Investigational Products in Clinical Investigations (Clinical Trials)
(FDA Information Sheets, 1998 Update)

The use of an investigational (not approved by FDA) drug or biologic in a clinical investigation requires approval of the IRB and the submission of an IND.  The IND is usually obtained by the sponsor of the clinical trial.  In the case of investigational devices, sufficient information must be given in the protocol for the sponsor and the IRB to determine (1) whether the device presents significant or non-significant risk and (2) whether the study itself should be approved.  A significant risk device is defined as a device that presents a potential for serious harm to the health, safety, or welfare of a subject and is an implant, is used in supporting or sustaining human life, is of substantial importance in diagnosing, curing, mitigating or treating disease, otherwise prevents impairment of human health, or otherwise presents a potential for serious risk to the health, safety or welfare of the subject.  It is the intrinsic risk of the device that must be determined rather than whether the device is more or less risky than those presently approved for use.

Subjects (patients) cannot be charged for the use of an investigational product unless approved by the FDA and the IRB.  The IRB will consider the ethics of such charges for each protocol.

Subjects or their third party insurance may be charged for products that become approved during the course of the research.
 

Expanded Access to Investigational New Drugs
(FDA Information Sheets, 1998 Update)

Investigational products are sometimes used for treatment of serious or life-threatening conditions either for a single subject or for a group of subjects.  The procedures that have evolved for an investigational new drug (IND) used for these purposes reflect the recognition by the Food and Drug Administration (FDA) that, when no satisfactory alternative treatment exists, subjects are generally willing to accept greater risks from test articles that may treat life-threatening and debilitating illnesses.  The following mechanisms expand access to promising therapeutic agents without compromising the protection afforded to human subjects or the thoroughness and scientific integrity of product development and marketing approval.

Open Label Protocol or Open Protocol IND

These are usually uncontrolled Studies, carried out to obtain additional safety data (Phase 3 studies).  They are typically used when the controlled trial has ended and treatment is continued so that the subjects and the controls may continue to receive the benefits of the investigational drug until marketing approval is obtained.  These studies require prospective Institutional Review Board (IRB) review and informed consent.

Treatment IND

The treatment IND [21 CFR 312.34 and 312.35} is a mechanism for providing eligible subjects with investigational drugs for the treatment of serious and life-threatening illnesses for which there are no satisfactory alternative treatments.  A treatment IND may be granted after sufficient data have been collected to show that the drug “may be effective” and does not have unreasonable risks.  Because data related to safety and side effects are collected, treatment INDs also serve to expand the body of knowledge about the drug.

There are four requirements that must be met before a treatment IND can be issued:

 • the drug is intended to treat a serious or immediately life-threatening disease;
 • there is no satisfactory alternative treatment available;
 • the drug is already under investigation, or trials have been completed; and
 • the trial sponsor is actively pursuing marketing approval.

Treatment IND studies require prospective IRB review and informed consent.  A sponsor may apply for a waiver.  A sponsor may apply for a waiver of local IRB review under a treatment IND if it can be shown to be in the best interests of the subjects, and if a satisfactory alternate mechanism for assuring the protection of human subjects is available, e.g. by a central IRB.  Such a waiver does not apply to the informed consent requirement.  An IRB may still opt to review a study even if FDA has granted a waiver.

Group C Treatment IND

The “Group C” treatment IND was established by agreement between FDA and the National Cancer Institute (NCI).  The Group C program is a means for the distribution of investigational agents to oncologists for the treatment of cancer under protocols outside the controlled clinical trial.  Group C drugs are generally Phase 3 study drugs that have shown evidence of relative and reproducible efficacy in a specific tumor type.  They can generally be administered by properly trained physicians without the need for specialized supportive care facilities.  Group C drugs are distributed only by the National Institutes of Health under NCI protocols.  Although treatment is the primary objective and patients treated under Group C guidelines are not part of a clinical trial, safety and effectiveness data are collected.  Because administration of Group C drugs is not done with research intent, FDA has generally granted a waiver from the IRB requirements [21 CFR 56.105].  Even though FDA has granted a waiver for these drugs, an IRB may still choose to conduct a review under its policies and procedures.  The usage of a Group C drug is described in its accompanying “Guideline Protocol” document.  The Guideline Protocol contains a FDA-approved informed consent document which must be used if there has been no local IRB review.

