Parallel is a prescription-only digital therapeutic device intended to provide cognitive behavioral therapy for adults aged 22 years of age and older who have been diagnosed with Irritable Bowel Syndrome (IBS). Parallel is indicated as a 3 month treatment for patients with IBS. Parallel treats IBS by reducing the severity of symptoms and is intended to be used together with other IBS treatments.

Device Description

Parallel is a web-based program designed to deliver Cognitive Behavioral Therapy (CBT) to patients with IBS who continue to have symptoms despite other forms of medical therapy. It is a responsive, web-based application that is intended to be a prescription device for use in the home for patients with IBS under the management of a qualified health care professional for the treatment of their IBS. Parallel is comprised of browser-delivered digital therapy that provides the CBT content. A desktop or laptop computer with a web browser and internet connectivity is required for use.

CBT works by targeting problematic thoughts, feelings, and behaviors, building adaptive coping skills, and interrupting the cycle that is perpetuating the targeted symptoms. CBT can be delivered in-person by a mental health practitioner with adequate training in CBT. A critical component of treatment outcome is the degree to which CBT is administered competently, reliably, and as intended. Parallel treatment uses psychoeducation and teaching behavioral and cognitive skills and techniques to alter patterns of behavior and change unhelpful thoughts.

Parallel is accessed via a secure website. Initially, the patient will receive a secure email containing an access link for the Parallel web application. Upon receiving the email invitation, the user can register electronically to begin their prescription. Once registered, patients are presented with onboarding material that introduces the program. Upon completion of reading the onboarding material, the patient can start the program.

Parallel consists of eight CBT sessions, which include interactive components. The interactive components help patients remember the guidance and concepts, reflect, and engage in the therapeutic processes of CBT. In each session, patients review key points from the previous session and review their homework, thereby reinforcing previous learning. The patient must complete the sessions in sequential order. However, a patient may go back to a previously completed session. The prescription is for 90 days and patients should complete the eight sessions within that 90-day period. After the 90 days, patients can still access the sessions that they have completed.

AI/ML Overview

Here's a breakdown of the acceptance criteria and the study that proves the Parallel device meets them, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

Acceptance Criteria (from "Special Controls" and "Benefit-Risk Determination")	Reported Device Performance
1. Clinical Data
a. Describe a model of therapy for the indicated gastrointestinal conditions.	The device implements Cognitive Behavioral Therapy (CBT) for IBS, addressing problematic thoughts, feelings, and behaviors, and building adaptive coping skills. The eight sessions cover understanding IBS, symptom assessment, managing symptoms and eating, exercise and activity, identifying thought patterns, alternative thoughts, relaxation/sleep/stress management, and processing emotions/managing flare-ups.
b. Validate the model of therapy as implemented by the device using a clinically defined endpoint.	The ACTIB Pivotal Trial demonstrated a clinically meaningful benefit of >50 points in IBS-Symptom Severity Score (IBS-SSS) for the Parallel arm compared to the Treatment as Usual (TAU) arm at 3 months post-randomization (actual difference: 53 points).
c. Evaluate all adverse events.	Adverse events (AEs) were collected and analyzed. The proportion of individuals reporting at least one AE was similar across all treatment arms (TAU: 27.3%, telephone: 30.1%, Parallel: 26.5%). Most common SOCs were Psychiatric Disorders, Gastrointestinal Disorders, and Infections and Infestations. The Parallel arm showed slightly higher rates for abdominal pain, generalized pain, diverticulitis, and depression, but only one severe AE (diverticulitis) was reported in the Parallel group. Only one AE in the Parallel arm (abdominal pain) was considered "remotely" related to the device.
2. Software Documentation
Described in detail in SRS and SDS.	The De Novo request provided appropriate software documentation consistent with a "Minor" level of software concern.
Software verification, validation, and hazard analysis performed.	Performed and documented. (Explicit mention of "hazard analysis" for software is within the "Delayed access to treatment due to device software failure" risk mitigation).
Documentation demonstrates effective implementation of the behavioral therapy model.	The software provides browser-delivered digital therapy that provides the CBT content. The eight sessions are described with their mechanisms of action and session targets. (Implied by the device description and the clinical success at 3 months).
3. Usability Assessment
Demonstrate that the intended user(s) can safely and correctly use the device.	A usability assessment was conducted per FDA Guidance "Applying Human Factors and Usability Engineering to Medical Devices." It identified no critical tasks associated with the use of the Parallel software, thus a human factors study was not required.
4. Labeling Requirements
Instructions for use, including images.	Provided.
Patient and physician labeling listing minimum OS requirements.	Provided.
Patient and physician labeling including a warning that the device is not intended for use in lieu of standard therapeutic intervention or as a substitute for medication.	Provided.
Patient and physician labeling including a warning to seek medical care if having thoughts of harming self or others.	Provided.
Physician and patient labeling summarizing clinical testing.	Provided, indicating clinical benefit at 3 months.

