Manual for Conducting Human Subject Research

Use of Drugs and Devices Beyond the Context of "Research"

FDA has recognized circumstances where a drug, device, or biologic may be made available for use in patients with life-threatening or other serious diseases, for which no satisfactory alternative treatments exist.

9.1 Emergency Use

The following requirements apply to the use of an investigational or unapproved drug, biologic, or device in situations in which these products are needed to save the life of a patient or to prevent irreversible morbidity. This does not permit the research use of unapproved products for "emergency research" purposes (e.g., in a trauma-type study), which is governed by the requirements in Section 7.5.5, or the treatment use in serious, but not truly life-threatening situations, which is governed by Section 9.4.

Legal criteria for use. On occasion, physicians may seek to administer an investigational drug or device to an individual patient on an emergency basis, before formal review and approval of an HRRC can be granted. Typically, the drug or device will be subject to an IND or IDE, but the proposed use falls outside of the FDA approved application (or is to be used by a physician who is not part of the approved study). This use is permitted only in strict accordance with the following legal requirements:
1. The patient is facing a life-threatening condition (life-threatening includes serious diseases or conditions such as sight-threatening or limb-threatening conditions or other situations involving risk of irreversible morbidity) and no generally acceptable treatment is available;
2. Because of the immediate need to use the product, there is insufficient time to obtain IRB approval [such use requires FULL, not expedited review];
3. The use is reported in writing to the IRB within 5 working days; and
4. The use is one time only. Any subsequent use is subject to IRB review (requires HRRC approval of a protocol and consent), except under exceptional circumstances. 21C.F.R. 56.102, 56.104.
Obtain prior permission for use. Prior to administering the investigational product, the physician must contact the HRRC Chair or Executive Chair to inform him or her of the nature of the intended use and to ensure that such individual agrees that the use is appropriate. This review is not considered to be an HRRC "approval", however, since approval would require full HRRC review.
Follow legal requirements for obtaining product. Follow legal requirements for obtaining product. Emergency use of an investigational drug/biologic requires an IND from FDA. The usual procedure to obtain the drug is to contact the manufacturer to determine if the product can be made available under its IND. If there is no time to submit an IND, FDA may authorize the drug to be shipped to the investigator over the telephone or by FAX (see 21 C.F.R. 312.36). Emergency use of an investigational device does not require prior FDA approval but requires the sponsor to report the use to FDA within 5 working days. The investigator should obtain authorization from the IDE sponsor, if an IDE exists. Investigators should contact the HRRC Support Office for current information on how to legally obtain shipment of the investigational product.
Obtain informed consent. Obtain informed consent. Informed consent (Section 7.3) from the patient or legal representative must be obtained (but see section 9.2, for emergency waiver of informed consent).
Concurrence of uninvolved physician. Concurrence of uninvolved physician. For device use, FDA expects that the physician will obtain an independent assessment of the use.
Written notification to HRRC after administration. After giving the drug/device, the physician must submit a written report to the HRRC including: a description of the emergency, the rationale for the product’s use, the source of the drug/device and IND/IDE number, exactly what was given or done (dosage, route, date given, etc.), the outcome, the patient’s name and hospital number. The written consent should be attached to the HRRC notification. After giving the drug/device, the physician must submit a written report to the HRRC including: a description of the emergency, the rationale for the product’s use, the source of the drug/device and IND/IDE number, exactly what was given or done (dosage, route, date given, etc.), the outcome, the patient’s name and hospital number. The written consent should be attached to the HRRC notification.
Written notification to IDE sponsor or FDA. Written notification to IDE sponsor or FDA. For emergency device use, the physician is also required to notify the IDE sponsor, if one exists, or FDA IDE Staff if there is no IDE, in writing of the summary of the conditions constituting the emergency, patient protection measures that were followed, and patient outcome information.

9.2 Emergency Use Without Informed Consent

Even with emergency use (9.1), the investigator is required to obtain informed consent. However, FDA allows the investigational product to be administered without consent under the following circumstances:

1. The investigator and a physician who is not otherwise participating in the clinical investigation certify in writing all of the following:

The human subject is confronted by a life-threatening situation necessitating the use of the test article;
Informed consent cannot be obtained from the subject because of an inability to communicate with, or obtain legally effective consent from, the subject;
Time is not sufficient to obtain consent from the subject’s legal representative;
There is available no alternative method of approved or generally recognized therapy that provides an equal or greater likelihood of saving the life of the subject; and
The documentation required will be submitted to the IRB within five working days of using the test article.

If there is not time prior to giving the article to obtain an independent physicians concurrence, the investigator must obtain a review of what he or she did by an independent physician within 5 days of giving or using the article and submit that with the required documentation to the HRRC.

21 C.F.R. 50.23.

2. Obtain prior HRRC permission.
The HRRCs require prior review by the HRRC Chair or Executive Chair of this intended use. The Chair or Executive Chair’s review does not constitute HRRC approval however. The HRRCs require prior review by the HRRC Chair or Executive Chair of this intended use. The Chair or Executive Chair’s review does not constitute HRRC approval however.