Parallel Track

The FDA’s Parallel Track policy permits wider access to promising new drugs for AIDS/HIV related diseases under a separate expanded access protocol that “parallels” the controlled clinical trials that are essential to establish the safety and effectiveness of new drugs.  It provides an administrative system that expands the availability of drugs for treating AIDS/HIV.  These studies require prospective IRB review and informed consent.

Emergency Use IND

The need for an investigational drug may arise in an emergency situation that does not allow time for submission for an IND in the usual manner.  In such cases, FDA may authorize shipment of the drug for a specified use [21 CFR 312.36].  Such authorization is usually conditioned upon the sponsor filing an appropriate application as soon as practicable.  Prospective IRB is required unless the conditions for exemption are met [21 CFR 56.104(c)] and 56.102(d)].  Informed consent is required unless the conditions for exception are met [21 CFR 50.23]. – See Emergency Use of Investigational Drug or Biologic.

 “Off-Label” and Investigational Use of Marketed Drugs, Biologics and Medical Devices
(FDA Information Sheets, 1998 Update)

“Off-Label” Use of Marketed Drugs, Biologics and Medical Devices

Good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics and devices according to their best knowledge and judgment.  If physicians use a product for an indication not in the approved labeling, they have the responsibility to be well informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the product’s use and effects.  Use of a marketed product in this manner when the intent is the “practice of medicine” does not require the submission of an Investigational New Drug Application (IND), Investigational Device Exemption (IDE) or review by an Institutional Review Board (IRB).  However, the institution at which the product will be used may, under its own authority, require IRB review or other Institutional oversight.

Investigational Use of Marketed Drugs, Biologics and Medical Devices

The investigational use of approved, marketed products differs from the situation described above.  “Investigational use” suggests the use of an approved product in the context of a clinical study protocol [see 21 CFR 312.3(b)].  When the principal intent of the investigational use of a test article is to develop information about the product’s safety or efficacy, submission of an IND or IDE may be required.  However, according to 21 CFR 312.2(b)(1), the clinical investigation of a marketed drug or biologic does not require submission of an IND if all six of the following conditions are met:

1. it is not intended to be reported to FDA in support of a new indication for use or to support any other significant change in the labeling for the drug;
2. it is not intended to support a significant change in the advertising for the product;
3. it does not involve a route of administration or dosage level, use in a subject population, or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product;
4. it is conducted in compliance with the requirements for IRB review and informed consent [21 CFR parts 56 and 50, respectively];
5. it is conducted in compliance with the requirements concerning the promotion and sale of drugs [21 CFR 312.7]; and
6. it does not intend to invoke 21 CFR 50.24 [Exception from informed consent requirements for emergency research].

For additional information on whether or not an IND or IDE is required in a specific situation, your may contact:

For DRUG PRODUCTS contact:
Drug Information Branch (HFD-210)
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, Maryland 20857
301-827-4573

For a BIOLOGICAL DRUG product, contact:
Office of Blood Research and Review (HFM-300)
Center for Biologic Evaluation and Research
Food and Drug Administration
1401 Rockville Pike
Rockville, Maryland 20852
301-827-3518

For a BIOLOGICAL VACCINE product, contact:
Office of Vaccines Research and Review (HFM-400)
Food and Drug Administration
8600 Rockville Pike
Bethesda, Maryland 20892-0001
301-827-0648

For a BIOLOGICAL THERAPEUTIC product, contact:
Office of Therapeutics Research and Review (HFM-500)
Food and Drug Administration
1451 Rockville Pike
Rockville, Maryland 20852-1420
301-594-2860

For a MEDICAL DEVICE product, contact:
Program Operations Staff (HFZ-403)
Office of Device Evaluation
Center for Devices and Radiological Health
Food and Drug Administration
9200 Corporate Blvd.
Rockville, Maryland 20850
301-594-1190

