Guidance on IDE Policies and Procedures
This document is intended to provide guidance. It represents
the Agency's current thinking on the above. It does not create
or confer any rights for or on any person and does not operate
to bind the FDA or the public. An alternative approach may be
used if such approach satisfies the requirements of the applicable
statute, regulations, or both.
Comments and suggestions may be submitted at any time for Agency
consideration to the IDE Staff, HFZ-403, Office of Device Evaluation,
9200 Corporate Boulevard, Rockville, MD 20850. Comments may not
be acted upon by the Agency until the document is next revised
or updated. For questions regarding the use or interpretation
of this guidance contact the IDE Staff at (301) 594-1190. This
guidance replaces the guidance entitled, "Clarifications
of IDE Policies and Procedures" (September 13, 1991).
Additional Copies:World Wide Web/CDRH home page :http://www.fda.gov/cdrh
or CDRH Facts on Demand at 1-800-899-0381 or 301-827-0111, specify
number 882 when prompted for the document shelf number.
TABLE OF CONTENTS:
Chapter I General IDE Policies
Chapter III Expanded Access to Unapproved Devices 18
This document is intended to provide guidance1 to Office of Device
Evaluation (ODE) reviewers on issues frequently encountered during
the review of Investigational Device Exemptions (IDE) applications.
In the first chapter of this document, general issues pertinent
to the review of IDE applications are presented. This is followed
by a discussion in Chapter II of several new regulations which
affect the IDE Program. Finally in Chapter III, the four main
mechanisms by which unapproved devices may be made available
to patients faced with life-threatening or serious conditions
are discussed.
In some cases, rather than repeating information that has been
previously provided in ODE Blue Book Memoranda or other guidances,
only summary information is presented. Whenever possible, however,
specific procedures to be followed are identified, including references
to appropriate ODE Blue Book Memoranda and IDE boilerplate letters.
In order to facilitate the initiation of clinical trials under
the IDE regulation, the Food and Drug Administration (FDA) encourages
sponsors to begin communicating with the ODE reviewing division
prior to the submission of the original IDE application. This
communication may take the form of a "Pre-IDE" meeting
and/or a "Pre-IDE" submission.
Two types of pre-IDE meetings are possible: meetings in which
FDA provides "informal guidance" and meetings where
FDA provides "formal guidance" as provided for in Section
201 of the FDA Modernization Act of 1997.
Sponsors are encouraged to meet with the ODE reviewing division
before the IDE application is submitted for review so that the
reviewing division can provide any advice/guidance which can be
used in the development of supporting pre-clinical data or the
investigational plan for incorporation into the IDE application.
These meetings may take the form of telephone conference calls,
video conferences, or face-to-face discussions. Regardless of
the form of the pre-IDE meeting, all meetings should be recorded
by the ODE reviewing division and reported on a quarterly basis
to ODE senior management. Minutes of the meeting should include
the date of the meeting, the attendees, whether material was submitted
prior to the meeting for discussion/review by ODE staff, a summary
of the discussion, and any recommendations or guidance provided
by FDA.
A sponsor or applicant may submit a written request for a meeting
to reach an agreement with FDA regarding FDA's review of an investigational
plan (including a clinical protocol). As required by the statute,
this meeting should take place no later than 30 days after receipt
of the request. The written request should include a detailed
description of the device, a detailed description of the proposed
conditions of use of the device, a proposed plan (including a
clinical protocol) for determining whether there is a reasonable
assurance of effectiveness, and, if available, information regarding
the expected performance of the device.
If an agreement is reached between FDA and the sponsor or applicant
regarding the parameters of an investigational plan (including
a clinical protocol), the terms of the agreement should be put
in writing and made part of the administrative record by FDA.
Detailed procedures for implementing this new requirement will
be issued in the near future.
Sponsors are encouraged to submit pre-IDE submissions to the ODE
reviewing division while the sponsor is preparing a formal IDE
submission whenever the sponsor requires informal FDA guidance
on troublesome parts of the IDE application, e.g., clinical protocol
design, pre-clinical testing proposal, pre-clinical test results,
protocols for foreign studies when the studies will be used to
support future marketing applications to be submitted to FDA,
or other information.
Pre-IDE submissions are logged into the pre-IDE tracking system
by the Document Mail Center (DMC). After logging-in the document,
the DMC will jacket the submission in a white folder, attach a
tracking sheet, print an acknowledgment letter to the pre-IDE
sponsor, and forward the submission and letter to the appropriate
review division. The division should verify that the submission
belongs in their division and, after signing the acknowledgment
letter and placing a copy of it in the pre-IDE, mail the letter
to the sponsor.
Upon completion of the review of the pre-IDE submission, the division
is responsible for issuing a response to the sponsor in a timely
manner, usually within 60 days of receipt. The response may take
the form of a letter or comments provided during a meeting or
telephone conference call. If FDA's response is provided via
comments during a meeting or a telephone conference call, a memo
of the meeting or conference call should be prepared. The division
is responsible for ensuring that all memos, reviews, letters,
etc. are included in the jacketed file copy for documentation.
Upon completion of the review, the document should be returned
to the DMC for filing.
See Blue Book Memorandum#D95-1, entitled, "Goals and Initiatives
for the IDE Program" for additional guidance.
