Date of Origin: 05/1999
 

Regence does not cover the cost of investigational new drugs (IND) as these are considered to be the responsibility of the manufacturer.  Investigational medications are defined as medications that do not have final approval of a new drug application (NDA) from the FDA for marketing for any indication.  For off-label uses of FDA approved medications, refer to the Regence Medication Policy Manual,  Off Label Use of FDA Approved Drugs (see Cross References). 

Regence does not cover the cost of investigational devices as these are considered to be the responsibility of the manufacturer.  Investigational devices are defined as devices that do not have PMA, 510(k), or HDE  approval from the FDA. 

Regence does not cover medical costs directly associated with clinical trials related to investigational treatments that fail to meet the research urgent criteria detailed above.

Clinical trial phases

• Phase I

• Phase II

• Phase III

• Phase IV

Clinical trials may be categorized into four phases as follows (1-3,14):

Initial studies to determine the actions and side effects of treatments in humans and to gain early evidence of effectiveness.  Phase I studies may include healthy participants and/or patients.
Phase I clinical trials usually, but not always, are the first time a new device or treatment is used in humans. Phase I trials generally involve small populations (20-100 participants) and are short-term in nature (3-12 months). The goal of phase I trials is to evaluate the safety of a new treatment, determine a safe treatment ranges, and identify side effects. Most often study participants are healthy volunteers, but phase I clinical trials may be offered to patients for whom no other treatment has worked. Phase I trials do not include control groups. The data obtained from phase I trials are used to design phase II trials.

As noted above, phase I trials are not necessarily limited to "first-time-in-human" trials. "Secondary" phase I trials evaluate new therapies or new uses of existing therapies. These trials may also assess treatment outcomes or device function in different patient populations (e.g., children) that were not previously studied.

Controlled clinical studies conducted to evaluate the effectiveness of treatments for particular indications in patients with the condition under study.  Phase II studies are conducted to determine the common short-term side effects and risks of the treatment.

In phase II trials, the study treatment is given to a larger group of people (50-500) who have the disease under study to determine if it is effective, to further evaluate its safety, and to further refine optimal device use or procedure technique. Phase II clinical trials can be randomized and may be blinded, placebo or standard therapy-controlled trials. Depending on the treatment under study, the Phase II trials may take from several months to several years to complete.

After preliminary evidence suggesting effectiveness of a treatment has been obtained, Phase III studies are conducted to gather additional information to evaluate the overall benefit-risk relationship of the treatment and provide guidance on patient selection or labeling requirements.   

In phase III trials, the study treatment is given to large groups of people (hundreds to thousands) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the treatment to be used safely. Less common side effects may be identified in phase III trials due to the larger numbers of study participants. Phase III trials usually include control groups, are randomized, and may include blinding of the participants and/or researchers. In addition, these trials may involve multiple institutions. Phase III trials may take from several months to several years to complete, with some lasting 10 years or longer.

Also known as post-marketing studies, Phase IV studies are generally conducted to delineate additional information including a treatment's risks, benefits, and optimal use.

Devices

• 510(k)

510(k) approval is granted by the FDA for devices that are determined to be substantially equivalent to devices already placed into one of three classification categories. (7)

• HDE

• IDE

• PMA

A humanitarian use device (HUD) is a device that is intended to benefit patients by treating or diagnosing a disease or condition that affects fewer than 4,000 individuals in the United States per year. (8) A device manufacturer's research and development costs could exceed its market returns for diseases or conditions affecting small patient populations, so the FDA developed and published this regulation to provide an incentive for the development of devices for use in the treatment or diagnosis of diseases affecting these populations.

An HDE application is exempt from effectiveness requirements.  It is not required to contain the results of scientifically valid clinical investigations demonstrating that the device is effective for its intended purpose. The application, however, must contain sufficient information for the FDA to determine that the device does not pose an unreasonable or significant risk of illness or injury, and that the probable benefit to health outweighs the risk of injury or illness from its use, taking into account the probable risks and benefits of currently available devices or alternative forms of treatment. Additionally, the applicant must demonstrate that no comparable devices are available to treat or diagnose the disease or condition, and that they could not otherwise bring the device to market.

An approved HDE authorizes marketing of the HUD. However, an HUD may only be used after IRB approval has been obtained for the use of the device for the FDA approved indication. The labeling for an HUD must state that the effectiveness of the device for the specific indication has not been demonstrated.

An IDE (Investigational Device Exemption) allows an investigational device to be used in a clinical study in order to collect safety and effectiveness data required to support a PMA application or a 510(k) submission to the FDA. (9) Investigational use also includes clinical evaluation of certain modifications or new intended uses of legally marketed devices. All clinical evaluations of investigational devices, unless exempt, must have an approved IDE before the study is initiated.

PMA (Premarket Approval) approval by the FDA is the required process of scientific review to ensure the safety and effectiveness of Class III devices, which are defined as devices that support or sustain human life or are of substantial importance in preventing impairment of human health or present a potential, unreasonable risk of illness or injury. (6)

Medications

• Approved NDA

• IND
  
  
  
• Orphan drug

An approved NDA (New Drug Application)  is considered final FDA-marketing approval for the purposes of this policy. (11)

Note:  The FDA may require post marketing surveillance for certain medications that have received final marketing approval.

Medications that have an IND (Investigational New Drug) have not received final approval from the FDA and may not be marketed. (10)

The term "orphan drug" refers to a product that treats a rare disease affecting fewer than 200,000 Americans. (12) Orphan drugs may be in either an IND or NDA status.  For the purposes of this policy, orphan drug status has no significance in the evaluation of research urgent treatments.