Use of Investigational Products when a Subject Enters a Second Institution

Several issues are raised when a subject who is participating in a research study at one institution is admitted to another facility. To help illustrate, the following will serve as the model for this information sheet: Regional Medical Center (RMC) has developed a research protocol; the study has been reviewed and approved by the RMC institutional review board (RMC-IRB); each subject receives a test drug for a 16 week period (4 weeks inpatient, 12 weeks outpatient); some research subjects will live in a distant town with a local health care facility, Memorial Hospital (MH). For these subjects, participation at RMC will involve considerable travel time and costs. While several examples can be imagined, the three scenarios below may help to illustrate some key points.
1. The least complex (first) scenario is when a subject's treatment/hospitalization is not related to the research. Procedures should be in place for rapidly identifying test drugs and devices (e.g., an emergency contact number and unblinding procedure). For this example, we will assume that hospitalization at MH is medically necessary and that the local physician has determined that it is appropriate to continue the subject (now patient) on the test drug. In this case, MH is providing incidental medical care and is not participating as a research site. Therefore, MH staff are not investigators and the MH-IRB does not need to review the protocol. The usual procedures for dealing with drugs prescribed out-of-facility would be followed (often, this is a pharmacy department policy). The investigator at RMC remains responsible for test drug administration and follow-up and therefore, should be aware of the hospitalization. The RMC investigator may need to report the event as an unexpected adverse incident, if it is possibly related to use of the test article. The RMC-IRB remains the IRB of record.
2. For the second scenario, the involvement of MH is reasonably foreseen and is an anticipated part of the study protocol (e.g., the need for inpatient care is anticipated for the condition under study, or the need for subjects to return home and receive medical follow-up). The RMC-IRB should be aware that other institutions and/or providers will be providing medical care/follow-up and should ensure that adequate reporting and safety systems are in place before approving the study. In this example, the protocol allows the test drug to be sent to the subjects' regular health care providers. Even though the test article is being given at MH, only routine medical monitoring is conducted by the local provider with little or no reporting to the RMC investigator, who remains responsible for the test drug administration and collects research data when the subject returns to RMC. The involvement of MH is incidental to the study (i.e., research data are not collected) and thus, it is not participating as a research site.
In the first two scenarios, prior to continuing the investigational drug, the local physician should obtain from the clinical investigator the information necessary to safely continue the investigational drug. The information conveyed might include a description of treatment procedures, warnings of possible adverse reactions, emergency procedures, a copy of the signed informed consent document (which is a research summary as well as documentation of consent).
3. For the third scenario, MH is designated as an extension of the research milieu. In this instance, the second institution (MH) is responsible for a portion of the research protocol. For this example, a physician at MH has been identified in the protocol as a sub-investigator for subjects residing in that local catchment area. As sub-investigator, this physician is responsible for conducting examinations of subjects to monitor status and measure effects of the test drug (data collection). These research data are systematically reported to the RMC investigator.
Because MH is conducting research, it is responsible for complying with the applicable research regulations. The MH-IRB may review, approve and be responsible for monitoring the portion of the research conducted at MH just as it would for any other research in the facility or, MH may agree to accept the RMC-IRB as the responsible IRB. If the RMC-IRB is to accept responsibility for other sites, it should consider the rationale for transferring or referring subjects to another institution; the circumstances under which responsibility will be shared; the instructions that will be given to the sub-investigators; the monitoring procedures that will be followed; and the informed consent process.

Informed Consent
Although not specifically discussed in the FDA regulations, requiring the subject to sign a second research consent document for the secondary facility should be avoided when feasible. In the first and second scenarios, research is not being conducted at MH and therefore, no research consent is needed for the second facility (however, consent for medical treatment may be required). Since the medical need in the first scenario is unexpected, the informed consent document would not describe such involvement. In the second scenario, because MH involvement is planned, the informed consent document should describe the activities to be carried out at MH. When some of the research activities are carried out at a secondary location, the investigator and the IRB should consider whether any additional information, such as a local emergency contact number, needs to be included in the informed consent document.
The third scenario is the most complex. Because MH is involved in research, the informed consent process should include a description of this activity. As appropriate, this could be included in the consent document presented to all subjects, or a separate informed consent document could be prepared for those subjects entering MH. If the RMC-IRB is accepting responsibility for other sites, it would review and approve the informed consent document(s). If MH does not agree to cooperative review, however, MH-IRB may accept the RMC informed consent document if it adequately describes the involvement of MH (i.e., not require a second document). MH-IRB may also decide to develop its own informed consent document. In this case it is important that the subject not receive conflicting information and the two IRBs should work to resolve such issues. If there are two consent documents, generally the RMC document would cover the overall study and the MH document would only detail the specific procedures involved while at that facility.
 

