Computerized Assessments of Cognitive and Subjective Drug Effects Used in Clinical Trials
Computerized assessments can be used to measure the pharmacodynamic response to a study drug in clinical trials. Pharmacodynamics measure the effects of the drug on the body, such as physiological changes or biomarkers. However, especially for drugs that act on the central nervous system (CNS), drug effects can also encompass changes in cognitive performance and subjective effects, such as change in mood, feelings, and perceptions. Computerized assessments can be used to capture such effects. Types of assessments include:
- Subjective assessments: Subjective assessments are rating scales and questionnaires completed by the participant to allow the participant to report their subjective experience after study drug administration. Depending on the nature of the assessment, a baseline measure may be obtained where tracking changes from baseline is applicable. These assessments may ask study participants to rate their feelings, mood, symptoms, adverse reactions, abuse potential measures (for example, drug liking, feeling high, ), specific drug effects (for example, feeling drowsy/alert, changes in visual perception, feeling of being at one with the universe, etc.), satisfaction with life, daily functioning, persisting life changes, and so on.
- Observer and informant assessments: Observer assessments are performed by physicians or trained clinic staff, whereby the assessor rates the participant’s condition, reaction to the drug, symptoms, and so on. These assessments may involve interaction with and questioning of the participant, but the final response is recorded by the observer, per their judgement. Informant assessments are a related type of assessments, where someone well-acquainted with the participants, such as a friend or loved one, provides information about the participant. For example, the informant could assess perceived changes in the participant’s mood or daily functioning. Similar to observer assessments, responses are made independent of the participant’s perceptions.
- Cognitive testing: Cognitive testing involves the participant completing computerized cognitive tasks to measure their performance with regard to various aspects of cognition, such as reaction time, memory, executive functioning, attention, and so on. Participants’ performance could be compared before and after study treatment to assess treatment effects. Participants’ performance could also be compared to normative data – the performance of test-takes who are comparable to the participant in background (e.g., age, sex, educational attainment). This allows for an understanding of whether the participant’s cognitive performance is better, similar, or worse than what would be expected of them.
Computerized assessments of cognitive and subjective effects can provide valuable information for various purposes, such as:
- Capture the time course of in-the-moment effects, provide an overall assessment at the end of the dosing session, and measure long-term effects at follow-up visits.
- Rule out cognitive adverse effects (e.g., impaired memory, reaction time, or divided attention). This may be of value for CNS programs trying to attract funding by de-risking the molecule.
- Demonstrate an improvement in cognitive performance or mood when that is the intended effect.
What Kinds of Early-Phase Studies Use Computerized Pharmacodynamic Assessments?
Dose-Finding/Dose-Escalation Studies of Central Nervous System (CNS) Drugs:
Computerized assessments can be applied in a Phase 1 dose escalation study design to measure the drug response to guide dose escalation decisions and dose selection decisions for subsequent efficacy trials. This is especially relevant for psychedelic studies:
- Microdose psychedelic studies: Microdose dose-escalation psychedelic studies aim to identify the highest dose level that is not associated with psychedelic effects. Repeated computerized assessments can be performed at multiple time points after dosing to assess for any drug effects.
- High-dose psychedelic studies: High-dose psychedelic studies aim to identify a dose that is associated with a well-tolerated psychedelic experience. Computerized assessments at appropriate feasible times after dosing can be performed to assess the drug effects.
Read our blog on High and Microdosing Psychedelics in Clinical Research Trials Here.
Human Abuse Potential/Human Abuse Liability (HAP/HAL) Studies:
HAP studies evaluate whether a novel CNS drug may have potential to be abused; that is, used non-therapeutically for its psychoactive effects. HAL studies evaluate whether a potential abuse deterrent formulation reduces the abuse liability of a marketed drug already known to be abused, such as opioids.
Computerized assessments can be used to measure the subjective drug experience, which is the primary endpoint of HAP and HAL studies, including measures of drug liking, feeling high, good effects, bad effects, any effects, overall drug liking, interest to take drug again, and others. Computerized assessments can also be used during the Qualification Phase of HAP and HAL studies to establish participant eligibility for the main study phase (the Treatment Phase) based on their ability to discriminate the active control from placebo.
Examples of Scale Types
Visual analogue scale (VAS): VAS ask individuals to rate their experience by selecting a point on a line that represents how they feel. The response is converted to a score from 0 to 100. There are two types of VAS scales:
- Two-anchor VAS: These VAS have two anchors on the opposite ends of the line representing opposite responses, such as “Not at all” vs. “Extremely,” “No, not more than usually” vs. “Yes, much more than usually,” or opposite feelings, e.g., “Happy” vs. “Sad.” Examples of assessments utilizing two-anchor VAS are Feeling High VAS, Good Effects VAS, Bad Effects VAS, Any Effects VAS, Hallucinations VAS, Bowdle VAS (psychedelic effects), Bond-Lader VAS (mood), 5-Dimensional Altered States of Consciousness Rating Scale (5D‑ASC; psychedelic effects), and Ego-Dissolution Inventory (EDI; psychedelic effects).