By communicating frequently with the regulated industry during
the IDE review process, rather than only at the completion of
the review, deficient information can be addressed within fewer
review cycles. This is of significant benefit to both industry
and ODE staff. Therefore, ODE reviewers, with the concurrence
of their supervisors, should feel free to use the telephone or
telefacsimile to aid in the interactive review process. Documentation
of this communication should be included in the IDE record, and
hardcopies of information transmitted by telefacsimile should
be logged into the IDE database.
See Blue Book Memorandum #D95-1 for additional guidance on the
interactive review process and the IDE Telefacsimile Policy.
As part of the IDE process, ODE staff reviews and approves sample
informed consent documents (ICDs). The sample ICD should comply
with 21 CFR 50 and be consistent with the approved protocol.
When reviewing an ICD, reviewers should ensure that the eight
basic elements identified in section 50.25(a) are adequately addressed,
but should recognize that each reviewing IRB routinely modifies
the language and format of the ICD to be consistent with their
institution's policies and requirements. Once FDA approves a
sample ICD, the sponsor is responsible for ensuring that the ICD
used at each participating institution includes the required informed
consent elements. If the IRB requires significant changes in
any of the required elements, the IDE sponsor should submit the
modified ICD to FDA for review and approval before using the document
at the institution. It is the sponsor's responsibility to determine
whether the changes warrant FDA review.
On occasion, after FDA has approved a sample ICD, the agency will
receive a modified version of the document, along with certification
of IRB approval. FDA should review the ICD to ensure that the
document still conforms with Part 50. If the document no longer
complies with the regulation, a letter should be issued acknowledging
IRB approval and describing how the ICD deviates from the sample
ICD already approved by FDA. The letter should also remind the
sponsor of his/her obligation to ensure that each ICD conforms
to the sample ICD already approved by FDA.
Under certain circumstances, FDA may require an IDE sponsor to
submit additional information within an established time period.
For example, an IDE sponsor is required to provide FDA with certain
additional information within 45-days of the date of a
conditional approval letter. An IDE sponsor is also required
to respond to FDA within 45-days of receiving notice of a deficient
progress report.
If a sponsor is not able to provide the requested information
within the established time period, a sponsor may request an extension
of time. Such a request should be submitted to FDA in writing
as an IDE supplement. FDA's approval of an extension request
may be oral or in writing, depending on the length of time requested.
FDA's approval of a request for up to 60 additional days may
be oral, i.e., handled in a telephone conversation. If FDA's
approval is oral, a memo of the conversation approving the request
should be included in the IDE file. FDA's approval of a request
for an extension of time beyond 60 days, however, should be in
writing. Extensions of more than 60 days are normally granted
for extenuating circumstances such as pre-clinical testing that
cannot be completed within the established time frame, or when
a United States (U.S.) sponsor cannot obtain the requested information
from a foreign entity within the established time frame.
The IDE regulation requires that the sponsor identify
the name and address of the monitor and provide written monitoring
procedures. While the IDE regulation does not specify the content
of the written monitoring procedures, the agency has published
a guideline (53 FR 4723, February 17, 1988) on acceptable approaches
to monitoring clinical investigations involving FDA-regulated
products. The Center for Devices and Radiological Health (CDRH)
has identified the following procedures that sponsors should follow
with respect to monitoring clinical investigations:
"Your application [does not include/includes only minimally acceptable] monitoring procedures. We have enclosed the FDA guideline (53 FR 4723, February 17, 1988) which presents acceptable approaches to monitoring clinical investigations. Your procedures may vary, but should be sufficient to assure the protection of the rights and safety of the subjects involved in the clinical investigation and the quality and integrity of the resulting data."
When FDA receives an IDE supplement requesting expansion
of a study from a sole investigator at a single site to
multiple investigators at either a single site or multiple sites,
the reviewer should assure the adequacy of the monitoring procedures.
In either situation, the reviewer should issue a deficiency letter
if written monitoring procedures were not included or were not
adequate in the IDE supplement.
ODE's policy on counting investigational sites is as follows:
For some IDE studies, however, participating institutions may
not have their own IRBs. Instead, one IRB may have oversight
responsibility for more than one participating institution. If
the same investigator is conducting the study at each institution
and the institutions are located in close proximity to the IRB,
these institutions may be counted as one site. If, however, additional
physicians are conducting the investigation and their use of the
device is not under the immediate direction of the investigator,
these physicians are considered investigators and these institutions
are counted as additional sites even though the sites are under
the same IRB.
NOTE: If one IRB assumes responsibility for more than one institution and the institutions are geographically separated, then each institution counts as one site. For example, if a California IRB has oversight of a study being conducted at both a California and New Jersey institution, this would count as two investigational sites.
As stated above, FDA does not have jurisdiction over clinical study sites located outside the U.S. As a result, sponsors may proceed at those sites at their own discretion. FDA, however,
encourages sponsors to follow a uniform protocol at the domestic
and foreign investigational sites.
Although FDA does not have jurisdiction over clinical study sites
located outside the U.S., FDA may accept, in support of a premarket
approval application (PMA), the data generated from such sites.