Study Proving Device Meets Acceptance Criteria

The study that proves the Parallel device meets the acceptance criteria is the Assessing Cognitive behavioral Therapy in Irritable Bowel (ACTIB) Pivotal Trial.

Here's the detailed information regarding the study:

2. Sample Size Used for the Test Set and Data Provenance:

Test Set Sample Size (Clinical Study): 558 patients were randomized in total:
- Telephone arm: 186 patients
- Parallel arm: 185 patients
- TAU arm: 187 patients
- Due to drop-out, complete cases at the end of the trial were:
  - Telephone arm: 136
  - Parallel arm: 124
  - TAU arm: 131
Data Provenance: The study was a multicenter clinical trial. While the exact country of origin is not explicitly stated, the reference for the study ("Everitt, H., et al., Therapist telephone-delivered CBT compared with treatment as usual in refractory irritable bowel syndrome: the ACTIB three-arm RCT. Health Technol Assess, 2019. 23(17): p. 1-154.") suggests it was likely conducted in the UK, as "Health Technology Assessment" is a journal associated with the UK's National Institute for Health Research (NIHR). The study design was prospective (Randomized Multicenter Clinical Trial).

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

The ground truth for the effectiveness of the therapy was based on the IBS-Symptom Severity Score (IBS-SSS), a validated patient-reported outcome measure. Therefore, there wasn't a separate panel of experts establishing ground truth for individual cases; rather, the "ground truth" of symptom severity was derived from patient self-reporting using a standardized, validated questionnaire.
The therapy in the "Telephone" arm was provided by "a therapist with training in CBT." No specific number or qualifications for these therapists (e.g., years of experience, specific certifications) are provided in the document. For the Parallel arm, the therapy is delivered by the software itself, with "three 30-minute telephone support calls" not explicitly stated to be therapeutic in nature but rather for ensuring adequate website resource use.

4. Adjudication Method for the Test Set:

There was no explicit "adjudication method" described for the test set in the conventional sense of expert review of individual cases to determine a definitive outcome. The primary outcome measure (IBS-SSS) is a patient-reported questionnaire scored objectively.
The clinical significance of the IBS-SSS change was defined based on a previously published Minimum Clinically Important Difference (MCID) of 50 points, which was agreed upon by the FDA.

5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study was done:

No, a Multi Reader Multi Case (MRMC) comparative effectiveness study was not explicitly done in the context of comparing human readers' performance with and without AI assistance for tasks like image interpretation. This device is a therapeutic software, not a diagnostic imaging AI.
The study was a comparative effectiveness study, comparing the device (Parallel) to telephone-delivered CBT and Treatment As Usual (TAU).
- Effect Size of Human Readers (Therapists) with vs. without AI assistance: Not applicable in this context, as the "human readers" were therapists delivering CBT (Telephone arm) or providing support (Parallel arm), not interpreting data in an "AI-assisted" diagnostic workflow.
- However, if we broadly interpret "human readers" as "human therapists," the study does compare purely human-delivered therapy (Telephone CBT) to AI-assisted/delivered therapy (Parallel, which has minimal human support).
  - Telephone (Human-delivered CBT) vs. TAU:
    - 3 months: 69 points
    - 6 months: 58 points
    - 12 months: 62 points
  - Parallel (AI-delivered CBT with minimal human support) vs. TAU:
    - 3 months: 53 points (meets MCID of 50)
    - 6 months: 35.7 points (does not meet MCID)
    - 12 months: 35.5 points (does not meet MCID)
  - Comparison of Human-delivered CBT vs. AI-delivered CBT (Parallel):
    - At 3 months, human-delivered CBT yielded a 69-point improvement, while Parallel yielded a 53-point improvement. This indicates that the purely human-delivered CBT had a larger effect size at 3 months (difference of 16 points). The human-delivered CBT continued to show a significant effect at 6 and 12 months, whereas Parallel's effect diminished below the MCID after 3 months.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done:

