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This is a new policy published on 8/25/2020. It will be effective on 9/26/2020 or later.
  
Horizon BCBSNJ
Uniform Medical Policy ManualSection:Treatment
Policy Number:164
Effective Date: 09/26/2020
Original Policy Date:08/25/2020
Last Review Date:
Date Published to Web: 08/25/2020
Subject:
Prescription Digital Therapeutics for Substance Abuse

Description:
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IMPORTANT NOTE:

The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.

Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.

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The World Health Organization defines substance abuse as “the harmful or hazardous use of psychoactive substances”, which include alcohol, cocaine, marijuana, stimulants, benzodiazepines and opiates. Treatments for drug addiction include behavioral counseling and skills training, which can be given as part of a cognitive-behavioral approach. The first prescription mobile app, developed to supplement or replace individual or group therapy, delivers a cognitive-behavioral approach developed specifically for substance use disorder in a series of interactive lessons.

PopulationsInterventionsComparatorsOutcomes
Individuals:
    • With substance use disorder
Interventions of interest are:
    • Prescription digital therapeutics (eg reSET or reSET-O)
Comparators of interest are:
    • Treatment as usual
Relevant outcomes include:
    • Symptoms
    • Change in disease status
    • Morbid events
    • Quality of life
    • Medication use

BACKGROUND

Substance Use Disorder

The World Health Organization defines substance abuse as “the harmful or hazardous use of psychoactive substances, including alcohol and illicit drugs”, which include alcohol, cocaine, marijuana, stimulants, benzodiazepines and opiates. The American Psychiatric Association, in the Diagnostic and Statistical Manual of Mental Disorders, details 11 problematic patterns of use that lead to clinically significant impairment or distress. Mild substance use disorder (SUD) is defined as meeting 2 to 3 criteria, moderate as 4 to 5 criteria, and severe as 6 or more criteria. The 11 criteria are as follows:

    1. Often taken in larger amounts or over a longer period than was intended.
    2. A persistent desire or unsuccessful efforts to cut down or control use.
    3. A great deal of time is spent in activities necessary to obtain, use, or recover from the substance’s effects.
    4. Craving or a strong desire or urge to use the substance.
    5. Recurrent use resulting in a failure to fulfill major role obligations at work, school, or home.
    6. Continued use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by its effects.
    7. Important social, occupational, or recreational activities are given up or reduced because of use.
    8. Recurrent use in situations in which it is physically hazardous.
    9. Continued use despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance.
    10. Tolerance.
    11. Withdrawal.

Treatment

Treatments for drug addiction include behavioral counseling, skills training, medication, treatment for withdrawal symptoms, treatment for co-occurring mental health issues, and long-term follow-up to prevent relapse. For patients with primary opioid use disorder (OUD), medication assisted treatment is the most common approach. U.S. Food and Drug Administration (FDA) approved drugs for opioid use treatment include a full opioid agonist (methadone), a partial opioid agonist (buprenorphine), and an opioid antagonist (naltrexone). These are used to suppress withdrawal symptoms and reduce cravings, and may be used in combination with counseling and behavioral therapies.

One common psychosocial intervention is cognitive-behavioral therapy (CBT). CBT is an established therapy based on social learning theory that addresses a patient’s thinking and behavior. CBT has proven positive effects for the treatment of SUD.1, There are 2 main goals of CBT: first, recognize thoughts and behaviors that are associated with substance abuse, and second, expand the repertoire of effective coping responses. Specific goals for SUD and OUD include a better understanding of risk factors for use, more accurate attributions of cause and effect, increased belief in the ability to address problems, and coping skills. Specific skills may include motivation, drink/drug refusal skills, communication, coping with anger and depression, dealing with interpersonal problems, and managing stress.

