(228 days)
EndeavorOTC is a digital therapeutic indicated to improve attention as measured by computer-based testing in patients 18 and older with primarily inattentive or combined type ADHD, who have a demonstrated attention issue. Patients who engage with EndeavorOTC 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. EndeavorOTC is not intended to be a replacement for any form of treatment and should be used as part of a therapeutic program that may include clinician-directed therapy, medicational programs, which further address symptoms of the disorder.
EndeavorOTC is software-as-a-medical device (SaMD) that resides on the user's mobile device and can be executed at home. It is an over-the-counter (OTC) digital therapeutic indicated to improve attention function as measured by computer-based testing in patients 18 and older with primarily inattentive or combined type ADHD, who have a demonstrated attention issue. Patients who engage with EndeavorOTC 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. EndeavorOTC is not intended to be a replacement for any form of treatment and should be used as part of a therapeutic program that may include clinician-directed therapy, medication, and/or educational programs, which further address symptoms of the disorder. The device is built on Akili's proprietary, patented, technology platform. EndeavorOTC 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. EndeavorOTC 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 EndeavorOTC 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 recommended regimen (approximately 25 minutes per day, 5 days per week, for 6 weeks).
Here's a summary of the acceptance criteria and the study proving the EndeavorOTC device meets those criteria, based on the provided FDA 510(k) summary:
Device Acceptance Criteria and Performance Study: EndeavorOTC
Device Name: EndeavorOTC
Regulatory Class: Class II
Product Code: QFT
Indication for Use: Digital therapeutic indicated to improve attention as measured by computer-based testing in patients 18 and older with primarily inattentive or combined type ADHD, who have a demonstrated attention issue.
1. Table of Acceptance Criteria and Reported Device Performance
The primary acceptance criteria for EndeavorOTC are based on demonstrating an improvement in attention, as measured by the Test of Variables of Attention (TOVA®) Attention Comparison Score (ACS), and showing a favorable safety profile in the indicated adult population. The 510(k) summary refers to "clinical performance study support[ing] the performance and safety of EndeavorOTC in the adult age range" and "a statistically significant positive mean change from baseline to study day 42 in the TOVA".
Based on the provided document, the key efficacy performance criterion appears to be a statistically significant positive change in the TOVA-ACS.
| Acceptance Criteria (Implicit from Study Design & Outcomes) | Reported Device Performance (STARS-Adult Study, K233496) |
|---|---|
| Statistically significant positive change in TOVA-ACS from baseline to exit | Mean change in TOVA-ACS: 6.460 (SD 6.9522) 95% CI: [5.349, 7.570] P-value: < 0.0001 (Highly statistically significant) |
| Favorable safety profile (low incidence of adverse events, no serious adverse events) | Any TE-ADE: 11 (5.0%) of 221 subjects Most common TE-ADEs: Nausea (1.8%), Headache (1.4%), Decreased frustration tolerance (0.9%) Serious Adverse Device Events (SAEs): None reported Severity of TE-ADEs: All mild or moderate |
2. Sample Size and Data Provenance
- Test Set (Clinical Study Population):
- Safety Population (ITT): 221 participants
- Efficacy Population (mITT): 153 participants (all enrolled subjects with sufficient data at baseline and exit to calculate change scores)
- Data Provenance: The study was a "multicenter open-label study enrolled 221 subjects... across the US (a mix of institutional sites and private practice centers)." It was a prospective clinical performance study.
3. Number of Experts for Ground Truth and Qualifications
The provided document does not specify the number of experts used to establish the ground truth for the test set or their specific qualifications (e.g., "Radiologist with 10 years of experience").
However, the diagnosis of ADHD was determined in study participants using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria as confirmed by the Mini-International Neuropsychiatric Interview (MINI) for ADHD adult version 7.0.2. This implies the involvement of trained clinicians (likely psychiatrists or psychologists) to administer and interpret these diagnostic tools. The TOVA® test itself is a standardized, computer-based assessment of attention.
4. Adjudication Method for the Test Set
The document does not describe a formal adjudication method (e.g., 2+1, 3+1) for the interpretation of the primary outcomes. The primary outcome (TOVA-ACS) is a quantitative, digitally assessed measure, which generally does not require traditional expert adjudication of results in the same way image interpretations might. The ADHD diagnosis was clinician-confirmed using standardized interviews.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No, a multi-reader multi-case (MRMC) comparative effectiveness study was not explicitly mentioned or performed. This study was a single-arm, open-label study, primarily evaluating the device's effect on attention in the target population. It was not designed to compare human readers' improvement with or without AI assistance, as the device is a direct therapeutic intervention, not an AI-assisted diagnostic tool.
6. Standalone (Algorithm Only) Performance
EndeavorOTC is a therapeutic device (software-as-a-medical device) that directly interacts with the user as a game-like experience. Its performance is the algorithm's effect on the user's attention, measured by standardized tests like TOVA. Therefore, the clinical study results represent the standalone performance of the device's algorithm in a human-in-the-loop context (the human being the patient using the device). It's not an AI model that outputs a diagnostic interpretation for a human to review.
7. Type of Ground Truth Used
The primary ground truth for efficacy was objective, digitally assessed measures (Test of Variables of Attention - TOVA-ACS). The patient's ADHD diagnosis, which defined the study population, was established by clinician-administered standardized diagnostic interviews (MINI) based on DSM-5 criteria.