- Three-anchor VAS: These VAS have a neutral point at the middle of the line (e.g., “Neither like nor dislike,” “Neither drowsy nor alert,” “Do not care”) and two opposite responses at the two ends, respectively (e.g., “Strong disliking” vs. “Strong liking,” “Very drowsy” vs. “Very alert,” “Definitely not” vs. “Definitely so”). Examples of assessments utilizing three-anchor VAS are Drug Liking VAS, Alertness/Drowsiness VAS, Overall Drug Liking VAS, and Take Drug Again VAS.
Likert rating scales: Likert scales ask individuals to rate their experience from a set number of response options, which can vary from scale to scale. The responses are assigned numeric values for scoring.
Responses can represent increasing intensity of experience such as; 1=None, 2=Mild, 3=Moderate, 4=Strong, and 5=Extreme.
Response options can also utilize a symmetric agreement/disagreement scale with a neutral middle point, such as Strongly Disagree, Disagree, Neutral, Agree, Strongly Disagree.
Examples of assessments that use Likert scales are Subject‑Rated Assessment of Intranasal Irritation (SRAII), Modified Observer’s Assessment of Alertness/Sedation (MOAA/S), 30-item Mystical Experience Questionnaire (MEQ30), Challenging Experience Questionnaire (CEQ; psychedelic effects), Persisting Effects Questionnaire (PEQ; psychedelic effects), State‑Trait Anxiety Inventory (STAI), Satisfaction With Life Scale (SWLS), and NEO Personality Inventory-Revised (NEO‑PI‑R).
True/False scales: True/False scales ask individuals to rate whether a certain statement is true or false of their experience or attitude. An example of an assessment utilizing True/False responses is the Addiction Research Centre Inventory (ARCI; subjective effects of psychoactive drugs).
Advantages of Computerized Assessments
- Quicker administration: Computerized assessments may be less time-consuming to administer than paper-based measures.
- Less staff involvement: Computerized assessments require less staff involvement to administer, which reduces site burden.
- Direct data capture: Computerized assessments provide direct data capture, which eliminates the need for data entry from paper source documents. This is more efficient and reduces risk of errors that can occur during data entry.
- Automatic scoring: Results are automatically scored by the software, which eliminates the need for error-prone manual scoring (especially for VAS and cognitive testing, see more below).
- Immediate access to data upon testing completion: As data is directly captured digitally, it is immediately available for review upon assessment completion.
- Can easily create interim summaries: Since data is immediately available in digital format, interim summaries can promptly be created, such as for qualification assessment in HAP/HAL studies and for safety review meetings in dose escalation .
- Can capture nuanced data: Computerized assessments can capture aspects of performance that paper-and-pencil measures are insensitive to, such as subtle differences in reaction time. Meta-data (aspects of task performance not directly captured via traditional outcome measures, such as the strategies a participant uses to complete a task) is also more readily available via computerized tests.
When to Use Computerized vs Paper-Based Pharmacodynamic Assessments?
Type of scales: While Likert rating scales are simple to administer either on paper or digitally, VAS are much easier to administer as computerized assessments. For VAS, the length of the line has to be precise, as well as the measurement of the selected response location on the line. If VAS is administered on paper, it needs to be ensured that the lines are always printed at the correct length, and the manual scoring needs to be verified. This paper-based process requires additional quality control (QC) steps and increases risk of errors. Computerized administration of VAS ensures accurate scale presentation and precise computation of responses by the software.
Amount of assessments and number of participants: Depending on the amount of assessments and number of participants, computerized assessments may be more cost-effective. At a certain point, the greater efficiency of computerized assessments with the direct data capture outweighs the higher set-up costs, making it cheaper than paper-based assessments.
Cognitive testing: Cognitive testing is best done using computerized assessments, as it provides modern tasks that are easy to administer in a clinical trial setting. Traditional neuropsychiatric cognitive tests require a trained professional for administration, such as a psychometrist or neuropsychologists, and only one participant can be tested at a time by the same tester. This is more costly, slower, and requires availability of specialized personnel. Computerized cognitive assessments have several advantages:
- More sophisticated assessments can be performed that require a computerized system and cannot be administered in paper-based form.
- They are designed to be administered by regular clinic staff provided with general training about the administration procedures.
- Several participants can be tested in parallel using multiple tablets.
- Administration is highly standardized, including built-in training for participants.
- Performance is automatically scored by the software.
- BioPharma Services routinely works with Cambridge Cognition, a leading neuroscience technology company providing computerized cognitive assessments.