Yes, to a significant extent, the Parallel arm represents a standalone (or near-standalone) algorithm-only performance. Patients in the Parallel arm were asked to complete the website program "at home on their own time." While they received "three 30-minute telephone support calls," these were "intended to ensure that participants were adequately using the website resources, and were not equivalent to the therapy sessions provided to the Telephone arm." This suggests the primary therapeutic delivery was via the algorithm without significant human intervention for the CBT itself. The 53-point improvement at 3 months for the Parallel arm is the standalone (or near-standalone) performance.

7. The Type of Ground Truth Used:

The ground truth for the clinical effectiveness outcome (reduction in IBS symptoms) was based on patient-reported outcomes (PROs) using a validated psychometric scale (IBS-SSS). The clinical significance was determined by an agreed-upon Minimum Clinically Important Difference (MCID).

8. The Sample Size for the Training Set:

The document does not explicitly state a separate "training set" sample size for the Parallel device in the context of how the AI/CBT algorithm was initially developed or optimized.
The ACTIB trial focuses on the validation of the implemented device. CBT models are typically developed based on established psychological principles and clinical experience, not necessarily through a "training set" in the machine learning sense from a specific clinical trial.
The document mentions "access to the Parallel software in an earlier pilot trial" as an exclusion criterion, implying there might have been prior studies or development phases, but details regarding these are not provided.

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

As a therapeutic device providing CBT, the "training set" and "ground truth" for developing the CBT content likely came from:
- Established psychological and medical literature: The principles of CBT for IBS, its mechanisms of action, and session targets detailed in the device description are well-documented clinical practices.
- Expert consensus/clinical experience: The design of the eight sessions and their content likely reflects the input of clinical experts in CBT and IBS.
- Prior pilot studies (implied): The exclusion criterion regarding prior access to Parallel suggests there were earlier developmental or pilot phases where efficacy and user experience may have been iteratively improved, thereby establishing a de facto "training" or optimization process. However, specific details on how ground truth was established within these phases are not provided in this document.

Summary

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DE NOVO CLASSIFICATION REQUEST FOR PARALLEL

REGULATORY INFORMATION

FDA identifies this generic type of device as:

Computerized behavioral therapy device for treating symptoms of gastrointestinal conditions. A computerized behavioral therapy device for treating symptoms of gastrointestinal conditions is a prescription device intended to provide a computerized version of condition-specific therapy as an adjunct to standard of care treatments to patients with gastrointestinal conditions.

NEW REGULATION NUMBER: 21 CFR 876.5960

CLASSIFICATION: Class II

PRODUCT CODE: QMY

BACKGROUND

DEVICE NAME: Parallel

SUBMISSION NUMBER: DEN200029

DATE DE NOVO RECEIVED: April 30, 2020

SPONSOR INFORMATION:

Mahana Therapeutics, Inc. Jean-Noel Courvoisier 230 California Street. Suite 302 San Francisco, California 94111

INDICATIONS FOR USE

The Parallel is indicated as follows:

LIMITATIONS

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The sale, distribution, and use of the Parallel are restricted to prescription use in accordance with 21 CFR 801.109.

In the clinical study, IBS-Symptom Severity Score (IBS-SSS) that exceeded a minimum clinically-important difference (MCID) of 50 points in the Parallel treatment group compared to the Treatment as Usual (TAU) group was limited to 3 months.

Parallel is intended to be used together with the patient's other IBS treatments and is not intended to be used as a stand-alone therapeutic. Parallel does not replace care by a provider and is not a substitute for other IBS treatments the patient may be using.