If the foreign clinical study was not conducted pursuant to the
IDE regulation, the PMA regulation requires that the PMA applicant
verify in the marketing application that the data generated from
the foreign study site(s) are valid and that the investigators
at the foreign site(s) conducted the study(ies) in accordance
with the "Declaration of Helsinki" or the laws and regulations
of the foreign country(ies), whichever afforded greater protection
to the human subjects. If the country's standards are used, the
PMA applicant should state in detail any differences between the
country's standards and the "Declaration of Helsinki"
and explain why the country's standards afforded greater protection
to the human subjects. (See 21 CFR 814.15)
In order for FDA to acknowledge a transfer in sponsorship of an
IDE, the following minimal information should be submitted by
the former sponsor as an IDE supplement:
The new sponsor should provide the former sponsor with the following
minimal information for inclusion in the IDE supplement:
If a new sponsor is correctly identified and the required information
is provided, FDA will acknowledge the change in sponsorship by
issuing IDE boilerplate G-41. If the above referenced minimal
information has not been submitted, FDA will issue IDE boilerplate
G-42 indicating that FDA is unable to acknowledge change of sponsorship.
In order to obtain complete documentation of the transfer of sponsorship,
the following information is required to be submitted by the new
sponsor. This information may be submitted in the original transfer
of sponsorship request or it may be submitted after FDA acknowledges
the transfer:
It should be noted that the IDE regulation does not permit foreign
entities to sponsor clinical studies in the U.S. (21 CFR 812.18(a)).
Therefore, if a non-U.S. sponsor is identified as the new sponsor
of the study, the supplement should be disapproved. Boilerplate
letter G-42A should be used when disapproving a supplement under
these circumstances.
As stated above, pursuant to 21 CFR 812.18(a), clinical studies
conducted in the U.S. cannot be sponsored by foreign entities.
Therefore, an IDE application cannot be approved in the absence
of a U.S. sponsor. If an original IDE application is submitted
from an entity outside the U.S., the application will be considered
incomplete until a U.S. sponsor is identified. Similarly, if
an IDE supplement is submitted for a proposed change in sponsorship
to a foreign entity, the supplement will be disapproved. See boilerplate
Letter G-42A.
The procedures for closing an IDE vary depending upon at what
point in the process the decision to close the IDE occurs. If
FDA has not yet approved the IDE, the sponsor may simply request
to withdraw their IDE from FDA review. If the sponsor submits
such a request, FDA will acknowledge the request by issuing boilerplate
G-39 and the IDE will then be considered closed. After this point,
if the sponsor decides to pursue an investigation of the device,
a new IDE would need to be submitted; however, the closed IDE
may be referenced in the new application.
If FDA has approved the IDE but no subjects have been enrolled,
the sponsor may still request withdrawal of their IDE. In this
case, however, the sponsor should state that no subjects had been
enrolled and account for all devices (i.e., state that no devices
were shipped or that all shipped devices have been returned, destroyed
or otherwise disabled).
Once subjects have been enrolled in the study, the sponsor should
not terminate the IDE until all enrolled subjects have completed
follow-up in accordance with the approved investigational plan.
The sponsor may cease enrollment in the study, but complete follow-up
should be obtained for all subjects already entered into the study.
Boilerplate G-35 may be used to acknowledge termination of subject
enrollment. This letter reminds the sponsor of the need to follow
all subjects in accordance with the investigational plan.
When follow-up is complete for all enrolled subjects, the sponsor
should submit a final report to FDA and all reviewing IRBs within
six months. The ODE Guidance entitled "Suggested Format
for IDE Final Report" outlines the information that should
be included in a final report. Boilerplate G-33 acknowledges
termination of the study and submission of the final report and
closes the IDE. Boilerplate G-34 is used when the final report
is inadequate and additional information is requested. The IDE
is not officially closed until the final report is complete.
It should be noted that the sponsor may reference a PMA or 510(k)
application to fulfill the IDE requirement for submitting a final
report. If the PMA or 510(k) application contains a summary of
the progress of the device investigation, the sponsor may submit
a letter to FDA stating that a marketing application has been
submitted and where the progress report can be located in the
marketing application (i.e., PMA or 510(k) number, date of submission,
volume and pages).
The bases for withdrawal of approval of an IDE are listed in 21
CFR 812.30(b). Due to the seriousness of this regulatory action,
ODE senior management and the IDE staff should be involved at
the earliest stages of consideration of this action. If it is
believed that withdrawal of approval of an IDE should be considered,
it should be ensured that the following actions precede
the actual issuance of a proposal to withdraw approval of the
IDE application:
If, after following the above procedures, the sponsor does not
provide a satisfactory response and it is determined that
no other regulatory mechanism will bring the sponsor into compliance
with the regulations, the reviewing division should draft a proposal
to withdraw approval of the IDE application. Note: This
determination is made by the reviewing division, IDE Staff and
ODE senior management. When issuing such a proposal, boilerplate
G-30, Proposing Withdrawal of Approval of an IDE Application,
should be used. As stated in 21 CFR 812.30(c)(2), the proposal
should include a complete discussion of the reasons for this action.
In accordance with this section, an IDE sponsor has the right
to request a regulatory hearing under Part 16, but should do so
within 10 working days of receipt of FDA's letter. If a hearing
is not requested, the sponsor has 30 days in which to respond
to the letter with their corrective action plan.
