The Implications of Modifying Study Eligibility Post ...

1 The Implications of Modifying Study Eligibility Post-Initiation of RecruitmentCOLLEEN ALLEN MPH CCRAR ecruitmentCOLLEEN ALLEN, MPH, CCRATHE EMMES CORPORATIONTHE SOCIETY FOR CLINICAL TRIALS35 THANNUAL MEETING35 ANNUAL MEETINGMAY 19, 2014 PHILADELPHIA, PENNSYLVANIAB ackground Ideally, Eligibility criteria are not changed after recruitment begins Under certain circumstances, it is necessary to revise the criteriathe criteria The pros and cons, from a data management, regulatory, and statistical perspective , must be gy,pp,weighed Presentation draws on experiences and lessons ld dif i li ibilit it i ti iti ti learned Modifying Eligibility criteria post-initiation of recruitment for a large, multi-center protocol within a multi- Study clinical trials networkyNIDA CTN Clinical Trials Network (CTN) of the National ()Institute on Drug Abuse (NIDA) Multi-site, multi-protocol network designed to Study pharmacological and behavioral interventions for the treatment of substance use disorders in community treatment programstreatment programs The EMMES Corporation has a contract to serve as the Data and Statistics Center (DSC) for the networkthe Data and Statistics Center (DSC) for the networkCase Study NIDA CTN-0049: Project HOPE: Hospital Visit as 49jpOpportunity for Prevention and Engagement for HIV-Infected Drug Users 10 site, 800 participant, 3 arm, randomized trial to assess impact of intervention on HIV viral suppression in hospitalized HIVinfected drug userssuppression in hospitalized, HIV-infected drug usersCase Study (cont.)

2 Original Eligibility criterion required a detectable ggyqHIV viral load (>200 copies/mL) and baseline CD4 <350 cells/uL in the past 6 months Shortly before the Study launched (March 2012), the Department of Health and Human Services released updated HIV treatment guidelines which released updated HIV treatment guidelines, which recommended anti-retroviral therapy (ART) for all HIV-infected individuals; previously, ;py,recommendation had been to start ART in those with a CD4 count <350 cells/uLCase Study (cont.) Study opened to recruitment in July 2012ypy Decision was made in November 2012 to revise the protocol Allow for patients with higher CD4 counts to be included, in part to reflect the change in clinical practice Instituted new pre-screening process to streamline screening Instituted new prescreening process, to streamline screening process and to reduce participant and staff burdenStatistical and Scientific Considerations Need to ensure that changes do not change the ggoriginal assumptions upon which the sample size and Study design were based Need to understand the impact of changes on generalizability of Study resultsScientific and Statistical Considerations.

3 CTN-0049 Study was designed as an effectiveness Study , rather ygy,than an efficacy Study , so it was important that the results be applicable to real-world practice, which hd hdhad changed Change in Eligibility criteria did not impact ability to assess primary outcome of Study or modifications to assess primary outcome of Study or modifications to sample size calculations Approximately 48% of the targeted sample size had Approximately 48% of the targeted sample size had been randomized at the time the amendment was approved at all sitesRegulatory Considerations Protocol amendments will require review and qapproval by a number of agencies and boards DSMB f h i ii i ( b l ) IRBs for each participating site (or by central IRB) FDA, if Study under IND or IDE Must weigh time required for regulatory review and Must weigh time required for regulatory review and approval with time remaining in Study for amendment to be in effectRegulatory Considerations.

4 CTN-0049 Required review and approval by the DSMB qppy Study is not conducted under IND, so no submission to FDA required 10 participating sites, each with their own IRB Took ~3 months for all sites to obtain IRB approval for the dtamendment Recruitment continued for one year post-implementation of amendmentimplementation of amendmentTraining Considerations Project staff, both at the site level and at the j,coordinating centers, will need to be trained on the new criteria Method for training may vary depending on scope of change Written memo Written memo Conference call Webcast In-person meeting/on-site trainingTraining Considerations CTN-0049 Coordinating center and protocol operations staff gppwere re-trained during regular weekly operations conference calls Site staff were re-trained during regular weekly national conference callsSit it i i it l id d tit Site monitoring visits also provided an opportunity to confirm re-training and assess understanding of protocol changesprotocol changesOperational Considerations In addition to amending the protocol, revisions may gp,yalso be required to the following: Operations manualS d h kli d d Study checklists and source documentsOperational Considerations.

5 CTN-0049 In conjunction with making the protocol changes, jgpg,the Manual of Operations (MOP), Study source documents, and Study checklists were also modified d d t d i di t ib t d t t d itand updated versions were distributed to Study sitesData Considerations Case Report Forms will likely need to be revised to pyreflect the protocol amendment Updates to the data system can take a few weeks to a few months depending on the complexity of the change, to adequately implement and test the changeD ii t b d b t hth t dl Decision must be made about whether to delay implementation of the amendment until the data system changes are completed; may require a back-system changes are completed; may require a backup data collection planData Considerations: CTN-0049 Modifications to electronic data capture system py(EDC) took approximately 4 months to complete and were made concurrently with IRB reviews Modifying the enrollment form to reflect the revised Eligibility criteria was straightforward and not time consumingconsuming Most of the time was integration of the pre-screening process into existing enrollment/randomization process into existing enrollment/randomization process and implementing programming to account for rolling IRB approval Conclusion Modifications to Study Eligibility criteria post-yg ypinitiation of recruitment are permissible and may be warranted Must weigh the pros and cons of making such changes, as the changes impact many areas of trial conduct and require time and resources to conduct and require time and resources to implement properlyAcknowledgements This project has been funded in whole or in part with pjpFederal funds from the National Institute on Drug Abuse, National Institutes of Health.

6 Department of Hlth d H Si d Ctt N Health and Human Services, under Contract No. HHSN271201200017C Thank you to Dr. Paul Van Veldhuisen, NIDA CTN DSC Principal Investigator Lauren Yesko NIDA DSC Principal Investigator, Lauren Yesko, NIDA CTN DSC Lead Data Manager, and other members of the NIDA CTN DSC