Description

Clinical trials (interventional studies) are research studies that involve human volunteers (participants) to answer specific health questions, as opposed to studies that use animals or are carried out in laboratories. Clinical trials test new ways to prevent, detect, diagnose or treat diseases to determine if they should be approved for wider use in the general population.

In an interventional clinical trial, participants receive specific interventions (e.g., a biologic [e.g., vaccine, blood product, gene therapy], diagnostic test, drug, medical device or procedure) according to the research plan or protocol created by the clinical investigators. Clinical trials may compare a new medical approach to a standard one that is already available, to a placebo that contains no active ingredients or to no intervention. Some clinical trials assess existing interventions by comparing them to each other to evaluate effectiveness. The clinical investigators try to determine the safety and efficacy of the intervention by measuring certain outcomes in the participants.

Observational Studies

Observational studies assess health outcomes in predefined groups of individuals. Participants in an observational study may receive diagnostic, therapeutic, or other interventions, but the investigator does not assign specific interventions to them. This includes when participants receive interventions as part of routine medical care, and a researcher studies the effect of the intervention.

Observational studies may be retrospective, prospective or cross-sectional. A patient registry is a type of observational study and is defined as including an organized system that uses observational methods to collect uniform data (clinical and other) for a population defined by a particular disorder/disease, condition (including susceptibility to a disorder) or exposure (including products, healthcare services and/or procedures) and that serves a predetermined scientific, clinical or policy purpose. Patient registries may be single purpose or on-going data collection programs that address one or more questions.

Clinical Trials Phases

1. Phase I: Researchers test a new drug or treatment in a small group of people (usually 20 to 100) for the first time to evaluate its safety, determine a safe dosage range and identify side effects. The participants are usually healthy volunteers; however, there may be circumstances in which individuals with specific medical conditions are used, such as those who are at the end stage of their disease and lack other treatment options (e.g., individuals with cancer or human immunodeficiency virus [HIV]). Phase I usually spans several months and participants are generally paid for taking part in the study.
2. Phase II: The drug or treatment is given to more people (usually 100 to 300) to see if it is effective for a certain condition and to further evaluate its safety. Many phase II studies are randomized trials. This means that one group of participants will receive the experimental drug or treatment, while the second group (referred to as a control group) will receive an existing standard treatment or a placebo.

Often these studies are blinded; neither the participants nor the researchers know who is getting the experimental treatment and who is getting the standard or placebo. This reduces the likelihood of any bias on the part of the researchers or the study participants.

Phase III:

The drug or treatment is given to larger groups of people (usually several hundred to several thousand) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments and collect information that will allow the drug or treatment to be used safely. It usually takes place over a period of one to four years. In addition to continuing to monitor safety and effectiveness, treatment outcomes of those who are receiving the experimental treatment are compared to results from participants who underwent standard treatment for the same condition. As a rule, a study moves forward to phase III only if phase I and phase II results are promising.

Phase IV:

This final phase, also known as the post-marketing phase, takes place after a new procedure or treatment has been marketed and is in wide use. The study continues in order to collect information about the drug or treatment’s safety and effectiveness in various populations and any side effects associated with long-term use.

• Category A (experimental/investigational) device, refers to a device for which absolute risk of the device type has not been established (initial questions of safety and effectiveness have not been resolved) and the FDA is unsure whether the device type can be safe and effective.
• Category B (nonexperimental/noninvestigational) device, refers to a device for which the incremental risk is the primary risk in question (initial questions of safety and effectiveness of that device type have been resolved), or it is known that the device type can be safe and effective because, for example, other manufacturers have obtained FDA premarket approval or clearance for that device type.

Coverage with Evidence Development (CED) is a model by which Medicare allows items and services, if they are furnished in the context of approved clinical studies or with the collection of additional clinical data, to assess their appropriateness. CEDs allow Medicare beneficiaries to have access to innovative technologies with potential clinical benefit, while maintaining systematic participant safeguards. Some examples of CEDs include, but may not be limited to, artificial hearts, cochlear implantation and leadless pacemakers.

Coverage Determination

Commercial Plan members: requests for coverage for a clinical trial require review by a medical director.

Any state mandates for clinical trials take precedence over this medical coverage policy.

Please refer to the member’s applicable pharmacy benefit to determine benefit availability and the terms and conditions of coverage for medication (if part of routine costs) to be used in a clinical trial.

Medication (drug or biological) that is part of the clinical trial is generally provided by the study at no expense to the member or the Plan.

All applicable plan limitations regarding coverage for out-of-network care apply to routine care costs in clinical trials.

Medicare Members

The Centers for Medicare and Medicaid Services (CMS) allows coverage only for routine care items and services related to Category A IDE device studies approved by CMS (or its designated entity) and listed on the CMS Coverage Website. The devices involved in Category A IDE device studies are not eligible for payment under Medicare.^3,4

All requests for coverage related to routine care and services costs* of a Category A IDE must be referred to the Part A/Part B Medicare Administrative Contractor (A/B MAC) for the geographic jurisdiction where the services will be rendered.