If the IDE sponsor does not request a regulatory hearing and the
sponsor's response to the proposed withdrawal letter does not
provide reasonable assurance that the corrective actions will
rectify the situation, FDA may proceed with the final order withdrawing
approval of the IDE. As with the proposal, the final order should
include a complete statement of the reasons for withdrawal. When
issuing a final order, boilerplate G-30A, Final Order Withdrawing
Approval of an IDE Application, should be used.
In the Fall of 1993, the IDE Staff and the division of Bioresearch
Monitoring (BIMO) agreed that the development of standard operating
procedures (SOPs) would help to maintain efficient and effective
communication between the two staffs and reduce the likelihood
of inconsistent actions by the two offices.
The ODE reviewing division should inform BIMO, by means of a memo
through the IDE staff, whenever the division:
See November 12, 1993, memo regarding SOPs for BIMO and IDE Staff Interactions for further guidance.
A manufacturer who wishes to export an unapproved device for investigational
use may export the device under section 801(e)(2) or 802(c) of
the act, depending on where, i.e., to what country, the device
is being exported. For instance, pursuant to section 801(e)(2)
of the act, an unapproved device intended for investigational
use may be exported to any country, if, in addition
to meeting the requirements of 801(e)(1) of the act, the exporter
submits information to FDA that would enable the agency to determine
that exportation is not contrary to the public health or safety
and that the foreign country approves of the exportation.
Section 801(e)(1) of the act provides that a device intended for
export should meet the following requirements: (1) complies with
the laws of the foreign country; (2) meets the foreign purchaser's
specifications; (3) is labeled for export on the shipping carton;
and (4) is not sold or offered for sale in domestic commerce.
Alternatively, in accordance with section 802(c) of the act, an
unapproved device intended for investigational use may be exported
to Australia, Canada, Israel, Japan, New Zealand, Switzerland,
South Africa or member countries of the European Economic Area
(EEA) without FDA authorization if the unapproved device
is exported in accordance with the laws of that country. Devices
being exported under 802(c) are not required to meet the requirements
of the IDE regulation, however, compliance with the basic export
requirements of 802(f) of the act and the recordkeeping requirements
in 802(g) of the act is required. As explained above, exportation
of an unapproved device for investigational use to any country
other than the countries identified above should be authorized
by FDA.
Manufacturers who wish to export unapproved medical devices either
for marketing or in anticipation of marketing approval by a foreign
entity, should consult with the Import/Export Staff, Office of
Compliance at (301) 594-4699.
This chapter summarizes the provisions of several new regulations
that affect the IDE Program. Guidance is available for Medicare
coverage of certain investigational devices (see below). In other
cases, guidance is being developed and will be issued in the near
future.
In the Federal Register of September 19, 1995 (60 FR 48417),
the Health Care Financing Administration (HCFA) announced that
it would consider for Medicare coverage certain devices with an
FDA-approved IDE that have been categorized as nonexperimental/investigational.
For the purposes of consideration for reimbursement under the
Medicare program, FDA categorized all FDA-approved IDEs into either
Category A (experimental) or Category B (nonexperimental/investigational).
Only those IDEs placed in Category B by FDA would be eligible
for Medicare coverage consideration. The final coverage decision,
however, will encompass other factors and thus will be made by
HCFA
As discussed in the FDA/HCFA Interagency Agreement, an experimental
(Category A) device refers to an innovative device believed to
be in Class III for which "absolute risk" of the device
type has not been established; i.e., initial questions of safety
and effectiveness have not been resolved, and FDA is unsure whether
the device type can be safe and effective. A nonexperimental/investigational
(Category B) device refers to a device believed to be in Class
I or II, or a device believed to be in Class III for which the
incremental risk is the primary risk in question; i.e., underlying
questions of safety and effectiveness of the device type have
been resolved, or it is known that the device type can be safe
and effective because, e.g., other manufacturers have obtained
FDA approval of that device type.
For those IDEs that are either approved or conditionally approved,
a HCFA categorization determination should be included in the
IDE letter to the sponsor. When determining the proper categorization
for an approved IDE, the reviewer should utilize the categorization
checklist found in IDE Boilerplate H-1. When a reviewer determines
that an IDE should be placed in Category A, the reviewer shall
obtain concurrence from his/her branch chief and the IDE Staff.
Alternatively, when a reviewer determines that an IDE should
be placed in Category B, concurrence from only the branch chief
is required.
The Health Care Financing Administration is to be copied on all
approval and conditional approval letters. The Document Mail
Center is responsible for ensuring that HCFA receives copies of
all such letters. In addition, new boilerplates have been developed
for reviewer use. These boilerplates are the HCFA Reimbursement
Checklist (H-1), described above; Reconsideration of HCFA Category
Determination (H-2); and Change of HCFA Reimbursement Category
(H-3). The latter two boilerplates should be used when responding
to a sponsor's request for reconsideration of a HCFA categorization
determination or when revising the original HCFA categorization
determination due to new information or approval of a similar
device, respectively.
For further guidance, see ODE Blue Book Memo #D95-2 entitled,
"Implementation of the FDA/HCFA Interagency Agreement Regarding
Reimbursement Categorization of Investigational Devices."
