Placebo response is a potentially devastating component of CNS trials, particularly those with subjective patient-reported outcomes and high levels of interaction with clinical staff. In pain, depression, and other psychiatric studies using subjective primary endpoints, high placebo rates contribute substantially to the late-stage failure of promising treatments.

VeraSci is now offering a scientifically-backed instrument, the Placebo Control Reminder Script (PCRS), through the Pathway eCOA system. The PCRS, developed by the Hassman Research Institute, is a brief script read to participants immediately before administering study assessments. It educates and reminds them about placebo response factors and has been shown to decrease placebo response.

Data from a study of the PCRS were presented at the 2020 Annual Meeting of the American Society of Clinical Psychopharmacology (ASCP). The study examined the PCRS in subjects with major depressive disorder or with a psychotic disorder who had at least moderate depression. Subjects were randomized to either the intervention group or the control group. The intervention group was read the PCRS before administering the baseline and each subsequent assessment. The PCRS was not read to the control group. Subjects were told they had a 50% chance of receiving either the placebo or an active drug, but all subjects received a placebo. Subjects in the intervention group reported significantly smaller reductions in depression than the control group (i.e., a smaller placebo response). The intervention group also reported fewer adverse events. These findings indicate the PCRS is a useful tool to mitigate elevated placebo response rates that are often seen in failed late phase trials.

The PCRS is easy to implement. It doesn’t take long to administer, the language in the script is straightforward and easy to understand, and the administration is streamlined within Pathway. PCRS and Pathway provide a scientifically-backed mechanism for mitigating placebo response in a way that doesn’t significantly increase the burden on clinical sites or subjects.

To learn more about placebo response mitigation, download our whitepaper.

 

References

Cohen, E.A., Hassman, H.H., Walling, D.P., Wyka, K., Horan, W.P., Keefe, R.S.E., Grindell, V.M., Glass, S.J., Ball, R.R., Styczynski, J., Lobb, J.M., Ereshefsky, L. (2020, May) The Placebo-Control Reminder Script in Depression and Psychosis Trials: An Antidote for the Placebo and Nocebo Response. The American Society of Clinical Psychopharmacology (ASCP), Virtual Meeting

Cohen, E.A., Hassman, H.H., Walling, D.P., Hoover, S., Wyka, K. Ball, R.R., Joseph, A.V., Lobb, J.M., Hazzard-Rudolph, D., Ereshefsky, L. (2018, November) A First-Time Investigation of a Subject Intervention to Reduce the Placebo and Nocebo Effects: A Multicenter, Randomized, Single-Blind, All Placebo Study of a Placebo-Control Reminder Script for Subjects with Major Depression. CNS Summit, Boca Raton, FL

As more sponsors utilize electronic clinical outcome measures (eCOA) in their international clinical trials, these tools will also need to be accurately translated and culturally adapted for use in numerous languages and countries. eCOA translations must ensure that the scientific rigor of the paper-based clinical outcome measures (COA) is retained in the electronic version and can be used in trials around the world.

Benefits of eCOA 

eCOA and other eClinical solutions such as electronic patient-reported outcomes (ePRO) have ushered in a new era of efficiency and precision in clinical trials. Using eCOA and ePRO to perform assessments can eliminate transcription errors, improve rater performance, and reduce missing data. These systems’ ease of administration and convenience of use enables patients and investigators to complete assessments effortlessly.  Further, time-stamped entries and blocked skipping of questions result in more complete responses and more precise data. Automatic backups and built-in audit trails that track unique user IDs and patient credentials help to bolster data security.  

Translation and Technology Cooperation

Timing is critical throughout eCOA development and the translation process. As soon as the study needs are identified, linguists and programmers should work in parallel to complete the various language versions of the eCOA assessments needed to service global trial sites.

VeraSci is the only language services provider to have a team of experienced developers, scientists, clinicians, and certified linguists in-house. This allows translations to happen in tandem with development activities. Scientific experts provide input throughout the process. Our commitment to quality is our mission and is backed up with 15 years of experience in the clinical trial industry. To support our in-house team, many of the VeraSci certified translators are also subject matter experts. Our processes are ISO 9001 and ISO 17100 certified, meaning that our resources and processes meet international standards for quality translations and client services.