8. Sample Size for the Training Set
The document does not specify the sample size for the training set of the adaptive algorithms (Selective Stimulus Management Engine - SSME™). It notes that the science behind EndeavorOTC was developed at the University of California, San Francisco by Adam Gazzaley, M.D., Ph.D. The algorithms are "adaptive" and "in a closed-loop system, automatically adjust the difficulty level," implying continuous adaptation rather than a single, fixed training dataset in the typical machine learning sense.
9. How Ground Truth for Training Set was Established
Given that 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," and adjusts difficulty "for a personalized treatment experience," the "ground truth" for the training of these adaptive algorithms is inherently tied to the patient's real-time performance within the game and their physiological responses or attentional engagement.
The document does not detail how the initial parameters or underlying "training" for these adaptive algorithms were established. It mentions the algorithms were "developed at the University of California, San Francisco by Adam Gazzaley, M.D., Ph.D." This suggests a research-based, iterative development process informed by neuroscience and cognitive psychology, rather than a single, labeled dataset typical of supervised machine learning. The "ground truth" for fine-tuning the adaptive difficulty would likely be the user's performance and implicit learning within the game itself.
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June 14, 2024
Akili Interactive Labs, Inc. % Bhupinder Singh Head of Quality and Regulatory Affairs 22 Boston Wharf Rd 7th Floor Boston, MA 02110
Re: K233496
Trade/Device Name: EndeavorOTC Regulation Number: 21 CFR 882.5803 Regulation Name: Digital therapy device for attention deficit hyperactivity disorder Regulatory Class: Class II Product Code: QFT Dated: May 16, 2024 Received: May 16, 2024
Dear Bhupinder Singh:
We have reviewed your section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (the Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Additional information about changes that may require a new premarket notification are provided in the FDA guidance documents entitled "Deciding When to Submit a 510(k) for a Change to an Existing Device"
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(https://www.fda.gov/media/99812/download) and "Deciding When to Submit a 510(k) for a Software Change to an Existing Device" (https://www.fda.gov/media/99785/download).
Your device is also subject to, among other requirements, the Quality System (QS) regulation (21 CFR Part 820), which includes, but is not limited to, 21 CFR 820.30. Design controls; 21 CFR 820.90. Nonconforming product; and 21 CFR 820.100, Corrective and preventive action. Please note that regardless of whether a change requires premarket review, the OS regulation requires device manufacturers to review and approve changes to device design and production (21 CFR 820.30 and 21 CFR 820.70) and document changes and approvals in the device master record (21 CFR 820.181).
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801); medical device reporting of medical device-related adverse events) (21 CFR Part 803) for devices or postmarketing safety reporting (21 CFR Part 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR Part 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR Parts 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
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Sincerely,
Robert Kang -S
for Pamela Scott, MS Assistant Director DHT5B: Division of Neuromodulation and Physical Medicine Devices OHT5: Office of Neurological and Physical Medicine Devices Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K233496
Device Name EndeavorOTC
Indications for Use (Describe)
EndeavorOTC is a digital therapeutic indicated to improve attention as measured by computer-based testing in patients 18 and older with primarily inattentive or combined type ADHD, who have a demonstrated attention issue. Patients who engage with EndeavorOTC 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. EndeavorOTC is not intended to be a replacement for any form of treatment and should be used as part of a therapeutic program that may include clinician-directed therapy, medicational programs, which further address symptoms of the disorder.
| Type of Use (Select one or both, as applicable) | |
|---|---|
| ------------------------------------------------- | -- |
Prescription Use (Part 21 CFR 801 Subpart D)
X Over-The-Counter Use (21 CFR 801 Subpart C)
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7. 510(k) Summary
This 510(k) summary of safety and effectiveness information is prepared in accordance with 21 CFR § 807.92.
| Date Prepared: | October 30, 2023 |
|---|---|
| Legal Manufacturer: | Akili Interactive Labs, Inc.71 Commercial StMailbox 312Boston, MA 02109 |
| Primary Contact Person: | Bhupinder SinghHead of Quality and Regulatory AffairsPhone: +1 (408) 832-7124E-mail: bsingh@akiliinteractive.com |
Regulatory Information
| Device Trade Name: | EndeavorOTC |
|---|---|
| Device Classification Name: | Digital Therapeutic Software for Attention DeficitHyperactivity Disorder |
| Regulation Number: | 21 CFR § 882.5803 |
| Classification Product Code: | QFT |
| Review Advisory Committee: | Neurology |
| Device Classification: | Class II |
| 510(k) Number | K233496 |
| Predicate Device Information | |
| Device Manufacturer: | Akili Interactive Labs, Inc. |
| Submission Number: | DEN200026 |
| Device Name: | EndeavorRx |
| Other Reference Device | EndeavorRx (K231337) |
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Device Description:
EndeavorOTC is software-as-a-medical device (SaMD) that resides on the user's mobile device and can be executed at home.
It is an over-the-counter (OTC) digital therapeutic indicated to improve attention function as measured by computer-based testing in patients 18 and older with primarily inattentive or combined type ADHD, who have a demonstrated attention issue. Patients who engage with EndeavorOTC 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. EndeavorOTC is not intended to be a replacement for any form of treatment and should be used as part of a therapeutic program that may include clinician-directed therapy, medication, and/or educational programs, which further address symptoms of the disorder.