In the Federal Register of October 2, 1996 (61 FR 51498),
FDA issued a final rule amending its informed consent regulation
to harmonize with the Department of Health and Human Services'
(DHHS) policies on emergency research and to clarify when such
research can proceed without obtaining an individual subject's
informed consent. The purpose of the final rule is to permit
the study of potential improvements in the treatment of life-threatening
conditions where current treatment is unproven or unsatisfactory,
in order to improve interventions and patient outcomes. The final
rule was effective November 1, 1996.
FDA recognizes that persons with life-threatening conditions who
cannot either give informed consent or refuse enrollment are a
vulnerable population. The lack of autonomy and inability of
subjects to give informed consent requires additional protective
procedures in the review, approval, and operation of emergency
care research. Therefore, the exception from the informed consent
requirement permitted by the final rule is conditioned upon documented
findings by an institutional review board (IRB).
According to 21 CFR 50.24(a), an IRB may approve a clinical investigation
involving critical care research without requiring that informed
consent of the research subjects be prospectively obtained if
the IRB (with the concurrence of a licensed physician who is a
member of or consultant to the IRB and who is not otherwise participating
in the clinical investigation) finds and documents each of the
following:
Additional protections of the rights and welfare of the subjects
include:
The final rule applies to all clinical investigations involving
an exception from the informed consent requirements. Such research
should be performed under an investigational device exemption
(IDE) that is submitted and reviewed by FDA. Protocols that include
subjects who are unable to provide informed consent should be
submitted in a new IDE application even if an IDE for the device
already exists. The new application will need to reference the
existing IDE, contain a protocol for the clinical investigation
that includes a description of how the investigation proposes
to meet the conditions of this regulation and contain only the
study-specific information required by 21 CFR 812.20 and 812.25.
When an IDE application requesting a waiver from informed consent
for emergency research is received in the review division, the
reviewer should immediately notify the IDE staff that the division
received such an application. The IDE Staff will assist the division
with the review of the application to ensure that all applicable
safeguards have been satisfied and that all of the criteria identified
in the regulation (see above) have been adequately addressed before
the application can be approved.
The reviewing division should note that the IDE tracking sheets
include a field to indicate whether or not the original IDE application
included a request for exception from informed consent. It is
important that the division indicate on the tracking sheets if
an exception from informed consent was requested, so that ODE
can properly track these applications.
Finally, the regulation requires that the sponsor of the IDE submit
certain information from the IRB concerning the public disclosure
of the investigation to the community where the investigation
is to take place. This information is to be submitted to the
IDE and to Dockets Management (21 CFR 812.47(a)). The public
may request this information by submitting a request under the
Freedom of Information Act (21 CFR 812.38(b)(4)).
Further guidance on this regulation is under development by the
Agency.
In the Federal Register of November 5, 1996 (61 FR 57277),
FDA issued a final rule amending its informed consent regulation
(21 CFR Part 50) to:
In the Federal Register of March 14, 1997 (62 FR 12087),
FDA issued final provisions for the disqualification of clinical
investigators. These provisions apply to all cleared or approved
and pending device applications containing or relying upon clinical
investigations performed by disqualified investigators. Such
applications include IDEs, premarket notifications (510(k)s),
and PMAs.
Pursuant to the final rule, clinical investigator disqualification
proceedings may be initiated if FDA has information indicating
that the investigator has: (1) repeatedly or deliberately failed
to comply with the requirements of 21 CFR Parts 812, 50, or 56;
or (2) repeatedly or deliberately submitted false information
either to the sponsor of the investigation or in any required
report.
Upon disqualification, FDA shall examine each approved IDE and
each cleared 510(k) or approved PMA containing data reported by
an investigator who has been determined to be ineligible to receive
investigational devices, i.e., disqualified. The purpose of this
examination is to determine whether the investigator has submitted
unreliable data that are essential to the continuation of the
investigation or essential to the clearance/approval of the marketing
application.
If the Commissioner determines, after the unreliable data submitted
by the investigator are eliminated from consideration, that the
data remaining are inadequate to support a conclusion that it
is reasonably safe to continue the investigation, the Commissioner
will notify the sponsor, who shall have an opportunity for a regulatory
hearing under 21 CFR Part 16. Furthermore, if the Commissioner
determines, after the unreliable data submitted by the investigator
are eliminated from consideration, that the continued clearance
or approval of the marketing application for which the data were
submitted cannot be justified, the Commissioner will proceed to
withdraw approval or rescind clearance of the medical device in
accordance with the applicable provisions of the act and the agency's
regulations.
The Division of Bioresearch Monitoring, OC is preparing a guidance
document on this regulation.
Treatment use of investigational devices is addressed by a new
Treatment IDE regulation (21 CFR 812.36). This regulation parallels
the Treatment IND regulation, and in so doing, facilitates broader
availability of promising new therapeutic and diagnostic devices
to desperately ill patients as early in the device development
process as possible. Under this new regulation, patients faced
with a serious or life-threatening disease/condition for which
no alternative device exists may receive investigational devices
outside of the controlled clinical trial.
This regulation is discussed in detail in Chapter III under "Treatment
Use of Investigational Devices."
