Investigator Handbook
Chapter 7: INVESTIGATIONAL DRUGS, AGENTS, BIOLOGICS, AND DEVICES

The Food and Drug Administration (FDA) regulates clinical investigations that involve drugs, agents, biologics and devices to assure that such test articles being introduced to the public are safe and effective for its claimed indication.  Research activities that involve FDA regulated test articles are subject to FDA and DHHS regulations and UTHSC-H HRP PP VIII.01 Research with Investigational or Unlicensed Test Articles (Drugs) http://www.uth.tmc.edu/orsc/policies/VIII.1.htm.  The Investigator is also expected to abide by ICH Section E.6 “Good Clinical Practice” Guidelines (see Appendix).

Investigational New Drug (IND) Applications

The sponsor of a clinical trial is often a pharmaceutical, biotech, or medical device company who does not actually conduct the research, but establishes contracts with investigators to conduct a study under a sponsor-initiated protocol.  Research may also be sponsored by governmental agencies (e.g., the National Institutes of Health) which award grants to various investigators for the development of research protocols or the conduct of research through an established protocol.  On occasion, an investigator may initiate a research protocol with departmental or personal funds and is therefore referred to as the “Sponsor-Investigator.” 

Regardless of sponsorship, the sponsor of a clinical trial must obtain an Investigational New Drug (IND) approval from the FDA.  [See 21 CFR (Code of Federal Regulation) 312]  In order for an investigational drug, agent or biologic to be used in clinical research at UT Health Science Center-Houston, an IND must be on file with the FDA and an IND number granted.  An IND application must be filed by the sponsor for any new drug or for drugs that are already approved but the intent of the study is to generate data that will lead to:

• Approval of a new clinical indication;
• New advertising claim; or
• A new formulation of the product.

Trial Phases Involving Investigational Drugs and Biologics

Phase I Drug Trial
Phase I trials include the initial introduction of an investigational new drug into humans. These studies are typically conducted with healthy volunteers; sometimes, where the drug is intended for use in the patients with a particular disease such patients may participate as subjects. Phase I trials are designed to determine the metabolic and pharmacological actions of the drug in humans, the side effects associated with increasing doses (to establish a safe dose range), and, if possible, to gain early evidence of efficacy. They are typically closely monitored. The ultimate goal of Phase I trials is to obtain sufficient information about the drug's pharmocokinetics and pharmacological effects to permit the design of well-controlled, sufficiently valid Phase II studies. Other examples of Phase I studies include studies of drug metabolism, structure-activity relationships and mechanisms of actions in humans as well as studies in which investigational drugs are used as research tools to explore biological phenomena or disease processes. The total number of subjects involved in Phase I studies is generally in the range of 20-80.

Phase II Drug Trial
Phase II trials include controlled clinical studies conducted to evaluate the drug's effectiveness for a particular indication in patients with the disease or condition under study, and to determine the common short-term side effects and risks associated with the drug. These studies are typically well-controlled, closely monitored, and conducted with a relatively small number of patients, usually involving no more than a few hundred subjects.

Phase III Drug Trial
Phase III trials involve the administration of a new drug to a larger number of patients in different clinical settings to determine its safety, effectiveness, and appropriate dosage. They are performed after preliminary evidence of efficacy has been obtained, and are intended to gather necessary additional information about efficacy and safety for evaluating the overall benefit-risk relationship of the drug, and to provide an adequate basis for physician labeling. In Phase III studies, the drug is used the way it would be administered when marketed. When these studies are completed and the sponsor believes the drug is safe and effective under specific conditions, the sponsor applies to FDA for approval to market the drug. Phase III trials usually include several hundred to several thousand subjects.

Phase IV Drug Trial
Concurrent with marketing approval, FDA may seek agreement from the sponsor to conduct certain post-marketing studies to delineate additional information about the drug's risks, benefits, and optimal use. These studies could include, but are not limited to, studying different doses or schedules of administration than were used in Phase II studies, use of the drug in other patient populations or other stages of the disease, or use of the drug over a longer period of time (21 CFR 312.85).