The device is built on Akili's proprietary, patented, technology platform. EndeavorOTC 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.
EndeavorOTC 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 EndeavorOTC 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 recommended regimen (approximately 25 minutes per day, 5 days per week, for 6 weeks).
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Indications for Use: EndeavorOTC is a digital therapeutic indicated to improve attention function as measured by computer-based testing in patients 18 and older with primarily inattentive or combined type ADHD, who have a demonstrated attention issue. Patients who engage with EndeavorOTC 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. EndeavorOTC is not intended to be a replacement for any form of treatment and should be used as part of a therapeutic program that may include clinician-directed therapy, medication, and/or educational programs, which further address symptoms of the disorder. Limitations EndeavorOTC may not be appropriate for users with photo-sensitive
epilepsy, color blindness, or physical limitations that restrict use of a mobile device. It is recommended that users speak to their health care provider before starting EndeavorOTC treatment. EndeavorOTC is not for persons who have a comorbid psychiatric condition in addition to ADHD. When using this device it is recommended that users seek care from a medical health care provider in conjunction with its use.
NOTE: This single arm study did not include a sham control group and it is therefore possible that observed effects were due to bias or placebo effects. Akili has conducted and published additional studies that support the lack of a placebo effect on the TOVA2-2. Patients and health care providers should consider the totality of the clinical evidence in light of this before using this product.
² Yerys BE, Bertollo JR, Kenworthy L, et al. Brief Report: Pilot Study of a Novel Interactive Digital Treatment to lmprove Cognitive Control in Children with Autism Spectrum Disorder and Co-occurring ADHD Symptoms. J Autism Dev Disord. 2019;49(4):1727-1737. doi:10.1007/s10803-018-3856-7
2 Keefe RSE, Cañadas E, Farlow D, Etkin A. Digital Intervention for Cognitive Deficits in Major Depression: A Randomized Controlled Trial to Assess Efficacy and Safety in Adults. Am J Psychiatry. 2022;179(7):482-489. doi:10.1176/appi.ajp.21020125
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Summary of Technological Characteristics
| Attribute | Subject Device:EndeavorOTC | Predicate Device:EndeavorRx (DEN200026) | Comparison |
|---|---|---|---|
| Manufacturer | Akili Interactive Labs, Inc. | Akili Interactive Labs, Inc. | Same |
| DeviceClassificationName | Digital TherapeuticSoftware for AttentionDeficit HyperactivityDisorder | Digital Therapeutic Software forAttention Deficit HyperactivityDisorder | Same |
| Product Code | QFT | QFT | Same |
| RegulationNumber | 21 CFR § 882.5803 | 21 CFR § 882.5803 | Same |
| Intended use | Digital therapeutic adaptivestimulus software for theclosed-loop treatment ofpsychiatric disorders andcognitive dysfunctionassociated with medicalconditions. | Digital therapeutic adaptivestimulus software for the closed-loop treatment of psychiatricdisorders and cognitivedysfunction associated withmedical conditions. | Same |
| Indication ofUse | EndeavorOTC is an over thecounter digital therapeuticindicated to improveattention function asmeasured by computer-based testing in patients 18and older with primarilyinattentive or combinedtype ADHD, who have ademonstrated attentionissue. Patients who engagewith EndeavorOTCdemonstrate improvementsin a digitally assessedmeasure, Test of Variablesof Attention (TOVA®) ofsustained and selectiveattention and may notdisplay benefits in typicalbehavioral symptoms suchas hyperactivity. | EndeavorRx is a digitaltherapeutic indicated toimprove attention function asmeasured by computer basedtesting in children ages 8-12years old with primarilyinattentive or combined-typeADHD, who have ademonstrated attention issue.Patients who engage withEndeavorRx demonstrateimprovements in a digitallyassessed measure Tests ofVariables of Attention (TOVA) ofsustained and selectiveattention and may not displaybenefits in typical behavioralsymptoms, such ashyperactivity. EndeavorRxshould be considered for use aspart of a therapeutic program | Substantiallyequivalent.EndeavorOTC isindicated for 18years of age orolder, comparedto the predicatedevice (8-12years). Thedifference in agerange do notchange theintended use ofthe device, andclinical testingdemonstratesthe subjectdevice is safeand effective inthe adultpopulation. |
| EndeavorOTC is notintended to be areplacement for any form oftreatment and should beused as part of atherapeutic program thatmay include clinician-directed therapy,medication, and/oreducational programs,which further addresssymptoms of the disorder | that may include: clinician-directed therapy, medication,and/or educational programs,which further address symptomsof the disorder. | Productindication waschanged from Rxto OTC. SeeAccess rowbelow forfurtherdiscussion. | |
| SystemComponents | Patient facing video gameapplication | Patient facing video gameapplication | Same |
| Mobile device platform | Mobile device platform | ||
| ProprietaryAlgorithm | Selective StimulusManagement Engine(SSMETM) | Selective Stimulus ManagementEngine (SSMETM) | Same |
| BasicOperations | Steering, Tapping, Multi-tasking | Steering, Tapping, Multi-tasking | Same |
| Presentation | Structured manner acrossgame "Challenges" and"Worlds" | Structured manner across game"Challenges" and "Worlds" | Same |
| MobilePlatformCompatibility | iOS and Android | iOS and Android | Same |
| Access | Over-the-counter use. It isrecommended that patientsspeak to their health careprovider before startingEndeavorOTC treatment.See section, "Summary ofClinical Performance Data"below for supporting data. | Prescription use only.Authorized and overseen by alicensed health care provider. | Labelingmodificationswere made tosupport over-the-counter use,and humanfactorsvalidationtesting confirmsthe change toOTC does notraise differentquestions. |
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Summary of Non-Clinical Performance Data: Bench software testing has been performed on the EndeavorOTC and demonstrates compliance with the following international and FDArecognized consensus standards and FDA guidance documents:
- ISO 14971:2019 Medical devices - Application of risk management to medical devices
- IEC 62304 Edition 1.1 2015-06 CONSOLIDATED VERSION Medical device software - Software life cycle processes
- IEC 82304-1 Edition 1.0 2016-10 Health software - Part 1: General requirements for product safety
- FDA Guidance Document for Industry and FDA Staff -Content of Premarket Submissions for Device Software Functions - Guidance for Industry and Food and Druq Administration Staff (Final Guidance issued June 14, 2023)
- . FDA Guidance Document for Industry and FDA Staff -Cybersecurity in Medical Devices: Quality System Considerations and Content of Premarket Submissions: Guidance for Industry and Food and Drug Administration Staff (Final Guidance issued September 27, 2023)
The results of bench software verification and validation testing supports that EndeavorOTC functions as intended.