Section 201 of the FDA Modernization Act of 1997 requires FDA,
within one year of enactment of the new law, to establish regulations
to provide procedures and conditions that would allow certain
device or protocol changes to be made under an existing IDE without
requiring FDA approval of a supplement. Changes that would be
permitted without FDA approval are:
A change or modification as described above may be made if (i)
the sponsor of the investigation determines, on the basis of credible
information (to be defined by FDA) that the above applicable conditions
are met; and (ii) the sponsor submits to FDA, not later than 5
days after making the change or modification, a notice of the
change or modification.
The implementing regulation for this section of the law is currently under development.
According to the statute and FDA regulations, an unapproved medical
device may normally only be used on human subjects when the device
is under clinical investigation and when used by investigators
participating in the clinical trial. FDA recognizes, however,
that there may be circumstances under which a health care provider
may wish to use an unapproved device to save the life of a patient,
to prevent irreversible morbidity, or to help a patient suffering
from a serious disease or condition for which there exists no
other alternative therapy. Below is a discussion of the four
main mechanisms by which FDA may make unapproved devices available
to patients/physicians faced with circumstances such as those
described. These mechanisms are consistent with the Expanded
Access provisions of the FDA Modernization Act of 1997 (See section
561 of the Federal Food, Drug, and Cosmetic Act). FDA plans to
modify existing guidance in minor ways, as needed, to track the
language in the new law.
Procedures governing the emergency use of an investigational device
are covered in two separate documents: the IDE regulation (21
CFR Part 812) and FDA's "Guidance for the Emergency Use of
Unapproved Medical Devices," (hereinafter referred to as
the Emergency Use Guidance) which appeared in the Federal Register
of October 22, 1985 (50 FR 42866).
The IDE regulation recognizes that emergency situations may arise
in which there will be a need to use an investigational device
in a manner inconsistent with the approved investigational plan
or by a physician who is not part of the clinical study. Therefore,
the regulation permits deviations from the investigational plan
when necessary to protect the life or physical well-being of a
subject in an emergency. (See 21 CFR 812.35(a)). Prior approval
for shipment or emergency use of the investigational device is
not required, but the use should be reported to FDA by the IDE
sponsor via a supplement within 5 working days from the time the
sponsor learns of the use. The supplement should contain a summary
of the conditions constituting the emergency, the patient protection
measures that were followed (as discussed below), and patient
outcome information.
In addition to the IDE regulation, emergency use is also addressed
in an FDA guidance document. The Agency issued the Emergency
Use Guidance because the IDE regulation does not address emergency
use comprehensively (e.g., by not defining the term "emergency
use," identifying the patient protection measures that should
be followed in such situations, or addressing emergency use of
devices not covered by an IDE). This guidance defines an unapproved
medical device as a device that is utilized for a purpose, condition,
or use for which the device requires, but does not have, an approved
application for premarket approval under section 515 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 360e)(the act) or an approved
IDE under section 520(g) of the act (21 U.S.C. 360j(g)). As discussed
in the Guidance, an unapproved device should normally only be
used in human subjects if it is approved for clinical testing
under an IDE and if it is used by an investigator for the sponsor
in accordance with the terms and conditions of the application.
Emergency use of an unapproved device, however, may also occur
when: (i) an IDE for the device does not exist, (ii) when a physician
wants to use the device in a way not approved under the IDE, or
(iii) when a physician is not an investigator under the IDE.
The Emergency Use Guidance document was intended to address these
emergency situations. As stipulated in the guidance,
a physician who intends to treat a patient with an unapproved
medical device in an emergency situation should conclude that:
FDA expects the physician to make the determination that the patient's
circumstances meet the above criteria, to assess the potential
for benefit from the use of the unapproved device, and to have
substantial reason to believe that benefits will exist. In the
event that a device is used in circumstances meeting the criteria
listed above, the physician should follow as many patient protection
procedures as possible. Such patient protection procedures include
obtaining:
Although not provided for under this guidance, often times a physician,
who is faced with an emergency situation as described above, will
contact FDA to discuss his/her patient's condition. In this situation,
ODE acts in an advisory role, rather than in an approving role.
The ODE employee who receives the call should discuss the emergency
use criteria with the physician, but the responsibility for making
the decision as to whether the situation meets the emergency use
criteria and whether the unapproved device should be used lies
with the physician. If the physician decides to proceed with
the emergency use of the device, the ODE employee should advise
the physician of the above patient protection procedures to be
followed before the emergency use occurs and fill out the Emergency
Use Checklist. This checklist helps to ensure that the criteria
for emergency use have been met and that the physician has been
informed that he/she is expected to follow as many patient protection
procedures as possible. After discussing the situation with the
physician and completing the checklist, it should be filed in
the Emergency Use Report File located in the Program Operations
Staff.
After the emergency use occurs, the treating physician is responsible
for ensuring that certain follow-up procedures occur. If an IDE
exists for the device, the physician should provide the IDE sponsor
with sufficient patient follow-up information to allow the sponsor
to comply with the reporting requirements of the IDE regulation.
If no IDE exists, the physician should submit a follow-up report
on the use of the device to the IDE Staff. This report should
contain a summary of the conditions constituting the emergency,
patient protection measures that were followed, and patient outcome
information.
