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EndeavorRx is a digital therapeutic indicated to improve attention as measured by computer-based testing in children ages 8-17 years old with primarily inattentive or combined-type ADHD, who have demonstrated attention issue. Patients who engage with EndeavorRx demonstrate improvements in a digitally assessed measure Tests of Variables of Attention (TOVA) of sustained and selective attention and may not display benefits in typical behavioral symptoms, such as hyperactivity. EndeavorRx should be considered for use as part of a therapeutic program that may include: clinician-directed therapy, medication, and/ or educational programs, which further address symptoms of the disorder.

EndeavorRx is a modification to the previously granted EndeavorRx (DEN200026) with the primary difference being the expansion of the indicated patient population from 8-12 years old to 8-17 years old. In addition, minor software changes were made to improve app accessibility and user engagement. The core therapeutic software technology was not changed.

EndeavorRx is a prescription-only digital therapeutic software indicated for use in the treatment of attention impairment in pediatric patients (8-17 years of age) with primarily inattentive or combinedtype ADHD. EndeavorRx is a software-as-a-medical device (SaMD) that resides on the user's mobile device and can be executed at home.

EndeavorRx is engineered as a therapeutically active treatment for attention in pediatric patients affected by ADHD. EndeavorRx is built on Akili's proprietary, patented, technology platform and uses adaptive algorithms (also known as Selective Stimulus Management Engine, SSME™) to deliver stimuli that are designed to engage the patient in a manner that improves their attention function. In a closedloop system, the adaptive SSME™ algorithms automatically adjust the difficulty level for a personalized treatment experience that is tailored to the needs of each individual patient.

EndeavorRx is delivered through a video game experience which leverages art, music, storytelling, and reward cycles to keep patients engaged. The adaptive algorithm constantly pushes patients precisely at predefined performance bounds relative to each individual, such that they are continuously encouraged to exceed their historic performance. The science behind EndeavorRx was developed at the University of California, San Francisco by Adam Gazzaley, M.D., Ph.D., Founding Director of the University of California San Francisco's Neuroscape and Akili's Chief Science Advisor.

The basic program inputs are steering, which is accomplished by using the mobile device's internal accelerometer to measure the degree to which it is tilted, and tapping, which is accomplished using the touch screen to measure correct and incorrect targeting. The basic outputs are the visual display of the game progression along with audio, which is accomplished by using the internal high resolution display and internal speaker. The program includes features to ensure it is used per the prescribed regimen (approximately 25 minutes per day, 5 days per week, for 4 weeks or as recommended by the health care provider).

Here's a breakdown of the acceptance criteria and the study proving the device meets them, based on the provided FDA 510(k) summary for EndeavorRx (K231337):

Device Name: EndeavorRx
Indication for Use: Digital therapeutic indicated to improve attention as measured by computer-based testing in children ages 8-17 years old with primarily inattentive or combined-type ADHD, who have demonstrated attention issue.

1. Table of Acceptance Criteria and Reported Device Performance

The provided document primarily details efficacy results rather than explicitly stated "acceptance criteria" as pass/fail thresholds for regulatory approval outside of the comparison tables for substantial equivalence. However, the core acceptance criterion for efficacy appears to be a significant positive mean change from baseline in the TOVA-ACS score.

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EndeavorRx is a digital therapeutic indicated to improve attention function as measured by computer-based testing in children ages 8-12 years old with primarily inattentive or combinedtype ADHD, who have a demonstrated attention issue. Patients who engage with EndeavorRx demonstrate improvements in a digitally assessed measure Test of Variables of Attention (TOVA) of sustained and selective attention and may not display benefits in typical behavioral symptoms, such as hyperactivity. EndeavorRx should be considered for use as part of a therapeutic program that may include: clinician-directed therapy, medication, and/or educational programs, which further address symptoms of the disorder.

EndeavorRx is a digital therapeutic indicated to improve attention as measured by computerbased testing in children ages 8-12 years old with primarily inattentive or combined-type ADHD, who have a demonstrated an attention issue. The EndeavorRx program is a software-as-medical device (SaMD) that resides on the user's mobile device and can be executed at home. EndeavorRx is engineered as a therapeutically active treatment for attention in pediatric affected by ADHD. EndeavorRx is built on Akili's proprietary, patented, technology platform and uses adaptive algorithms (also known as Selective Stimulus Management Engine. SSME™) to deliver stimuli that are designed to engage the patient in a manner that improves their attention function. In a closed-loop system, the adaptive SSME™ algorithms automatically adjust the difficulty level for a personalized treatment experience that is tailored to the needs of each individual patient. EndeavorRx is delivered through a video game experience which leverages art, music, storytelling, and reward cycles to keep patients engaged. The adaptive algorithm constantly pushes patients precisely at predefined performance bounds relative to each individual, such that they are continuously encouraged to exceed their historic performance. The basic program inputs are steering, which is accomplished by using the internal accelerometer to measure the degree to which the mobile device is tilted, and tapping, which is accomplished using the touch screen to measure correct and incorrect targeting. The basic outputs are visual display of the game progression along with audio, which is accomplished by using the internal high-resolution display and internal speaker.