Clinical Trials Effective Date:

09/28/2023

Revision Date:

09/28/2023

Review Date:

09/23/2023

Policy Number: HUM-0410-024

Page: 5 of 13

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

For information about Medicare coverage related to IDE (Category A or B) studies, please refer to CMS Approved IDE Studies.

For criteria regarding Medicare CED clinical studies, please refer to the CMS - Coverage with Evidence Development website.

Commercial Members and Medicare Members in a Category B IDE Trial

The following applies to ALL Commercial members enrolled in ANY clinical trial AND Medicare members enrolled in a Category B IDE trial.

Humana members may be eligible under the Plan for routine care and services costs* associated with interventional clinical trials, when the following criteria are met:

• Phase I, II, III, or IV clinical trial for the prevention, detection or treatment of cancer or other life-threatening illness that falls under one of the following categories:
• Federally funded or approved trial by one of the following:
  • Agency for Healthcare Research and Quality (AHRQ); OR
  • Centers for Disease Control and Prevention (CDC); OR
  • Centers for Medicare & Medicaid Services (CMS); OR
  • National Institutes of Health (NIH); OR
  • A cooperative group or center of any of the above-listed entities or the Department of Defense (DoD) or Department of Veterans Affairs (VA); OR
  • A qualified nongovernmental research entity identified in the guidelines issued by the NIH for center support grants;

Clinical Trials Effective Date: 09/28/2023

Revision Date: 09/28/2023

Review Date: 09/23/2023

Policy Number: HUM-0410-024

Page: 6 of 13

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version.

Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

The Departments of VA, DoD or Energy (DoE) if the trial has been reviewed and approved through a system of peer review comparable to the system used by the NIH and that ensures unbiased review of the highest scientific standards by qualified individuals who have no interest in the outcome of the review; AND

• The member’s referring health care professional is a network provider and has concluded that participation is appropriate OR the member provides medical and scientific information establishing that participation in the trial would be appropriate; AND
• To qualify for consideration for reimbursement of certain costs, a clinical trial must meet the following:
  1. A written protocol, including selection criteria, that describes a scientifically sound study that has been approved by all relevant institutional review boards (IRBs) before participants are enrolled; AND
  2. All aspects of the trial are conducted according to the appropriate standards of scientific integrity; AND
  3. Principal purpose of the trial is to test whether the intervention potentially improves the participants’ health outcomes; AND
  4. The trial must be designed with therapeutic intent (e.g., it should be looking at preventing, detecting, treating, or curing a disease or illness); it should not be exclusively to test toxicity or disease pathophysiology; AND
  5. Trial design is appropriate to answer the research question being asked in the study; AND
  6. Trial must be in compliance with Federal regulations relating to the protection of human subjects (e.g., FDA, NIH); AND
  7. Trial must be well supported by available peer-reviewed medical literature or is intended to clarify or establish the health outcomes of interventions already in common clinical use; AND
  8. Trial should not unjustifiably duplicate existing studies; AND
  9. Trials for therapeutic interventions must enroll members with diagnosed diseases rather than healthy volunteers; trials of prevention, detection or diagnostic interventions may enroll healthy participants in order to have a proper control group

Routine care and services costs in clinical trials include:

• Costs of medically necessary treatments for conditions that result as unexpected consequences (complications) of a clinical trial; OR
• Items or services required solely for the provision of the investigational item or service (e.g., the administration of a noncovered chemotherapeutic agent), the clinically appropriate monitoring of the effects of the item or service or the prevention of complications; OR
• Items or services that are typically provided for conventional care, regardless of whether or not a member is enrolled in a clinical trial

Note: The criteria for Category A IDE clinical trials and the commercial coverage exclusion of Category B IDE devices are not consistent with the Medicare National Coverage Policy, and therefore may not be applicable to Medicare members.

Clinical Trials Effective Date: 09/28/2023
Revision Date: 09/28/2023
Review Date: 09/23/2023
Policy Number: HUM-0410-024
Page: 7 of 13

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version.

Refer to the CMS website for additional information.

Coverage Limitations

Humana members may NOT be eligible under the Plan for coverage for clinical trials for any of the following indications:

• Items or services that are typically provided for conventional care, regardless of whether or not a member is enrolled in a clinical trial, detection or treatment of cancer or other life-threatening disease or condition; OR
• Nonhealth care items and services (e.g., transportation, lodging, meals, special food products, personal care services) required as a result of the member's enrollment in the clinical trial

Clinical Trials Effective Date: 09/28/2023
Revision Date: 09/28/2023
Review Date: 09/23/2023
Policy Number: HUM-0410-024
Page: 8 of 13

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

These are considered not medically necessary as defined in the member's individual certificate. Please refer to the member's individual certificate for the specific definition.

Humana members may NOT be eligible under the Plan for coverage for clinical trials for any of the following indications:

• Cost of the investigational item or service itself (with the exception of Category B IDE devices in approved studies for Medicare members only); OR
• Cost of data collection; OR
• Items and services customarily provided by the research sponsors free of charge for any enrollees in the trial; OR
• Items and services provided solely to satisfy data collection and analysis needs that are not used in the direct clinical management of the participant (e.g., monthly computed tomography [CT] scans for a condition usually requiring only a single scan); OR
• Observational studies, including patient registries; OR
• Service that is clearly inconsistent with widely accepted and established standards of care for a particular diagnosis

These are considered experimental/investigational as they are not identified as widely used and generally accepted for the proposed uses as reported in nationally recognized peer-reviewed medical literature published in the English language.

