LBH IRB Guide # 16B: Expanded Access Mechanisms Page 2 of 10

DEPARTMENT OF RESEARCH

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.

LBH IRB Guide # 16b: Expanded Access Mechanisms Page 1 of 10

Ver. 2 – 06/16/08 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.

Ver. 2 – 06/16/08 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:

Ver. 2 – 06/16/08 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

Ver. 2 – 06/16/08 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:

1) Either the IND sponsor or a licensed practitioner can submit a treatment IND protocol (21 CFR 312.35), 2) If the IND is held by the sponsor, the licensed physician must first seek to obtain the drug from the sponsor under a treatment protocol. The sponsor will provide instructions and paperwork necessary to obtain the investigational drug. (Note: A sponsor may charge for an investigational drug under a treatment use IND only with prior FDA approval.) 3) A licensed physician who receives an investigational drug under a sponsor’s treatment use IND protocol is an “investigator'' under the protocol and must comply with applicable investigator responsibilities under the IND regulations and the human subjects and IRB regulations (21 CFR 50, 56, & 312).

Ver. 2 – 06/16/08 4) If the sponsor does not hold the IND, the licensed physician must apply for a Treatment IND. The application must contain: . a. A cover sheet (Form FDA 1571) b. Information (when not provided by the sponsor) on the drug's chemistry, manufacturing, and controls, and prior clinical and non-clinical experience with the drug. c. A statement of the steps taken by the practitioner to obtain the drug under a treatment protocol from the drug sponsor. d. A treatment protocol containing:  The intended use of the drug.  An explanation of the rationale for use of the drug.  A brief description of the criteria for patient selection.  The method of administration of the drug and the dosages.  A description of clinical procedures, laboratory tests, or other measures to monitor the effects of the drug and to minimize risk. e. A statement of the practitioner's qualifications to use the investigational drug for the intended treatment use. f. The practitioner's statement of familiarity with information on the drug's safety and effectiveness derived from previous clinical and non-clinical experience with the drug. g. Agreement to report safety information to FDA

5) Following treatment IND use of a test item, a follow-up report should be submitted to the sponsor or directly to the FDA, similar to that described for Single Patient or Small Group Use in Section B1A above. SAEs must be reported to either the sponsor or the FDA, and must be reported to the IRB.

B) Devices (Treatment IDE)

The treatment IDE regulations (21 CFR 812.36) parallel the treatment IND regulations and extend those provisions to cover treatment use of investigational devices.

1) The general criteria for treatment IDE use are the same as for treatment IND use (see B2A above). 2) Application information must include:

a. The name, address, and telephone number of the sponsor of the treatment IDE, b. The intended use of the device, the criteria for patient selection, and a written protocol describing the treatment use, c. An explanation of the rationale for use of the device, d. A description of clinical procedures, laboratory tests, or other measures used to evaluate the effects of the device and to minimize risk, e. Written procedures for monitoring the treatment use and the name and address of the monitor, f. Instructions for use for the device and all other labeling as required under 21 CFR 812.5a & b, g. Information that is relevant to the safety and effectiveness of the device for the intended treatment use. Information from other IDEs may be incorporated by reference to support the treatment use, h. A statement of the sponsor's commitment to meet all applicable responsibilities under 21 CFR 56 (Institutional Review Boards) and to ensure compliance of all participating investigators with the informed consent requirements of 21 CFR 50 (Protection of Human Subjects),

Ver. 2 – 06/16/08 i. An example of the agreement to be signed by all investigators participating in the treatment IDE and certification that no investigator will be added to the treatment IDE before the agreement is signed, and j. If the device is to be sold, the price to be charged and a statement indicating that the price is based on manufacturing and handling costs only.

3. Group C Treatment IND

The Group C mechanism was developed in the 1970s as a response to the lag time between the end of clinical trials that identified promising drugs and actual market availability of cancer drugs. The program began under a joint National Cancer Institute - Food and Drug Administration agreement. Drugs are categorized into group C by NCI application to FDA. The criteria are that the drug has reproducible efficacy in one or more specific tumor types and can be safely administered by trained physicians. Administration is according to a guideline protocol. Physicians wanting to use these drugs must register and submit an FDA Form 1572. The drug agents are obtained from the NCI. FDA has waived local IRB approval. Finally there are data submission requirements to allow the FDA to continue to collect data on the product. Group C products generally become available during Phase III and continue being available through marketing approval. The only Group C investigational drug currently available is 5-azacitidine for Refractory Acute Myelogenous Leukemia. For details see: http://ctep.cancer.gov/handbook/append_14.html

4. Parallel Track

The parallel track policy is a disease-specific form of expanded access. It is intended to make promising investigational drugs for AIDS and other HIV-related diseases available to individuals who have no therapeutic alternatives and who cannot participate in the controlled clinical protocols that are more widely available, and are essential to establish the safety and efficacy of a new drug. Such protocols are developed by the sponsor and filed as an IND supplement.

