Current perspectives on monitoring in clinical trials:

Clinical Trials Transformation Initiative update and recommendations

Dr Martin Landray Reader in Epidemiology & Honorary Consultant Physician

Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU)

University of Oxford

Need for reliable evidence from clinical trials

• Essential for appropriate decision making concerning the benefits and risks associated with clinical interventions.

• Decisions made in the absence of reliable evidence (either because relevant trials have never been performed or because those that have been performed were poorly designed or conducted) may harm individual patients and public health.

FDA Clinical Trials Transformation Initiative

Mission

• To identify practices that through broad adoption will increase the quality and efficiency of clinical trials

• Seek incremental improvements to current system

• Identify and shape potential transformational changes to the system

Strategy

Encouraging Incremental Change

• Develop evidence that may generate recommendations for improvement and inform regulatory guidance

• Involve all sectors in selection, conduct, and interpretation of projects

• Identify and eliminate activities in the conduct of trials that do not add value

• Understand incentives to maintain non-value-added activities

• Maintain an open and respectful dialogue across sectors

• Develop solutions that are mindful of the needs of patients and all sectors in the clinical research enterprise

• Objectives 1. Describe the range of current monitoring practices and

examine factors that drive their adoption (What’s happening?)

2. Define key quality objectives for monitoring clinical trials (What’s the aim?)

3. Examine ways to build quality into trials to enable more focused and efficient monitoring (How can we improve?)

• Leaders – Martin Landray PhD FRCP (U. of Oxford) – Briggs Morrison MD (Pfizer, Inc.) – Rachel Sherman MD (OMP, CDER, FDA)

Monitoring Project

Results: Survey of Monitoring Practices

Results consistent with hypotheses:

• Wide variety of monitoring practices in use

• Choice of monitoring approach depends on type of organizational sponsor

• Rationale for using any specific monitoring approach does not appear to be evidence-based

*Poster of results on CTTI Website: https://www.trialstransformation.org/projects/effective-and-efficient-monitoring/monitoring-project-workstream-1

Results: Range of Monitoring Practices

• On-site monitoring

– Industry and CROs: ≥80%

– Academic coordinating centers/cooperative groups/ government organizations combined: <33%

• Despite availability of central data, ≤33% organizations use centralized data monitoring to guide, target, or replace site visits

Major quality objectives are to:

• Protect participant rights, safety and wellbeing

• Ensure the reliability of the study results

• Maintain adherence to the protocol

Monitoring also provides:

• An opportunity for focused training

• Feedback that can improve study processes

Monitoring objectives

www.ctti-clinicaltrials.org

• Primary focus should shift from post-hoc monitoring / inspection to incorporation of quality into the scientific and operational design of a trial

• No single monitoring approach is appropriate or necessary in all circumstances

• Monitoring approach (which may combine several methods) should be tailored to the needs of the particular clinical trial

How can we improve?

www.ctti-clinicaltrials.org

Building Quality into Trials

Focus on what is important:

• Importance of proper randomization

– no foreknowledge of likely treatment allocation

– minimize post-randomization withdrawals

– minimize loss to follow-up

• Sufficient numbers of relevant clinical outcomes

• Unbiased ascertainment and analysis of study outcomes

Building Quality into Trials

Oversight should focus on those errors most likely to adversely affect trial quality:

• Data elements vary in their impact on the safety of participants or on the reliability of trial results

• Single-minded focus on checking/ensuring accuracy of every data point is misguided

• Sponsors and regulators should agree up front what data points are critical and need to be verified

• Sponsor should institute metrics to prospectively ensure the quality of critical data

Hypothetical example: Minimal impact of adding false events or of missing real events

Active

(10,000)

Control

(10,000)

OR(& 95%CI) Z score

True events 800 1000 0.78 (0.71-0.86) 4.9

Extra false events (evenly distributed)

+ 10% 890 1090 0.80 (0.73-0.88) 4.7

+ 20% 980 1180 0.81 (0.74-0.89) 4.6

Missing real events (unevenly distributed)

- 10% 720 900 0.78 (0.71-0.87) 4.7

- 20% 640 800 0.79 (0.71-0.88) 4.4

HPS: Effects of simvastatin-allocation on ADJUDICATED major vascular events

HPS: Effects of simvastatin-allocation on UN-ADJUDICATED major vascular events

Monitoring Recommendation

Build quality into the scientific and operational design and conduct of clinical trials

• Focus on what matters – “Quality” is defined as the absence of errors that matter

(i.e. errors that have a meaningful impact on patient safety or interpretation of results)

– Determine what matters for the specific trial

• Develop a quality management plan – Initiate in parallel with protocol development

– Focus on areas of highest risk for generating errors that matter

– Seek regulatory review of plan

• Assess performance in important parameters – Prospectively measure error rates of important parameters

– Tailor monitoring approach (e.g. site visits, central, statistical) to the trial design and key quality objectives

• Improve training and procedures – Base on measured parameters

• Report findings of quality management approach – Include issues found, actions taken, impact on analysis and interpretation of results

– Incorporate into regulatory submissions and publications

– Encourage inclusion in ICMJE requirements www.ctti-clinicaltrials.org

Ancillary Recommendations

• Share knowledge and experiences

– Collaboration between academia, industry, and regulators to share methodologies and data

• Encourage appropriate regulatory guidance

– Emphasize key principles of quality trials (i.e. human subjects protection, reliable results, protocol adherence)

– Encourage risk-focused oversight of trials

• Promote education and awareness

– Audience: those involved in design, implementation, analysis, interpretation, regulation, inspection, and publication of clinical trials

– Include users of results (e.g. health care providers, doctors, patients)

• Seek international adoption and harmonization

– Facilitate global adoption of proposed changes

Draft US FDA Guidance on a risk-based approach to monitoring (August 2011)

“There is a growing consensus that risk-based approaches to monitoring, such as focussing on the most critical data elements, are more likely to ensure subject protection and overall study quality, and will permit sponsors to monitor the conduct of clinical investigations more effectively than routine visits to all clinical sites and 100% data verification.”

Quality by Design (QbD)

Protocol

(Plan)

- assess key risks

(likelihood, impact)

- plan mitigation

- plan evaluation

Operations

(Do)

- organization, training,

systems and procedures

tailored to the protocol

Monitoring

(Check)

- measure and evaluate

performance

Make improvements

(Act)

- re-assess risks

- make appropriate changes

to protocol, operations or

monitoring

Landray 2011

• Objectives – Develop principles

– Review case-studies

– Develop skills

– Explore evaluation methods

– Dissemination of results

• Leaders – Martin Landray (University of Oxford)

– Briggs Morrison (Astra-Zeneca)

– Ann Meeker-O’Connell (OSI, CDER, FDA)

Quality by Design Project

References

• Academy of Medical Sciences: A new pathway for the regulation and governance of health research. http://www.acmedsci.ac.uk/p99puid209.html

• Morrison BW, Cochran CJ, White JG et al. Monitoring the quality of conduct of clinical trials: a survey of current practices. Clin Trials 2011;8(3):342-349.

• CTTI Monitoring Recommendations https://www.trialstransformation.org/projects/ctti-recommendations

• FDA Draft Guidance: Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring htttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM269919.pdf

• EMA Reflection Paper on risk based quality management in clinical trials. Draft for consultation. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/08/WC500110059.pdf

• MRC/DH/MHRA Joint Project report on risk-adapted approaches to the management of clinical trials of investigational medicinal products http://www.mhra.gov.uk/home/groups/l-ctu/documents/websiteresources/con111784.pdf