Here's an analysis of the acceptance criteria and the study that proves the EndeavorRx device meets those criteria, based on the provided text:

Acceptance Criteria and Reported Device Performance

The acceptance criteria for the EndeavorRx device are primarily driven by clinical performance demonstrating effectiveness and safety. The text doesn't explicitly state a table of "acceptance criteria" with specific thresholds prior to reporting results; rather, the clinical studies presented here serve as the evidence to establish that the device does meet the necessary criteria for regulatory approval. Based on the "Special Controls" section, the key criteria are demonstrated effectiveness using a validated measure and capture of adverse events.

Here's a table summarizing the implicit acceptance criteria (derived from "Special Controls" and the results presented) and the reported performance:

• Primary Endpoint Met: Statistically significant improvement from baseline in the TOVA API compared to digital control (0.93 vs 0.03; p=0.006).
• Secondary Endpoints: Numerically favored EndeavorRx over control for ADHD-RS Total, ADHD-RS Inattention, and IRS. Trend observed in favor of EndeavorRx on IRS.
• Clinically Meaningful Improvement: 34.5% of EndeavorRx treated participants moved into the normative range on at least one objective measure of attention across all studies.

STARS-Adjunct Study:

• IRS (Parent/Clinician-rated impairment): Significant improvement for both On Stimulants (-0.7, p1%): decreased frustration tolerance (2.8%), headache (1.7%), emotional reaction (1.1%). Mostly transient and mild (3 moderate). No AEs led to discontinuation.

STARS-Adjunct Study:

• 37 (18%) participants experienced device-related AEs across two treatment months.
• Most common AEs: decreased frustration tolerance (13.1%), headache (1.9%), irritability (1.5%). All mild or moderate. No SAEs.
• 3 participants discontinued due to treatment-related AE (all decreased frustration tolerance).

ADHD POC Study:

• 9 AEs reported over all study phases, none judged related to EndeavorRx.

Overall: Of 538 EndeavorRx participants across all studies, 50 (9.3%) experienced treatment-related AEs. No SAEs. AEs generally transient. Only 3 led to discontinuation. |
| 2. Software Verification, Validation, and Hazard Analysis | FDA review of the software documentation found to be acceptable. (MODERATE level of concern, prior to risk mitigation). |
| 3. Labeling Requirements | Labeling found to be sufficient and consistent with clinical data, covering hazards and clinically relevant information (e.g., instructions for use, OS requirements, not standalone, not a substitute for medication, summary of clinical performance, warnings for photosensitive epilepsy, color blindness, physical limitations, frustration, seizure, potential screen addiction, decreased sleep quality). |

Study Details

Given the multiple studies described, I'll focus primarily on the STARS-ADHD study as it's identified as the "pivotal" study, and briefly mention key aspects of the others where relevant.

1. Sample Sized Used for the Test Set and Data Provenance:

• Pivotal Study (STARS-ADHD):

  • Total Screened: 857 children
  • Test Set (Randomized): 348 children
    • EndeavorRx group (treatment): 180 children
    • Digital Control group: 168 children
  • Data Provenance: Multi-center randomized controlled trial conducted at 20 sites in the USA.
  • Retrospective/Prospective: Prospective. This was a randomized, double-blind, digital controlled study.

• STARS-Adjunct Study:

  • Total Enrolled: 206 participants (130 "On Stimulants", 76 "No Stimulants")
  • Data Provenance: Not explicitly stated, but likely multi-center and prospective, similar to STARS-ADHD.
  • Retrospective/Prospective: Prospective.

• ADHD Proof of Concept (POC):

  • Analyzed Sample: 40 children in ADHD group, 40 Healthy Controls.
  • Data Provenance: 3 sites in the US.
  • Retrospective/Prospective: Prospective (open-label study).

2. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications:

The concept of "ground truth" for a diagnostic accuracy study (e.g., classifying an image) doesn't directly apply here, as EndeavorRx is a therapeutic device, not a diagnostic one. The "test set" in this context refers to the participant cohorts in the clinical trials.

• Diagnosis of ADHD: Inclusion criteria for ADHD diagnoses were based on the DSM V (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition), and confirmed with a MINI-KID (Mini International Neuropsychiatric Interview for Children and Adolescents) and ADHD-RS (ADHD Rating Scale) Total score. TOVA API score was also used to identify a "demonstrated attention issue."
• Experts involved: Clinicians at each of the 20 sites (STARS-ADHD) or 3 sites (ADHD POC) would have made the formal ADHD diagnoses. The document does not specify the number or specific qualifications (e.g., years of experience) of the individual diagnosing clinicians, but presumably, they were qualified medical professionals (e.g., pediatricians, child psychiatrists, clinical psychologists) experienced in diagnosing ADHD.

