1 Focus Groups and Surveys The PECARN Seizure Study Community Consultation Experience RAMPART Investigator Meeting Jill Baren, MD, MBE, FACEP, FAAP January 2008

Objectives  Describe the PECARN Seizure Study focus group and face to face survey methodologies for community consultation  Provide a justification for the use of focus groups and face to face surveys as effective community consultation methods  Draw parallels between the PECARN Seizure Study and RAMPART

What is PECARN?  First federally-funded multi-institutional research network in pediatric emergency medicine  4 nodes, > 20 ED affiliates  Academic, community, urban, rural, general, and children's hospitals  Network serves approximately 800,000 acutely ill and injured children/year

PECARN Seizure Study  Two part study funded by NICHD through the BPCA mechanism  Lorazepam identified as highest priority drug for study to obtain FDA label  Study 1: Pharmacokinetics (completed)  11 sites; 65 subjects; dose established at 0.1 mg/kg  Significant consent and enrollment barriers identified  Study 2: Randomized controlled trial of lorazepam vs. diazepam for pediatric status epilepticus  Efficacy and safety study

Efficacy and Safety- the 10/30 rule  How efficacious is lorazepam compared to diazepam at stopping seizures within 10 minutes?  How efficacious is lorazepam compared to diazepam at maintaining seizure cessation at 30 minutes?  How safe is lorazepam compared to diazepam in terms of need for assisted ventilation or intubation within 4 hours of dosing?

PECARN Seizure Study Regulatory History  Negotiation with FDA/NICHD on consent issues  18 months pre-trial activity seeking Exception from Informed Consent  Included national panel on “Emergency Research in Children: Ethical, Regulatory, and Clinical Challenges”  IND approved July ’07 using 21 CFR regulations  Community consultation and public disclosure required as additional human subjects’ protections  Ongoing activities at all active sites (10)  Drop out of one site due to administrative denial of trial  Possible addition of another site  Full IRB approval at 3 sites  IRB approval to move forward with CC/PD at all sites  Patient enrollment beginning January ’08 with 3 sites ready

Study cohorts Cohort 2: Exception from Informed Consent (SE) Cohort 1: Pre-consented during healthcare visit

Study management  Co-PI structure at national level  Coordinating scientific investigator  Protocol development  Human subjects coordinating investigator  Develop and implement all aspects of regulatory process and human subjects protections  Create an overall EFIC plan  Joint activities  Steering committee leadership  IND preparation  Interface with sponsor  Trial preparation and conduct

Regulatory process  IRB templated cover letter (7/06)  Initial meeting with IRB chair (9/06)  Resource binder provided  Community consultation methods discussed  IRB appointed liaison (9/06)  IRB educational sessions (12/06)  Initial protocol submission (12/06)  Requested two step approval process  Step 1: Approval of EFIC plan (1/07-3/07)  Justification for study to be carried out under 21 CFR  Specific community consultation methods approved (1/07)

IRB resource binder

Regulatory process  Community consultation carried out (3/07-8/07)  IRB received report of interim results  Final IRB submission prepared including analysis of results of community consultation (9/07-11/07)  Step 2: final IRB submission (12/07)  Full committee review of community consultation results (12/07)  Full approval of scientific protocol granted (1/08)  Frequent ongoing communication

Focus Group Methodology  69 parents and patients recruited from ED, neurology clinic and inpatient floors  Trained facilitator who participated in development of topic guide  IRB liaison present at 3 of 4 focus groups  Study representative available to answer technical questions  Linked to an opt-out registry or possible prospective consent  Discussion recorded and transcribed

Focus Group Results  22 participants (31% of those recruited)  Participants generally in favor of research being performed without consent  Common themes:  Concerns about side effects  Community awareness of study  How to “opt-out”  Concerns diminished after further discussion  All adolescents expressed willingness to participate  91% parents expressed willingness to enroll their child in study  2 parents completed opt-out forms for clinical reasons

Focus group strengths and weaknesses  In-depth qualitative method that generates detailed and rich information  Dedicated time to examine the attitudes of a small group of individuals  Selects for interested parties who are more likely to provide meaningful input  Potential for greater interaction among the participants  Generates conversation directed by the group participants  Information obtained is likely to be of high quality and useful in IRB deliberations  Diversity of information will be dictated by the composition of the groups  Cost will depend on the number conducted  Minimal to moderate in relation to overall study costs (~$1000/group)

IRB response  Interim reports sent to IRB chair after each focus group  IRB liaison provided progress report during full committee meetings  Asked to conduct one additional focus group involving parents and teens without seizure disorder  Summaries and individual transcripts made available for IRB deliberations  Protocol fully approved for conduct under 21 CFR after community consultation results reviewed

Survey methods  Adults accompanying a child in the ED or neurology clinic  No requirement for complaint related to seizure in ED  Aimed to capture population where the clinical investigation will be conducted and from which the subjects will be drawn  Cost-effective way to capture group that may represent first time seizure patients  Process linked to opt-out or possible prospective consent

Survey Results  170 surveys completed  80% of participants felt study was important and would allow their child to participate  17 participants completed opt-out forms  Common themes  Concerns about side effects  Concern about consent process  Lorazepam not FDA approved for children  High agreement that medical research and “experiments” in emergency care are important but expressed concern about enrolling without consent  65% felt that emergency research without consent was acceptable within their communities

Survey Strengths and Weaknesses  More controllable way to disseminate information  One on one technique allows for greater interaction between the investigator and participant and avoids group bias  Time consuming and can be costly depending on personnel used  Potential for influence on the part of the survey administrator  Information produced is of moderate to high quality and likely to inform IRB deliberations  Random digit dialing telephone surveys mimic this but often do not provide two way communication unless non-study personnel know how to answer study specific questions  Less bias but do not have complete knowledge of study True intent of community consultation is two-way communication!

Seizure Study/RAMPART parallels  Condition studied: Status epilepticus  Both studies compare drugs in common use, and have similar pharmacologic and adverse event profiles  Study drug comparator is unlabeled  Study population will be drawn from those who are known to have the condition as well as those developing the condition for the first time

EFIC and RAMPART  Much of the rationale for conducting the PECARN Seizure Study under 21 CFR applies to RAMPART  e.g. narrow therapeutic window of 5 min  Similar justification may be made in an overall EFIC plan  Many of the additional human subjects protections (community consultation) that have been used in the Seizure Study may be useful for RAMPART

Important Lessons Learned  This is not a random process and it takes a lot of thought and time  Don’t assume that IRBs are more educated about the regulations than you are  Do not take a “one size fits all” approach  IRBs, investigators AND communities are characterized by local customs and practices  There are a huge number of misconceptions about the regulations that you must correct  Do not assume that your materials are getting the right message across

Successful Strategies  Develop a plan and a strategy for global administration of the human research protections aspects of the trial  Appoint a “human subjects czar”  Investigator initiated IRB guidance through the process is essential  Investigator-IRB communication is the cornerstone of the process  Correcting misconceptions about the regulations  e.g. community consultation ≠ community consent  Pilot material and be willing to make changes based on community input (“glitch detection”)

Questions?