The community reinforcement approach (CRA) is a form of CBT that has a goal of making abstinence more rewarding than continued use. CRA increases non-drug reinforcement by teaching skills and encouraging behaviors that help improve employment status, family/social relations and recreational activities. CRA was originally developed for alcohol dependence and cocaine use, and has been shown to be more effective than usual care in reducing the number of substance use days.

Contingency management may also be a component of addiction treatment. Contingency management, also known as motivational incentives, provides immediate positive reinforcement to encourage abstinence and attendance. Positive reinforcement may range from a verbal/text acknowledgement of completion of a task to monetary payment for drug-negative urine specimens. Contingency management is based on the principles of operant conditioning as formulated by B.F. Skinner, which posits that rewarding a behavior will increase the frequency of that behavior. Contingency management is typically used to augment a psychosocial treatment such as CRA.

The combination of CRA plus contingency management was shown in a 2018 network meta-analysis of 50 RCTs to be the most efficacious and accepted intervention among 12 structured psychosocial interventions, including contingency management alone, in individuals with cocaine or amphetamine addiction.2, Positive reinforcement with voucher draws (eg, from a fishbowl) of variable worth that range from a congratulatory message to an occasional high dollar value are as effective as constant monetary vouchers. Studies conducted by the National Drug Abuse Treatment Clinical Trials Network have shown that intermittent reinforcement with incentives totaling $250 to $300 over 8 to 12 weeks both increases retention in a treatment program and reduces stimulant drug use during treatment.3,

Software as a Medical Device

The International Medical Device Regulators Forum, a consortium of medical device regulators from around the world which is led by the FDA, distinguishes between 1) software in a medical device and 2) software as a medical device (SaMD). The Forum defines SaMD as "software that is intended to be used for one or more medical purposes that perform those purposes without being part of a hardware medical device".4,

FDA's Center for Devices and Radiological Health is taking a risk-based approach to regulating SaMD. Medical software that "supports administrative functions, encourages a healthy lifestyle, serves as electronic patient records, assists in displaying or storing data, or provides limited clinical decision support, is no longer considered to be and regulated as a medical device".5,

Regulatory review will focus on mobile medical apps that present a higher risk to patients.

    • Notably, FDA will not enforce compliance for lower risk mobile apps such as those that address general wellness.
    • FDA will also not address technologies that receive, transmit, store, or display data from medical devices.
The agency has launched a software pre-cert pilot program for SaMD that entered its test phase in 2019. Key features of the regulatory model include the approval of manufacturers prior to evaluation of a product, which is based on a standardized "Excellence Appraisal" of an organization, and its commitment to monitor product performance after introduction to the U.S. market. Criteria include excelling in software design, development, and validation. Companies that obtain pre-certification participate in a streamlined pre-market review of the SaMD. Pre-certified organizations might also be able to market lower-risk devices without additional review. In 2017, FDA selected 9 companies to participate in the pilot program, including Pear Therapeutics.

Regulatory Status

In 2017, reSET® (Pear Therapeutics), received de novo marketing clearance from the FDA to provide CBT as an adjunct to contingency management, for patients with substance use disorder who are enrolled in outpatient treatment under the supervision of a clinician (DEN160018). This is the first prescription digital therapeutic to be approved by the FDA. FDA product code: PWE

In 2018, reSET-O® (Pear Therapeutics) was cleared for marketing by the FDA through the 510(k) pathway as a prescription-only digital therapeutic to “increase retention of patients with opioid use disorder (OUD) in outpatient treatment by providing cognitive behavioral therapy, as an adjunct to outpatient treatment that includes transmucosal buprenorphine and contingency management” (K173681). FDA determined that this device was substantially equivalent to existing devices. The predicate device was reSET®.

Related Policies

  • Drug Testing in Pain Management and Substance Use Disorder Treatment Settings (Policy #068 in the Pathology Section)

Policy:
(NOTE: For Medicare Advantage, Medicaid and FIDE-SNP, please refer to the Coverage Sections below for coverage guidance.)

Prescription digital therapeutics for patients with substance use disorder is considered investigational.

