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Regulora™ is a prescription-only digital therapeutic device intended to provide behavioral therapy through gut-directed hypnotherapy for adults 22 years of age and older who have been diagnosed with Irritable Bowel Syndrome (IBS). Regulora is indicated as a 3-month treatment for patients with abdominal pain due to IBS and is intended to be used together with other IBS treatments.

Regulora™ is prescription-only digital therapeutic software indicated for use in the treatment of abdominal pain due to Irritable Bowel Syndrome (IBS). The Regulora program is Software as a Medical Device (SaMD) that resides on and is accessed through the user's mobile device and can be executed at home. Regulora digitizes scripted therapist-administered GDH behavior therapy and provides 7 unique treatment sessions, each lasting ~30 minutes, every other week over 12 weeks. The treatment sessions are designed to first induce deep physical and autonomic relaxation which is followed by metaphorical storytelling and a combination of direct and indirect suggestions targeted at somatic control mechanisms. Regulora also provides for IBS symptom tracking, which patients can share with their doctor in the management of their IBS.

The provided text describes the Regulora™ device, a prescription-only digital therapeutic for Irritable Bowel Syndrome (IBS), and outlines its performance and supporting studies for FDA clearance.

Here's an analysis of the acceptance criteria and study information:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly listed in a separate table within the document. However, based on the narrative, the primary clinical acceptance criteria for Regulora are related to improvements in abdominal pain intensity scores, as specified in the "Performance Testing - Clinical" section. The document also mentions Special Controls for product code QMY, which involve:

• Clinical data describing a model of therapy (validated in a clinical trial).
• Software development documentation (SRS, SDS, V&V, hazard analysis).
• Usability assessment.
• Labeling.

The reported device performance is primarily based on the EASITx clinical trial.

• Final 4 weeks of treatment: 30.9% of Regulora group vs. 21.5% of control group experienced ≥ 30% reduction.
• Throughout weeks 1-12: 29.3% of Regulora group vs. 18.8% of control group experienced ≥ 30% reduction. Regulora demonstrates clinically meaningful results within the intended use population. |
  | Demonstrate within-group improvement from baseline in IBS symptoms. | Within-Group Improvement (Regulora group, 4-week post-treatment):
• 44.9% experienced ≥ 30% improvement in proportion of stools with normal consistency.
• 50.3% were either a pain or stool responder (compared to 47% in predicate device).
• IBS-D subgroup (N=56): 48.2% experienced ≥ 50% reduction in days with loose or watery stools.
• IBS-C subgroup: 39.7% experienced ≥ 1 increased bowel movement per week.
• 64.0% reported Adequate Relief.
• 67.7% reported overall satisfaction.
  Note: These measures did not show statistically significant separation from control and therefore associated endpoints were not met. |
  | Absence of serious adverse events related to treatment. | No treatment-related serious adverse events reported. |
  | Minimal non-serious adverse events related to treatment. | Non-serious adverse events with reasonable possible relation to treatment: headache (0.5%, n=1), fatigue (0.5%, n=1), abdominal pain (0.5%, n=1), constipation (0.5%, n=1). |
  | Ability of subjects to use the program in the intended use environment (mobile device at home). | Clinical data showed study subjects could use the program by downloading, installing, and using Regulora on their mobile device at home. |
  | Compliance with Special Controls (pertaining to clinical data, software development, usability, labeling). | MetaMe complies with the special controls for product code QMY. Clinical data provided, software documented (SRS, SDS, V&V, hazard analysis), usability assessment performed, and labeling includes required instructions, warnings, and clinical summary. |

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

• Sample Size for Test Set: The "Performance Testing - Clinical" section states that 362 evaluable adult subjects with IBS were randomized 1:1 to either the Regulora group (n=181) or the control group (n=181). This entire cohort serves as the test set for evaluating the device's clinical performance.
• Data Provenance: The document does not explicitly state the country of origin. However, the study is referred to as the "EASITx clinical trial (Efficacy and Safety of IBS Digital GDH Treatment, EASITx -NCT04133519)", and NCT numbers are typically assigned to clinical trials registered on ClinicalTrials.gov, which often include studies conducted within the U.S. and internationally. The study design (randomized, controlled trial) indicates it is a prospective study.