In order to use Parallel, the patient must be able to read and comprehend English, have a desktop or laptop computer with a web browser and internet connectivity, and be familiar with the use of web applications.

The ability to use Parallel may be limited for patients who are visually impaired.

Users should seek medical care if they have feelings or thoughts of harming themselves or others while using Parallel.

PLEASE REFER TO THE LABELING FOR A COMPLETE LIST OF WARNINGS, PRECAUTIONS AND CONTRAINDICATIONS.

DEVICE DESCRIPTION

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The eight sessions are described below.

Session	Mechanism of Action	Session Targets(What do patients learn/do in the session?)
Session 1:Understandingyour IBS	KnowledgePsychoeducation of treatmentmodelPersonalized feedback	Learn possible causes of IBS and physiology ofthe digestive system along with the functionalchanges that occur in the gut as a result of IBSand how these relate to specific symptoms.Learn how the autonomic nervous system ('fight-or-flight' stress system) may interact with theenteric nervous system.Complete IBS-SSS; receive a score andexplanation of what that score means.
Session 2:Assessingyoursymptoms	AwarenessBeliefs about consequences	Complete a self-assessment of the interactionbetween thoughts, emotions, and behaviors, andhow these impact stress levels and GI symptoms.Develop a personal model of IBS thatincorporates these elements.Learn how to complete the symptom diary.Homework: Complete daily diaries of the severityand experience of IBS symptoms, in conjunctionwith stress levels and eating routines/behaviors.
Session 3:Managingsymptoms andeating	Beliefs about consequences andperceived susceptibilityAttentional processesBehavioral regulationBuilding accurate awareness andreinterpretation of symptomsDecreasing hypervigilance toIBS symptomsReducing avoidance and safetybehaviors	Review the symptom diary.Learn behavioral management of the symptoms ofdiarrhea and constipation, and resolve commonmyths in this area.Learn effective goal setting, the importance ofhealthy, regular eating, and not being overlyfocused on elimination of foods.Homework: Set goals for managing symptomsand regular/healthy eating.
Session	Mechanism of Action	Session Targets(What do patients learn/do in the session?)
Session 4:Exercise andactivity	Behavioral cueingBehavioral regulationChanging behavioral responsesAttention & decisional processesReducing avoidance and safetybehaviors	Learn the importance of exercise in symptommanagement; Identify problematic activitypatterns (e.g., resting too much in response tosymptoms or an all-or-nothing style of activity).Begin graded exposure to avoided situations inwhich IBS sensations are anticipated (e.g., eatingat restaurants, long road trips) while decreasingand ultimately discontinuing safety behaviors(e.g., additional clothing in case of an accident).Homework: Set goals for regular exercise andmanage unhelpful activity patterns, if relevant.
Session 5:Identifyingyour thoughtpatterns	AwarenessAttention to threat appraisalsReinterpretationTolerance of uncertainty	Identify unhelpful thoughts (negative automaticthoughts) in relation to high personal expectationsand IBS symptoms. Link between these thoughts,feelings, behaviors and symptoms is reinforced.Homework: Goal setting plus daily thoughtrecords of unhelpful thoughts related to personalexpectations and patterns of over activity.
Session 6:Alternativethoughts	Change IBS-specific cognitionsChallenge threat-laden appraisalsDecrease attentional biasestowards threat	Introduce steps for generating alternatives tounhelpful thoughts using the patient's personalexamples.Homework: Goal setting plus daily thoughtrecords including coming up with realisticalternative thoughts.
Session 7:Learning torelax,improvingsleep,managingstress andemotions	Behavioral regulationEmotion regulationAttentional & decision-makingprocessesReducing avoidance behaviorswith new adaptive behavioralresponses	Learn basic stress management and sleep hygiene;Instructional audio and videos teachdiaphragmatic breathing, progressive musclerelaxation and guided imagery relaxation; Learnto identify common positive and negativeemotions, and the patient's ways of dealing withthese; Introduce new strategies to facilitateexpression of emotion as well as coping withnegative or difficult emotions.
Session 8:Processingemotions,managingflare-ups andthe future	Skills generalizationProactive problem-solvingAcceptance of slips	Homework: Goal setting for stress management,good sleep habits and emotional processing.Learn to accept and manage emotions; completeinteractive tasks to reflect on these concepts. Theprobability of flare-ups is discussed. Patients areencouraged to develop achievable, long-termgoals, and to continue employing learned skills tomanage flare-ups and ongoing symptoms.