Additional information about clinical trials may be found from the following websites:

• Background
• National Cancer Institute
• National Institute of Health-ClinicalTrials
• National Library of Medicine
• US Food & Drug Administration

Clinical Trials Effective Date: 09/28/2023
Revision Date: 09/28/2023
Review Date: 09/23/2023
Policy Number: HUM-0410-024
Page: 9 of 13

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

Medical Alternatives

Physician consultation is advised to make an informed decision based on an individual's health needs.

Any CPT, HCPCS or ICD codes listed on this medical coverage policy are for informational purposes only. Do not rely on the accuracy and inclusion of specific codes. Inclusion of a code does not guarantee coverage and or reimbursement for a service or procedure.

Provider Claims Codes

CPT® Code(s)

Description

Comments

No code(s) identified

CPT® Category III Code(s)

Description

Comments

No code(s) identified

HCPCS Code(s)

Clinical Trials Effective Date: 09/28/2023
Revision Date: 09/28/2023
Review Date: 09/23/2023
Policy Number: HUM-0410-024
Page: 10 of 13

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version.

Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

Blinded administration of convulsive therapy procedure, either electroconvulsive therapy (ECT, current covered gold standard) or magnetic seizure therapy (MST, noncovered experimental therapy), performed in an approved IDE-based clinical trial, per treatment session

Clinical Trials Effective Date: 09/28/2023
Revision Date: 09/28/2023
Review Date: 09/23/2023
Policy Number: HUM-0410-024
Page: 11 of 13

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version.

Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

References

1. American Society of Clinical Oncology (ASCO). Policy Statement Update. The critical role of phase I trials in cancer research and treatment. https://www.asco.org. Published January 20, 2015. Accessed August 17, 2023.
2. Centers for Medicare & Medicaid Services (CMS). Guidance for the public, industry and CMS staff: coverage with evidence development. https://www.cms.gov. Published November 20, 2014. Accessed August 17, 2023.
3. Centers for Medicare & Medicaid Services (CMS). Medicare Benefit Policy Manual. Medical devices. https://www.cms.gov. Published January 1, 2015. Accessed August 17, 2023.
4. Clinical Trials Effective Date: 09/28/2023 Revision Date: 09/28/2023 Review Date: 09/23/2023 Policy Number: HUM-0410-024 Page: 12 of 13
5. Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.
6. Centers for Medicare & Medicaid Services (CMS). Medicare Claims Processing Manual. Billing requirements for special services. https://www.cms.gov. Published March 16, 2023. Accessed August 17, 2023.
7. Centers for Medicare & Medicaid Services (CMS). National Coverage Determination (NCD). Routine costs in clinical trials (310.1). https://www.cms.gov. Published October 9, 2007. Accessed August 17, 2023.
8. National Cancer Institute (NCI). Cancer clinical trials at the National Institutes of Health Clinical Center. https://www.cancer.gov. Published September 6, 2019. Accessed August 17, 2023.
9. National Institutes of Health (NIH). NIH clinical research trials and you – the basics. https://www.nih.gov. Published October 3, 2022. Accessed August 18, 2023.
10. National Library of Medicine - National Institutes of Health (NLM-NIH). ClinicalTrials.gov. Learn about clinical studies. https://www.nlm.nih.gov. Accessed August 18, 2023.
11. National Library of Medicine - National Institutes of Health (NLM-NIH). ClinicalTrials.gov. Protocol registration data element definitions for interventional and observational studies. https://www.clinicaltrials.gov. Published October 1, 2020.

10. US Department of Labor (DOL). Employee Benefits Security Administration. FAQs about Affordable Care Act implementation part XXXI, mental health parity implementation, and women’s health and cancer rights act implementation. https://www.dol.gov/ebsa/healthreform. Published April 20, 2016. Accessed August 18, 2023.
11. US Food & Drug Administration (FDA). FDA's role: ClinicalTrials.gov information. https://www.fda.gov. Published May 26, 2023. Accessed August 18, 2023.

    Clinical Trials Effective Date: 09/28/2023
    Revision Date: 09/28/2023
    Review Date: 09/23/2023
    Policy Number: HUM-0410-024
    Page: 13 of 13

    Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

12. US Food & Drug Administration (FDA). Guidance for Industry. Investigator responsibilities – protecting the rights, safety and welfare of study subjects. https://www.fda.gov. Published October 2009. Accessed August 18, 2023.
13. US Food & Drug Administration (FDA). Inside clinical trials: testing medical products in people. https://www.fda.gov. Published November 6, 2014. Accessed August 18, 2023.
14. US Food & Drug Administration (FDA). The drug development process. Step 3: clinical research. https://www.fda.gov. Published January 4, 2018. Accessed August 18, 2023.