Medicare Coverage:


Medicaid Coverage:

For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.

FIDE SNP:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.



[RATIONALE: This policy was initially created with a search of the PubMed database through May 6, 2020.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Prescription Digital Therapeutics for Substance Use Disorder

Clinical Context and Therapy Purpose

Substance abuse is a serious health problem in the U.S. A 2018 survey from the Substance Abuse and Mental Health Services Administration found that 21.2 million people age 12 or older in the U.S., or 7.8 percent of the U.S. population, needed substance use treatment.6, The most common substances reported in the survey are alcohol, followed by tobacco and marijuana. Illicit drug use and prescription drug misuse occur in a lower percentage of the population.

Significant barriers to treatment exist for patients with substance use disorder (SUD) and opioid use disorder (OUD). There are an insufficient number of clinicians who are trained for substance abuse treatment, particularly in rural areas, and access to outpatient programs may be difficult and time consuming. Patients typically present to their primary care provider, who may not have sufficient time or training to treat patients with substance abuse. In addition, the stigma of substance abuse may prevent individuals from seeking treatment. Digital technologies could potentially increase access to specialty care for patients who may not otherwise be able to attend a treatment program. Digital technologies might also reduce the need for attendance in a clinic for patients who avoid treatment due to stigma or other factors.

A computer-delivered cognitive-behavioral therapy (CBT) program named CBT4CBT (Computer-Based Training for Cognitive Behavioral Therapy) has been developed to provide therapy for patients with substance abuse. The program includes 7 core CBT skills delivered by on-screen narration, graphic animation, quizzes, and interactive exercises. In a 2018 randomized controlled trial (RCT), both clinician and computer delivery of CBT reduced the frequency of substance use more than treatment as usual (TAU).7, In addition, patients who received the computer-based CBT with minimal monitoring had the best treatment retention, learning of CBT concepts, and 6 month outcomes compared to either clinician-delivered CBT or TAU. A computer-based community reinforcement approach (CRA) plus vouchers was reported in a 2008 study to lead to similar levels of abstinence as patients who received clinician-guided CRA plus vouchers.8, These results suggest that computerized CRA (CCRA) could potentially substitute for clinician-guided therapy and increase access to treatment.

In 2017 and 2018, the first prescription mobile apps (ie, reSET and reSET-O) were cleared for marketing by the U.S. Food and Drug Administration (FDA). These have the potential to increase access to substance abuse treatments in patients who have SUD or OUD. These 2 apps are intended to provide CCRA as an addition to traditional therapy in the context of an outpatient program.

The question addressed in this policy is: do prescription mobile apps that provide CCRA improve the net health outcome in patients with SUD or OUD?

The following PICO was used to select literature to inform this review.

Patients

The prescription mobile apps are indicated for patients with SUD and OUD.

ReSET is indicated for adult patients with SUD, who are not currently on opioid replacement therapy, who do not abuse alcohol solely, or who do not abuse opioids as their primary substance of abuse. Patients with SUD should be enrolled in outpatient treatment under the supervision of a clinician.

ReSET-O is indicated for adult patients with OUD who are in outpatient treatment with transmucosal buprenorphine and contingency management under the supervision of a clinician.

Interventions

ReSET and ReSET-O are prescription-based mobile device apps that deliver behavioral therapy in a series of interactive therapy lessons. The lessons include a CBT component and skill building exercises, which may be delivered with videos, animations, and graphics. Both apps are modeled on the CRA. The mobile apps provide a way for patients to self-report cravings and triggers, and in the case of ReSET-O, buprenorphine use. The module sequence and progress with the lesson modules can be selected and viewed by the treating clinician.

Comparators

The comparator for both reSET and reSET-O is treatment as usual (TAU) in a clinician supervised outpatient program with contingency management. In the pivotal studies described below, TAU for SUD consisted of group or individual therapy sessions for 4 to 6 h per week and urine drug testing. TAU for OUD included 3 times per week sublingual buprenorphine administration and urine drug testing with contingency management, and in person meetings with a clinician every other week.

