Joy Ostroff, RN, BSN, OCN©Administrative Director, UNC Cancer Network

Sherrie Reynolds, RN, BSN, CCRP®QA Supervisor

Seidman Cancer Center

Risk-Based Monitoring Onsemble

September 18, 2013

Overview

• Past methods of monitoring– Resource intensive– Applied uniformly through life of the trial– High cost

• $1.2 billion (pre-clinical to market)• 25-30% of clinical trial costs

– No quarantine of good data, compliance, or safety• Health authorities transition to risk-based approach• Institute of Medicine (IOM) reports US Cancer Crisis• AACI CRI supports SIG looking for ways to explore,

define and operationalize best practices

IOM Report (9/10/2013)

“Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis”

• Crises– growing demand– costs of cancer care– shrinking work force– complex disease and treatment

• 1.6 million new cases each year (14 million survivors)• 2.3 million (45% inc.) new diagnoses 2030 (18 million survivors)

Year Cost of Cancer Care

2004 72 billion

2010 125 billion

2020 173 billion

Recommendations

• Engage patients• Adequately staffed, trained, and coordinated

work force• Evidence-based cancer care• A learning health care information technology

system• Translation of evidence into practice, quality

measurement, and performance improvement• Accessible and affordable cancer care

– Fee-for-service reimbursement system encourages a high volume of care, but fails to reward the provision of high-quality care

Change Monitoring Practices

• Rising costs of clinical trials– More sites, less patients at each site– Complexity of the trial– Wider geographic area (International)

• Real time assessment– Study status ,data, site performance

• Acceptance of adaptive approach– Scientific and business models

• Acceptance by regulatory agencies and health authorities• EMR, CTMS, Internet

Health AuthoritiesTransition to Risk-Based Monitoring

Federal Drug Administration (FDA)• Guidance on Monitoring of Clinical Investigations, 1988

• Guidance on Providing Clinical Evidence of Effectiveness for Drug and Biological Products, acceptance on different levels of documentation of data quality, 1998

• Human Subject Protection/Bioresearch Monitoring (HSP/BIMO) Concept Paper, 2007

• Guidance for Industry Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring,

Draft 8/ 2011

• Guidance for Industry Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring,

Procedural 8/ 2013

International Conference on Harmonisation (ICH)• ICH E6 addresses flexibility in how trials are monitored which includes reduced or no on site monitoring,

1996

European Medical Agency (EMA)• Reflection Paper, 2011

Medicines and Healthcare products Regulatory Agency (MHRA) UK• Risk-adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Products, 2011

The Clinical Trials Transformation Initiative (CTTI)• Public-private partnership (2007) identifying practices to increase quality and efficiencies

TransCelerate BioPharma• Risk-Based Monitoring Methodology, Position Paper (2013)

Monitoring vs. Auditing

Monitoring Auditing

- Continuous process - Snapshot in time

- On-site/off-site - On-site

- All patients on trial - Subset of patients

- Data driven - Compliance driven

Risk-Based Monitoring

An adaptive approach to clinical trial monitoring that directs monitoring focus and activities to the evolving areas of greatest

need which have the most potential to impact subject safety and data quality.

Position Paper: Risk-Based Monitoring Methodology Final 30May2013 TransCelerate BioPharma Inc

Adaptive Design

Current Monitoring Practices

There is a wide range.

• 4-8 weeks intervals on site with 100% source verification

• Web based platforms can be monitored and queried daily

• Every 3 year audit (cooperative groups)

General Recommendations FDA Procedural August 2013

– On-site monitoring, centralized monitoring– Standard checks of range, consistency, completeness of data,

unusual distribution of data between sites– Target on site monitoring for data anomalies or higher frequency

of errors, protocol violations, or dropouts relative to other sites– Data trends not detected by on-site monitoring– Source data and CRFs can be assessed remotely– Data quality of real-time data entry, e.g., missing data,

inconsistent data, data outliers, deviations– Statistical analyses of study data to identify sites that are

outliers, evaluate subject data for plausibility and completeness– Analyses of site characteristics, performance metrics (high

screen failure rates, eligibility violations, delays in reporting data), characteristics correlated with poor performance or noncompliance