Research Not Requiring an IND

Clinical investigations of drugs, agents, or biologics that are lawfully marketed in the United States are exempt from IND requirements if all six (6) of the following conditions are met:

1. The use of the investigational drug, agent, or biologic is not intended to be reported to the FDA in support of a new indication for use nor support any significant change in labeling for the product;
2. The use of the investigational drug, agent, or biologic is not intended to support a significant change in the advertising of the product;
3. The use of the product does not involve a route of administration, dosage level, and/or use in a subpopulation, or other factors that significantly increase the risks, or decrease the acceptability of the risks associated with the use of the drug, agent, or biologic;
4. The use will be conducted in compliance with CPHS approval and informed consent procedures;
5. The use will be conducted in compliance with the requirements concerning the promotion and sale of the drug, agent, or biologic (21 CFR Sec. 312.7); and
6. The use does not intend to invoke exception from the informed consent requirements for emergency use.

The investigator may use lawfully marketed drugs and biologics in research without an IND under the above circumstances.  However, CPHS review and approval is required prior to initiating research activities.

Investigator Responsibilities Under INDs

An investigator administering an investigational drug, agent, or biologic is responsible for the research to be conducted in accordance with the plan of investigation as described in the FDA-approved IND, the signed investigator statement, and the CPHS-approved investigational plan.

Responsibility for Study Subjects
Informed consent from subjects or subjects’ legally authorized representative must be  prospectively obtained, unless a wavier of consent has been granted by the CPHS and the rights, safety, and welfare of the subjects in the study must be protected by the investigator.

Responsibility for Control of Drugs
The investigator may not give the investigational drug to any person not authorized under the protocol to receive it. The drug, agent, or biologic may only be used in subjects under the investigator’s personal supervision or under the supervision of physicians who are directly responsible to the investigator. Additionally, the investigator is required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects.

If the investigational drug is subject to the Controlled Substances Act, the investigator must take adequate precautions, including storage of the investigational drug in a securely locked, substantially constructed cabinet, or other securely locked enclosure, access to which is limited, to prevent theft or diversion of the substance into illegal channels of distribution.

Responsibility for Maintaining Records
In order to maintain adequate records, it is expected that the investigator will keep case histories that record all observations and other data needed in the investigation for each individual receiving the investigational drug.  Each case history should include the signed and dated consent forms and medical records including progress notes of the physician, the individual’s hospital chart, and the nurses’ notes.  It is important to document in the case history that informed consent was obtained prior to participation in the study.

The records should be retained for a period of 2 years following the date a marketing application is approved for the drug for the indication for which it is being investigated.  If no application is to be filed or the application is not approved for such indication, records are kept until 2 years after the investigation is discontinued and FDA is notified.  The sponsor may have record retention requirements specified in the clinical trial agreement that must be followed instead of the 2 year minimum. 

Responsibility to the Sponsor of the Drug
The investigator must furnish all reports to the sponsor of the drug who is responsible for collecting and evaluating the results obtained.  The sponsor is required to submit annual reports to the FDA on the progress of the clinical investigations.

Serious or unexpected adverse events must be reported to the sponsor immediately.   Non-serious adverse events must be reported promptly.

The investigator must provide the sponsor with accurate financial information to allow an applicant to submit complete and accurate certification of disclosure statements as required. 

After completion of the study, the investigator must provide the sponsor with a report.

Responsibility to Committee for the Protection of Human Subjects (CPHS)
The investigator must provide copies of all FDA correspondence to CPHS.  Additional responsibilities are covered in other sections of the Handbook, such as adverse event reporting (chapter 8), initial protocol review (chapter 3), and the informed consent process (chapter 4).

Responsibility to Federal Agencies
In the event that an employee of the FDA requests access to records or reports made by the investigator (at a reasonable time), the investigator may permit such access for copying or verifying.  However, the investigator is not required to divulge subject names unless the records of particular individuals require a more detailed study of the cases, or unless there is reason to believe the records do not represent actual case studies.

Treatment use of Investigational Drugs

The FDA regulations have certain provisions for individuals not enrolled in clinical trials to obtain access to investigational products through various methods.  These include Group C treatments, open-label protocols, parallel track studies, and treatment INDs, including single-patient use, and all of them require CPHS  review and approval prior to treatment and must meet informed consent requirements.

Open-Label Protocol
Open-label protocols are designed to provide continued treatment to individuals after a controlled trial has ended, therefore, allowing subjects to continue receiving the benefits of the investigational drug, agent, or biologic until marketing approval is obtained and to gather additional safety data.

Parallel Track
Parallel Track studies are permitted by the FDA to allow wider access to promising new drugs, agents, or biologics made available to those persons with AIDS and other HIV-related diseases.  These drugs, agents, or biologics are utilized to establish protocols that “parallel” the controlled clinical trials and are essential to establish the safety and effectiveness of these new drugs, agents, or biologics.  