- Appropriate assessments and time points are identified during the protocol development stage based on literature review, expertise, and experience.
- A user requirement specifications (URS) document is generated to specify the requirements for the computerized assessments’ software set-up. The URS undergoes reviews and updates to ensure it meets study requirements.
- Cambridge Cognition programs the study-specific computerized assessment software configuration per the URS.
- The software undergoes testing both by BioPharma Services and Cambridge Cognition to ensure it operates as expected.
- Any necessary adjustments are made, and the software is finalized for use.
Implementation and Related Considerations
Staff training: Study staff receive training for two roles: participant trainer and rater (performs testing of participants). For participant trainers, training is provided by the clinical pharmacology scientist, who prepares the participant training material and has expertise in cognitive and subjective assessments. For raters, training is provided both by Cambridge Cognition on use of their system and general testing principles, as well as by the clinical pharmacology scientist to ensure all important details are covered.
Participant training: Ensuring that participants understand how to complete the computerized assessments is paramount to attaining valid results. As such, participant training takes place prior to dosing and the first testing session. Training covers general testing expectations and logistics, overview of the types of scales used, and practice, if appropriate. Information is presented in a non-leading way, so as to not bias participant responding during the study, and participants are provided with an opportunity to ask questions. For cognitive assessments, training can also be done to overcome practice effects and establish a stable baseline.
Participant testing: Participant testing is performed in a distraction-limited setting, ensuring focus on the assessments. During testing, participants are not allowed to use their personal electronic devices or talk to other participants. Clinic staff observe participants throughout testing to ensure compliance.
Managing expectancy effects: Experience of drug effects is susceptible to a placebo response due to the mere expectancy of certain effects occurring. Thus, managing expectancy is crucial in reducing its impact on reported effects. Use of a double-blind, placebo-controlled, randomized design can help manage expectancy, as a participant will know that they may not receive the active drug.
Also, depending on the nature of the drug and type of study, the way information about potential drug effects is presented can also help manage expectancy. For example, in a low-dose psychedelic study, it can be noted that the doses used in the study are not expected to be associated with psychedelic effects, which participants may otherwise expect.
Interim unblinding: In some cases, interim treatment unblinding may be required for evaluation of the results of the subjective assessments, such as:
- HAP/HAL studies: In HAP/HAL studies, treatment randomization is unblinded after completion of the Qualification Phase in order to evaluate whether participants met qualification criteria for entry into the Treatment Phase, such as adequate discrimination between placebo and the active control.
- Dose escalation studies: If subjective responses are part of the dose escalation criteria (e.g., target magnitude of response or aim to identify a sub-perceptual dose), then treatment may be unblinded if stopping criteria are reached in order to confirm that the observations meeting the stopping criteria are from the active treatment, rather than placebo.
Upon completion of the clinical portion of the study, a final data reconciliation and transfer is performed. Cambridge Cognition performs a final check of the data to ensure any queries are resolved. Once confirmed, data is transferred to BioPharma Services for formal incorporation into the database prior to database lock. All statistical analyses for the clinical study report are performed using the final transferred data.
How can BioPharma Services help with Computerized Assessments?
Computerized assessments of cognitive and subjective drug effects are valuable tools for measuring the pharmacodynamic response to a study drug in clinical trials, particularly for drugs that act on the central nervous system (CNS). These assessments can capture changes in cognitive performance and subjective effects, such as changes in mood, feelings, and perceptions. They can provide valuable information for various purposes, such as capturing the time course of in-the-moment effects, rule out cognitive adverse effects, and demonstrating an improvement in cognitive performance or mood.
These assessments can be used in early-phase studies, such as dose-finding studies and human abuse potential studies. Visual analogue scales, observer assessments, and cognitive testing are examples of computerized assessments used in clinical trials to measure the effects of drugs. Overall, computerized assessments are essential in providing accurate and reliable data to ensure the safety and efficacy of study drugs.
Not sure how BioPharma Services can help with cognitive assessments? Here’s a brief summary of our capabilities:
- Established relationship with Cambridge Cognition, a leading company providing computerized assessments.
- Have iPads for conducting the assessments, with sufficient quantity to allow parallel testing of large groups of participants.
- Scientific team with expertise to help identify scales and time points, work closely with Cambridge Cognition on software set-up, train clinic staff, and evaluate results.
- Experienced clinical team for performing the computerized assessments reliably.
- Knowledgeable statistical team for data analysis, including for prompt interim analyses.
Written By: Sofia Raitsin, PhD.
BioPharma Services, Inc., a Think Research Corporation and clinical trial services company, is a full-service Contract Clinical Research Organization (CRO) based in Toronto, Canada, specializing in Phase 1 clinical trials 1/2a and Bioequivalence clinical trials for international pharmaceutical companies worldwide. BioPharma has clinical facilities both in the USA and Canada with access to healthy volunteers and special populations.