Outcomes

The outcome which is most frequently cited as the most important outcome for patients is abstinence from the substance of abuse.9, This primary outcome should be measured during therapy, at the end of therapy, and at longer-term (eg, 3, 6, and 12 mo) follow-up to assess the durability of the treatment.

Other outcomes that have been reported as important to patients are drug craving, employment, and stable relationships. A semi-structured assessment of 7 potential problem areas in substance-abusing patients is the Addiction Severity Index.10, The domains are medical status, employment and support, drug use, alcohol use, legal status, family/social status, and psychiatric status. The Addiction Severity Index provides severity ratings of the client’s need for treatment and composite scores which measure problem severity during the prior 30 days.

The Maudsley Addiction Profile is a brief standardized interview that assesses treatment outcomes in domains of substance abuse, health risk behavior, physical and psychological health, and personal social functioning.11,

Retention in a treatment program is commonly used in addiction research but is an indirect measure of treatment success. Observational data from the Drug Abuse Treatment Outcome Studies suggest that most addicted individuals need at least 3 months in treatment to significantly reduce or stop their drug use and that the best outcomes occur in patients who participate in longer treatment.12,13,

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

    • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
    • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies;
    • To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought;
    • Studies with duplicative or overlapping populations were excluded.
Review of Evidence

The 2 pivotal RCTs for the prescription digital apps for SUD (resSET) and OUD (reSET-O) are described below and in Tables 1 and 2. The technology was developed by the National Institute of Drug Abuse-funded Center for Technology and Behavioral Health as the Therapeutic Education System (TES), which was subsequently submitted to the FDA for a mobile platform by Pear Therapeutics.

Campbell et al (2014) reported the pivotal multicenter trial for reSET, in which patients with SUD or OUD completed 20 to 30 min multimedia modules on a desktop while in the clinic or at home.14,15, The active treatment was the TES, which combined CCRA plus contingency management, and was compared to TAU (therapy alone) at 10 community-based outpatient treatment programs as part of the National Drug Abuse Clinical Trials Network. Clinicians were able to access reports on computer activity and discussed module completion in the individual therapy sessions. Contingency management consisted of random selection of vouchers, which ranged from a congratulatory message to $100 cash, for module completion and negative urine drug results. The mean dollar earned was $277 (SD $226) over the 12 weeks. Although the study was intended to replace some of the hours of therapy, the TES group received the same number of therapy session as the control group, so the combined program was effectively in addition to counseling alone.

The co-primary outcomes were abstinence from drug/heavy alcohol use in the last 4 weeks of treatment and retention in the treatment program. In the analysis by Campbell et al (2004)14,, TES reduced drop-out from the treatment program (hazard ratio=.72 [95% CI: 0.57 to 0.92], P=.010), and the odds of achieving abstinence was 1.62 fold greater in the group with CCRA and contingency management group (p=.010). However, the beneficial effect of TES was observed only in patients who were not abstinent at baseline. For patients who were abstinent at baseline, TES did not increase abstinence, and at 3 and 6 mo follow-up, the effect of TES was no longer significant. Subsequent analyses of the trial found that TES was not associated with improvements in social functioning compared to standard outpatient care.16,.

In the FDA analyses of the trial15,, results were analyzed for the entire cohort and for cohorts that excluded patients who reported opioid use. Abstinence during weeks 9-12 and total abstinence with CCRA plus contingency management was significantly greater in the cohort as a whole and more so in the analyses that excluded primary opioid users. For example, abstinence during weeks 9-12 was 40.3% in the SUD subgroup who received CCRA + vouchers compared to 17.6% in the group who received only therapy (P<.001). Total abstinence, defined as the number of half weeks with a negative urine drug test, was 11.9 half weeks in the SUD subgroup who received the experimental treatment and 8.8 half weeks in controls (p=.003).

