Randomization is the process by which allocation of subjects to treatment groups is done by chance, without the ability to predict who is in what group. It eliminates the selection bias, balances the groups with respect to many known and unknown confounding or prognostic variables, and forms the basis for statistical tests. Randomization procedures are an integral component of ~95% of clinical trials.
Common, simple randomization designs, including straight, blocked, stratified, and unequal, may be inadequate for balance and cost efficiency for many study designs. Clinical trials or those with patient populations within certain therapeutic areas or indications may demand more complex randomization designs.
IVRCC’s custom programmed systems achieve a faster, lower cost trial with the goal of statistically better data by collaborating and implementing Sequential Parallel Comparison Design (SPCD) as a placebo response reduction strategy for a Ph 2 CNS study.
Objectives of SPCD Randomization
- To reduce number of false positive placebo responses that could significantly skew results, resulting in smaller drug-placebo differences.
- To account for and “neutralize” the expected higher 30-40% rates (Klerman 1986; Morris et.al.;Rogers and Clay 1975) of placebo responders in CNS therapeutic area sub-groups of subjects with Depressive Disorders.
- To achieve adequate power while enrolling only as many subjects needed and minimizing duration of treatment period required.
- To lower overall cost of study for higher quality data and faster completion of study.
Capabilities and Benefits of IVRCC’s Technology Solutions
- IVRCC’s integrated IRT-eCOA system facilitates randomization and re-randomization in real-time any day or time.
- IRT System collects, scores, and compare subject’s validated instrument survey answers at Baseline v. a specific post treatment visit to determine placebo non-responder status and eligibility to participate in Stage 2 re-randomization.
- System enforces randomization limits to prevent over-enrolling.
- Effects of placebo response are significantly reduced.
- Power of the trial is improved despite reduced sample sizes.
- There is no need to collect additional data from placebo non-responders as the data is collected once and utilized twice.
- Data is accessible in the case of an adverse event that requires unblinding.
- Study durations are reduced with shorter timelines.
- For the appropriate study designs and therapeutic areas, SPCD randomization solutions result in better overall trial data and lower overall costs.
Study Statistics
- A Phase 2, Randomized, Double-blind, Placebo-controlled Study
- Sequential Parallel Comparison Design (SPCD) study comprised of 2 Stages
- Indication: Major Depressive Disorder (MDD)
- ~130 subjects, 20-30 study sites
Study Design
Sequential Parallel Comparison Design (SPCD) study comprised of 2 Stages.
Each of two study stages were comprised of 4-week treatment periods plus a one-week taper period.
Stage 1: subjects would be randomized to an unbalanced 2:2:3:3:3 (2:2:9) ratio, two dose regimens of active study drug and three Placebo.
Response to treatment is collected from subjects through use of the Primary Efficacy instrument, HAMD17 survey, which would be completed and scored at Baseline, and at the end of each week of Stage 1 treatment period.
Stage 2: Based on change from Baseline in the HAMD17 score, the IVRCC system performs re-randomization : Stage 1 Placebo non-responders (estimated to be 54 subjects) would be re-randomized in a 1:1:1 ratio to receive one of three treatments (2 active dose regimens, 1 placebo) with number of subjects capped to active treatment. All other subjects would be re-randomized to receive placebo.
Challenges
The required entries and event recording must be made for most visits in chronological order, within each visit time window and in real-time.
Initial randomization needs to be properly implemented according to the Stage 1 rules and 2:2:3:3:3 ratio of active and placebo treatments.
Most HAMD17 surveys must be recorded as completed and entered into the visit record in real-time since it is a primary efficacy assessment, and is used for determination to randomize and re-randomize subjects.
HAMD17 surveys scores must be valid since used as a determinator for randomization and re-randomization, comparing certain visit HAMD17 to meet requirement for triggering next trial event.
Re-randomization needs to be properly implemented according to the Stage 2 rules and 1:1:1 ratio of active and placebo treatments for placebo non-responders.
IVRCC Solutions to Meet Challenges
IVRCC systems integrate to share data with other e-systems, in real-time. Critical data points are collected or generated once and saved to data base. They are available for use as needed throughout the study. The data includes subject ID, demographic information, other necessary events recorded at visits.
IVRCC web-based applications are programmed to guide site users through clinical visits with on-screen instructions and questions upon log-in. Managing data entry into correct visit, controlling out-of-window entries, etc. Our systems permit valid data entry.
HAMD17 survey answers are recorded at required visits in real-time, as a parameter for visit completion. HAMD17 scores calculated by the IVRCC system are a Primary Efficiency Assessment and integral to the system performing real-time re-randomizations according to protocol.
Summary
IVRCC utilizes its hybrid custom programming model and modular configurability platform design to provide key functions crucial to simple or complex randomized trials by:
- Real-time data collection.
- Push-pull integrations between internal and external e-systems.
- Automated-survey score calculations with real-time comparisons between data points.
- Stage 1/stage 2 randomizations/re-randomizations management.
- Resultant solutions utilizing technology, expertise, personnel engagement, clinical experience, and forward looking design.
Sponsor Outcome
The Sponsor announced positive results from the clinical study for Major Depressive Disorder (MDD). Sponsor reported that the data from the study demonstrated the drug compound significantly reduced depressive symptoms across a range of standard measures using the study’s primary outcome measure, and the Hamilton Depression Rating Scale (HAMD17). Sponsor planned to advance into a pivotal development program.
How was IVRCC the right choice for this study?
IVRCC’s 30+ years of building interactive applications for clinical trials ensured high quality recommendations and innovative design suggestions for the specific challenges of this study.
SOPs and full electronic audit trails back our randomization regulatory, programming, security, privacy, validation and documentation activities. .
IVRCC robust custom systems perform real-time push-pull and transfer integrations between relevant electronic systems, providing triggers for critical trial events, e.g., randomizations, based on data collected within various integrated modules of electronic systems.
Real-time reporting, notifications and reminders via web page, email, SMS, etc., throughout the study provide real-time guidance, confirmation, and documentation of study conduct.
IVRCC monitors trial events throughout the study, handling practical day-to-day issues using continuous automated controls combined with personal attention and intervention as needed. We build hard stops with notifications for manager review, and we resolve results of mis-entered stratification factors and mis-randomizations by investigator sites.
IVRCC’s core capabilities include design and electronic implementation of simple to complex randomization algorithms, along with automated and hands-on subject and visit workflow support, Clinical Trial Materials management and more.