Octo ber 2013

www.ctti-clinicaltrials.org

October 2013

DIA Clinical Forum Workshop

Pamela Tenaerts


The Clinical Trials Transformation Initiative

Public private partnership co-founded by Duke and FDA in late 2007All stakeholders involvedThrough a MOU with FDA, Duke convenes the initiative

MissionTo identify and promote practices that will increase the quality and efficiency of clinical trialsVisionA high quality clinical trial system that is patient-centered and efficient, enabling reliable and timely access to evidence-based prevention and treatment options


Why CTTI Formed U.S. clinical trials in crisis

Trial start-up times lengtheningEnrollment slowingCosts increasingMany investigators pulling out of clinical research

Increasing need for reliable evidenceTo evaluate new devices, drugs, biologicsTo determine best medical practiceTo compare effectiveness of diagnostic and

therapeutic alternatives


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 may harm individual patients and public health

relevant trials have never been performed trials that have been performed were poorly designed or conductedtrials have been performed but results are not known


Strategy

Identify and shape potential transformational changes to the system

Seek incremental improvements to current system

Consider portfolio improvements of clinical trials being done relative to public health needs


How does CTTI seek to effect incremental change?

Involve all sectors in selection, conduct, and interpretation of projectsIdentify and eliminate activities in the conduct of trials that do not add valueUnderstand incentives to maintain non-value-added activitiesMaintain an open and respectful dialogue across sectorsDevelop solutions that are mindful of the needs of patients and all sectors in the clinical research enterprise


Organization

Executive Committee (EC) Provides oversight and strategic directionGives input into strategy and project selection. Conducts projects and develops strategies for implementation of project resultsEngages patient advocates as integral part of CTTI activities

Support projects and organization in pursuit of mission

Steering Committee (SC)(member organizations representatives)

CTTI Staff

Patient Leadership Council (PLC)


EC Members

8

Co-chairsRobert Califf (Duke) Rachel Sherman (FDA/CDER)MembersHans-Georg Eichler (EMA) Richard Platt (Harvard) Dalvir Gill (TransCelerate) Nancy Roach (Patient Rep)Louis Jacques (CMS) Jean Rouleau (Montreal Heart) Richard Kuntz (Medtronic) Joe Selby (PCORI)Michael Lauer (NIH/NHLBI) Robert Temple (FDA/CDER)Elliott Levy (BMS, SC rep) Veronica Todaro (PLC rep) Freda Lewis-Hall (Pfizer) Tom Walley (NIHR)Deven McGraw (CDT) Bram Zuckerman (FDA/CDRH) Briggs Morrison (AstraZeneca)


SC Membership

9

Category # OrganizationsAcademic institutions 17

Pharmaceutical and biotech companies 16

Professional societies/Trade organizations 9

US Government Members & Liaisons 7

Clinical investigator groups 4

Clinical research organizations 3

Device companies 3

Institutional Review Boards 2

Professional Service Organizations 2

Private Equity Firm 1

Standard Setting Organization 1

Total 65

Patient Representatives 2


Patient Engagement Patient representatives serving on Steering Committee

and Executive Committee Included in workshops, expert meetings, and projects

CTTI’s Patient Leadership Council (PLC) Collective voice with patient advocacy organizations

(PAO) and voluntary health agencies (VHA) to work together to affect systemic improvement within the clinical trials enterprise

Initiate patient-driven panels, events and projects that improve the quality and efficiency of clinical trials


Patient EngagementIn 2012, CTTI conducted interviews with key thought leaders in patient advocacy to gain an understanding of the patient perspective on clinical trials. Issues were raised around:• Informed consent• Inefficiencies in the system such as multiple IRB reviews• Waste of patient time and participation• Lack of access to research findings• Lack of meaningful inclusion of patient advocates in the

clinical trial enterprise from study design to dissemination of research results


Financial resources from public and private sources annual membership fees

infrastructure and projectsFDA cooperative agreement

additional support for projectsIn kind contributions of effort from FDA and membership organizations

Finances


“Because of the broad array of engaged stakeholders, CTTI is in a unique position to drive major changes in the clinical trial system in the midst of massive global

reforms.”