In the pivotal study reported by Christensen et al (2014), CCRA was added to TAU in patients who had opioids as the primary substance of abuse.17,18, TAU in this second trial included clinic visits 3 times per week with a reward for a negative urine drug screen (maximum of $997.50), sublingual buprenorphine/naloxone, and a clinician visit every 2 weeks. Patients who did not show up for any of the thrice weekly clinic visits were considered to have a positive drug screen, and were considered drop-outs if they missed 3 visits in a row. The primary outcomes were the longest continuous abstinence and total abstinence.The study was powered to detect a 3 week difference between groups in mean weeks of continuous abstinence. In the 84 day treatment program there were 9.7 more days of abstinence in the CCRA group (67.1 days) than in the control group (57.4 days, P=.01), but the trial did not meet 1 of the primary outcomes of a significant difference between the 2 groups in the longest abstinence (5.5 days P=.214). The group using the computerized therapy had an increase in medication Addiction Severity Index scores (P=.04) , but did not show a significant improvement on the overall Addiction Severity Index (P>.16). The data on abstinence and Addiction Severity Index was not reported in the 510(K) Summary for the U.S. Food and Drug Administration.18,

Both trials reported a significant increase in retention during the 12 week programs. The SUD subgroup had a 23.8% drop out rate compared to 36.8% in the control group (P=.004). The addition of CCRA to TAU in patients with OUD also increased retention, with a hazard ratio for dropping out of treatment of 0.47 (0.26 to 0.85).

Both trials had a number of limitations in relevance and in design and conduct that preclude determination of the effect of the intervention on relevant health outcomes (Tables 3 and 4).

    • A major limitation for the reSET and reSET-O mobile apps regards the generalizability of results from these trials. Both studies were conducted with desktop computers, used primarily during the clinic visits. In the study by Christensen et al (2014) CCRA was only available in the clinic to avoid confounding the efficacy of the program with compliance issues. Regular use of a mobile app without close supervision and outside of the constraints of a trial setting is unknown. Although a proposed benefit of digital technology is to increase access to evidence-based treatments, particularly in rural areas or where there are other limitations to specialist care, consistent use of a mobile device in the home and the resources and expertise of local providers to supervise addiction treatment is uncertain.
    • An additional major concern in the study of Campbell et al (2014) is that the experimental group received both the web-based CCRA and a reward for a negative drug test. The trial was designed to assess the combined treatment approach, and not specifically the CCRA program. Because a reward for a negative drug screen is known by itself to increase both retention and abstinence during a trial,3, the contribution of the digital technology to the increase in abstinence in patients with SUD cannot be determined. Notably, abstinence was not improved at the 3 and 6 month follow-up, raising further questions about whether the increase in abstinence during the trial was due to contingency management rather than the CCRA.
    • A limitation of both trials is the choice (eg, retention) and timing (eg, during treatment) of the outcome measures. Abstinence after a treatment program is a main objective of therapy. In Christensen et al (2014), the main effect of the technology was on retention, and there was no follow-up after 12 weeks. In Campbell et al (2014), abstinence was greater during the trial, but not improved at the 3 and 6 month follow-up.
    • An additional limitation is the potential for performance bias among the volunteers in these unblinded studies. Nearly half of patients who qualified for the Campbell et al (2014) study chose not to participate. There may have been greater motivation to use the new technology in patients who agreed to participate in the study. While acknowledging the difficulty of blinding with this type of intervention, providing a control intervention of similar intensity, such as computer time that is not based on CRA, is feasible.
Given all of these limitations, further study in well designed trials is needed to determine the effects of the technology on addiction.

