building quality into clinical trials -...

Jan Dugas

IntroductionQuality in Clinical TrialsChanging LandscapeForces for Change/Quality IssuesElements of Quality Clinical TrialsBuilding Quality into Clinical Trials

Clinical Research and Compliance Consulting 2

Safe & Effective Medical ProductsTrial ComplexityIndustry Challenges

Rising CostsDelaysCompliance to Global Quality

Globalization and outsourcingAligning industry practices with FDA Compliance


Increases concerns and decreased confidence

FDA promotes quality from start and on-going

Quality in clinical trials

Quality’s characterization


Produce and approved high quality products

With minimal regulatory oversight

High benefits and lower risks

By ensuring protection and welfare of our patients



FDA:Can’t “inspect in” quality retrospectively –need to build in prospectively

Expect shift from data-heavy IDE/IND submissions to “knowledge-rich”, i.e. with insights gained from Quantitative Risk Management (QRM) approaches

Involve regulators proactively in agreeing quality definitions for programs


EU:Identify risks prospectively

Comprehensive/holistic approach:Organizational levelProject level

In clinical program, apply concept at early program design stage, before individual trials are running

Both are working on moving quality by design (QbD) into studies in humans

This is part of the strategy of the agency to “develop more robust clinical infrastructure” –Janet Woodcock.

Provide “high-quality data” – strong enough to support the sponsor’s labeling claims.


Well recognized and in place for manufacturing of products.Implementing QbD system prospectively into clinical development is more effective than overhauling of processes, changing SOP’s and resources retrospectively.Increasing focus on having quality systems in place during planning stages.Systematic approach will produce more reliable and useful data.


Established out of shared visionMission/Scope:

To identify practices that through broad adoption will increase the quality and efficiency of clinical trialsGenerate evidence how to improve design and execution


ProjectsQbD is a major current interest since August 2011.Plan to expand beyond drug studies and sponsors.

PrinciplesProtect and promote public health.Generate adequate and timely information:– Prevention, diagnosis, treatment.Need to protect human subjects and their privacy.Work together to move the system forward.


Quality assurance has relied on audits and inspection but now under scrutiny

Protocol complexities and decline in study performance, subject recruitment and retentionGlobalizationMultiple outsourcing partners


Increased mergers and acquisitions

Digital revolution Electronic medical recordsTelemedicineMobile technologyIncreased regulatory requirements

Timelines


Consequences of poorly conducted research can be significant

Delay Potential harm Inaccurate product labelingLegal consequences


What Is Quality?“Quality” is characterized by the ability to

Effectively and efficiently answer the intended question about the benefits and risks of a medical product (therapeutic or diagnostic) or procedure

While

Ensuring protection of human subjectsOct. 2008, Dr. Rachel Behrman, CTTI and presently Director of CDE Office of

Medical Policy


Scientific valid and ethically sound protocolIndependent review prior to finalizationInclusion/exclusion unnecessarily restrictiveFeasible to carry out protocol requirements in all regions trial may be conductedMinimize protocol changes/amendments

Adequate protection of subject‘s rights, safety, and welfare


Qualified personnel - not just a CVAdequate time, staff, equipment, etc. Knowledge of regulations and requirementCommitment to researchWillingness to complete training requirements


Adequate monitoringSelection of monitorsStudy Monitoring PlanStudy specific training

Current complete and accurate data


4 common problems in a clinical trialProtocol DesignProceduralRecording (both random and fraudulent)Analytical


Focus on developing Quality System during clinical developmentDefine quality objectives

Exam investigational productPlan clinical trialsExam existing clinical trial processesIdentify potential risksDefine controls to prevent errorsIdentify problems and intervene before serious


Designing optimal infrastructureOptimizing processes and systemsDe-risking clinical programs “Fit-for-purpose” training and communicationEnhancing GCP compliance and reducing audit/inspection findingsMeeting health authority expectationsReduce costly errorsGetting it right first time – minimizing need for laborious “fixes”


FDA recommendsSay what you doDo what you sayProve itImprove it


Say what you doQualified management team to govern whole clinical trial processRobust oversight of outsourced activitiesPolicies and procedures for key clinical processes

Protocol development to clinical study reportsGood procedures can mitigate potential risks


Do what you sayEducation and training Protocol and study requirementsSystem and standardization

Policies and proceduresAll team members know their responsibilityMonitors it’s not just matching dataSite selection and learning curveProtection of clinical trial subjectsQuality assurance and auditing


Prove It - Requires new approaches:Risk-based monitoring

Process management & verification of critical activities including quality controlsCo-monitoring to ensure compliance to monitoring planRepeat/supplemental training as necessaryReplacement of monitors as necessary

Trend analysisLooks at data as compliance intelligenceStatistical monitoring


Enabled an integrated, cross-functional approach to proactively build quality into the clinical trialsThe team, collectively, developed a much better appreciation for what could go wrongResulted in greater ability to systematically manage qualityEnabled the team to take ownership of quality


There is a cost to poor qualityHigher quality leads to lower costsThis can be a win-win if done prospectively and correctlyContinuously improve!


Build quality into scientific and operational designFocus on what matters –subject safety and data integrityDevelop a quality management planProspectively measure the error rates of important parametersMonitoring tailored to trial design and quality objectivesImprove training and proceduresReport quality issues found, action takes, understand impact on analysis and interpretation of results


Innovations in study designs are critical for success of clinical development:

SimulationsAdaptive DesignsBayesian Networks

New initiatives to translate animal data into early human testing Build in quality in advance instead of fixing things afterwards


Compliance to quality requirements is the cornerstone of a scientifically valid and ethically sound clinical trialContinuous vigilance and continuous process improvementOverall objective

Subject protectionData quality/integrityProtocol compliance


QUESTIONS?


Thank YouJan Dugas, PresidentGlobal Clinical Advisor

Clinical Research & Compliance Consulting, LLChttp://dugasclinicalresearch.com/

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http://dugasclinicalresearch.com/

FDA.May2006.GuidanceforIndustry,Q8Pharmaceutical Development. Available at www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm128029.pdf.FDA. June 2006. Guidance for Industry, Q9 Quality Risk Management. Available at www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm128053.pdf.21 CFR 312 & 812US Food and Drug Administration. How well is the agency’s quality control system working? http://www.fda.gov/Safety/SafetyofSpecific Products/ucm180546.htm. Institute of Medicine. Assuring data quality and validity in clinical trials for regulatory decision making: workshop report. http://www.iom.edu/Reports/Assuring-Data-Quality-and-Validity-in- Clincal-Trials-for-Regulatory-Decision-Making-Workshop-Report .aspx..Eisenstein EL, Collins R, Cracknell BS, et al. Sensible approaches for reducing clinical trial costs. Clin Trials 5:75–84.Duley L, Antman K, Arena J, et al. Specific barriers to the conduct of randomized trials. Clin Trials 5:40–48.Williams GW. The other side of clinical trial monitoring; assuring data quality and procedural adherence. Clin Trials 3:530–537.Knatterud GL, Rockhold FW, George SL, et al. Guidelines for quality assurance in multicenter trials: a position paper. Control Clin Trials 19:477–493.Clinical Trials Transformation Initiative. Scope statement. http:// www.trialstransformation.org/scope.Code of Federal Regulations Title 21. US Food and Drug Administration, Department of Health and Human Services. Subchapter D: drugs for human use.

http://www.fda.gov/Safety/SafetyofSpecific

http://www/

http://www.trialstransformation.org/scope

building quality into clinical trials -...

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