Human factors validation testing was performed to ensure that EndeavorOTC is safe and effective for intended users, use, and use environments, and demonstrates compliance with the following additional standards and guidance document:
- ANSI/AAMI/IEC 62366-1:2015/ Amd 1: 2020 Medical Devices -Part 1: Application of Usability Engineering to Medical Devices - Amendment 1
- ANSI/AAMI/IEC 62366-2:2016 Medical Devices Part 2: ● Guidance on the application of usability engineering to medical devices
- FDA Guidance Document for Industry for Industry and FDA Staff - Applying Human Factors and Usability Engineering to Medical Devices, issued February 3, 2016
The results of the human factors validation testing supports the usability of EndeavorOTC in intended users, for the intended use, in the intended use environment.
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Summary of Clinical Data: Clinical performance testing was conducted to evaluate the efficacy and safety of EndeavorOTC in adults 18 years of age and older. 3 Efficacy was determined primarily by the change from baseline in a digitally assessed measure of sustained and selective attention, the Test of Variables of Attention (TOVA®), after 6 weeks of treatment. The multicenter open-label study enrolled 221 subjects with inattentive or combined-type ADHD. A diagnosis of ADHD was determined in study participants using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria as confirmed by the Mini-International Neuropsychiatric Interview (MINI) for ADHD adult version 7.0.2. All 221 participants who were enrolled in the adult study were included in the Safety population (also known as ITT or intent to treat population, is all subjects enrolled in the study), and 153 participants were included in the Efficacy Population (also known as the mlTT or modified intent to treat population, is all enrolled subjects with drop outs excluded). Safety population is all participants who were exposed to AKL-T01 intervention. Efficacy population is all participants who took the AKL-T01 intervention home and completed both baseline and day 42 exit visit assessments (including TOVA).
Seventy-five participants (33.9%) discontinued the study: the most common reason for study discontinuation was withdrawal by participant. Reasons for withdrawal by participants include the following: experiencing technical bugs or technical issues; game took too much time away from school, work, or other activities; did not like AKL-T01; did not want to complete the on-site study activities any further. Three (1.7%) participants discontinued the study due to adverse events (1 headache, 2 nausea).
For further description of the adult study in comparison to the predicate studies, see Table 1 - comparison of clinical study design description.
The results of the clinical performance study support the performance and safety of EndeavorOTC in the adult age range. Analysis of the primary efficacy endpoint in the Efficacy Population (N=153) showed a statistically significant positive mean change from baseline to study day 42 in the TOVA of 6.460 (SD 6.9522 [95% Cl: 5.349, 7.570]; P < 0.0001). Figure 1 below compares the mean TOVA-ACS score from participants in the STARS-Adult study (subject study) with STARS-Adolescents (K231337) and STARS-ADHD (DEN200026) studies. Analysis of the
3 Stamatis, C. A., Mercaldi, C., & Kollins, S. H. (2023). A Single-Arm Pivotal Trial to Assess the Efficacy of Akl-T01, a Novel Digital Intervention for Attention, in Adults Diagnosed With ADHD. Journal of the American Academy of Child & Adolescent Psychiatry, 62(10), S318
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secondary efficacy endpoints in the Efficacy Population (N=153) showed improvements in the ADHD-RS total score by a mean of 8.3 points (SD: 7.74) and in the ADHD-RS inattentive score by a mean of 5.1 points (SD: 4.78). The improvements observed did not meet clinically meaningful improvement, which is estimated as 10-point difference in Total Score based on literature.4 For a comparison of clinical study outcomes between the subject and predicate studies, see Table 2.
Figure 1. Mean TOVA-ACS Score Bar Chart Comparison across Subject and Predicate Studies
Image /page/11/Figure/3 description: This image is a bar graph comparing the mean TOVA-ACS with a 95% confidence interval for three age groups: 18y+, 13-17y, and 8-12y. The data is presented for both the baseline and exit stages. The y-axis represents the mean TOVA-ACS with a 95% confidence interval, ranging from -10 to 10. The sample sizes for each age group at baseline are: Ages 18y+ N=221, Ages 13-17y N=162, and Ages 8-12y N=179, while at exit, the sample sizes are: Ages 18y+ N=153, Ages 13-17y N=146, and Ages 8-12y N=170.
