The Implications of Modifying Study Eligibility Post-Initiation of Recruitment

Transcription

1 The Implications of Modifying Study Eligibility Post-Initiation of Recruitment COLLEEN ALLEN, MPH, CCRA THE EMMES CORPORATION THE SOCIETY FOR CLINICAL TRIALS 35 TH ANNUAL MEETING MAY 19, 2014 PHILADELPHIA, PENNSYLVANIA

2 Background Ideally, eligibility criteria are not changed after recruitment begins Under certain circumstances, it is necessary to revise the criteria The pros and cons, from a data management, regulatory, and statistical perspective, p must be weighed Presentation draws on experiences and lessons learned modifying i eligibility ibilit criteria i post-initiation iti ti of recruitment for a large, multi-center protocol within a multi-study clinical trials network

3 NIDA 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 programs The EMMES Corporation has a contract to serve as the Data and Statistics Center (DSC) for the network

4 Case Study NIDA CTN-0049: Project HOPE: Hospital Visit as Opportunity 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, HIV-infected drug users

5 Case Study (cont.) Original eligibility criterion required a detectable HIV viral load (>200 copies/ml) and baseline CD4 <350 cells/ul in the past 6 months Shortly before the study launched (March 2012), the U.S. Department of Health and Human Services released updated HIV treatment guidelines, which recommended anti-retroviral therapy (ART) for all HIV-infected individuals; ;previously, recommendation had been to start ART in those with a CD4 count <350 cells/ul

6 Case Study (cont.) Study opened to recruitment in July 2012 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 process and to reduce participant and staff burden

7 Statistical and Scientific Considerations Need to ensure that changes do not change the original assumptions upon which the sample size and study design were based Need to understand the impact of changes on generalizability of study results

8 Scientific and Statistical Considerations: CTN-0049 Study was designed as an effectiveness study, rather than an efficacy study, so it was important that the results be applicable to real-world practice, which had changed Change in eligibility criteria did not impact ability to assess primary outcome of study or modifications to sample size calculations Approximately 48% of the targeted sample size had been randomized at the time the amendment was approved at all sites

9 Regulatory Considerations Protocol amendments will require review and approval by a number of agencies and boards DSMB IRBs for each participating i i 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 effect

10 Regulatory Considerations: CTN-0049 Required review and approval by the DSMB 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 amendment Recruitment continued for one year post- implementation of amendment

11 Training Considerations Project staff, both at the site level and at the coordinating centers, will need to be trained on the new criteria Method for training may vary depending on scope of change Written memo Conference call Webcast In-person meeting/on-site training

12 Training Considerations CTN-0049 Coordinating center and protocol operations staff were re-trained during regular weekly operations conference calls Site staff were re-trained during regular weekly national conference calls Site monitoring i visits it also provided d an opportunity to confirm re-training and assess understanding of protocol changes

13 Operational Considerations In addition to amending the protocol, revisions may also be required to the following: Operations manual Study checklists and source documents

14 Operational Considerations: CTN-0049 In conjunction with making the protocol changes, the Manual of Operations (MOP), study source documents, and study checklists were also modified and updated d versions were distributed ib t d to study sites

15 Data Considerations Case Report Forms will likely need to be revised to reflect 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 change Decision i must be made about whether to delay implementation of the amendment until the data system changes are completed; may require a back- up data collection plan

16 Data Considerations: CTN-0049 Modifications to electronic data capture system (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 consuming Most of the time was integration of the pre-screening process into existing enrollment/randomization process and implementing programming to account for rolling IRB approval

17 Conclusion Modifications to study eligibility criteria post- initiation 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 implement properly

18 Acknowledgements This project has been funded in whole or in part with Federal funds from the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, under Contract t No. HHSN C Thank you to Dr. Paul Van Veldhuisen, NIDA CTN DSC Principal Investigator, Lauren Yesko, NIDA CTN DSC Lead Data Manager, and other members of the NIDA CTN DSC team.

19 Questions?