For more information on emergency use of investigational devices,
see 50 FR 42866 and 21 CFR 812.35(a).
As discussed above, the IDE regulation and the Emergency Use Guidance
address those situations in which an investigational or unapproved
device, respectively, is needed to save the life of a patient
or to prevent irreversible morbidity. FDA recognizes, however,
that there are circumstances in which an investigational device
is the only option available for a patient faced with a serious,
albeit not life-threatening condition (hereinafter referred to
as "compassionate use"). In these circumstances, FDA
uses its regulatory discretion in determining whether such use
of an investigational device should occur.
Unlike emergency use of an unapproved device, prior FDA approval
is needed before compassionate use occurs. In order to obtain
Agency approval, the sponsor should submit an IDE supplement requesting
approval for a protocol deviation under section 812.35(a) in order
to treat the patient. The IDE supplement should include:
The sponsor should not treat the patient identified in the supplement
until FDA approves use of the device under the proposed circumstances.
(IDE boilerplate G-16A has been developed for reviewers to use
when addressing this type of request.) In reviewing this type
of request, FDA will consider the above information as well as
whether the preliminary evidence of safety and effectiveness justifies
such use and whether such use would interfere with the conduct
of a clinical trial to support marketing approval.
If the request is approved, the attending physician should devise
an appropriate schedule for monitoring the patient, taking into
consideration the investigational nature of the device and the
specific needs of the patient. The patient should be monitored
to detect any possible problems arising from the use of the device.
Following the compassionate use of the device, a follow-up report
should be submitted to FDA as an IDE supplement in which summary
information regarding patient outcome is presented. If any problems
occurred as a result of device use, these should be discussed
in the supplement and reported to the reviewing IRB as soon as
possible.
The above compassionate use criteria and procedures can also be
applied when a physician wishes to treat a few patients rather
than an individual patient suffering from serious disease or condition
for which no alternative therapy adequately meets the medical
need. In this case, the physician should request access to the
investigational device through the IDE sponsor. The sponsor should
submit an IDE supplement that includes the information identified
above and indicates the number of patients to be treated. Such
a supplement should include the protocol to be followed or identify
deviations from the approved clinical protocol. As with single
patient compassionate use, a monitoring schedule should be designed
to meet the needs of the patients while recognizing the investigational
nature of the device. Follow-up information on the use of the
device should be submitted in an IDE supplement after all compassionate
use patients have been treated.
In the Federal Register of September 18, 1997 (62 FR 48940),
FDA established procedures to allow for the treatment use of investigational
devices. These procedures are intended to facilitate the availability
of promising new therapeutic and diagnostic devices to desperately
ill patients as early in the device development process as possible,
i.e., before general marketing begins, and to obtain additional
data on the device's safety and effectiveness. These procedures
apply to patients with serious or immediately life-threatening
diseases or conditions for which no comparable or satisfactory
alternative device, drug, or other therapy exists.
Under the final rule, treatment use of an investigational device will be considered when:
If a sponsor is considering submitting a treatment IDE, the sponsor
should consult with the appropriate review division in order to
determine if the device/indication would meet the criteria for
approval. Note that treatment IDEs are limited to those devices/indications
which meet the criteria defined above. According to 21 CFR 812.36,
requests for treatment use should be submitted as a supplement
to the existing IDE and should include:
As with all IDEs, treatment IDEs may begin 30 days after FDA receives
the application, unless FDA notifies the sponsor earlier than
30 days that the treatment use may or may not begin. The Agency
may approve the treatment use as proposed, approve it with modifications/conditions,
or disapprove it. FDA may withdraw approval of the treatment
IDE if it is determined that the above criteria are no longer
met.
In order to protect the rights, safety, and welfare of human subjects
involved in the clinical trial, while at the same time facilitating
the development of beneficial device therapies, FDA included certain
safeguards in the Treatment IDE process. Some of these measures
were already in place as part of the IDE regulation, while other
safeguards were specifically designed for treatment use. Safeguards
for this process include: the distribution of the device through
qualified experts; maintenance of adequate manufacturing facilities;
the submission of reports pursuant to 21 CFR 812.150; and compliance
with the regulations governing informed consent and institutional
review boards. Sponsors should review these sections of the regulation
when preparing a Treatment IDE application to ensure that these
issues are properly addressed.
When an IDE supplement requesting approval for treatment use is
received in the reviewing division, the reviewer should immediately
notify the IDE Staff. The IDE Staff will assist the division
with the review of the application to ensure that all applicable
safeguards have been satisfied and that all of the criteria identified
in the regulation (see above) have been adequately addressed before
the application can be approved. Three boilerplate letters are
available for responding to requests for treatment use: G-46
for approval, G-47 for conditional approval, and G-48 for disapproval.
ODE review divisions should note that the IDE tracking sheets
include a reason-for-submission code for Treatment IDE supplements.
It is important that the division indicate on the tracking sheets
that the application was a Treatment IDE, so that these applications
can be properly tracked.
The Treatment IDE regulation is effective on January 16, 1998.
For further guidance on Treatment IDEs, see the Federal Register
of September 18, 1997 (62 FR 48940) or contact the IDE Staff at
(301) 594-1190.
