DEPARTMENT OF RESEARCH
LBH IRB Guide # 16b: Expanded Access Mechanisms Page 2 of 10
Ver. 2 – 06/16/08
Institutional Review Board
Expanded Access for an Unapproved Drug, Biologic, or Device
Guidelines
An unapproved test item (i.e., drug, biologic, or medical device) may only be used on human subjects through a Food and Drug Administration (FDA)-approved clinical study in which patients meet certain criteria and the test item is only used in accordance with an approved protocol by a clinical investigator participating in the clinical trial. However, in a number of defined circumstances, patients (through their physicians) can obtain access to test items that are under investigation. Institutional review boards (IRB) have been assigned varying degrees of oversight of this type of expanded access even though treatment rather than research is the intent.
The key to understanding the various access types is to become familiar with 1) the access type definition or applicability standards, 2) the patient eligibility criteria, and 3) the availability of each access type during the test item’s development /marketing /approval process. The expanded access mechanisms under which a health care provider may use a test item to save the life of a patient or to help a patient suffering from a serious disease or condition for which no other alternative therapy exists are described below.
A. EMERGENCY ACCESS TO DRUGS, BIOLOGICAL PRODUCTS, AND DEVICES
Emergency Use refers to treatment of an individual with an immediately life-threatening condition (for which there is no comparable or satisfactory treatment available) with an experimental, unregistered product, outside of a clinical trial. Emergency use of an unapproved test item is intended to benefit a single patient who is not eligible for a study approved at the treating institution. Generally, emergency use of a test item requires either an Investigational New Drug (IND) application (http://www.fda.gov/cder/Regulatory/applications/ind_page_1.htm) or an Investigational Device Exemption (IDE) (http://www.fda.gov/cdrh/devadvice/ide/index.shtml). Although the FDA regulations do not provide for expedited IRB approval in emergency situations, they do provide an “emergency use” exemption (21 CFR 56.104c and 21 CFR 56.102d) from rules requiring prior IRB review and approval. However, reporting emergency use to the IRB is required by the FDA, and whenever possible LifeBridge Health (LBH) requires consultation with the LBH IRB prior to use.
The use of a non-FDA approved test item in human subjects requires an IND or IDE, IRB approval, and informed consent. However, these conditions may be expedited or waived in circumstances where the following emergency use criteria [21 CFR 56.102(d)] are satisfied:
· The situation is life-threatening or severely debilitating (i.e., major irreversible morbidity)
· There is no standard acceptable treatment available, and
· There is not sufficient time to obtain IRB approval.
1. Emergency use of Drugs and Biological Products
A) Expedited IND Process: Emergency use requires an IND. An investigator must request an emergency IND through the FDA. The FDA has 24-hour emergency contact information for these purposes available on its web site at: http://www.fda.gov/oc/ohrt/irbs/drugsbiologicsNEW.html. Current numbers are listed in Table 1.
B) Waiver of IRB Approval: IRB approval is not required for emergency use, but the investigator must notify the IRB after emergency use. Some sponsors may require advance notice to the IRB or documentation from the IRB concerning the emergency use. Prior notification or documentation of awareness does not imply IRB approval. FDA regulations require the investigator to file a report of the emergency use of a test item with the IRB within 5 days of its use.
C) Waiver of Informed Consent for Emergency Use: Emergency use requires informed consent unless both the investigator and a physician who is not otherwise directly involved with either the patient’s treatment or the “clinical trial” certify in writing all of the following:
1) The situation is life threatening, necessitating the use of the test item,
2) Informed consent cannot be obtained from the subject because of an inability to communicate with, or obtain legally effective consent from, the subject,
3) Time is not sufficient to obtain consent from the subject's legal representative, and
4) There is no alternative method of approved or generally recognized therapy that provides an equal or greater likelihood of saving the life of the subject.
The consulting physician’s affidavit may be provided subsequent to use of the test item if both of the following criteria are met:
5) Immediate use of the test item was required to preserve the subject's life, and
6) Time was insufficient to obtain an independent physician's evaluation concerning the first four criteria listed above.