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SUMMARY OF NONCLINICAL/BENCH STUDIES

SOFTWARE AND CYBERSECURITY

Parallel is Software as a Medical Device (SaMD). The software was reviewed according to the "Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices," dated May 11, 2005. The De Novo request provided appropriate

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software documentation consistent with a "Minor" level of software concern. Parallel supports the following browsers: Chrome, Firefox, and Safari and the following Operating systems: Windows and Mac.

Cybersecurity was reviewed according to FDA guidance document "Content of Premarket Submission for Management of Cybersecurity in Medical Devices" dated October 2, 2014. Appropriate cybersecurity documentation was provided.

HUMAN FACTORS

Parallel was evaluated per FDA Guidance "Applying Human Factors and Usability Engineering to Medical Devices." The usability assessment identified that there are no critical tasks associated with the use of the Parallel software application. Therefore, a human factors study was not required to support safe use by the intended user population.

SUMMARY OF CLINICAL INFORMATION

A randomized multicenter clinical trial, Assessing Cognitive behavioral Therapy in Irritable Bowel (ACTIB) Pivotal Trial, was conducted to support the intended use of Parallel.1

Study Overview

The study included three arms: treatment as usual (TAU), telephone CBT with treatment as usual (telephone), and web-based CBT with treatment as usual (Parallel). The telephone arm received guided therapy provided by a therapist with training in CBT over the telephone. Participants in the Parallel arm were asked to complete the website program at home on their own time. The TAU arm received no CBT. Participants in all three arms of the trial continued treatment as usual, i.e. IBS medications were continued throughout the duration of the study. Prior to randomization, all participants were evaluated for the severity of their IBS using IBS-SSS.

IBS-SSS is a questionnaire that includes five questions with each question having a maximum score of 100 points. The total score range is from 0 to 500. Individuals without IBS have a symptom severity score < 75. Individuals with mild, moderate and severe cases of IBS have scores 75 to 175, 175 to 300, and > 300, respectively. The questionnaire includes an assessment of pain, distention, bowel score, and quality of life. The pain component of the assessment includes the severity and duration of pain. The distention score includes both distention and tightness in the abdomen due to the differences between men and women. The quality of life component includes assessment of global well-being and an overall view on quality of life as it relates specially to irritable bowel syndrome. According to Francis et al. 1997. "a change of 50 was adequate to detect improvement." Therefore, equal to or greater than a 50-point difference defines the MCID for the IBS-SSS. Also. "this scoring system is specifically designed to assess

· Everitt, H., et al., Therapist telephone-delivered CBT compared with treatment as usual in refractory irritable bowel syndrome: the ACTIB three-arm RCT. Health Technol Assess, 2019. 23(17): p. 1-154.

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the severity of irritable bowel syndrome in a patient at a particular point in time and is not intended to be used for initial diagnosis of the condition."2

Inclusion criteria

. Patient aged 18 years old or over
. Patient had clinically significant symptoms (defined as an Irritable Bowel Syndrome Symptom Severity Scale [IBS-SSS] score > 75)
. Patient fulfilled ROME III criteria
- a. ROME III Criteria is defined as recurrent abdominal pain or discomfort at least 3 days per month in the last 3 months associated with 2 or more of the following:
  - . Improvement with defecation
  - Onset associated with a change in frequency of stool .
  - Onset associated with a change in form (appearance) of stool3 .
. Patient was offered first-line therapies (e.g., anti-spasmodics, antidepressants, or fiberbased medications) but still had continuing IBS symptoms for 12 months or more
If over 60 years old, patient must have had a medical specialist review in the previous 2 . years to confirm symptoms are related to IBS and to exclude other serious bowel conditions