Rachel Sherman, M.D., Director for the Office of Medical Policy at the FDA’s CDER

Co-chair of the CTTI Executive Committee

Why CTTI Works


Key CTTI Accomplishments Generated evidence and formulated implementable

recommendations that have informed regulatory guidance

Created an inclusive forum that is influencing policy

Increased patients’ voice to improve clinical research

Raised questions about the portfolio of clinical trials as it relates to public health needs


Focused on transformationStrong, balanced portfolio of projects that inform and support policies and practices

Continue needed incremental improvementsAssist in transforming trials by better integrating clinical research with clinical practiceLarger number of projects/initiatives

Better engagement of stakeholders to facilitate meaningful change (members, patients, collaborators)

Future Direction


Methodology


Portfolio of CTTI ProjectsInvestigational Plan Study Start-Up Study Conduct Analysis &

Dissemination

Completed Central IRB Site Metrics

Adverse Event ReportingMonitoring

Ongoing Antibacterial Drug DevelopmentLarge Simple TrialsLong-Term Opioid DataPatient Engagement*Pregnancy TestingQbD & QRMUses of Electronic Data

*EC approval pending

Central IRB AdvancementGCP TrainingInformed ConsentRecruitment & Retention

IND SafetySafety Case Studies

State of Clinical Trials

PROJECT PORTFOLIO – September 2013


GCP Training

Objectives

• To improve the efficiency of GCP training imparted to investigators and site personnel conducting clinical trials


Deliverables

• Summary of current practices and issues related to GCP training

• Recommendations on key elements of GCP training content and frequency

• Recommendations to facilitate a more efficient GCP training process

Anticipated Impact

• Improve the efficiency and reduce the cost of clinical trials by streamlining the GCP training requirements


Informed Consent

Objectives

• Understand the needs of patients and existing initiatives to address those needs

• Understand barriers to concisely communicating required elements of informed consent

• Identify tools and technology that improve the informed consent process


Deliverables

• Publication describing current landscape and best practices

• Recommendations to improve the informed consent process

Anticipated Impact

• A more efficient and higher quality informed consent process


Objectives

• To understand the real and perceived barriers that have limited the adoption of LST designs for regulatory submissions or other purposes


Deliverables

• Publish summary of current practices and issues

• Recommendations to facilitate the use of LST designs

Anticipated Impact

• LSTs will be used more often for appropriate trials conducted for regulatory submissions and other purposes

Large Simple Trials


Objectives

• Understand nature of patient groups and their engagement in clinical trials

• Understand current practices for how research sponsors engage patient groups

• Identify best practices for engaging patient groups that will lead to more efficient and successful clinical trials


Deliverables

• Recommendations for best practices to engage patient groups

• Toolkit to help research sponsor implement recommendations

Anticipated Impact

• Greater collaboration between patient groups and sponsors will lead to more efficient and quality-driven clinical trials

Patient Engagement


Recruitment and Retention

Objectives

• Address the barriers to recruitment and retention of patients in clinical trials


Deliverables

• Summarize the barriers to successful trial enrollment and retention

• Issue recommendations for strategies to address those barriers

Anticipated Impact

• More trials that answer important questions will meet their recruitment targets

• The recruitment process will become more efficient


Site Metrics

Objectives

• Identify and quantify components of study start up (SSU) so that standard metrics can be developed and then used to measure and improve important SSU activities


Deliverables

• The US clinical trials enterprise lacks standards regarding terms, definitions, and milestones for SSU activities

• Within individual companies, data elements are often collected in different departments and the collection is tied to a sponsor’s processes and cannot easily be changed

• Factors associated with shorter cycle times:

• Use of central IRB• Private practice or

independent site

Anticipated Impact

• SSU metrics can be developed using the information collected in this project and taking into account the identified barriers to standardization


State of Clinical Trials

Objectives

• Characterize the U.S. clinical trials enterprise

• Facilitate the analysis of data in ClinicalTrials.gov

• Develop and validate a methodology for analyzing trials by clinical specialty


Deliverables

• Annual report of the state of clinical trials

• Database for the Aggregate Analysis of ClinicalTrials.gov (AACT), updated annually

• Manuscripts and presentations on the state of clinical trials enterprise as a whole and within medical specialties

Anticipated Impact

• Identify trends in how clinical trials are conducted, including improvements over time

• Improve the quality of studies done using data from ClinicalTrials.gov

• Opportunity to ensure that research is aligned with public health needs


Objectives

• Assess the feasibility of using the M-S Distributed Database (MSDD) to facilitate recruitment & follow-up of participants in randomized clinical trials, including both individual and cluster randomized trials


Deliverables

• White Paper with recommendations for using the MSDD for clinical trials, including:• Approaches to obtain

informed consent and related privacy considerations

• Implications of use of M-S data to conduct research (as opposed to public health surveillance)

• Implementation and oversight of such research

Anticipated Impact

• A clinical trial will be done using the MSDD, as a proof of concept

• Cost and time savings as electronic health data are increasingly used in the conduct of clinical trials

Uses of Electronic Data


Safety Projects

Original SAE project (2009-2010)IND Safety Assessment and CommunicationSAE case studies project


2009-11 CTTI ProjectFocused on expedited reporting from sponsors to site investigatorsInvestigators had complained of a large volume of expedited reports that were not interpretable as individual cases

Recommendations:

Decrease the volume of uninterpretable and irrelevant safety reports to investigators

Supply investigators with meaningful reports that would improve investigators’ understanding of a drug’s safety (benefit-risk) profile.