3. Provide written documentation after use.
The physician must document the information in paragraph 1 above information in writing, and provide it to the HRRC within 5 days of its use.

NOTE: This use should not be confused with the FDA/OHRP informed consent waiver for research designed to evaluate interventions in emergency settings (Section 7.5.5).

9.3 Individual Patient Access to Investigational Products for Serious Conditions

Under the FDA Modernization Act of 1997, a patient--acting through a licensed physician--may request that a manufacturer or distributor provide the physician with an investigational drug/device for the diagnosis, monitoring, or treatment of a serious disease or condition, but not life-threatening condition, if certain requirements are met: the physician must determine that there is no comparable or satisfactory therapy and the risk from the product is not greater than the probable risk from the disease or condition; FDA must have determined there exists enough evidence of safety and effectiveness for use of the device and that its use will not interfere with clinical investigations in support of marketing approval; and the sponsor or clinical investigator must have submitted a clinical protocol to FDA describing use of the product in a single patient or small group of patients.

FDA has issued guidance on this use with regard to investigational devices. The guidance sets forth the specific criteria that must be submitted to FDA in the IDE supplement to obtain the device for this use. The guidance also requires the using physician to devise an appropriate schedule for monitoring the patient, taking into account the investigational nature of the device and needs of the patient. A follow-up "Compassionate use” report is required to be sent to FDA.

This use (drug and device) requires the investigator to obtain prior FDA approval

The HRRCs will review applications for individual use prior to the initiation of the protocol in accordance with standard review procedures (Section 6). The investigator should ensure that the informed consent document is explicit regarding the use of an investigational drug in a health care setting, and the assessment of the risk/benefit relationships.

9.4 Treatment Use of Investigational Drug/Device

Treatment use allows physicians to treat patients outside of the clinical study, but for the same use that is being studied in the approved IND/IDE. This use is only permitted under a "Treatment IND/IDE@ submitted by the sponsor. See 21 C.F.R. 312.24-25; 21 C.F.R. 812.36. Treatment IND/IDEs facilitate the availability of promising test articles to seriously ill patients (they are only available for serious or immediately life-threatening situations where no comparable/satisfactory treatment exists) as early in the development process as possible, and allow the collection of additional data on the test article's safety and effectiveness. Section 402 of the FDA Modernization Act of 1997 codified expanded access under treatment INDs/IDEs into law.

The HRRC reviews treatment INDs/IDEs in the same manner as any initial research study. Although FDA may waive the requirement for review, under the UNMHSC FWA, these protocols still require HRRC review. As part of the submission, the HRRC will review documentation submitted by the principal investigator showing the sponsor=s permission to initiate the treatment use. The investigator should be specific in the consent form about the use of a test article in a health care setting, and the assessment of the risk/benefit relationships. These issues will be taken into account in reviewing the application.

9.5 Humanitarian Use Devices

To encourage the discovery and use of devices to treat rare conditions or diseases--where manufacturers are unlikely to expend resources due to lack of demand--FDA may grant marketing approval for certain devices in the absence of a reasonable assurance of effectiveness that would otherwise be required. Under this rule, FDA will designate a device to be a humanitarian use device ("HUD") if the manufacturer establishes that it is intended to treat or diagnose a disease or condition that affects or is manifested in fewer than 4,000 individuals in the United States. FDA may grant the humanitarian device exemption ("HDE") if, among other things, the applicant submits information to show that there is a reasonable basis from which to conclude that the probable benefit of use of the device outweighs the risk or illness or injury, taking into account the probable risks and benefits of currently available devices and alternative treatments. The HUD device may only be used in a facility having an IRB and under IRB oversight (although the law now allows emergency use of an approved HDE when IRB review cannot be obtained in time, with subsequent reporting to the IRB see Section 9.1).

For a HUD to be considered for use at the UNMHSC or the NMVAHCS, an investigator must submit a completed HUD application. The HRRC is required to approve the use of the HUD in a facility and must grant continuing approval in accordance with the requirements set forth in Section 6.1. The HRRC may approve use of the HUD under a protocol or on a case-by-case basis. In their review, the HRRCs will focus on those criteria that are applicable to the use of a product in a treatment context. The investigator should submit information to the HRRC that will allow it to consider the patient’s need for the HUD and the likelihood that the device is appropriate for the patient’s condition or disease state. Informed consent as set forth in Section 7.3 is not strictly required, as HUD devices are not considered investigational and their use is not considered to be research. The HRRC will work with the investigator to devise a consent form if needed. Many sponsors provide an information or 'patient labeling' booklet that contains information about the potential risks and benefits of the HUD and any procedures associated with its use. If used, the consent form or information booklet should state that the device is a humanitarian use device and effectiveness for the labeled indication has not been demonstrated.