Treatment INDs or Biologics
A treatment IND is a specific type of IND that provides eligible subjects with the availability of promising new products as early in the drug development process as possible for the treatment of serious and life-threatening illnesses for which there are no satisfactory alternative treatments.

The FDA defines serious and life-threatening disease as a stage of a disease in which there is a reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment.  The FDA will allow an investigational drug to be used under a treatment IND after sufficient data have been collected to show the drug “may be effective” and does not have unreasonable risks associated with use.  Four requirements must be met before a treatment IND can be issued, and they include the following.

1. The drug is intended to treat a serious or immediately life-threatening disease;
2. There are no satisfactory alternatives available;
3. The drug is already under investigation or trials have been completed; and
4. The trial sponsor is actively pursuing marketing approval.

Group C Treatment INDs
Group C treatment INDs provide oncologists access to investigational drugs, agents, or biologics for the treatment of cancer under protocols outside controlled clinical trials.  Group C drugs, agents, or biologics usually have demonstrated evidence of relative and reproducible efficacy in a specific tumor type.  Although the FDA typically grants a waiver for use of most drugs in group C treatment IND protocols, the CPHS requires review and approval prior to treatment of patients.

Single Patient or Compassionate Use
The use of an investigational drug, agent, or biologic outside of a controlled clinical trial for a patient, usually in a desperate situation, who is unresponsive to other therapies or in a situation where there is not an approved or generally recognized treatment available may be granted access under a single-use protocol.  Under these conditions, there is little evidence that the proposed therapy will be useful.  However, use may be plausible on theoretical grounds or anecdotal evidence.

Access to investigational drugs, agents, or biologics for single-patient use may be gained either through the sponsor under a treatment protocol, or through the FDA, by first obtaining the drug from the sponsor and then submitting a treatment IND to the FDA requesting authorization to use the investigational drug for treatment use.  Prospective CPHS review and approval is required.

Consenting Individuals Under INDs

The use of investigational new drugs, agents or biologics is subject to all informed consent requirements.  Claims are not to be made which state or imply the investigational drug, agent, or biologic is safe or effective for the purpose under investigation or that the drug is in any way superior to another drug. The informed consent document includes statements that the product is “investigational” (not currently approved by the FDA) and that the FDA may have access to the subject’s medical record as it pertains to the study.  In addition, the investigator must assure that, throughout the consenting process and study participation, the subject comprehends that the investigational drug, agent, or biologic is under investigation, and that its benefit for the condition of the study is unknown.  Under treatment IND circumstances, the investigator and CPHS must assure that the informed consent process and documents detail the risks of such use.

Devices

Medical devices are defined as any health care product that does not achieve its primary intended purposes by chemical action or by being metabolized.  Examples include surgical lasers, wheelchairs, sutures, pacemakers, vascular grafts, intraocular lenses, and orthopedic pins. 

Clinical Investigations of medical devices must comply with both the FDA informed consent and UTHSC-H HRP PP VIII.02 Research with Investigational or Unlicensed Test Articles (Devices) http://www.uth.tmc.edu/orsc/policies/VIII.2.htm.  Except for certain low risk devices, each manufacturer who wishes to introduce a new medical device to the market must submit a premarket notification to FDA. Because of the many levels of risk, existing medical devices, and patient needs, there are varying categories into which the device would be categorized.  There are determinants of each device of whether or not they are risk or non-risk; exempt or non-exempt; investigational or humanitarian. 

Investigational Medical Devices

Unless exempt by the IDE regulations, all medical devices utilized in human research activities must be classified as a Significant Risk (SR) or a Non-Significant Risk (NSR).

Determining Non--Significant Risk and Significant Risk

The sponsor or manufacturer of the medical device initially makes a determination that the device will be categorized as a Non-Significant Risk (NSR) or a Significant Risk Device (SR).  If it is determined that it is a SR device, the sponsor or manufacturer must submit a request for an IDE from the FDA.  Research involving the use of a SR device must be conducted in accordance with the full requirements of the FDA and must have an IDE.

When the sponsor or manufacturer determines that the device is a NSR device, an IDE is not required and research must be conducted in accordance with the “abbreviated” requirements of the FDA  as described in Federal regulations 21 CFR 812.2(b) and CPHS approval of a study as a NSR can be sought, thus expediting the process.  If CPHS agrees that the study is NSR, then submission to or review by FDA is not necessary before starting studies in humans.  However, if CPHS considers the study to be SR, the sponsor must obtain an IDE from FDA.