The Price of Bad Translations 

Substandard eCOA translations are a real threat to data integrity. In order to be considered valid, measurements from eCOA need to be equivalent to the data gathered from paper versions of the assessments. Incorrect translations of an eCOA can invalidate assessments performed in those languages, resulting in lost time and cost overruns.

Strict adherence to a scientific translation process ensures that eCOA translations stay true to the source and true to the science. Our process includes the preparation of a style guide, two independent forward translations, reconciliation of forward translations into one translation, back translation, internal quality assurance review of back translation against source text, scientific consultation, editing/reviewing of QA comments, implementation into software, and up to three rounds of screenshot review.

Using eCOA and ePRO can have many advantages. Carefully selecting a quality translation provider to tailor eClinical assessments to your global clinical trial reduces the risk of costly errors and invalid data. Don’t allow assessment translations to be an afterthought, but instead incorporate language solutions into the software development process. Our team can help maximize the accuracy of your data by providing scientifically sound translation and cultural adaptation services for eClinical software used in global clinical trials.

Learn more about VeraSci Global Language Solutions 

This blog series shares what’s happening day-to-day in our Innovation Lab long before we share the results in publications or at conferences. The VeraSci Innovation Lab was created to pair scientific knowledge with cutting-edge technology to improve the tools and measurements available for use in clinical trials.

Wearables present an incredible opportunity to collect data in ways that simply haven’t been feasible before. We can gather information that reflects patients’ daily living activities rather than looking at how they behave in a hospital or clinic setting. Here at the VeraSci Innovation Lab, one of our current interests is evaluating industry-grade wearable devices for real-time functional assessment. We are interested in devices that could have broad applicability to our therapeutic areas of interest, such as Alzheimer’s Disease and other forms of dementia, schizophrenia, and depression. Our focus is on devices that have the potential to produce reliable endpoints that may ultimately pass the high bar set for use in regulated clinical trials. One device type we’re evaluating is a wrist-worn device that offers continuous measurement of heart rate, motor activity, skin temperature, Galvanic skin response, and sleep. In a previous post, we discussed the selection criteria for the devices we chose.

From the outset, we understood that any device would have challenges, and we would need to learn to resolve or mitigate the difficulties in order to capitalize on the benefits of wearables. We understood based on the device selection process that we were making some trade-offs. Some of these challenges we accepted upfront because the benefits provided by other aspects of the device made handling the challenges worth it. Some challenges were unanticipated, or we underestimated the magnitude of the challenge. As we’ve started working with the devices, both in using them ourselves in the lab and conducting some preliminary non-interventional studies in study subjects, we’ve run into several practical challenges.

Device Pairing

The wrist-worn devices we are using in our study need to pair to the smartphone using Bluetooth to transfer data. Due to limited internal memory, if the device goes without pairing for too long there is the potential that data would be lost. Blue tooth is an inherently unstable connection, so we anticipated that the connection would drop from time to time. What we hadn’t expected was that occasionally the connection between the devices would not be re-established automatically when the devices were back in range. However, we have found that with support, most subjects are willing and able to maintain the Bluetooth connection required to keep data transmitting to the cloud server.

Unhelpful Alerts

The wrist-worn devices we selected generate a number of alerts. The most common is an alert related to the Bluetooth disconnects mentioned above. Most of the time the Bluetooth connection repairs without any need for user intervention. Unfortunately, the wrist worn device does not allow adjustment of the alert settings (e.g. length of disconnection before activating an alert), so the subject is alerted to even these momentary drops in the Bluetooth connection. Although we tell all subjects that momentary drops in the Bluetooth connection are nothing to worry about, some subjects are nonetheless concerned by the alerts and call our help desk for guidance.

Compliance Monitoring 

A major consideration in our choice of wrist-worn actigraphy device was the ability to see the data as it was collected and thereby monitor subject compliance during the study. This ability has allowed us to intervene early in the study when a subject hasn’t used the device as instructed. For example, when we noticed that a subject wasn’t wearing the device overnight, we were able to remind them to wear the device to bed. For our study, we feel that the ability to monitor subject compliance and intervene as necessary has outweighed the difficulty of supporting a somewhat finicky Bluetooth setup.

That’s it for this month. Check back next month to find out what’s new in the VeraSci Innovation Lab!

The COVID-19 pandemic and associated social distancing measures are creating unprecedented challenges for everyone working in clinical trials and drug development. In this series, we’re sharing some of the ways VeraSci is addressing these challenges.