Table 1. Summary of Key RCT Characteristics
Study; TrialCountriesSitesParticipantsInterventions
ActiveaComparator
Campbell et al (2014) FDA Sumary DEN160018 14,15,U.S.10507 adult patients with self-report of drug use, with a subset of 305 who did not have primary use of opioids treated at community health centers12 weeks of TAU + CCRA (62 modules on a desktop) + CM for module completion and negative drug screen (n=255)12 weeks of TAU consisting > 2 individual or group therapy sessions per week (n=252)
Christensen et al (2014) FDA summary K17368117,18,US1170 opioid-dependent adults12 weeks of CCRA (69 modules on a desktop in the clinic) + CM + buprenorphine/ naloxone (n=92)12 weeks of CM + buprenorphine/ naloxone (n=78)
CCRA: computer-based community reinforcement approach; CM: contingency management; RCT: randomized controlled trial; TAU: treatment as usual.
a
CCRA consisted of 20 to 30 min multimedia computer modules. Patients completed a mean of 36.6 (SD 18.1) out of 62 total CCRA modules in the study by Campbell et al. There were a total of 69 CCRA modules in the study by Christensen et al.

Table 2. Summary of Key RCT Results
StudyAbstinenceTotal AbstinenceRetentionDropping Out of TreatmentASI overallASI Medication Subscale
Campbell et al (2014) FDA Submission DEN16001814,15,Rate During Weeks 9-12Half weeks
Entire Cohort (n=507)Excluding Primary Opioid Abusers (n=399)Entire Cohort (n=507)Excluding Primary Opioid Abusers (n=399)Entire Cohort (n=507)Excluding Primary Opioid Abusers (n=399)Entire Cohort (n=507)Excluding Primary Opioid Abusers (n=399)
TAU + CCRA + CM29.7%40.3%10.911.972.2%76.2%27.8%23.8%
TAU16.0%17.6%8.68.863.5%63.2%36.5%36.8%
P.008<.001.002.003.03.004
Christensen et al (2014) K173681 17,18,Longest Abstinence in Days (+ SD)Total Days + SDTreatment Completion
CRA + CM5567.1 + 19.380.4%17.6%
CM49.557.4 + 28.064.1%31.6%
HR/Diff/OR (95% CI)Diff: 5.5Diff: 9.7 (2.3 to 17.2)OR: 2.30 (1.15 to 4.60)HR: 0.47 (0.26 to 0.85)
P.214.011.0224>.24.04
ASI: Addiction Severity Index; CI: confidence interval; CM: contingency management; CCRA: computer-based community reinforcement; HR: hazard ratio; OR: odds ratio; RCT: randomized controlled trial; TAU: treatment as usual.

Table 3. Study Relevance Limitations
StudyPopulationaInterventionbComparatorcOutcomesdFollow-Upe
Campbell et al (2014); FDA Submission DEN1600114,15,4. The study volunteers may not be representative of the general population with substance use disorder.2. Was an earlier desktop technology and was conducted mostly in the clinic3. The comparator did not include contingency management with vouchers. Delivery was not a similar intensity as the intervention.1. Uncertain signficance of retention as an outcome.5. The minimal clinically important difference for abstinence was not pre-specified
Christensen et al (2014 ) K173681 17,18,2. Was an earlier desktop technology and was conducted in the clinic3. Delivery was not a similar intensity as the intervention.1. Uncertain significance of retention as an outcome.5. The minimal clinically important difference for abstinence was not pre-specified1. The study did not extend after 12 week treatment period, limiting inferences on efficacy for abstinence.
The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
a
Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
b
Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
c
Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
d
Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
e
Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 4. Study Design and Conduct Limitations
StudyAllocationaBlindingbSelective ReportingcData CompletenessdPowereStatisticalf
Campbell et al (2014); FDA Submission DEN16001814,15,1. Participants and investigators were not blinded to treatment assignment.2. Subgroup analyses in the FDA Summary were not pre-specified
Christensen et al (2014) K173681 17,18,1. Participants and investigators were not blinded to treatment assignment.
2. Data on abstinence was not included in the FDA Summary
The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
a
Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
b
Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
c
Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
d
Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
e
Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
f
Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Summary of Evidence

