Industry and CRO Perspective on Clinical Trial Quality - PowerPoint Presentation

Industry and CRO Perspective on Clinical Trial Quality David J. Hewitt Vice President of Medical and Scientific AffairsVice President and Global Head MSA Neurology and Pain IMMPACT June 2015

Currently working for inVentiv Health a CRO/CCO Involved in multiple trials for large and small biopharmaceutical companies Large commercial group that works with multiple biopharmaceutical companiesMerckJohnson & JohnsonDisclosures

Quality by DesignNeed more than a good protocolIt all starts with a thorough preclinical assessmentClinical trial design Investigator and Site selectionTrial ExecutionClinical Trial Quality Overview

Significant time to think, rethink, and reconsider decisions and then things change. Can impact quality Big pharma: Complex decision making process with significant input from hierarchical reporting structureSmall pharma : Smaller number of stake holders: VCs, CEO and board may have opinionsMoney impacts quality of the studySmall companies can burn through cash quickly just waiting for FPIWant to be sold or go publicBig pharma has the cash, but there are limitsSites might enter patients into higher paying (less complex) studies The Biopharmaceutical Companies and Quality

Focus is on study execution: quality and speedDoing one thing over and over again should make you good at what you do Project teamCROs have benefit of experience running multiple studies in the same areaSponsor may not have steady stream of studies in the area of interestFor small companies there is no other way CRAs are where the rubber meets the road. They need to be experienced. Central role in ensuring quality at the site levelContract Research Organizations and Quality

Sites: often well knownContracts: experience in working with academic institutions and research sites Regulatory: experience in country specific concernsScientific input: physicians in particular have a unique opportunity to see how different sponsors approach developing studies for a particular indication Contract Commercial Organization: protocol is reviewed with an understanding of the current market dynamics Contract Research Organizations and Quality

Portfolio of products requires decision on which compounds to move forward in developmentMost likely to be safe and effective What mechanisms to pursue Shots on goal versus….. De-risking assets: ensures quality of clinical trials that followSignificant investment in preclinical and early stage development to Demonstrate target engagementProof of pharmacology SafetySelection of optimum dose range for phase 2Quality Clinical Trials Begins with Early Drug Development

Tension between Stopping clinical development early and….. Recognition that a number of successful drugs have required champions and would otherwise been discontinuedDrugs tend to collect more adverse events over course of developmentClinical development plan and life cycle management Significant focus on de-risking developmentFocus on customer needs: patient, caregiver, physician, etcFocus on potential need for PROsHealth economic considerationsDiscuss with KOLsDiscuss with PatientsQuality Clinical Trials an Ongoing Process

Focus on choice of primary, co-primaries and secondary endpointsDesign study that is fit for new therapy and a specific mechanismQST: not all sites have.Need adequate training for consistency across sites Large number of outcome measures and instruments Provide evidence for payersBut patient and site burden can negatively impact the studyProtocol complexity is sometimes necessary, but complex studies can negatively impact qualityPI will work on less complex study everything else being equalClinical Trial Design

Blind investigator and staff to entry criteria: blind to start of study drugUse of algorithm can decrease variability and blind investigator Adaptive designs should be considered More efficientAdd or remove dosesDetermine efficacy and safetyMinimize harm Placebo and active controlled clinical studiesA failed study suggests a problemClinical Trial Design

Placebo EffectInvestigator enthusiasm for a drug can kill a promising drug Need to train staff and patientTherapeutic misconception: Patients confuse participation in a clinical trial with primary care for their conditionStudy subject is a partner in clinical research and not a patientPeople who are under insured could use participation in a clinical trial as a way to get medical care KOL/PI may know best how to assess patientConsistency of assessment is more importantConduct of Clinical Trials: Rater Training

Need dedicated team with expertiseEnsures the quality of the data collected Ensures that all sites are thinking the same wayProvide significant materials to understand the placebo effectOngoing training of patientsOngoing training of PI and study staff Conduct of Clinical Trials: Rater Training

Partners or patientsDo they exist? Patients are study subjects with a specific skill set to be good observers Just as inclusion and exclusion criteria define a population, the ability to participate in a study is not a given.Protocol might define a population that is too enrichedInclusion/exclusion criteria: are they too restrictive or lenient Study Execution: Patients

What is the benefit for patient to participate?Are they really seeking primary care?Are they refractory pain patients? Are there co-morbidities that will impact results?The rise of the professional patientShould subsets of patients be assessed based onQST, Physical examination, biomarker statusStratification purposes or to support demonstration of efficacy Study Execution: Patients

Important decisions on geographic diversity for commercial and regulatory purposes U.S., Western, Eastern Europe, Russia, Asia Pacific countries, Latin AmericaPlacebo effect may be regionalDifferent practice patternsDifferent start up timesImportation issues if controlled drug Academic versus….There are a number of top quality research sites and research networksStudy Execution: Sites

Large number of sites can enroll faster, but can sacrifice qualityLonger to get sites up and runningMore contractsMore IRBs/Ethics committees with differing concernsAdds significant variability to the data based on country, regional, and site differencesEach expert knows best how to assess a patient with a given instrument but…. Need standardization and agreement among ratersConsider visit to site to get to know PI and coordinatorStudy Execution: Sites

Value of Face to face investigator meeting Develop relationships that extend beyond a particular study or program Web based meetings are less desirable For protocols with commonly used designNeed more sites in minority areaStudy Execution: Sites

Yes it canPushing for faster enrollment might lead investigators to enroll subjects who may not be exactly qualifiedNegative and failed studies can have positive first half and negative second halfSome investigators pride themselves on high recruitmentEnrollment tends to increase over timeMore sites up and running Sites more comfortable with the protocolUnknown factorsAudit sites early in study proccessDoes Speed of Enrollment have Negative Impact Quality

Paper diaries: should they still be used?Electronic diaries Assess compliance during run in Avoid the “hood” effect that occurs with paperEvidence supports that paper diaries can be filled out retrospectivelyCan determine whether eDiary is filled out retrospectively or prospectively Assumption is that more accurate data increases quality of the study resultsTranslation: is it the same thing in different languagesNeed to instruct patients Quality: Diaries

SafetyLook for alerts, trends in the dataClinical monitoring: CRAs Medical monitoring: MDsPharmacovigillanceEfficacyMonitors work with sites to ensure quality of study conduct and answer questionsReview of blinded data Assess for concordance between outcome measuresToo much or too little If pain is going down, function should improveAssess regional and country differencesQuality: Monitoring Study

Insure inclusion and exclusion criteria are being followedNeed to identify major protocol deviations Independent DMC to review unblinded dataNeed independent statisticianSafety To stop study, ask questions Efficacy Stop for futility: no longer have therapeutic equipoiseStop due to overwhelming efficacyQuality: Monitoring Study

Risk based monitoringElectronic trigger that diary is being completed Electronic trigger that drug is being taken Speed versus Quality: Audit sites early in study process Quality: Monitoring Study

Use of flags Programming of data checksFollow up on SAEs Follow up on events of clinical interest.Clean the data in a continuous organized process: soft locksConsider the use of soft locksCheck programmingRun tables, listings and figures on blinded dataRemote data monitoring Need to ensure the patient is taking drug andNot taking too much…overdoseThe Data

Quality by designNeed more than a good protocolIt all starts with a thorough preclinical assessmentClinical trial design Investigator and Site selectionTrial ExecutionCollaborative partnership among sponsor, CRO, site and study subject partnerConclusions