With many study subjects isolating themselves at home and many sites concerned about seeing subjects in-person for routine study visits, we are seeing an increased interest in remote visits. Sponsors that consider this for their studies often choose to complete the remote visits with video conferencing tools in order to allow more interaction between sites and subjects. Even for those with experience using video in clinical trials, using it in a home-based setting brings unique challenges.

IRB / Consent Updates

It is expected that changes to the protocol and what subjects are being asked to do will require updates to consent forms and IRB / Ethics Committee approval. Consent Form language may need to include elements such as whether the video conferences are being recorded and, if so, where any recordings are being stored.

Data Security 

There are a number of technology platforms available for remote visits and videoconferencing. The US Department of Health and Human Services (DHHS) in their Notification of Enforcement Discretion for Telehealth Remote Communications During the COVID-19 Nationwide Public Health Emergency provides both a list of providers that should not be used as well as a list of technology vendors that represent that they are HIPAA-compliant and will enter into HIPAA business associate agreements (BAAs). Video platforms may also require validation. We recommend that sponsors complete their own evaluation of any vendor they use to ensure they meet study needs applicable security and privacy regulations. The sponsor may also need to generate their own procedures to outline the appropriate use of any product that is chosen. Additionally, if the video will be set up in a way where the patient’s face or other identifying information is visible and being recorded, this would constitute Protected Health Information (PHI) under HIPAA and would need to be treated accordingly. If the videos are recorded, the sponsor or their video vendor may need to consider options to de-identify the video in order to obscure any audio or visual identifiers that are included in the recording.

Non-participants

Videoing study participants in their homes rather than in a clinic setting brings about potential issues related to non-participants ending up on video. In the clinic, you’d never experience another family member wandering into the video, but this is something that does happen when you’re recording in someone’s home. Non-participants typically fall into two groups—those who incidentally end up in the video and those who are needed for the video. The incidental group includes people walking through the background, coming over to talk to the participant during the visit, or even in pictures in the background of the video. Most of these issues can be mitigated by preparing the subject ahead of time. Ask the subject to go to a private area for the study visit and instruct others in the household not to come in during the visit and to remove any visible photos or items with identifying information (e.g. diplomas). These steps should minimize the risks of capturing video of people not involved in the study. Depending on the study and the patient population, it may be necessary to include another person in the video to help with set-up or provide other assistance. Studies in elderly patient populations may require a caregiver or family member to assist in setting up the technology. In these cases, you may need to get consent from the caregiver or family member, particularly if the video is being recorded.

Logistical Challenges 

There may be logistical challenges in setting up video for at home visits. It is important to think the issues through in advance keeping in mind the specific needs of the study and the patient population. It may be necessary to provision devices, device stands and/or internet connectivity solutions to subjects prior to the home visit. Providing detailed instructions for set-up in advance of the visit will make things go more smoothly.

Providing Support 

Adding video home visits to studies will require increased support for both technology and logistics. Project teams and technology providers need to be prepared to provide more intensive support than is usually needed. VeraSci’s comprehensive training approach includes step-by-step set-up guides for subjects and raters. In addition, raters are trained on any scale modifications, the equipment they will need to use during the session, and equipment the subject will need to use during the session. There should be Helpdesk staff available to address and resolve questions and issues from site staff.

If you have questions or are interested in more information about implementing video for remote visits and assessments, contact us.

Many rare diseases lack the well-characterized endpoints that we associate with outcome measures in more common diseases and disorders. Given that most clinical trials for rare diseases are small and often rely on assessments that are not designed specifically for the disease, it is important that every assessment is administered and scored correctly. In trials conducted in very small populations, missing, erroneous, or invalid data can have an outsized impact.

In an effort to determine the types and frequency of errors made in these types of trials, one of VeraSci’s scientific experts reviewed assessments from 135 visits with 37 patients in international clinical trials for mucopolysaccharidoses (MPS). MPS are a group of rare, inherited lysosomal storage disorders that can lead to neurological symptoms, including impaired cognition, difficulties in language and speech, behavioral abnormalities, sleep problems, and seizures.