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

The concept of "ground truth" concerning patient outcomes (like IBS symptom improvement) is typically established through patient-reported outcomes (PROs) using validated questionnaires and scales, rather than expert consensus on individual cases. The document mentions "clinically validated independent instruments" for measuring outcomes but does not refer to a panel of experts establishing the ground truth for each patient's reported symptoms or improvement. The "ground truth" for efficacy in this context is the patient's change in symptoms as measured by these validated scales.

4. Adjudication Method for the Test Set

As the "ground truth" is predominantly based on patient-reported outcomes from validated instruments, there is no mention of an adjudication method (like 2+1 or 3+1) for the test set. Adjudication methods are typically employed when expert interpretation of data (e.g., medical images) is required to establish ground truth.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, If So, What Was the Effect Size of How Much Human Readers Improve with AI vs Without AI Assistance

No, an MRMC comparative effectiveness study involving human readers or AI assistance in interpretation was not done. Regulora is a digital therapeutic device that delivers behavioral therapy directly to the patient; it is not an AI-powered diagnostic or interpretive tool that assists human "readers" (e.g., radiologists). Therefore, this question is not applicable.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done

Yes, in a sense, a "standalone" performance evaluation was done. Regulora is designed as a direct-to-patient digital therapeutic. Its clinical performance, as assessed in the EASITx trial, is the outcome of the algorithm/program itself delivering the gut-directed hypnotherapy. There isn't a human-in-the-loop scenario where a clinician is interpreting output from Regulora; rather, Regulora is the intervention. The study directly measures the effect of the Regulora program on patient outcomes.

7. The Type of Ground Truth Used

The ground truth used for clinical efficacy evaluation is based on patient-reported outcomes (PROs) derived from validated instruments and definitions. Specifically, the primary endpoint was a "clinically meaningful 30% reduction in abdominal pain intensity scores," following FDA guidance for Irritable Bowel Syndrome. Other measures included improvements in stool consistency, responder rates (pain or stool), and Adequate Relief, all of which are patient-reported metrics.

8. The Sample Size for the Training Set

The document does not specify a separate "training set" in the context of machine learning model development. Regulora delivers pre-scripted, therapist-administered GDH behavioral therapy; it is described as digitizing existing therapy. While software development involves training for various components, there's no indication of a machine learning model being trained on a specific patient data set to generate the therapy content or personalize it in a way that requires a separate "training set" in the common AI/ML sense. The clinical trial data (n=362) served as the validation set for the device's efficacy.

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

Since a "training set" for an AI/ML model to generate therapy is not explicitly mentioned as being part of Regulora's development, the establishment of ground truth for such a set is not detailed. The therapy itself (Gut-Directed Hypnotherapy) is established behavioral therapy, and the "ground truth" for its effectiveness comes from existing medical literature and clinical practice, which informed the content digitized by Regulora.

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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.

Parallel is a Prescription Digital Therapeutic (PDT) mobile application designed to deliver Cognitive Behavioral Therapy (CBT) to patients with Irritable Bowel Syndrome (IBS). PDTs are a new class of treatment using software to treat medical diseases. The Parallel CBT program has been tailored for patients with IBS. The rationale for applying CBT to treat IBS is grounded in the biopsychosocial model. This model states that one's biology, thoughts, and behaviors influence IBS symptom expression in a bidirectional way. The biological substrate of these interactions that affect IBS outcomes is the "brain-gut axis". The brain-gut axis underlies the pathways (e.g., psychological, behavioral functioning, and physiological interactions) that contribute to IBS symptom manifestation. CBT allows patients to influence brain-gut communication in order to reduce the severity of IBS. Parallel is available by prescription only and is intended to provide 3 months of cognitive behavioral therapy for adult patients, aged 22 years and older, with IBS. Parallel is intended to provide CBT, as an adjunct to any other IBS treatments. The Parallel mobile application uses the patient's mobile phone or tablet to deliver therapy on demand as a complement to the provider's care. Typical length of the therapy period is 3 months and is composed of ten (10) sessions. The first session explains IBS symptoms, the key features of the brain-gut axis, and the personalization of the rationale for CBT. The next nine (9) sessions provide personalized treatment for IBS by asking patients and getting them to complete interactive tasks. Each session contains several pages of content which may be text, audio files, video files, or interactive components. During the program, patients are provided short tasks to complete during the week. Patients are also asked to complete questionnaires from time to rate the severity of their IBS symptoms and the impact symptoms are having on their life and mood.