Exclusion Criteria

. Patient had unexplained rectal bleeding or weight loss
. Patient had diagnosis of inflammatory bowel disease, celiac disease, peptic ulcer disease, and/or colorectal carcinoma
. Patient was unable to participate in CBT due to speech or language difficulties
. Patient did not have access to an internet computer to be able to undertake the WCBT
. Patient received CBT for IBS in the last 2 years
Patient had access to the Parallel software in an earlier pilot trial .
. Patient was concurrently participating in an IBS/intervention trial

Treatments

Telephone: 186 patients received six 60-minute telephone CBT sessions over 9 weeks . and two 60-minute booster sessions at 4 and 8 months (8 hours therapist time).
Parallel: 185 interactive, tailored CBT using Parallel, three 30-minute telephone support . calls over 9 weeks and two 30-minute boosters at 4 and 8 months (2.5 hours therapist time). The 30-minute telephone support calls were intended to ensure that participants were adequately using the website resources, and were not equivalent to the therapy sessions provided to the Telephone arm.

2 Francis. C.Y., J. Morris, and P.J. Whorwell. The irritable bowel severity scoring system: a simple method of monitoring irritable bowel syndrome and its progress. Aliment Pharmacol Ther, 1997. 11(2); p. 395-402. 3 Longstreth G.F., et al., Functional Bowel Disorders. Gastroenterology, 2006. 130 (5): p. 1480-1491.

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Both treatment arms also received TAU. TAU is defined as continuation of current . medications, and usual general practitioner follow-up with no psychological therapy for IBS.

Study Population

In total. 558 patients were randomized in the trial: 186 to the Telephone arm. 185 to the Parallel arm.

and 187 to TAU. During the trial, there was a higher than expected drop-out rate (30%). There was a total of 136 complete cases in the Telephone arm. 124 complete cases in the Parallel arm. and 131 complete cases in the TAU arm.

Efficacy Results

In the clinical study, treatment differences in IBS-SSS were evaluated at 3. 6. and 12 months after therapy. A difference of 35 points between treatment groups and TAU for IBS SSS at 12 months was considered clinically significant in the trial. However, FDA agreed with the previously published2MCID for IBS-SSS to be at least a 50-point difference between the treatment group and TAU. For the telephone arm, greater than a 50-point decrease in IBS-SSS,), was observed at each timepoint. The estimated trial arm differences for continuous outcomes of telephone versus TAU was 69 points at 3 months, 58 points at 6 months, and 62 points at 12 months. The estimated trial arm differences for continuous outcomes of Parallel versus TAU was 53 points at 3 months, 35.7 points at 6 months, and 35.5 points at 12 months (See Table 1). Parallel compared to TAU achieved a clinically meaningful benefit of a 50-point difference at 3 months post-randomization. The primary efficacy outcome was treatment differences in IBS-SSS at 12 months. However, only, at 3 months did the device demonstrate a minimum clinical important difference compared to TAU. IBS-SSS score at three months was pre-specified as a secondary outcome measure in the statistical analysis plan (SAP) without pre-specified hypothesis test or suitable multiplicity adjustment to control the overall type I error rate at 2sided 5%.

	Parallel vs. TAU	Telephone vs. TAU
3 months	53	69
6 months	35.7	58
12 months	35.5	62

			Table 1. Estimated trial arm differences for continuous outcomes

Work and Social Adjustment Scale (WASAS) was proposed as a coprimary endpoint in the trial. WASAS is a measure of impairment of functioning specific to the condition being studied. However, WASAS is not a validated measure for improvement of patients undergoing a intervention for IBS. Therefore, WASAS was not considered appropriate for evaluating the benefit of the device.

Uncertainty in these results was contributed to by loss to follow up for study subjects, potential inconsistency in treatment as usual, and post hoc statistical analysis of clinical study results.