We reviewed paper-based cognitive and adaptive behavior assessments that are sensitive to neurocognitive changes in MPS disorders, including the Vineland Adaptive Behavior Scale, Second Edition (VABS-II), Bayley Scales of Infant Development, Third Edition (BSID-III), and the Kaufman Assessment Battery for Children, Second Edition (KABC-II), to quantify the scoring and administration errors. Test administrators for the trials were Ph.D.-level neuropsychologists that had been trained previously. For the VABS-II, more than half of the assessments had no errors.

Of those with errors, the most common errors were summation errors, followed by table look up errors. A small number failed to follow the basal/ceiling rules. For the BSID-III, 45% had no errors. The most common error type was a double basal error, followed by failure to follow basal/ceiling rules and summation errors. A smaller number of KABC-II assessments were reviewed but scoring errors and incorrect administration of subtests were the most common errors. The impact of these errors was considerable. In some instances, the impact was an inaccurate calculation of endpoints. What can be done? We have a few recommendations:

  • A central rater can play a pivotal role in rare disease trials. Central raters can identify errors so that they can be corrected during the study.
  • Data quality review and remediation can have significant positive effects on signal detection.
  • Computer-based scoring programs can eliminate summation errors.
  • Rater training can be improved. In particular, we recommend explicit training on the double basal guideline for the BSID-III and provision of clear scoring guidelines for the KABC-II subtests.

We would like to express our appreciation to the sponsors who allowed us to review their assessments and trial data and the children and families who participated in this important research. Do you have questions about how to apply these lessons to your next clinical trial? Contact us.

References and Additional Information

Sanchez, CE, Kahn, A, Stern, L, Atkins, AS, Snyder, H, & Keefe, RSE (2018, February). Common Rater Errors for Assessment in Pediatric Rare and Orphan Diseases. Poster presented at the Annual Scientific Meeting of the International Society for CNS Clinical Trials and Methodology, Washington, D.C.

Shapiro, E. G., Escolar, M. L., Delaney, K. A., & Mitchell, J. J. (2017). Assessments of neurocognitive and behavioral function in the mucopolysaccharidoses. Molecular genetics and metabolism, 122S, 8–16. doi:10.1016/j.ymgme.2017.09.007

Centralized assessments are a method of testing clinical trial subjects that has significant potential advantages for rare and orphan disease trials. In a centralized assessment model, a small pool of trained and highly experienced raters conduct developmental and cognitive assessments either by traveling to the site or conducting the assessments remotely. So, what are the advantages of using centralized assessments in a rare disease trial?

Enable Remote Visits 

Centralized assessments can also be used to move some or all of the study visits to at-home visits. Centralized assessors can conduct many assessments either over the phone or through a videoconference. Remote visits can reduce patient burden by limiting the number of trips to a site, allowing patients who reside far from clinic sites to participate when they might otherwise not be able, and protecting immunocompromised patients’ from potential exposure to germs present in clinics and hospitals.

Increase the Number of Available Sites

In a standard trial, each clinical site would need to have a qualified rater and usually a back-up rater, available to conduct any developmental and cognitive assessments that are part of the schedule of events for each study. Depending on the specialty of physicians that are likely to see patients of a particular rare disease, availability of qualified raters can limit the number of eligible trial sites. Centralized assessments allow for a larger pool of potential sites to be included in a trial. Additionally, in rare disease trials, it is important to go where the patients are. By creating a larger pool of eligible sites, sponsors can ensure that sites will be located near the patients.

Reduced Rater Training

Centralized assessments can reduce costs associated with rater training. Centralized assessments use experienced, highly qualified raters that do not require additional training. Additionally, it may reduce the number of people who need to attend the investigator meeting and the duration of the investigator meeting, both of which can represent cost savings.

Calibrated and Standardized Scoring

Centralized assessments can also increase the quality of trial data. Utilizing a small pool of experienced, highly qualified raters reduces variability in the data. Also, because there isn’t a 1:1 relationship between sites and raters, site variability is reduced. Centralized raters help ensure assessment scores are calibrated and standardized across the study.

Making Centralized Assessments a Success

Although there are many advantages to using centralized assessments in rare disease trials, there are some hurdles that must be overcome to make them successful. These can be mitigated by selecting a provider with proven experience with centralized assessments. If the centralized assessments will take place on site, there are administrative steps that must be taken to ensure that raters will have access to the site on the date of the assessment. It’s also important that the raters are experienced in both the assessments being conducted and in working with similar patient populations in order to see improvements in data quality.

Are you interested in using centralized assessments for your next trial? Contact us.