Markers represent individual subject values. Two participants in STARS-ADHD-Adults were enrolled that did not meet inclusions criteria of baseline TOVA-ACS ≤ -1.8 and were reported as protocol violations. TOVA-ACS scores below zero suggest performance similar to individuals with ADHD.5
Study results were based on a modified intent-to-treat (mITT, also known as Efficacy population, is all enrolled subjects with drop outs excluded) population. This population included all enrolled participants with sufficient data at baseline and exit to calculate change scores (N=153) instead of the intent-to-treat (ITT, also known as Safety Population, is all subjects enrolled in the study) population (N=221).
4 Zhang S, Faries DE, Vowles M, Michelson D. ADHD Rating Scale IV: psychometric properties from a multinational study as a clinicianadministered instrument. Int J Methods Psychiatr Res. 2005;14(4):186-201. doi:10.1002/mpr.7
5 TOVA Clinical Manual 2020, p. 32 of 78: https://files.tovatest.com/documentation/9/Clinical%20Manual.pdf
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A sensitivity analysis using multiple imputation (MI) was performed to assess the impact of missing exit data in the ITT population. Change in TOVA-ACS was generally similar in the ITT population after imputation, with a mean [95% CI] of 6.144 [5.037, 7.273] as compared with the mITT population 6.460 [5.349, 7.570]. See Table 3 for a Modified Intent-to-Treat (mlTT) and Intent-to-Treat (ITT) Analysis with Multiple Imputation (MI) of the Primary Efficacy Endpoint - TOVA-ACS Change from Baseline to Exit.
Overall, 11 (5.0%) subjects experienced a treatment-emergent adverse device event (TE-ADE). Reports include 4 (1.8%) nausea, 3 (1.4%) headaches, 2 (0.9%) decreased frustration tolerance, and 1 each (0.5%) of arthritis, dizziness, fatigue, and somnolence. All TE-ADEs were mild or moderate. There were no serious adverse device events. See Table 4 for a comparison of clinical safety outcomes from the subject study with predicate studies.
Akili has conducted and published additional studies that support the lack of a placebo effect on the TOVA67 . Patients and health care providers should consider the totality of the clinical evidence in light of this before using this product.
The clinical performance study demonstrates that EndeavorOTC is safe and effective for its intended use in the indicated patient population.
NOTE: This single arm study did not include a sham control group and it is therefore possible that observed effects were due to bias or placebo effects. Users should consider the totality of the clinical evidence in light of this before using the product.
Some persons with known comorbid psychiatric conditions were excluded from this study and therefore the risk profile for persons with comorbid psychiatric conditions is not fully known.
6 Yerys BE, Bertollo JR, Kenworthy L, et al. Brief Report: Pilot Study of a Novel Interactive Digital Treatment to lmprove Cognitive Control in Children with Autism Spectrum Disorder and Co-occurring ADHD Symptoms. J Autism Dev Disord. 2019;49(4):1727-1737. doi:10.1007/s10803-018-3856-7
7 Keefe RSE, Cañadas E, Farlow D, Etkin A. Digital Intervention for Cognitive Deficits in Major Depression: A Randomized Controlled Trial to Assess Efficacy and Safety in Adults. Am J Psychiatry. 2022;179(7):482-489. doi:10.1176/appi.ajp.21020125
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Table 1. Clinical study design description comparison
| Subject DeviceK233496 | Predicate DeviceDEN200026 | ||
|---|---|---|---|
| STARS-Adult Study(ages 18+) | STARS Study (ages 8-12) | Comparison describing differences and arationale why it is acceptable | |
| Population | Verified ADHDdiagnosis withimpaired attention;on or off medication | Verified ADHDdiagnosis withimpaired attention;medicationexclusionary | SIMILAR - the adult study allowed formedication as long as use was stable for≥4 weeks prior to study enrollment andthroughout the study. A prior studydemonstrated benefits of intervention onthe pediatric population with ADHD bothon and off medication. |
| Study Design | Single arm, open-label, adaptivedesign | Randomized clinicaltrial | DIFFERENT - Presence of attentionalimprovement from treatment comparedto those on active control was establishedin the STARS study. The adult studyinvestigated the magnitude ofimprovement and safety in the new agerange. |
| The Adult study used an adaptive designbased on the total information asmeasured by the standard error of theprimary endpoint which would allow thetrial to be stopped prior to recruitment ofthe 325 participants derived from thesample size calculations. The adaptivedesign accounts for the uncertaintyregarding whether the variation in TOVA-ACS mean change differed between theadult and pediatric ADHD populations. | |||
| The safety and effectiveness of the exactsame device was established in an RCT DeNovo in a younger population. The primaryendpoint used in the current study wasidentical to the original STARS RCT. Basedon the predicate RCT, the primaryoutcome measure TOVA demonstratesless susceptibility to placebo effect in the | |||
