Download Expanded Access For An Unapproved Drug

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.
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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)
2)
3)
4)
Obtain independent assessment by an uninvolved physician,
Obtain informed consent from the patient or a legal representative,
Notify the Institutional Review Board (IRB), and
Obtain authorization from the IDE holder, if an approved IDE exists.
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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:
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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
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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.
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
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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).
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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),
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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
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
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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.
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Table 1: FDA Contacts Numbers for Emergency and Single-Patient Access. (Revised
April, 2008)
Product
Office/Division to Contact
Drug Products
Division of Drug Information
301-796-3400
Biological Blood Products
Office of Blood Research and Review
301-827-3518
Biological Vaccine Products
Office of Vaccines Research
301-827-3070
Drugs & Biologics on Nights
and Weekends
Office of Crisis Management & Emergency Operations
301-443-1240
Emergency Operations Devices
Office of the Center Director, CDRH
240-286-3939
Compassionate Use Device
Program Operations Staff, ODE
240-276-4040
Orphan Products
FDA Office of Orphan Products Development
301-827-3666
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Open Label
Group C Treatment IND
Treatment IND
Single Patient - Small group
Parallel Track
IND Clinical Study
Emergency Use
PREIND
IND
APPROVAL
IND
COMPLETION
MARKETING
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
PREIDE
IDE
APPROVAL
IDE
COMPLETION
MARKETING
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.
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