When an independent physician’s evaluation is not obtained prior to use of the test item, the investigator should document before treatment that each of the six criteria were satisfied. These determinations must be reviewed and evaluated in writing by an independent physician and submitted to the IRB within 5 working days after the use of the test item.
2. Emergency Use of Devices
A) Requirements for Emergency Use: Each of the following conditions must exist to justify emergency use of an unapproved device.
1) There is a life-threatening or severely debilitating condition that needs immediate treatment,
2) There is no generally acceptable alternative for treating the patient, and
3) Immediate need to use the device dictates that there is no time to use existing procedures to get FDA approval for its use.
Physicians should follow as many of the following subject protection procedures as possible:
1) Obtain independent assessment by an uninvolved physician,
2) Obtain informed consent from the patient or a legal representative,
3) Notify the Institutional Review Board (IRB), and
4) Obtain authorization from the IDE holder, if an approved IDE exists.
Note: IRB approval is not required for emergency use of an unapproved device, but the investigator must notify the IRB.
After an unapproved device is used in an emergency, the physician should:
1) Report to the IRB within five days and otherwise comply with provisions of the IRB regulations,
2) Evaluate the likelihood of a similar need for the device occurring again, and if future use is likely, immediately initiate efforts to obtain IRB approval and an approved IDE for the device's subsequent use, and
3) If an IDE for the device does exist, notify the sponsor of the emergency use, or if an IDE does not exist, notify FDA of the emergency use (Center for Devices and Radiological Health Program Operation Staff at 301-594-1190) and provide FDA with a written summary of the conditions constituting the emergency, subject protection measures, and results.
B. EXPANDED ACCESS TO DRUGS, BIOLOGICAL PRODUCTS, AND DEVICES
Expanded Access refers to non-emergency treatment INDs or Individual Patient Access to investigational drugs or devices for serious diseases. These mechanisms are intended to give seriously ill patients access to experimental drugs or devices where no comparable or satisfactory alternative treatment is available. Unlike Emergency Use access that is available from the pre IND or IDE period up to marketing approval, all other access types are available only after a clinical investigation has started (see Figures 1 & 2). All expanded access types allow patients with serious or life-threatening conditions who are not participating in a controlled clinical trial to receive treatment with promising investigational products prior to marketing approval by the FDA. Although the test item sponsor is expected to continue conventional clinical trials and diligently pursue marketing approvals, expanded access studies involve systematic use of experimental treatments, and generally require the same review and approval as research, including both LBH IRB and FDA approval in the form of an IND (drug/biologic) or IDE (medical device).
1. Single Patient or Small Group Use (aka Compassionate Use)
A) Drugs and Biological Products
A licensed physician may request a manufacturer or distributor to receive an investigational drug for the diagnosis, monitoring, or treatment of a serious disease or condition if:
1) The physician determines that there is no comparable or satisfactory alternative therapy available to patient, and that the probable risk from the investigational drug is not greater than the probable risk from the disease or condition;
2) The sponsor, or clinical investigator, of the investigational drug submits to FDA a clinical protocol that describes the use of the investigational drug in a single patient or a small group of patients, and
3) The FDA provides IND approval for use of the investigational drug for use in the proposed clinical protocol.
Procedure for obtaining a single patient IND:
1) Obtain permission from the manufacturer
2) Physician sends request letter (a facsimile may be sent followed by a letter) to the appropriate FDA review division containing the following:
a. Request for a single patient IND for Compassionate or Emergency Use should be stated at the top of the correspondence.
b. Brief clinical history of the patient including diagnosis, prior therapy, response to prior therapy, disease status, and rationale for requesting the proposed treatment.
c. Proposed treatment plan including dose, route, planned duration, monitoring procedures and modifications (e.g., dose reduction or treatment delay) for toxicity. Provide published reference if appropriate.
d. A drug supply reference statement naming the supplier or manufacturer.
e. A statement that a Letter of Authorization to cross reference an appropriate IND or Drug Master File (DMF) of the supplier/manufacturer is included. The physician must contact the supplier or manufacturer for such a statement.