Engage patient groups to discuss optimal systems for safety reporting to investigators and patients during the conduct of a trial; re-evaluate consent language

27


IND Safety Assessment and Communication Project

September 29, 2010: FDA issued a Final Rule on IND safety reporting (effective 3/28/2011)FDA intended to reduce the number of uninterpretable reports by clarifying sponsor and investigator responsibilities in reporting and analysis of serious, unexpected events suspected to be caused by the drug

28


FDA’s final IND safety rule

FDA specified that sponsors should report serious events in an expedited fashion only if the sponsor judged that there was evidence to suggest a causal relationship between the drug and the event

Stated purpose: enhance the ability of sponsors, FDA, investigators, and IRBs to focus on important safety issues

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Concerns raised by sponsors regarding the final IND safety rule

Responsibility for determining causality- not harmonized globally

US: Sponsor’s determination of causality should drive decision on reporting

EMA: If either sponsor or investigator considers the event causally associated, it should be reported

Methodological questions regarding assessment of causal associations across a development program

30


Objectives

• Understand sponsors’ practices for assessing safety of a pre-market product across all trials and communicating potential safety signals

• Facilitate discussion of practices and challenges in assessing and communicating IND safety information

Deliverables

• Summary of sponsors’ current safety practices

• Recommendations for future approaches that will support the intent of the final IND safety reporting rule

• Related deliverable - report of independent workgroup of biostatisticians on methodological issues

Anticipated Impact

• Greater responsible oversight of safety for pre-market products consistent with the intent of the FDA’s new IND safety rule

IND Safety


Safety Case Studies

Objectives

• Compare different strategies for expedited safety reporting

• Perform an informative analysis of individual, expedited safety reports


Deliverables

• Publish case studies on expedited safety reporting in two clinical trials completed prior to implementation of the FDA IND safety rule (effective March 28, 2011)

Anticipated Impact

• Sponsors can use the case studies to develop more efficient strategies for expedited safety reporting that complies with the FDA IND safety rule


Central IRB Advancement

Central IRBRecommendations

Central IRBs be used in multicenter clinical trialsSite and IRBs use a CTTI-

developed guide (considerations

document)Sponsors in a position to

require central IRB to review should do so

Adoption

Workshops and webinarsImproving considerations

documentDeveloping new tools and identifying best practices

Anticipated Impact

More institutions use IRB of record for multicenter

studiesStudy start up is faster

Treatments get to patients faster



Monitoring ProjectGoal

Identify best practices and provide sensible criteria to help sponsors select the most appropriate monitoring methods for a clinical trial, thereby ensuring reliable and informative trial results and human subjects’ protection

Work stream 1: Describe the range of current monitoring practices and examine factors that drive their adoptionWork stream 2: Define key quality objectives for monitoring clinical trialsWork stream 3: Examine ways to build quality into trials to enable more focused and efficient monitoring


WS1: 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


WS2: Key Quality Objectives

Major quality objectives are to

Protect participant rights, safety and wellbeingEnsure the reliability of the study resultsMaintain adherence to the protocol

Monitoring also provides

An opportunity for focused trainingFeedback that can improve study processes


WS3: Building Quality into TrialsPrimary 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


WS3: Building Quality into Trials

Focus on what is important:Importance of proper randomization

no foreknowledge of likely treatment allocationminimize post-randomization withdrawalsminimize loss to follow-up

Sufficient numbers of relevant clinical outcomesUnbiased ascertainment and analysis of study outcomes


WS3: Building Quality into TrialsOversight 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 resultsSingle-minded focus on checking/ensuring accuracy of every data point is misguidedSponsors and regulators should agree up front what data points are critical and need to be verifiedSponsor should institute metrics to prospectively ensure the quality of critical data


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

Focus on what matters

Develop a quality management plan

Assess performance in important parameters

Improve training and procedures

Report findings of quality management approach


Quality by Design (QbD) & Quality Risk Management (QRM)

MonitoringRecommendations

Quality needs to be built into the design and conduct

of trialsMonitoring approach for a

given clinical trial should be tailored to the needs of that

trial

Adoption

QbD principles documentWorkshops to teach QbD and QRM and allow stakeholders

to practice using the principles document

Anecdotes that industry is adopting

Anticipated Impact

Clinical trials will be more streamlined, fit for

purpose and quality driven focusing on the absence of

errors that matter


Octo ber 2013

Documents

Transcript of Octo ber 2013