– Complete administrative and regulatory requirements

Factors Influencing Study Quality and Integrity

– Well designed protocol– DMP study specific

• Mix of centralized and on-site monitoring practices

– eCRFs or CRFs • Study objectives• Critical data• Patient safety

– Qualified and trained• Investigators, staff, and monitors

“The most important tool for ensuring human subject protection and high-quality data is a well-designed and articulated protocol.” (FDA Draft Guidance August 2011)

Define Critical Data and Processes

– Data supporting primary and secondary objectives– Data critical to subject safety: SAEs and events

leading to treatment discontinuation– Data critical to trial design and statistical endpoints– Adherence to eligibility – Informed Consent process, prior to any study

related procedures– Documentation of administration of investigational

agent or treatment procedures

AACI/CRI

RRisk AAssessment TTool

Network and Sub sites SIGAdopt Risk Based Monitoring

• Number of Meetings:

2011 – 2013   (12 meetings)

• Risk Based Monitoring23 participants and 17 centers on last 2 call

Risk Based

• Describe the range of current monitoring practices – Survey Monkey – January 2011

• Define key quality objectives for monitoring clinical trials– Trial Complexity Form draft 2013

• Examine ways to build quality into trials to enable more focused and efficient monitoring– Next Step

• Guides for a Risk Based Approach to Monitoring

Risk Assessment per Trial

What is risk?

– Risk to the patients safety– Risk to future patients data– Risk to provider financial– Risk to sponsor litigation

AACI/CRI supported the development of a tool to determine potential risk to the institution as the sponsor.

AACI CRI Trial Complexity FormTool for Determining Institutional Monitoring Standards for

Investigator Initiated Trials

1. Funding Source

2. Phase

3. IND/IDE

4. Affiliate sites

5. International sites

6. Drug Administration

7. Number of modalities

8. Agent, Device, Treatment

9. GMP Facility

10. Collection of blood, tissue

11. Recruitment practices

12. Investigator and staff experience

Monitoring Levels

Monitoring Levels Ranges Action

Low 0 – 15 points Audit review only

Moderate 16 – 29 points Central monitoring and audit review

High > 30 points Site and central monitoring, and audit review

WorkshopAACI/CRI Annual Meeting

July 2013

Workshop• Protocol A

– Ph I/II Oxali/Docetaxel + Zactima Adv Esophagus and GE Junction• MC (4 sites), IND, IHC, EKG, placebo, Experienced PI

• Protocol B– Ph I Triapine + Pelvic RT +/- Weekly Cis for Locally Adv Gyn

• Single site, No IND (CTEP), biologic samples, multi modality, Inexperienced PI

• Protocol C – Ph I Revlimid + Docetaxel Q 3 weeks Hem Malignancies

• MC (1 site), No IND (CTEP), PK (several), Inexperienced PI

• Protocol D– Ph I Rebeccamycin + Oxali Refractory Solid Tumors

• MC (1 site), IND, biologic samples, Experienced PI

• Protocol E– Ph II Sorafenib RCC

• MC (1 site), IND, IHC, Experienced PI

Result of Tool1

Institution2

Institution3

Institution 4

InstitutionAverage Risk Across

Institutions PerProtocol

Protocol A 33 24 30 30 29

Protocol B 24 34 33 33 31

Protocol C 36 37 32 29 34

Protocol D 31 24 29 24 27

Protocol E 28 20 26 29 26

Average Risk Assessment Between

Institutions

30 28 30 29 29

Workshop Reveals

• More risk– Inexperienced PIs– PKs and biologic sampling– Multiple sites

• Less risk– IND holder

Process

• Conduct a risk assessment.

• Determine monitoring and/or auditing requirements to

adequately maintain oversight.

• Development a trial specific Data Monitoring Plan incorporating the proposed methodologies for oversight.

Institutional Challenges

• Staffing

• Funding

• Appreciation for the

importance and rigors of compliance

Discussion