IMPACT OF INCLUSION/ EXCLUSION CRITERIA ON ENROLLMENT

Transcription

1 2014 CTN Web Seminar Series IMPACT OF INCLUSION/ EXCLUSION CRITERIA ON ENROLLMENT Presented by: Robert Lindblad, MD & Gaurav Sharma, PhD NIDA Clinical Coordinating & Data and Statistics Centers The EMMES Corporation December 17, 2014 Produced by: NIDA CTN CCC Training Office "This training 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 No.HHSN C." Objectives Define areas to consider for eligibility in clinical research Understand implementation of eligibility criteria Understand implications of eligibility criteria Discuss case studies on eligibility criteria in CTN trials Ask questions at the end 2 1

2 INCLUSION EXCLUSION AREAS TO CONSIDER FOR DEVELOPMENT OF ELIGIBILITY CRITERIA 3 Eligibility Criteria 5 major areas to consider 1. Characteristics of patients 2. Characteristics of the disease and its treatment 3. Environmental and other factors 4. Results of screening examinations 5. Rationale for eligibility criteria 4 2

3 Characteristics of Patients Gender Age Weight Education Race Ethnicity Social/economic status Pregnancy/ lactation Tobacco Alcohol and drugs Diet/nutritional status Physiological limitations Surgical limitations Hypersensitivity Other medicines Emotional limitations 5 Characteristics of the Disease Disease being evaluated Concomitant meds Previous treatment Co-morbid conditions Present clinical status Previous hospitalizations Washout period 6 3

4 Environmental Factors Patient recruitment and cooperation Participation in another clinical trial (previous, concurrent, or future) Institutional or environmental status Occupation Geographical location Litigation and disability Prisoner status 7 Results of Screening Examinations Deciding on how to document meeting the criteria Accepting subjects that fail screening 8 4

5 Rationale for Eligibility Inclusion Population gender, age, DSM diagnosis, use, etc. Exclusion Safety medical conditions Retention and compliance issues reliability - unlikely to complete the study or adhere to study procedures Interference with study objective Currently enrolled for another therapy/study 9 IMPLEMENTATION OF ELIGIBILITY CRITERIA 10 5

6 The Usual Safety Valve NIDA CTN Have evidence of an acute psychiatric disorder as assessed by the study medical clinician that would make participation difficult or unsafe Have a serious medical illness that, in the opinion of the study medical clinician, would make participation medically hazardous Have a current pattern of alcohol, benzodiazepine, or other sedative hypnotic use, as determined by the study medical clinician, which would preclude safe participation in the study 11 The Usual Safety Valve NIDA CTN As assessed ; In the opinion ; as determined What does this mean and how is it consistent between study physicians? Example The Phone Call! 12 6

7 Implementation Deciding on how to document meeting the criteria Self report Laboratory confirmation Obtain medical records what records? Example - HIV 13 Examples of NIDA CTN Eligibility A medical or psychiatric condition that, in the judgment of the study physician, would make study participation unsafe or would make treatment compliance difficult. Examples of medical conditions that may compromise participant safety or study conduct include, but are not limited to: AIDS according to the current CDC criteria for AIDS Liver function tests greater than 3X upper limit of normal Serum creatinine greater than 2 mg/dl 14 7

8 Examples of NIDA CTN Eligibility History of a seizure disorder Experienced a closed head trauma with >30 minutes loss of consciousness within the past 12 months Psychiatric disorder requiring continued treatment with a psychotropic medication 15 Examples of NIDA CTN Eligibility Inclusion Criteria Male and female patients ( 18 years) accepted for outpatient, substance abuse treatment at a participating CTP study site. Self-report any substance use problem, including alcohol as long as they also report other substance use in addition to alcohol. (1) Report use of a drug of abuse within 30 days prior to screening or (2) have exited a controlled environment (e.g., detoxification unit, hospital, or correctional facility) within 30 days of screening and report use of a drug of abuse within 60 days prior to screening. This sample was selected to ensure a CTP-friendly and real-world oriented effectiveness trial. Participants must be within the first month of initiating treatment at a collaborating CTP to ensure that scheduled psychosocial interventions can be initiated early on in treatment for all participants. Self-report a planned substance abuse treatment episode of at least 3 months (the planned evaluation phase in this trial). Exclusion Criteria Individuals will be excluded if they are participants in Opioid Treatment Programs (OTPs) and/or receiving opioid replacement medication, as TAU differs considerably in OTPs relative to other outpatient programs. If participants in CTPs are receiving some non-opioid pharmacotherapy for their substance use disorder or psychiatric disorder, we will systematically track this and consider these medication data in planned analyses as appropriate. Individuals will be excluded if they plan to move out of the area within the next 3 months. Individuals will be excluded if they have insufficient ability to provide informed consent to participate. Individuals will be excluded if they lack sufficient ability to use English to participate in the consent process, the interventions or assessments. 16 8

9 Eligibility Waivers 17 Eligibility Waivers NO! 18 9

10 Protocol Example Excerpt of eligibility criteria: Inclusion Criteria Subjects must meet the following criteria to be enrolled in the trial: 1. Provide valid informed consent prior to any study procedure 2. Male or female subjects age 50 to 90 years Exclusion Criteria Subjects may be excluded from enrollment, if any of the following criteria are present: The PI may request a written waiver, which must be approved by the Medical Monitor and the Sponsor, for any exception to the following criteria. 19 Mini-Break for Questions 20 10

11 IMPLICATIONS OF ELIGIBILITY CRITERIA IN CTN STUDIES 21 Implications of Eligibility Who is eligible? Who is ineligible? Consider how generalizable Expected variability in response to intervention How hard will it be to recruit? 22 11

12 Implication of Eligibility on the Objective of the Study Eligibility impacts Efficacy vs. effectiveness CTN has conducted both of these types of studies Efficacy and effectiveness exist on a continuum Ref- Technical review (Agency for Healthcare Research and Quality (AHRQ) Pub. No ) 23 NIDA CTN Feasibility Study CTN-0052: A Randomized Controlled Trial of Buspirone for Relapse-Prevention in Adults with Cocaine Dependence (BRAC) Strict eligibility criteria (future efficacy study) Cocaine dependence based on DSM-IV criteria Self-report crack cocaine use 4X in the 28 days prior to inpatient admission 100 Screened 62 Randomized 24 12

13 NIDA CTN Efficacy/Effectiveness Study CTN-0048: Cocaine Use Reduction with Buprenorphine (CURB) Somewhat strict eligibility criteria Cocaine dependence on DSM-IV Past year opioid abuse/dependence or lifetime opioid dependence with past year use Opioid detoxified 712 Screened 302 Randomized 25 NIDA CTN Effectiveness Study CTN-0044: Web-Delivery of Evidence- Based, Psychosocial Treatment for Substance Use Disorders (WEB) Lax eligibility criteria Self-report substance use problem Self-report illicit drug use 30 days prior to screening 523 Screened 507 Randomized 26 13

14 NIDA CTN Feasibility Study CTN-0052 (Pre-Screened = 379, Randomized = 62) Not Meeting Eligibility Criteria at Pre-Screening % Being treated with psychotropic medication (DSMB) 65 31% Appears to meet criteria for opioid dependence 36 17% Crack use less than 4X in the past month 33 16% Unwilling to enroll in local outpatient/continuing care 21 10% Not Meeting Eligibility Criteria at Screening 37 37% Not cocaine dependent within last 12 months 13 34% Medical or psychiatric condition (DSMB) 12 32% Not willing to comply with procedures 7 18% Not able to complete the study 5 13% 27 NIDA CTN Efficacy/Effectiveness Study CTN-0048 (Pre-Screened = 2272, Randomized = 302) Ineligible at Pre-Screening % No current opioid use % No past year opioid use % Medical/mental health condition % Medication for medical/mental health condition % Ineligible at Screening % Did not meet opioid use criteria 94 23% Did not complete screening within 30 day window 90 22% Serious medical illness 46 11% Unsafe alcohol/bzo/sedative use 42 10% 28 14

15 NIDA CTN Effectiveness Study CTN-0044 (Pre-Screened = 1781, Randomized = 507) Ineligible at Pre-Screening % No drug use in past 30 days % <90 days available for study % In treatment >30 days 73 9% Ineligible at Screening 4 1% Not enrolled in treatment at the CTP 2 50% In treatment >30 days 2 50% No drug use in past 30 days 2 50% 29 Impact of Eligibility Criteria Strict eligibility criteria High screen fail rate, lengthy screening process Slow down recruitment Inference restricted to population sampled from Could increase adherence to study procedures, such as treatment fidelity Homogeneous sample (less variability) Lax eligibility criteria Could reduce retention and compliance Rapid recruitment and low screen fail rate Results more generalizable Heterogeneous sample (high variability) 30 15

16 Retention Metric Average monthly recruitment rate/site 12/16/2014 Recruitment Comparison Protocol 31 Retention Comparison Protocol 32 16

17 Regression to the Mean Inclusion Criteria More than 10 days of cocaine use in past 30 days at baseline visit (TLFB) Primary Outcome Number of days of cocaine use in past 30 days at 6-month visit (TLFB) Baseline 6-Month Mean Cocaine Use Days Conclusion Heavy cocaine users had a reduction in their cocaine use after 6-months. Is this correct? Intervention works or Regression to the mean? 33 Regression to the Mean If a variable is extreme on its first measurement, it will tend to be closer to the average on its second measurement. At baseline, participants had extreme values (> 10 days). These would tend to be less extreme on a follow-up visit

18 Caution! Avoid defining eligibility criteria based on primary outcome variable 35 Modifications to Eligibility Criteria Unwise to modify eligibility criteria after study initiation However, modification may be necessary because Safety issue develops New clinical information available Recruitment slower than expected Low study compliance 36 18

19 Implications of Changing Eligibility Criteria Mid-Stream Ensure that the modifications to eligibility 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 Weigh pros and cons from data management, regulatory, and statistical perspectives 37 Statistical Considerations Analysis must then stratify by eligibility cohort Modify SAP Potential loss of power May need to re-evaluate sample size if there is a loss in power Analytic method may need to be adjusted if changes are substantial Inference is non-trivial since source population not completely clear 38 19

20 Questions to Consider during Design Phase What is the objective? What population are you seeking to make inferences about? What is the target population? How does it impact recruitment, retention, and compliance? Missing any eligibility criteria? Are any unnecessary? 39 ELIGIBILITY CRITERIA SUMMARY 40 20

21 Recap Areas to consider for eligibility in clinical research 1. Characteristics of patients 2. Characteristics of the disease and its treatment 3. Environmental and other factors 4. Results of screening examinations 5. Rationale for eligibility Implementation of eligibility criteria Documenting eligibility Granting waivers 41 Recap Implications of eligibility criteria Who is in or out based on study objectives Efficacy vs. effectiveness Define criteria according to study objectives Make modifications only when necessary 42 21

22 Q&A QUESTIONS / COMMENTS Alternatively, questions can be directed to the presenter by sending an to CTNtraining@emmes.com. 43 A copy of this presentation will be available electronically after this session

23 Survey Reminder The NIDA CCC encourages all to complete the survey issued to participants directly following this webinar session, as this is the primary collective tool for rating your experience with this and other webinars, and for communicating the interests and needs of CTN members and associates. 45 THANK YOU FOR YOUR PARTICIPATION 46 23