3. Adjudication Method for the Test Set:

• STARS-ADHD: This was a double-blind study. This means neither the participants nor the investigators/clinicians interacting with them (who would be part of the "adjudication" of symptoms if it were a diagnostic study) knew whether the child was receiving EndeavorRx or the digital control. This inherent blinding serves as a robust form of "adjudication" against bias in assessing primary (TOVA) and secondary (ADHD-RS, IRS, CGI-I, BRIEF) outcomes. The TOVA is a computer-based, objective measure, which reduces subjective interpretation. Secondary measures like ADHD-RS and IRS are parent/clinician-reported, but the blinding helps mitigate bias.
• ADHD POC: This was an open-label study, meaning participants and investigators knew who was receiving EndeavorRx. This is a less rigorous design in terms of blinding.
• STARS-Adjunct: The summary does not specify blinding, but given the nature of the interventions (different game stimuli or no stimulants), full blinding might have been challenging for participants, though clinician assessment could have been blinded.

There is no mention of a formal adjudicated consensus process by an independent panel of experts reviewing cases, as might be done in studies of diagnostic imaging AI, but rather relies on the study design's blinding and validated assessment tools.

4. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and the Effect Size:

• No, an MRMC comparative effectiveness study was not done. MRMC studies are typically used to compare the performance of multiple human readers (e.g., radiologists) with and without AI assistance on a set of cases, primarily in diagnostic imaging. EndeavorRx is a therapeutic device for direct patient use, so this type of study design is not applicable.
• The studies demonstrated the therapeutic effect of the device compared to a control (e.g., digital control or baseline), not a human reader's improvement with AI.

5. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done:

• Yes, the primary evaluation was standalone. EndeavorRx is a "Software-as-Medical Device (SaMD)" that resides on the user's mobile device and is executed at home. The therapeutic effect (improving attention function) is largely driven by the device's adaptive algorithms (Selective Stimulus Management Engine - SSME™) acting directly on the patient. While it's used "as part of a therapeutic program that may include: clinician-directed therapy," the measured improvements in attention function (TOVA API) are attributed directly to the device's use. The studies measured the outcome of the algorithm's therapeutic delivery.

6. The Type of Ground Truth Used:

Again, "ground truth" as a diagnostic reference standard doesn't perfectly fit a therapeutic device. Instead, the "ground truth" for evaluating the effectiveness of EndeavorRx was:

• Objective Computer-Based Testing: The Test of Variables of Attention (TOVA) Attention Performance Index (API) / Attention Composite Score (ACS). This is an FDA-cleared continuous performance test measuring attention. This is considered an objective measure.
• Validated Rating Scales (Parent/Clinician-Reported):
  • ADHD-RS (Total, Inattentive, Hyperactive subscales)
  • ADHD Impairment Rating Scale (IRS)
  • CGI-I (Clinical Global Impression-Improvement)
• Academic Performance Measures: TOSREC (Test of Silent Reading Efficiency and Comprehension) and MFaCTS (Measured Functional Activities of Daily Living - for children).

These measures served as the "truth" against which the device's therapeutic impact was assessed.

7. The Sample Size for the Training Set:

The document does not specify a "training set" in the sense of a dataset used to train the adaptive algorithms (SSME™) of EndeavorRx.

• The device uses "adaptive algorithms (also known as Selective Stimulus Management Engine. SSME™) to deliver stimuli that are designed to engage the patient in a manner that improves their attention function." It "automatically adjust the difficulty level for a personalized treatment experience."
• This implies that the individual patient's performance during gameplay serves as the dynamic "training set" for the adaptive algorithm's real-time adjustments for that specific patient.
• The core algorithms themselves were developed at the University of California, San Francisco (by Adam Gazzaley, M.D.), likely drawing on neuroscience research; the initial development would have involved a form of "training" or optimization, but this wouldn't be referred to as a "training set" in the context of general clinical trial reporting for an AI/ML device like this. The effectiveness studies (STARS-ADHD, STARS-Adjunct, etc.) are evaluating the final, deployed algorithm's therapeutic effect.

8. How the Ground Truth for the Training Set Was Established:

Since there isn't a described "training set" in the conventional sense for the algorithm's initial development, the concept of "ground truth for the training set" as it applies to a supervised machine learning model isn't directly applicable here.

• The SSME™ adapts to individual player performance. Therefore, the "ground truth" for its adaptive mechanism is the real-time performance data of the player (e.g., accuracy, reaction time, consistency) which the algorithm uses to adjust difficulty and optimize the therapeutic challenge. This is an internal, dynamic "ground truth" established during each play session.
• The science behind EndeavorRx was developed academically (UCSF), which suggests a foundation in cognitive neuroscience principles guiding the design of the adaptive stimuli and feedback loops. The "truth" for this underlying scientific design would be established through decades of cognitive psychology and neuroscience research on attention and learning.

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