Personal Importation of Unapproved Products

FDA permits individuals to bring into the U.S., for their personal use, up to a three months supply of FDA-regulated products sold abroad but not approved in the U.S.  Importation may be in personal baggage or by mail.  All of the following four conditions must be met in order to permit importation:

1. The product was purchased for personal use.
2. The product is not for commercial distribution and the amount of product is not excessive (i.e. 3 month supply or less).
3. The intended use of the product is appropriately identified.
4. The patient seeking to import the product affirms in writing that it is for the patient’s own use and provides the name and address of the licensed physician in the U.S. responsible for his or her treatment with the product.

This importation policy applies to most drugs, biologics and medical devices intended for personal import, provided they are not fraudulently promoted and do not present an unreasonable risk.  Importation by a physician for use by his/her patients does not meet the requirements for personal importation.  Since the person using the product initiates the importation, that person is presumed to be knowledgeable about the product and its use.  Therefore, such personal importation is not regarded by the FDA to be research and an IND/IDE is not required.  Also, neither IRB review nor informed consent is required by FDA for such personal importation and use.

Food and Drug Administration (FDA) Classification of Drug Studies

FDA Regulations refer to various phases of drug studies.  Phase II and III conform to the definition of non-validated practices.  In general, Phase I studies do not, since the purpose of drug administration is to develop information about drug toxicity, metabolism and dynamics rather than to enhance the well-being of an individual patient or client.  While the recipients of drugs in Phases II and III are always patients for whom the drug is intended to provide a therapeutic effect.  In Phase I they are most commonly “normals”.  When Phase I studies are performed using patients for whom a therapeutic effect is intended, as in the development of most cancer chemotherapeutic agents, they may at times also be considered non-validated practices.  In Phase IV, the drugs may be either validated or non-validated, as in cases in which marketed drugs are being tested for safety and efficacy for new indications or new populations (e.g. children).

Phase I Studies

PHASE I CLINICAL PHARMACOLOGY is intended to include the initial introduction of a drug into man.  It may be in the usual “normal” volunteer subjects to determine levels of toxicity and, when appropriate, pharmacological effect and be followed by early dose-ranging studies in patients for safety and, in some cases, for early evidence of effectiveness.

Alternatively, with some new drugs, for ethical or scientific considerations, the initial introduction into man is more properly done in selected patients.  When normal volunteers are the initial recipients of a drug, the very early trials in patients which follow are considered part of Phase I.

Drug dynamic and metabolic studies, in whatever stage of investigation they are performed, are considered to be Phase I clinical pharmacological studies.  While some, such as the absorption studies, are performed in the early stages, others, such as efforts to identify metabolites, may not be performed until later in the investigations.

Phase II Studies

PHASE II CLINICAL INVESTIGATIONS consist of controlled clinical trials designed to demonstrate effectiveness and relative safety.  Normally, these are performed on closely monitored patients of a limited number.

Phase III Studies

PHASE III CLINICAL TRIALS are the expanded controlled and uncontrolled trials.  These are performed after effectiveness has been basically established, at least to a certain degree, and are intended to gather additional evidence of effectiveness for specific indications and more precise definition of drug-related adverse effects.

Phase IV Studies

PHASE IV POSTMARKETING CLINICAL TRIALS are of several types:

1. Additional studies to elucidate the evidence of adverse reaction, to explore a specific pharmacological effect of to obtain more information of a circumscribed nature.
2. Large scale, long-term studies to determine the effect of a drug on morbidity and mortality.
3. Additional clinical trials similar to those in Phase III, to supplement pre-marketing data where it has been deemed in the public interest to release a drug prior to acquisition of all data which would ordinarily be obtained before marketing.
4. Clinical trials in a patient population not adequately studied in the pre-marketing phase, e.g. children.
5. Clinical trials for an indication for which it is presumed that the drug, once available, will be used.

(Robert J. Levine, Ethics and Regulation of Clinical Research.  Baltimore Urban & Schwarzenberg, 1981 – pp. 4-5)