Once received, CPHS will determine if it is in agreement with the determination of NSR status by the sponsor and proceed with its reveiw.  If CPHS disagrees with the sponsor’s NSR ruling, the investigator must report the CPHS determination to the sponsor.  The sponsor will then decide if they wish to pursue approval through the FDA and obtain an IDE or cease attempts at seeking CPHS approval at this institution.

CPHS has the authority to disapprove research activities even when the FDA has granted approval of the device.

Depending on which category the device falls under, the Investigator must do the following in their CPHS protocol:

Exemptions for IDE Requirements

It is the responsibility of the sponsor to provide sufficient justification to support the exemption from IDE requirements based on the seven exemption categories provided by the FDA.  An exemption from the IDE requirement is not an exemption from the requirement for prospective CPHS review and informed consent requirements.  According to 21 CFR 812.2(c), the exemptions are:

• A device, other than a transitional device, in commercial distribution immediately before May 28, 1976, when used or investigated in accordance with the indications in labeling in effect at that time.
• A device, other than a transitional device, introduced into commercial distribution on or after May 28, 1976, that FDA has determined to be substantially equivalent to a device in commercial distribution immediately before May 28, 1976, and that is used or investigated in accordance with the indications in the labeling FDA reviewed under subpart E of part 807 in determining substantial equivalence.
• A diagnostic device, if the sponsor complies with applicable requirements in 809.10(c) and if the testing:
• Is noninvasive,
• Does not require an invasive sampling procedure that presents significant risk,
• Does not by design or intention introduce energy into a subject, and
• Is not used as a diagnostic procedure without confirmation of the diagnosis by another, medically established diagnostic product or procedure.
• A device undergoing consumer preference testing, testing of a modification, or testing of a combination of two or more devices in commercial distribution, if the testing is not for the purpose of determining safety or effectiveness and does not put subjects at risk.
• A device intended solely for veterinary use.
• A device shipped solely for research on or with laboratory animals and labeled in accordance with 812.5(c).
• A custom device as defined in 812.3(b), unless the device is being used to determine safety or effectiveness for commercial distribution.

Use of an Investigational Device

The investigator is responsible for the tracking and oversight of FDA-regulated devices in research and must meet the following requirements in order to use an investigational device in research:

• The investigational device must be used only by the investigator or under his or her direct supervision;
• The investigational device must be used only as approved by the FDA and as described in the currently approved CPHS documents;
• The investigator must not supply the investigational devices to any persons not authorized under the IDE; and
• Informed consent from the subject or the subject’s legally authorized representative must be prospectively obtained, unless waived by the CPHS.

Humanitarian Use Device

The CPHS must review and approve the use of all Humanitarian Use Devices (HUD) which are intended to benefit patients in the treatment and diagnosis of diseases or conditions that affect fewer than 4,000 individuals in the United States (HRP PP VIII.04 Humanitarian Uses Device http://www.uth.tmc.edu/orsc/policies/VIII.4.htm).  The 4,000 mark is decided by the FDA at the time of submission of the HUD application. 

In order for a HUD to be used in treatment, diagnosis or research, the CPHS must approve the use of the HUD for which a Humanitarian Device Exemption (HDE) has been issued before the protocol is submitted to CPHS. 

• The proposed use for the HUD must be in accord with the current labeling of the device and must not exceed the scope of the FDA-approved indication
• The CPHS may impose more rigid restrictions for use of the HUD as a means of additional protections, should it feel it is necessary
• If the device will be utilized under an approved research protocol, the CPHS does not have to review and approve individual uses of a HUD, as long as the HUD is within the FDA approved indication.  ,
• HUDs may be used off-label in an emergency situation to save the life or protect the physical well-being of a patient, but the physician should follow the emergency use procedures governing such use of unapproved devices (see chapter 8).

Informed consent is not necessary with an HUD because of its approval by the FDA; however, CPHS can require the use of an informed consent at its discretion, particularly if the HUD is the subject of the clinical investigation.

Physician or Health Care Responsiblities for the Use of HUD

The physician or health care provider may utilize the HUD when in agreement with the following:

• The physician or health care provider must utilize the HUD for treatment, diagnosis, or research in accordance with the labeling of the device, intended purpose, and in the designated population for which the FDA approved its use;
• The physician or health care provider must inform the patient that the HUD is a device authorized under Federal law for use; however, the effectiveness of the device for a specific indication has not been demonstrated; and
• The physician or health care provider will obtain informed consent when the use of the HUD involves research or when required by the CPHS.