For individuals with substance use disorder who receive a prescription digital therapeutic, the evidence includes 2 pivotal randomized controlled trials (RCTs). Relevant outcomes are symptoms, morbid events, change in disease status, quality of life, and medication use. Mobile digital technology is proposed to increase access to evidence based cognitive-behavioral treatments, particularly in rural areas or where there are other limitations to specialist care. Although it is theoretically appealing to replace in-person counseling with computer-based therapy, there are a number of limitations in the current evidence base that limit any conclusions regarding efficacy. Specifically, one of the trials assessed the combined intervention of computer-based learning and a reward for abstinence. Since reward for abstinence alone has been shown to increase both abstinence and retention, the contribution of the web-based program to the overall treatment effect cannot be determined. The treatment effect on abstinence was not observed at follow-up, raising further questions about the relative effects of the rewards and the web program. The second trial, conducted in patients with primary opioid use disorder, did not meet a primary objective of longest days of abstinence. While both RCTs reported a positive effect on the intermediate outcome of retention, the relationship between retention and relevant health outcomes in these trials is uncertain. In addition, both trials were conducted with an earlier technology (a desktop in a clinic) and were unblinded, so there are issues of possible performance bias and questions about generalizability of these results. Given all of these limitations, further study in well designed trials is needed to determine the effects of prescription digital therapeutics on relevant outcomes in patients with substance use disorder and opioid use disorder. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION

Practice Guidelines and Position Statements

The 2018 Principles of Drug Addiction and Treatment from the National Institute on Drug Abuse describes evidence-based approaches to drug addiction treatment.13, Behavioral therapies include cognitive-behavioral therapy (alcohol, marijuana, cocaine, methamphetamine, nicotine), contingency management (alcohol, stimulants, opioids, marijuana, nicotine), community reinforcement approach plus vouchers (alcohol, cocaine, opioids), motivational enhancement therapy (alcohol, marijuana, nicotine), the matrix model (stimulants), 12-step facilitation therapy (alcohol, stimulants, opiates) and family behavior therapy.

U.S. Preventive Services Task Force Recommendations

Not applicable

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 5.

Table 5. Summary of Key Trials
NCT No.Trial Name
Planned Enrollment
Completion Date
Ongoing
NCT04129580aA Randomized Clinical Trial of Comprehensive Cognitive Behavioral Therapy (CBT) Via reSET-O for a Hub and Spoke Medication Assisted Treatment (MAT) System of Care
200
Sep 2021
NCT: national clinical trial.
a
Denotes industry-sponsored or cosponsored trial.]
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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Prescription Digital Therapeutics for Substance Abuse
reSET
reSET-O

References:
1. McHugh RK, Hearon BA, Otto MW. Cognitive behavioral therapy for substance use disorders. Psychiatr Clin North Am. Sep 2010; 33(3): 511-25. PMID 20599130

2. De Crescenzo F, Ciabattini M, D'Alo GL, et al. Comparative efficacy and acceptability of psychosocial interventions for individuals with cocaine and amphetamine addiction: A systematic review and network meta-analysis. PLoS Med. Dec 2018; 15(12): e1002715. PMID 30586362

3. Stitzer ML, Petry NM, Peirce J. Motivational incentives research in the National Drug Abuse Treatment Clinical Trials Network. J Subst Abuse Treat. Jun 2010; 38 Suppl 1: S61-9. PMID 20307797

4. International Medical Device Regulators Forum. Software as a Medical Device (SaMD): Key Definitions. 2013. http://www.imdrf.org/docs/imdrf/final/technical/imdrf-tech-131209-samd-key-definitions-140901.pdf Accessed May 5, 2020.

