Rho, a contract research organization (CRO) focused on bringing new products to market through a full range of product development services, offers tips on how to limit the amount of data that goes uncollected during pain trials.
“Missing data can be a very serious challenge in clinical trials, particularly with pain trials,” said Karen Kesler, Ph.D. and senior statistical scientist for Rho. “Drop outs often occur in pain trials because side effects and a lack of efficacy. If you’re on the control arm and you’re not getting pain relief, you’re much more likely to drop out of the study,” added Dr. Kesler.
The National Academy of Sciences issued a report in 2010 on the prevention and treatment of missing data in clinical trials that has shaken up the status quo on how to deal with missing data. FDA just issued a draft guidance for analgesic indications, but the recommendations about missing data, while sound, are not very specific. Below, Rho provides tips on how to decrease missing data through study design and study execution.
Tips to Decrease Missing Data
- Study Design Strategies
- Consult with experts and practitioners during study design about aspects of the protocol that may negatively impact subject retention.
- Instead of the typical parallel arm study, consider other study designs. The FDA is open to enrichment or titrate-to-effect designs that might work well for your compound.
- Have a dialogue with the FDA early on in the program development and be plugged into the FDA pain division at the design stage about your method for analyzing missing data. It is unlikely they will accept last observation carried forward (LOCF), so be prepared for the need to conduct more complex analyses.
- Keep patient assessments simple. Collect only the data points you need to support your analysis, and try to limit the number of visits that will be required of the patients.
- Document a plan in the protocol for dealing with subject drop outs rather than reacting to issues as they occur.
- Attempt to continue collecting data on subjects that stop taking study drug.
- Try to work rescue medications into your design instead of having those subjects who need them drop out of the study. Sometime you can use the pain scores prior to a rescue medication and keep that subject in your analysis.
- Study Design Options
- Put subjects on increasing doses of active and control arms until they achieve pain relief.
- Can provide more information about dosing and subject variability
- Reduces dropout due to lack of pain relief as subjects continue to increase until they achieve pain relief.
Randomized withdrawal designs
- Start with everyone on active dose, after a set period of time, randomize subjects who achieve pain relief to move to placebo or stay on existing dose
- Your end-point comparison is at the end of second post-randomization period or time to resumption of pain
- Minimizes dropout rate due to not receiving analgesia because everyone starts with it
- Patients are more likely to buy into this design; you can shorten the period of follow up to reduce the amount of people you could lose after randomization
How a study is executed can also contribute to the reduction in missing data. Below are study execution tips from Rho
- Consider the burden on patients when determining how patient reported outcomes will be collected (i.e., paper diary, ePRO)
- Site selection is critical. The selection process should be robust and comprehensive
- High level of attention to data collection is crucial
- Staff training is key
- Having a properly trained staff is particularly important in pain trials because you are using pain scales that require subject diaries
- Site needs to be able to instruct patients properly to get necessary data
- Site needs to know how to review data they are receiving from patients to make sure it is accurate
- Advise sites to review patient diaries before subject leaves visit
- Communicate with the subject between visits. This helps manage subject population to maintain patients and prevent drop out
Rho, a privately-held, contract research organization (CRO) located in Chapel Hill, NC, provides a full range of clinical research services across the entire drug development process. For more than 25 years, Rho has been a trusted partner to some of the industry’s leading pharmaceutical, biotechnology, and medical device companies as well as academic and government organizations. Our commitment to excellence, our innovative technologies, and our therapeutic expertise accelerate time to market, maximize returns on investment, and lead to an exceptional customer experience. For more information, visit www.rhoworld.com.