Adverse Events

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Overall, the proportion of individuals reporting at least one Adverse Event (AE) was similar across the treatment arms, with 27.3% of TAU arm, 30.1% of telephone arm, and 26.5% of Parallel arm reporting at least one AE during the course of the ACTIB trial. The most common AE by System Organ Class (SOCs) included Psychiatric Disorders (6.1% of subjects overall). Gastrointestinal Disorders (5.6% of subjects overall), and Infections and Infestations (5.2% of subjects overall). With respect to the most commonly reported AEs reported by subjects in the Parallel arm (defined as events reported by > 2 subjects and with frequency rate that exceeds the rate observed for said event in the TAU arm), only abdominal pain, generalized pain, diverticulitis, and depression met this definition. The frequency rate of abdominal pain was 2.2% for the Parallel arm compared to 0.5% for the TAU arm; for generalized pain, the rates were 1.6% and 0.0% for the two arms, respectively; diverticulitis was reported by 1.1% and 0.0% of Parallel and TAU patients, respectively; and, for depression, the frequency rates were 2.2% for Parallel and 1.1% for TAU.

The frequency of related treatment-emergent AEs (TEAEs) revealed no notable differences between

treatment groups. The frequency of related TEAEs was 1.1%. 0.5%, and 0.5% in the Telephone. Parallel, and TAU arms, respectively. For the Parallel arm, the only related event was a case of abdominal pain that was considered "remotely" related to treatment with the device. The only AEs that

were deemed possibly related to treatment were reported for the TAU arm (3 subjects, 1.6%). These included abdominal pain (1), abdominal distension (1), and flatulence (1).

Summary

In summary, the study supporting the Parallel device as an adjunct to TAU showed a clinically meaningful benefit of > 50 points with the IBS-SSS in Parallel versus TAU populations at 3 months post randomization.

LABELING

The Sponsor provided labeling that included patient directions for use, a patient information sheet, and a clinician information sheet for Parallel. The patient directions for use addresses the known hazards and risks of the device for the intended use and incorporates safety statements to mitigate these risks. The labeling includes:

. Instructions intended to minimize the risk of improper use of Parallel including a summary of how to navigate the software.
. Contraindications and warnings to ensure the patient continues current medications and treatments under the guidance of a physician or other healthcare professional.
. The browser and hardware requirements to use the device, and language and technology skills needed to use the device.

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The patient and clinician information sheets include a summary of the clinical data stating a clinically meaningful benefit that included reduction in symptom severity that was observed 3 months after treatment with Parallel compared to the TAU study arm.

RISKS TO HEALTH

The table below identifies the risks to health that may be associated with use of Parallel and the measures necessary to mitigate these risks.

Identified Risks to Health	Mitigation Measures
Worsening of condition due to deviceproviding ineffective treatment.	Clinical dataLabeling
Delayed access to treatment due to devicesoftware failure.	Software verification, validation,and hazard analysisLabeling
Ineffective treatment due to use error/improper use of device	Usability assessmentLabeling
Treatment results in anxiety, depressedmood, depression, mental disorder(unspecified), stress or suicidal ideation	Clinical dataLabeling

In combination with the general controls of the FD&C Act, the Computerized behavioral therapy device for treating symptoms of gastrointestinal conditions is subject to the following special controls:

1. Clinical data must be provided to fulfill the following:
- Describe a model of therapy for the indicated gastrointestinal conditions; i.
- Validate the model of therapy as implemented by the device using a clinically ii. defined endpoint; and
- iii. Evaluate all adverse events.
1. Software must be described in detail in the software requirements specification (SRS) and software design specification (SDS). Software verification, validation, and hazard analysis must be performed. Software documentation must demonstrate that the device effectively implements the behavioral therapy model.
1. Usability assessment must demonstrate that the intended user(s) can safely and correctly use the device.
1. Labeling must include:
- Labeling must include instructions for use, including images that demonstrate i. how to interact with the device:
- ii. Patient and physician labeling must list the minimum operating system requirements that support the software of the device;
- iii. Patient and physician labeling must include a warning that the device is not intended for use in lieu of a standard therapeutic intervention or represent a substitution for the patient's medication ;.
- iv. Patient and physician labeling must include a warning to seek medical care if a patient has feelings or thoughts of harming themselves or others; and.

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Physician and patient labeling must include a summary of the clinical testing with V. the device.