| randomized, controlled trial utilized forthe de novo.Another consideration for the single armdesign is that the TOVA-ACS is lesssusceptible to placebo effects whenmeasuring attentional control processeswithin the context of ADHD, as supportedby the predicate RCT and multiplepublished studies in the literature. 8,9,10 | |||
| Intervention | EndeavorRx (AKL-T01) | EndeavorRx (AKL-T01)EVO: Words (Activecontrol) | SIMILAR - All use the same activeintervention, minor differences insoftware. |
| Treatmentregimen | 25 minutes/day for 5days/week | 25 minutes per day, 5days per week | SIMILAR |
| ParticipantDuration | Approximately 6weeks on treatment | Approximately 4weeks on treatment | DIFFERENT - In Adults, treatment durationwas adjusted to match duration used inpast adult studies using a similar SSME™-driven product |
| Diagnosis of ADHD | Yes - Diagnosis ofADHD combined orinattentive type,required according toDiagnostic andStatistical Manual ofMental Disorders,Fifth Edition (DSM-5)as confirmed byMini InternationalNeuropsychiatricInterview (MINI) forAttention - Deficit /Hyperactivity | Yes - Confirmed ADHDdiagnosis, anypresentation, requiredat Screening based onDSM-V criteria andestablished via theMINI-KID administeredby atrained clinician | SIMILAR - An age-appropriate version ofthe MINI was used in the adult study. |
| Disorders Studies(Adult) 7.0.2 | |||
| Sites | Multi-site: 14 sitesacross the US (a mixof institutional sitesand private practicecenters) | Multi-site: 20 sitesacross the US (a mix ofinstitutional sites andprivate practicecenters) | SIMILAR |
| Enrollment | 223 enrolled | 348 enrolled | SIMILAR - the larger N in STARS studytakes into account two arms. In Adults,sample size was determined by powercalculations. |
| Stably on or offADHD medications | Stably on or offstimulant medication(≥4 weeks) allowedStably on or off non-stimulant medication(≥4 weeks) allowed | Stimulant medicationuse not allowedUse of non- stimulantADHD medication notallowed | DIFFERENT - Another published study11demonstrated ADHD improvementoccurred similarly in patients both stablyon and off ADHD medications. Thiscriterion was adopted into the adult studydesign to better simulate real-world userbaseThe adult study allowed non-stimulantmedication use as long as stability 4-weeks before and after study enrollment ismaintained to better represent thediversity of patients who may use thedevice and to generalize to real-world userbase. |
| Stably on or offnonpharmacological treatments | Stably on or offnonpharmacologicaltreatments (≥4weeks) allowed | Stably on or offnonpharmacologicaltreatments (≥4 weeks)allowed | SIMILAR |
| Absence/Presenceof comorbidpsychiatricdiagnosis and/ortreatments thatmay confound | Presence ofcomorbid psychiatricdiagnosis and/ortreatments that mayconfound study notallowed | Presence of comorbidpsychiatricdiagnosis and/ortreatments that mayconfound study notallowed | SIMILAR |
| study | |||
| Absence/Presenceof conditions thatwould prevent theproper use of theinvestigationalproduct | Presence ofconditions thatwould prevent theproper use of theinvestigationalproduct not allowed | Presence of conditionsthat would preventthe proper use of theinvestigationalproduct not allowed | SIMILAR |
| Primary OutcomeMeasure | Change in TOVAattention comparisonscore (ACS) from pre-to post-intervention | Change in TOVAattention performanceindex (API, also knownas TOVA-ACS) frompre- to post-intervention | SIMILAR |
| SecondaryOutcomeMeasures | Mean changes in:• ADHD-Rating Scale-IV (ADHD-RS)InattentionSubscale Score• ADHD-RS TotalScale Score | Mean changes in:• ADHD-RS Total Score• ADHD-RS InattentionSubscale Score• ADHD-RSHyperactivitySubscale• BRIEF WorkingMemory percentile• BRIEF Inhibitpercentile• Impairment RatingScale (IRS)• Clinical GlobalImpression (CGI) | DIFFERENT -The predicate device used theImpairment Rating Scale (IRS) and theClinical Global Impressions Scale (CGI) toassess functional impairment, but sincethe IRS is a parent reported measure andthe CGI was not sensitive to treatmenteffects in the predicate study, neither wasused in the subject study, which used theAdult ADHD Quality of Life (AAQoL) Scaleas a measure of ADHD impairment inadults.Both studies had ADHD-RS as secondarymeasures. Whereas the STARS study listedmultiple secondary measures, the adultstudy focused on ADHD-RS as thesecondary measure, which the predicatestudy showed to be sensitive to the AKL-T01 treatment. |
| Outcome Measure | Clinical Study forEndeavorOTC(K233496) | Clinical Study used tosupport EndeavorRx(DEN200026) | Differences |
| Adults(ages 18+) | STARS(ages 8-12) | ||
| 1. pre-post changescore on TOVA ACS(Positive change | 6.46 | 0.93 | Adults show nearly 6 times theimprovement in TOVA-ACS than inSTARS. |
| indicatesimprovement) | Although the magnitude of benefitis different between EndeavorOTCand the predicate device, bothdevices show improvement inTOVA-ACS Score. | ||