The determinants of patient eligibility include all of the following:

a) The patient has clinically significant HIV-related illness or is at imminent health risk due to HIV-related immunodeficiency. b) The patient cannot participate in the controlled clinical trails because:  The patient does not meet the entry criteria for the controlled clinical trials,  The patient is too ill to participate,  Participation in controlled clinical trials is likely to cause undue hardship as defined by the protocol, or  The controlled clinical trials are fully enrolled. c) The patient cannot take standard treatment because it is contraindicated, cannot be tolerated, or is no longer effective.

Access is available during FDA-approved phase 2 clinical trial protocols. Patient enrollment can be initiated prior to or simultaneously with availability under the parallel track protocol. Local IRB review is not required for parallel track protocols.

5. Continued Access

A) Continued IND Access - Drugs

The open label protocol method of providing expanded access has no formal regulation with patient eligibility criteria or a standard application. Open-label means that the patient and

Ver. 2 – 06/16/08 investigator know what product is being received. Sponsors, who intend to make unapproved products available after conclusion of a clinical trial, develop a treatment protocol with eligibility criteria that is submitted to the FDA for review and approval. Unlike standard trials these protocols are not blinded, are not placebo controlled, and do not use control groups. Although, they do not meet the standard required to substantiate a claim for marketing approval, they can be used to gather additional information on safety. These protocols require IRB review and approval.

B) Continued IDE Access - Devices

The final category of expanded device access is available when clinical investigations are concluded. As with open-label IND studies, there are no formal FDA regulations. FDA permits sponsors to continue to enroll subjects at a pre-determined rate while a marketing application is being prepared by the sponsor or reviewed by the FDA if there is:

1) A public health need for the device, and 2) If there is preliminary evidence that the device is likely to be effective and no significant safety concerns have been identified for the proposed indication.

A sponsor’s request for an extended investigation must be submitted in writing as an IDE supplement. A continued access clinical investigation must be conducted under the IDE, IRB, and Informed Consent regulations (21 CFR 812, 56, & 50, respectively).

6. Access to Orphan Drugs

The Orphan Drug Act defines an orphan disease as a condition that affects fewer than 200,000 persons in the United States. More than 5,000 of these rare conditions exist in about 20 million Americans, according to the National Organization for Rare Disorders (NORD). Because few if any pharmaceutical companies would "adopt" the products to treat these diseases in the days before the law, they became known as "orphans."

In accordance with 21 CFR 316.28 (http://www.fda.gov/Orphan/21cfr316.html), the FDA provides a cumulative list of all orphan drug designations available to the public and updates that list monthly. A list of all orphan products including the Approved Designation, the Sponsor, and the Sponsor’s Contact Information can be found at: http://www.fda.gov/orphan/designat/list.xls.

Note that orphan drugs with specified indications can only be used for those indications under a single patient IND (see Section B1 above). The sponsor should be contacted for instructions on how to obtain access to an orphan drug with an indicated use. Indicated treatment with an orphan drug is considered experimental, and as such this activity must be monitored like any other clinical trial. Thus, the use of an orphan drug for a specified indication must be approved by the FDA and the LBH IRB.

Ver. 2 – 06/16/08 Table 1: FDA Contacts Numbers for Emergency and Single-Patient Access. (Revised April, 2008)

Product Office/Division to Contact

Division of Drug Information Drug Products 301-796-3400 Office of Blood Research and Review Biological Blood Products 301-827-3518 Office of Vaccines Research Biological Vaccine Products 301-827-3070

Drugs & Biologics on Nights Office of Crisis Management & Emergency Operations and Weekends 301-443-1240

Emergency Operations - Office of the Center Director, CDRH Devices 240-286-3939

Program Operations Staff, ODE Compassionate Use Device 240-276-4040

FDA Office of Orphan Products Development Orphan Products 301-827-3666

Ver. 2 – 06/16/08 Open Label

Group C Treatment IND

Treatment IND

Single Patient - Small group

Parallel Track

IND Clinical Study

Emergency Use

PRE- IND IND MARKETING IND APPROVAL COMPLETION APPROVAL

Figure 1: Drug and biological products expanded access options and availability in reference to the IND clinical study and other milestones along the route to marketing approval.

Continued Access

Treatment Use

Single Patient - Small group IDE Clinical Study

Emergency Use

PRE- IDE IDE MARKETING IDE APPROVAL COMPLETION APPROVAL

Figure 2: Device expanded access options and availability in reference to the IDE clinical study and other milestones along the route to marketing approval.

Ver. 2 – 06/16/08