As discussed in ODE's Blue Book Memorandum entitled, "Continued
Access to Investigational Devices During PMA Preparation and Review,"
(hereinafter referred to as the Continued Access Policy) the sponsor
of a clinical investigation is permitted to continue to enroll
subjects while a marketing application is being prepared by the
sponsor and/or reviewed by the Agency if there is:
The continued enrollment of subjects in an investigation while
a marketing application is being prepared by the sponsor and/or
reviewed by ODE is known as an "extended investigation."
Extended investigations permit patients and/or physicians continued
access to the devices while also allowing the collection of additional
safety and effectiveness data to support the marketing application
or to address new questions regarding the investigational device.
The Continued Access Policy may be applied to any clinical investigation
that meets the criteria identified above; however, it is intended
to be applied late in the device development process, i.e., after
the controlled clinical trial has been completed.
A sponsor's request for an extended investigation should be submitted
as an IDE supplement and include the following information:
The reviewer should consider all of the above factors, in addition
to ODE's progress in the review of the marketing application,
when determining whether to approve, approve with modifications,
or disapprove the proposed request for the extended investigation.
The above factors should also be considered when determining
the appropriate rate of enrollment, the number of investigators,
and the number of investigational sites for the extended investigation.
A sponsor's past compliance with applicable FDA regulations should
also be considered when making these decisions. For example,
sponsors who have been negligent in their monitoring responsibilities
or who have other unresolved compliance problems would not be
permitted to participate in an extended investigation.
It is important to recognize that there is significant overlap
between the treatment IDE regulation and the Continued Access
Policy. As discussed in the preamble to the treatment IDE final
rule, both the Continued Access Policy and the treatment IDE regulation
are intended to provide additional access to an unapproved device,
once preliminary evidence regarding safety and effectiveness is
available to FDA. However, because a treatment IDE can be submitted
earlier in the IDE process, i.e., once promising evidence of safety
and effectiveness has been collected under the IDE but while the
clinical study is ongoing, it could provide access to a wider
group of patients at an earlier stage in the IDE process. The
treatment IDE regulation also has a more narrow application than
the Continued Access Policy in that treatment use is intended
to address only those patients who have an immediately life-threatening
or serious disease or condition whereas the Continued Access Policy,
which is applied after completion of the clinical trial, may be
considered for any clinical investigation.
For further information, see ODE Blue Book Memorandum #D96-1 entitled, "Continued Access to Investigational Devices During PMA Preparation and Review."
| Expanded Access Mechanism | Regulatory Authority | Criteria for Use | When Can It Be Used? | Number of Patients to be Treated | FDA Approval Needed? | How is FDA Approval Obtained? | Patient Protection Measures |
|---|---|---|---|---|---|---|---|
| Emergency Use | "Guidance for the Emergency Use of Unapproved Medical Devices"
50 FR 42866 | 1. Life-threatening condition‡; 2. No alternative; and 3. No time to obtain FDA approval. |
Before or after initiation of clinical trial | Limited to few patients | No; submit report to FDA following device use | Not applicable | 1. Independent assessment by uninvolved doctor; 2. IRB chairperson's concurrence; 3. Institutional clearance; and 4. Informed consent |
| Compassionate Use | 21 CFR 812.35(a) | 1. Serious disease or condition and 2. No alternative. |
During clinical trial | Individual patient or small groups of patients | Yes | IDE supplement with: 1. Explanation of circumstances constituting need for the device; 2. Reasons alternatives not acceptable; 3. Deviations from protocol, if any; and 4. Patient protection measures. | 1. Independent assessment by uninvolved doctor; 2. IRB chairperson's concurrence; 3. Institutional clearance; and 4. Informed consent. |
| Treatment IDE | 21 CFR 812.36 | 1. Life-threatening or serious disease; 2. No alternative; 3. Controlled clinical trial; and 4. Sponsor pursuing marketing approval. | During clinical trial | Wide access; depends on patient/physician need | Yes | Trt IDE supplement with: 1. Intended Use, protocol, and patient selection criteria; 2. Rationale for trt use 3. Methods used to evaluate device use and minimize risks; 4. Monitoring plan; 5. Summary of S&E data 6. Instructions for use and device labeling; 7. Commitment to patient protection; 8. Investigator agreement; and 9. Price, if will be sold. | 1. IRB approval and 2. Informed consent. |
| Continued Access | "Continued Access to Investigational Devices During PMA Preparation and Review" ODE Blue Book IDE Memorandum #D96-1 | 1. Public health need; or 2. Preliminary evidence that device will be effective and no significant safety concerns. | After completion of clinical trial | Same rate of enrollment as study | Yes | IDE supplement with: 1. Justification for extended study; 2. Summary of S & E data and risks posed by the device; 3. Proposed enrollment rate; 4. Clinical protocol; and 5. Progress towards marketing approval. | 1. IRB approval and 2. Informed consent. |
‡As a matter of practice, FDA has expanded the
criteria of "life-threatening condition" to include
serious conditions such as sight-threatening and limb-threatening
conditions as well as other situations involving risk of irreversible
morbidity.
For questions or further information regarding the above table, contact the
IDE Staff at (301) 594-1190.
Updated March 30, 1998
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