduce the time and cost of phase 3 programs. Covington D, Veley K. Appl Clin Trials. February 1, 2015. Available from http://www.appliedclinicaltrialsonline.com/ remote-patient-centered-approach-clinical-research.

Thank you Joe Martinez, RPh, PDE, PPC jbmartinez56@gmail.com 609-213-6466

CTRP Added-Value Service 9 out of 10 patients had at least 1 intervention 4 out of 10 patient calls had at least 1 intervention More than half of the interventions were for high impact situations http://www.clinicaltherapeutics.com/article/s0149-2918(17)30126-1/abstract