5. U.S. Food and Drug Administration. Digital health innovation action plan. https://www.fda.gov/media/106331/download

6. U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration. Data and Dissemination. https://www.samhsa.gov/data. Accessed May 5, 2020

7. Kiluk BD, Nich C, Buck MB, et al. Randomized Clinical Trial of Computerized and Clinician-Delivered CBT in Comparison With Standard Outpatient Treatment for Substance Use Disorders: Primary Within-Treatment and Follow-Up Outcomes. Am J Psychiatry. Sep 01 2018; 175(9): 853-863. PMID 29792052

8. Bickel WK, Marsch LA, Buchhalter AR, et al. Computerized behavior therapy for opioid-dependent outpatients: a randomized controlled trial. Exp Clin Psychopharmacol. Apr 2008; 16(2): 132-43. PMID 18489017

9. Dennis BB, Sanger N, Bawor M, et al. A call for consensus in defining efficacy in clinical trials for opioid addiction: combined results from a systematic review and qualitative study in patients receiving pharmacological assisted therapy for opioid use disorder. Trials. Jan 06 2020; 21(1): 30. PMID 31907000

10. Denis CM, Cacciola JS, Alterman AI. Addiction Severity Index (ASI) summary scores: comparison of the Recent Status Scores of the ASI-6 and the Composite Scores of the ASI-5. J Subst Abuse Treat. Nov-Dec 2013; 45(5): 444-50. PMID 23886822

11. Marsden J, Gossop M, Stewart D, et al. The Maudsley Addiction Profile (MAP): a brief instrument for assessing treatment outcome. Addiction. Dec 1998; 93(12): 1857-67. PMID 9926574

12. Drug Abuse Treatment Outcome Studies (DATOS) Treatment retention findings. 2008 http://www.datos.org/adults/adults-retention.html. Accessed May 28, 2020

13. National Institute on Drug Abuse. Principles of Drug Addiction Treatment: A Research-Based Guide (Third Edition). 2018. https://www.drugabuse.gov/publications/principles-drug-addiction-treatment-research-based-guide-third-edition/principles-effective-treatment. Accessed May 28, 2020

14. Campbell AN, Nunes EV, Matthews AG, et al. Internet-delivered treatment for substance abuse: a multisite randomized controlled trial. Am J Psychiatry. Jun 2014; 171(6): 683-90. PMID 24700332

15. U.S. Food and Drug Administration. De Novo Classification Request for reSET. https://www.accessdata.fda.gov/cdrh_docs/reviews/DEN160018.pdf. May 16, 2016. Accessed May 5, 2020.

16. Marino LA, Campbell ANC, Pavlicova M, et al. Social functioning outcomes among individuals with substance use disorders receiving internet-delivered community reinforcement approach. Subst Use Misuse. 2019; 54(7): 1067-1074. PMID 30849925

17. Christensen DR, Landes RD, Jackson L, et al. Adding an Internet-delivered treatment to an efficacious treatment package for opioid dependence. J Consult Clin Psychol. Dec 2014; 82(6): 964-72. PMID 25090043

18. U.S. Food and Drug Administration. 510K Summary. 2019. https://www.accessdata.fda.gov/cdrh_docs/pdf17/K173681.pdf Accessed May 5, 2020.

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

    HCPCS


    * CPT only copyright 2020 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.

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    Medical policies can be highly technical and are designed for use by the Horizon BCBSNJ professional staff in making coverage determinations. Members referring to this policy should discuss it with their treating physician, and should refer to their specific benefit plan for the terms, conditions, limitations and exclusions of their coverage.

    The Horizon BCBSNJ Medical Policy Manual is proprietary. It is to be used only as authorized by Horizon BCBSNJ and its affiliates. The contents of this Medical Policy are not to be copied, reproduced or circulated to other parties without the express written consent of Horizon BCBSNJ. The contents of this Medical Policy may be updated or changed without notice, unless otherwise required by law and/or regulation. However, benefit determinations are made in the context of medical policies existing at the time of the decision and are not subject to later revision as the result of a change in medical policy

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