This document is a 510(k) premarket notification decision letter from the FDA to Mahana Therapeutics, Inc. for their Mahana Parallel Digital Cognitive Behavioral Therapy (CBT) Mobile Application for Irritable Bowel Syndrome (IBS). It primarily outlines the FDA's determination of substantial equivalence to a predicate device and the regulatory controls that apply.

Crucially, this document states that "no additional clinical studies are necessary to establish substantial equivalence between the web and mobile versions of Parallel, and to provide reasonable assurance of safety and effectiveness." This means that this 510(k) submission does not contain new clinical study data proving the device meets specific acceptance criteria based on performance. Instead, it relies on the predicate device's existing evidence and demonstrates that the mobile version's changes do not impact safety or effectiveness.

Therefore, I cannot provide the detailed information requested in the prompt's points 1 through 9 regarding acceptance criteria and a new study demonstrating the device meets those criteria. The document explicitly states that such studies were not deemed necessary for this particular submission due to the nature of the changes from the predicate device.

To answer your request, I will explain what would be provided if the document did contain the information, and then explicitly state what is missing based on this document.

What is present in the document (and why other information is absent for this 510(k) submission):

• Device Name: Mahana Parallel Digital Cognitive Behavioral Therapy (CBT) Mobile Application for Irritable Bowel Syndrome (IBS)
• Regulation Number: 21 CFR § 876.5960
• Regulation Name: Computerized Behavioral Therapy Device for Treating Symptoms of Gastrointestinal Conditions
• Regulatory Class: II
• Product Code: OMY
• Indications for Use: 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.
• Predicate Device: Parallel - DEN200029 (web version)
• Reason for no new clinical studies: "The core CBT skills that constitute the clinical basis of the predicate Parallel (web version) are unchanged and remain identical in the subject Parallel (mobile version). There is no impact to clinical functionality, and no new introduced or modified existing risks."

Based on the provided document, the following requested information cannot be extracted because the submission relies on the predicate device's data and asserts that no new clinical studies were necessary due to the nature of the changes from web to mobile:

1. A table of acceptance criteria and the reported device performance: This document does not present any new performance data against acceptance criteria. It states that the device is substantially equivalent to the predicate, implying it meets the predicate's established safety and effectiveness.
2. Sample sized used for the test set and the data provenance: No new clinical test set data is presented.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts: Not applicable as no new clinical test set data is presented.
4. Adjudication method (e.g. 2+1, 3+1, none) for the test set: Not applicable as no new clinical test set data is presented.
5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance: Not applicable. This is a digital therapeutic for IBS, not an imaging AI diagnostic aid.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done: The device is a prescribed therapeutic, used by patients to deliver CBT. Its performance is directly tied to user engagement and clinical outcomes, not an "algorithm-only" performance in the diagnostic sense. No new study of its direct performance is presented.
7. The type of ground truth used (expert concensus, pathology, outcomes data, etc): Not applicable as no new clinical test set data is presented. Performance relies on the predicate's established efficacy.
8. The sample size for the training set: Not applicable as no new clinical test set data from the mobile version's development is presented.
9. How the ground truth for the training set was established: Not applicable as no new clinical test set data from the mobile version's development is presented.

In summary, this 510(k) submission for the Mahana Parallel Digital CBT Mobile Application asserts substantial equivalence to a previously cleared web-based version. It explicitly states that "no additional clinical studies are necessary" because the changes are technological (web to mobile platform) and minor content adjustments that do not impact clinical functionality or introduce new risks. Therefore, the document does not contain the details of acceptance criteria or a study proving the device meets these criteria as if it were a novel device requiring new clinical evidence.

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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.

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.

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

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.

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