| 2. pre-post changescore on ADHD-RSInattentionsubscale(Negative changeindicatesimprovement) | -5.1 | -3.6 | Greater mean change than STARS.Although the magnitude of benefitis different between EndeavorOTCand the predicate device, bothdevices show improvement inADHD-RS Inattentive Scale Score,which did not reach a clinicallymeaningful threshold. Clinicallymeaningful improvement basedon literature for the ADHD-RS isestimated at 10-point difference.12 |
| 3. pre-post changescore on ADHD-RSTotal Score(Negative changeindicatesimprovement) | -8.3 | -6.2 | SIMILAR - Greater or comparablemean change to STARS. |
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8 Keefe RSE, Cañadas E, Farlow D, Etkin A. Digital Intervention for Cognitive Deficits in Major Depression: A Randomized Controlled Trial to Assess Efficacy and Safety in Adults. Am J Psychiatry. 2022;179(7):482-489. doi:10.1176/appi.ajp.21020125
9 Yerys BE, Bertollo JR, Kenworthy L, et al. Brief Report: Pilot Study of a Novel Interactive Digital Treatment to lmprove Cognitive Control in Children with Autism Spectrum Disorder and Co-occurring ADHD Symptoms. J Autism Dev Disord. 2019;49(4):1727-1737. doi:10.1007/s10803-018-3856-7
10 Murray DW, Childress A, Giblin J, Williamson D, Armstrong R, Starr HL. Effects of OROS methylphenidate on academic, behavioral, and cognitive tasks in children 9 to 12 years of age with attention-deficit/hyperactivity disorder. Clin Pediatr (Phila). 2011;50(4):308-320. doi:10.1177/0009922810394832
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11 Kollins, S.H., Childress, A, Heusser, AC and Lutz, J. (2021). Effectiveness of a digital therapeutic as adjunct to treatment with medication in pediatric ADHD. npj Digit. Med. 4, 58. https://doi.org/10.1038/s41746-021-00429-0 AKILI CONFIDENTIAL
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Table 2. Clinical Study Outcome Comparison Table
12 Zhang S, Faries DE, Vowles M, Michelson D. ADHD Rating Scale IV: psychometric properties from a multinational study as a clinicianadministered instrument. Int J Methods Psychiatr Res. 2005;14(4):186-201. doi:10.1002/mpr.7
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Table 3. Modified Intent-to-Treat (mlTT and Intent-to-Treat (ITT) Analysis with Multiple Imputation (MI) of the Primary Efficacy Endpoint – TOVA-ACS Change from Baseline to Exit
| Analysis | BaselineTOVA-ACS | ExitTOVA-ACS | Change fromBaseline |
|---|---|---|---|
| STARS ITT Population | |||
| n | 179 | 170 | 169 |
| Mean (SD) | -5.11 (0.22) | -4.16 (0.28) | 0.93 (0.24) |
| 95% CI | 0.45, 1.40 | ||
| p-value1 | 0.0002 | ||
| Adult Efficacy Population (mITT) | |||
| n | 153 | 153 | 153 |
| Mean (SE) | -8.739 (0.6089) | -2.279 (0.3978) | 6.460 (0.5621) |
| 95% CI | 5.349, 7.570 | ||
| p-value1 | <0.0001 | ||
| Adult Safety Population (ITT withMI2) | |||
| n | 221 | 221 | 221 |
| Mean (SE) | -8.644 (0.5249) | -2.489 (0.4542) | 6.155 (0.5698) |
| 95% CI | 5.037, 7.273 | ||
| p-value1 | <0.0001 |
Abbreviations: Cl = confidence interval; FCS = fully condition ITT = intent-to-treat, also known as Safety Population, is al subjects enrolled in the study; mITT = modified intent-to-treat, also known as Efficacy Population, is all enrolled subjects with drop outs excluded; MI = multiple imputation; SE = standard error
1 From a one-sample t-test of change greater than zero. Positive changes indicate improvement.
² Multiple imputation for participants with missing data at Day 42 was performed using FCS with 100 imputations and included covariates age, sex, race, ethnicity, education plan, age of ADHD symptom onset, concomitant stimulant use, treatment exposure defined as number of nonpractice missions completed, and baseline TOVA-ACS value. Estimates of mean and standard error at baseline were calculated for each imputation and combined using PROC MIANALYZE in SAS version 9.4.
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Table 4. Clinical Safety Outcome Comparison Table - Safety Outcomes for Participants who received AKL-T01 in STARS-Adults (Safety Population4) and STARS-ADHD (DEN200026) studies
| ADEs by PreferredTermn (%) | All StudiesN = 401 | Adults(K233496)N = 221 | STARS-ADHD(DEN200026)N = 180 | Comparison describingdifferences and a rationalewhy it is acceptable |
|---|---|---|---|---|
| Any ADE | 23(5.74%) | 11 (5.0%) | 12 (6.7%) | Compared to STARS study,fewer participants in the |
| Frustration tolerancedecreased | 7 (1.75%) | 2 (0.9%) | 5 (2.8%) | Adult study experiencedtreatment-emergent |
| Headache | 6 (1.5%) | 3 (1.4%) | 3 (1.7%) | adverse device effects (TE- |
| Nausea | 5 (1.25%) | 4 (1.8%) | 1 (0.6%) | ADE) overall. The only ADE |
| Dizziness | 2 (0.5%) | 1 (0.5%) | 1 (0.6%) | where adults reportedhigher incidence at greater |
| Emotional disorder | 2 (0.5%) | 0 (0%) | 2 (1.1%) | than 1% was nausea. All |
| Aggression | 1 (0.25%) | 0 (0%) | 1 (0.6%) | other incidences (fatigue, |
| Fatigue | 1 (0.25%) | 1 (0.5%) | 0 (0%) | somnolence, and arthritis) |
| Somnolence | 1 (0.25%) | 1 (0.5%) | 0 (0%) | remain low at <1%.Therefore, bothEndeavorOTC and thepredicate device are bothsafe for their intended use. |