f. Informed consent statement stating that informed consent and approval of an appropriate IRB will be obtained prior to initiating treatment.
g. Investigator qualification statement specifying the training, experience, and licensure of the treating physician. The first two pages of a Curriculum Vita typically contain this information and are usually sufficient.
h. FDA Form 1571 completed with the treating physician listed as the sponsor. Form 1571 and other FDA forms can be downloaded at: http://www.fda.gov/opacom/morechoices/fdaforms/cder.html
i. Contact telephone number and facsimile number. Upon approval, an IND number is issued and the FDA will contact the treating physician. The IND is considered active upon issuance of the number. The physician (i.e., the IND sponsor in this case) will then contact the drug supplier and provide the IND number. The supplier can then ship the drug directly to the physician.
j. Following compassionate use of a test item, a follow-up report should be submitted to FDA as an IND supplement in which summary information regarding patient outcome is presented. If any serious adverse events (SAE) occurred as a result of test item use, these should be discussed in the supplement and reported to the IRB. See IRB guidelines concerning SAE reporting at: http://www.lifebridgehealth.org/workfiles/irb/irb_guide_3.doc.
B) Devices
The conditions under which a licensed physician may request a manufacturer or distributor to receive an investigational device is essentially identical to that described above for drugs and biologics [Section B1A].
Procedure for obtaining a single patient IDE:
Application for Single Patient or Small Group Use involves the sponsor’s IDE supplement [21 C.F.R. 812.35a] requesting approval for a protocol deviation. Even the physician who is conducting a clinical investigation on a test item under an IDE must request the sponsor to submit such an amendment and receive FDA approval before using or making the device available for single patient-small group use. The IDE supplement should include:
1) A description of the patient’s condition and the circumstances necessitating treatment,
2) A discussion of why alternatives therapies are unsatisfactory and why the probable risk of using the investigational device is no greater than the probable risk from the disease or condition,
3) An identification of any deviations in the approved clinical protocol that may be needed in order to treat the patient, and
4) The patient protection measures that will be followed. (Informed consent, concurrence of IRB chairperson, clearance from the institution, independent assessment from uninvolved physician, authorization from IDE sponsor)
If the use request is approved by the FDA and the IRB, the treating physician using the device is required to develop a monitoring plan and to submit a follow-up report on the use to the FDA and the IRB. Problems should be reported to both the FDA and the IRB.
2. TREATMENT IND/IDE
The treatment IND (21 CFR 312.34 & 312.35) is a mechanism to facilitate the availability of promising new drugs to desperately ill patients as early in the drug development process as possible, before general marketing begins (Figures 1 & 2), and to obtain additional data on the drug’s safety and effectiveness.
A) Drugs and Biological Products (Treatment IND)
The primary distinction between the treatment IND and the single patient/small group process described above in Section B1A is that a drug obtained via the treatment IND process is always involved (current investigation) or has been involved (completed investigation) in a clinical trial and the trial sponsor is actively pursuing marketing approval from the FDA.
Treatment IND studies require prospective IRB review and informed consent. A sponsor may apply for a waiver of LBH IRB review under a treatment IND if it can be shown to be in the best interest of the patient, and if a satisfactory alternate mechanism for assuring the protection of human subjects is available (e.g., review by the NIH NCI Central IRB). Such a waiver does not apply to the informed consent requirement. The LBH IRB may still opt to review a study even if the FDA has granted a waiver.
A licensed physician may request a manufacturer or distributor to receive an investigational drug for the treatment of a serious disease or condition providing the following general criteria are met:
1) The drug is intended to treat a serious or immediately life-threatening disease,
2) There is no comparable or satisfactory alternative drug or other therapy available to treat that stage of the disease in the intended patient population,
3) The drug is under investigation in a controlled clinical trial under an IND in effect for the trial, or all clinical trials have been completed, and
4) The sponsor of the controlled clinical trial is actively pursuing marketing approval of the investigational drug with due diligence.
Procedure for obtaining a treatment IND: