Adaptive Research Designfor Substance Abuseclinical Trials

2013 CTN Web Seminar Series ADAPTIVE RESEARCH DESIGN FOR SUBSTANCE ABUSE CLINICAL TRIALS Presented by: Katharina Wiest, PhD Jennifer Sharpe Potter, PhD, MPH October 23, 2013 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.HHSN271201000024C." Objectives Distinguish between adaptive trial design and adaptive treatment/intervention design.

Review adaptive treatment/intervention design in the CTN. Caveat: Analytic approaches are outside the scope of this presentation. FOR FURTHER INFORMATION: LIVELINK: Adaptive treatment strategies Workshop presentations SMART design Supplementary material 2 What is meant by "Adaptive" in research descriptions Different ways adaptive used in clinical research within evolving fields. Different ways to adapt: Adaptive treatment/intervention

The intervention or delivery of the intervention in a trial. Adaptive design A current ongoing trial. Future trials. Common Feature - data collected informs trial decisions 3 Adaptive Research Design ADAPTIVE TRIAL DESIGN 4 Definition of Adaptive Trial Design ". a clinical study design that uses accumulating data to modify aspects of the study as it continues, without

undermining the validity and integrity of the trial.changes are made by design, and not on an ad hoc basisnot a remedy for inadequate planning." Gallo, et al, 2006 This trial design - primarily from research in the pharmaceutical industry; more limited public health applications. 5 Comparison between Conventional & Adaptive Clinical Trial Designs Features Design Treatment arms

Conventional trial Adaptive design More rigid Flexible Maximum two or three Many simultaneously Hypothesis Test the hypothesis under consideration

Fit data into a hypothesis Modifications Not allowed without protocol amendments Pre-specified modifications allowed Phases Statistical analysis Organization Interim analysis Role of IDMC* Regulatory view Phases IIII distinct, well-defined

Can be seamless phase II/III designs Use routine methods Uses more complex Bayesian approach Much simpler Complicated, requiring simulations Not routine (except safety) Done routinely & frequently More once trial/phase is over

Proactive role throughout the trial Well-endorsed Still speculative *IDMC: Independent data-monitoring committee Mahajan, 2010 6 Types of Adaptive Clinical Trial Designs (not adaptive treatment/interventions!) Brown et al., 2009, Adaptive design for randomized trials in public health, Annual Review of Public Health What is Adaptive

Based on Early Stopping Interim analysis of impact Re-allocation of dosages based on Optimal Dose estimated doseresponse relationship Sample Size Enrollment Procedure Interim analyses

Example Benefit Special Trial Requirement Requires short time Group sequential Reduced time / cost to for outcomes to be trial completing trial measured Dose finding trial Re-estimation of

variance components Caution Wider confidence intervals at planned trial end Requires short Efficient determination Confounding of dose by time for outcomes of dosages entry time to be measured Appropriate sample size

Limited enrollment Increased proportion Randomize before in traditional enrolled; decreased consent randomized design selection bias Run-in Prior to Run-in design to Prediction of drop-out Randomization lower drop-out Improved statistical

power Encouragement Predictors of adherence Allocation Probabilities Co-variates of prior subjects Motivational interviewing Co-variate adaptive

allocation Reduction in participation bias Enhanced balance in intervention assignment Follow-up Response on proximal targets Two-stage followup design Efficient design for follow-up

Requires short time for outcomes to be measured Inflated Type 1 error None Ethical concerns; especially with single consent design Multiple responses for baseline Selection bias;

effects of training None Modeling sensitive to assumptions none May introduce confounding with time Longitudinal follow-up None

7 Adaptive Research Design ADAPTIVE TREATMENT/INTERVENTION 8 Adaptive Treatment / Intervention Rationale Target Population? Individuals with a chronic relapsing illness or disease. Why? Heterogeneity of patients & environment Dosage &/or treatment varies between patients & within an individual over time.

Goal: provide the minimum treatment which provides the optimal response. How is this different from clinical judgment? 9 Adaptive Treatment / Intervention Rationale Continued Best Example within NIDA: SMART (Sequential Multiple Assignment Randomized Trial). Susan Murphy, PhD.