BENEFIT-RISK DETERMINATION

The risks of the device are based on data collected in the clinical study described above. The most common AE SOCs included Psychiatric Disorders (6.1% of subjects overall). Gastrointestinal Disorders (5.6% of subjects overall), and Infections and Infestations (5.2% of subjects overall). The risks associated with Parallel were comparable to the treatment as usual group.

With respect to the most commonly reported AEs reported by subjects in the Parallel group (defined as events reported by > 2 subiects and with frequency rate that exceeds the rate observed for said event in the TAU group), only abdominal pain, generalized pain, diverticulitis, and depression met this definition. Of those most commonly reported AEs. the only AE rated as severe was a single case of diverticulitis in the Parallel group. For the Parallel arm, the only related event was a case of abdominal pain that was considered remotely related to treatment with the device. The only AEs that were considered to be possibly related to treatment were reported for the TAU arm, which included abdominal distension, and flatulence.

The probable benefits of the device are also based on data collected in the clinical study described above.

Several factors, such as significant loss to follow up and post-hoc statistical analysis, contributed to uncertainty in the clinical data. Additionally, an MCID that exceeded 50 points for IBS-SSS was not achieved at 12 months in the trial. However, after 3 months a clinical benefit of greater than 50 points was seen with the IBS-SSS in the Parallel versus TAU populations. Therefore, the labeling includes a summary of the clinical data and includes a statement that a clinically meaningful benefit was observed 3 months.

Given that the device demonstrated clinical benefit with acceptable uncertainty at 3 months and provides increased access to CBT to treat IBS symptoms for patients that do not have access to other forms of CBT and the risks were minimal with little uncertainty and low severity, the probable benefits of the Parallel device outweigh the probable risks.

Patient Perspectives

Patient perspectives considered for the Parallel during the review include:

Several participants assigned to the Parallel intervention during the clinical trial were interviewed immediately upon completion of the treatment period and at the end of the trial.

Participants reported several benefits gained from the use of the product, including improvements in IBS symptoms, enhanced understanding of IBS as a condition, more control over IBS symptoms, and positive impact on their work and social life.

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Benefit/Risk Conclusion

In conclusion, given the available information above, for the following indication statement:

Parallel is a prescription-only digital therapeutic intended to provide cognitive behavioral therapy for adults aged 22 years of age and older who have been diagnosed with Irritable Bowel Syndrome (IBS). Parallel is indicated as a 3 month treatment for patients with IBS. Parallel treats IBS by reducing the severity of symptoms and is intended to be used together with other IBS treatments.

The probable benefits outweigh the probable risks for Parallel. The device provides benefits, and the risks can be mitigated by the use of general controls and the identified special controls.

CONCLUSION

The De Novo for the Parallel is granted and the device is classified as follows:

Product Code: QMY Device Type: Computerized behavioral therapy device for treating symptoms of gastrointestinal conditions Regulation Number: 21 CFR 876.5960 Class: II

Regulation Number and Section

§ 876.5960 Computerized behavioral therapy device for treating symptoms of gastrointestinal conditions.

(a)
Identification. A computerized behavioral therapy device for treating symptoms of gastrointestinal conditions is a prescription device intended to provide a computerized version of condition-specific therapy as an adjunct to standard of care treatments to patients with gastrointestinal conditions.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Clinical data must be provided to fulfill the following:
(i) Describe a model of therapy for the indicated gastrointestinal conditions;
(ii) Validate the model of therapy as implemented by the device using a clinically defined endpoint; and
(iii) Evaluate all adverse events.
(2) Software must be described in detail in the software requirements specification and software design specification. Software verification, validation, and hazard analysis must be performed. Software documentation must demonstrate that the device effectively implements the behavioral therapy model.
(3) Usability assessment must demonstrate that the intended user(s) can safely and correctly use the device.
(4) Labeling:
(i) 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 requirements that support the software of the device;
(iii) Patient and physician labeling must include a warning that the device is not intended for use in lieu of a standard therapeutic intervention or to represent a substitution for the patient's medication;
(iv) Patient and physician labeling must include a warning to seek medical care if a patient has feelings or thoughts of harming themselves or others; and
(v) Physician and patient labeling must include a summary of the clinical testing with the device.