| Arthritis | 1 (0.25%) | 1 (0.5%) | 0 (0%) |
1 Safety Population, also known as ITT or intent to treat population, is all subjects enrolled in the study.
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Substantial Equivalence EndeavorOTC has the same intended use and similar indications, technological characteristics, and principles of operation as the Discussion: predicate device, EndeavorRx (DEN200026). Moreover, EndeavorOTC complies with the same special controls as the predicate Endeavor Rx (DEN200026) set forth in 21 CFR § 882.5803. The expanded age range and minor software changes do not raise different questions of safety or efficacy.
Substantial equivalence was supported by clinical and non-clinical performance (verification and validation) tests, which complied with the requirements specified in the international and FDA-recognized consensus standards, ISO 14971, IEC 62304, and IEC 82304. The nonclinical testing included software testing, which verified the minor software changes in EndeavorOTC. Clinical testing validated the safety and effectiveness of EndeavorOTC for its intended use in the indicated patient age range of 18 years and older. The clinical trial results showed a significant improvement in the primary effectiveness measure, TOVA, a digitally assessed measure of sustained and selective attention. Results also showed improvements in ADHD symptoms as assessed in key secondary measures, the ADHD-RS inattention scale and ADHD-RS total score, which did not reach clinically meaningful significance estimated at 10-points in literature13. These results were similar to the findings of the prior clinical trial that supported the original clearance of EndeavorRx for 8-12 year-old patients under DEN200026. The clinical testing also showed no new or increased safety risks in the expanded patient population compared to the predicate device.
The results of these tests demonstrate that EndeavorOTC is as safe and effective as its predicate device. Therefore, EndeavorOTC is substantially equivalent.
Benefit-Risk Profile: No serious adverse events were reported. Of the 221 subjects who received AKL-T01 in the adult study supporting EndeavorOTC authorization for ages 18 years and above, 11 (5.0%) subjects experienced 13 treatment-emergent adverse device events (TE-ADE). Reports include 4 (1.8%) nausea, 3 (1.4%) headaches, 2 (0.9%) decreased frustration tolerance, and 1 each (0.5%) of arthritis, dizziness, fatigue, and somnolence. Three TE-ADEs (somnolence, fatigue, and arthritis) were considered unanticipated, and 3 TE-ADEs (1 occurrence of headache and 2 occurrences of nausea) resulted in study treatment discontinuation. All TE-ADEs were either mild or moderate in severity, and all were considered related to the study treatment.
43 Zhang S, Faries DE, Vowles M, Michelson D. ADHD Rating Scale IV: psychometric properties from a multinationadministered instrument. Int J Methods Psychiatr Res. 2005;14(4):186-201. doi:10.1002/mpr.7
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There were no serious adverse device events. All adverse events were resolved by the end of treatment.
EndeavorOTC showed a general improvement in attention associated with ADHD. The totality of the evidence demonstrated clinical benefit in attention, as measured by the TOVA in the adult population (18+ years) with ADHD with a demonstrated attention issue. Improvements in ADHD inattentive symptoms were comparable or greater than the improvements in ADHD inattentive symptoms seen in the pediatric population from the predicate studies. As noted, the risks associated with EndeavorOTC are minimal.
For EndeavorOTC, the AE rates were low, in mild-moderate severity range. There were no SAEs, and all TE-ADEs were resolved by the end of the clinical trial. Given the favorable safety profile, even small benefits in inattentive ADHD symptoms would justify use of the product.
The benefits of the EndeavorOTC have been found to outweigh the individual risks. After evaluating all benefits, risks and applicable considerations, it has been determined that the overall residual risk of the EndeavorOTC is acceptable, and the product is considered safe for use by the intended user within the intended use environment.
§ 882.5803 Digital therapy device for Attention Deficit Hyperactivity Disorder.
(a)
Identification. A digital therapy device for Attention Deficit Hyperactivity Disorder (ADHD) is a software intended to provide therapy for ADHD or any of its individual symptoms as an adjunct to clinician supervised treatment.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Clinical performance testing must demonstrate and document the following under the labeled conditions for use, which include considerations for the ability of the device to:
(i) Use a validated measure to evaluate effectiveness of device to provide therapy for ADHD or any of its individual symptoms; and
(ii) Capture all adverse events.
(2) Software must be described and provided in a clear and detailed manner to include all features and functions of the software implementing the digital therapy. Software verification, validation, and hazard analysis must also be provided.
(3) The labeling must include the following items:
(i) Patient and physician labeling must include instructions for use, including images that demonstrate how to interact with the device;
(ii) Patient and physician labeling must list the minimum operating system (OS) requirements that support the software of the device;
(iii) Patient and physician labeling must include a warning that the digital therapy device is not intended for use as a standalone therapeutic device;
(iv) Patient and physician labeling must include a warning that the digital therapy device does not represent a substitution for the patient's medication; and
(v) Physician labeling must include a summary of the clinical performance testing conducted with the device.