10 Definition of Adaptive Treatment / Intervention A sequence of individually tailored decision rules that specify whether, how, and/or when to alter the intensity, type, dosage, or delivery of treatment at critical decision points in the course of care. 11 Adaptive Treatment / Interventions Evaluate sequences of treatment decisions for individual patients or participants. Decisions incorporate time-varying information on: Treatment responses

Side effects Patient preferences Participants may be randomized multiple times at decision points based on rules of how & when treatments change. 12 Examples from SUD treatment 13 Example: Traditional Randomized Medication / Intervention Trial Design 14

Example: Adaptive Randomized Treatment / Intervention Trial Design 15 Another Example of Adaptive Treatment/Intervention Brooner, RK, Kidorf, M (2002) Using Behavioral Reinforcement To Improve Methadone Treatment Participation Sci Pract Perspect. 1(1): 3847. 16 Adaptive Research Design (adaptive intervention)

EXAMPLE WITHIN THE CTN 17 CTN-0030 POATS Study Does adding individual drug counseling to buprenorphine-naloxone (BUP-NX) + standard medical management (SMM) improve outcome: During initial detox Over a longer stabilization period? 18

18 POATS: Study Schema 19 19 Example SMART Design Scott, Levy, & Murphy 2007 20 20 The same SMART Design can be used to answer many different kinds of research questions: About components of an adaptive treatment strategy:

What is the effect of initial treatment assignment on long term outcome given specified treatments provided in the interim? Considering only patients who did not respond to the initial treatment, what is the best subsequent psychosocial treatment in the context of a 12 week buprenorphine/naloxone detoxification: IDC vs. CBT? 21 The same SMART Design can be used to answer many different kinds of research questions: Continued About entire strategies: What is the difference in long term outcomes

between two strategies that begin with a different treatment? Which of the four possible strategies is the best strategy (i.e., results in highest average long term outcome)? Scott, Levy, & Murphy 2007 22 RECAP AND HIGHLIGHTS 23 Adaptive Treatment/Interventions & Adaptive Clinical / Experimental Designs

These ideas are not (necessarily) related & may lead to terminology confusion. Adaptive treatment/interventions are a type of intervention design Adaptive experimental designs are particular type of experimental design SMARTs are not Adaptive Experimental Designs SMARTs do inform development of Adaptive Interventions 24 Recap of Adaptive Treatment / Interventions & Adaptive Clinical Trials Both require more pre-planning Design Statistical

Approval process Both provide important benefits Nimble Identify more optimal treatments &/or doses Within CTN More likely to use Adaptive Treatment/Interventions than Adaptive Designs 25 Q&A Questions / Comments Alternatively, questions can be directed to the presenter by sending an email to [email protected] 26 References Bierman, KL, Nix, RL, Maples, JL, et al (2006) Examining clinical judgment in an adaptive

intervention design: the fast track program. J Consult Clin Psychol. 74(3):468-481. Brooner, RK, Kidorf, M (2002) Using Behavioral Reinforcement To Improve Methadone Treatment Participation Sci Pract Perspect.1(1): 3847. Brown, CH, Ten Have, TR, Jo, B et al. (2009)Adaptive designs for randomized trials in public health. Annu Rev Public Health. 30:1-25. Coffey, CS, Levin, B, Clark, C, et al. (2012) Overview, hurdles, and future work in adaptive designs: perspectives from a National Institutes of Health-funded workshop. Clinical Trials. 9:671680. Gallo, P, Chuang-Stein, C, Dragalin, V, et al (2006) Adaptive designs in clinical drug development an executive summary of the PhRMA working group. J of Biopharmaceutical Statistics. 16:275283. Kairalla, J., Correy, C., Thoman, M. and Muller, K. (2012). Adaptive trial designs: A review of barriers and opportunities. Trials 13(145). PMCID: PMC3519822. Retrieved from 27 References Continued

King, VL, Kidorf, MS, Stoller, KB et al (2006) A 12 month controlled trial of methadone medical maintenance integrated into an adaptive treatment model. J Subst Abuse Treat. 31:385-393. Mahajan, R, Gupta, K (2010) Adaptive design clinical trials: Methodology, challenges and prospect. Indian J Pharmacol. 42(4):201-207. Marlowe, DB, Festinger, DS, Arabia, PL, et al. (2008) Adaptive interventions in drug court: a pilot experiment. Crim Justice Rev. 33(3):343-360. Murphy, SA (2005) An experimental design for the development of adaptive treatment strategies. Statistics in Medicine. 24:1455-1481. US Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research CBER. (2010). Guidance for industry: Adaptive design in clinical trials for drugs and biologics (Draft). Retrieved from 28 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. Upcoming Webinar GETTING MULTI-SITE TRIALS UP AND RUNNING ON TIME Wednesday, November 20, 2013 1:00 pm to 2:30 pm ET 29 A copy of this presentation will be available electronically after this session.

30 Thank you for participating. NIDA CTN Web Seminar Series 31

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