Review of IDEs for Feasibility Studies #D89-1 (blue book memo) (Text Only)

IDE Guidance Memorandum #D89-1

This guidance was written prior to the February 27, 1997 implementation of FDA’s Good Guidance Practices, GGP’s. It does not create or confer rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both. This guidance will be updated in the next revision to include the standard elements of GGP’s.

May 17, 1989




Review of IDEs for Feasibility Studies

The attached guidance details the purpose and procedure for the review
of IDE applications for feasibility studies involving limited numbers 
of human subjects. It was developed through review of a citizen 
petition submitted to the agency requesting amending the IDE 
regulation to provide for such studies, by review of ODE's procedures 
in reviewing early-phase studies, and from input from ODE Division 
Directors and other staff.  The concepts and procedures outlined in 
the guidance should be implemented immediately.

Attachment

ATTACHMENT

                      GUIDANCE ON THE REVIEW OF
         INVESTIGATIONAL DEVICE EXEMPTIONS (IDE) APPLICATIONS
                       FOR FEASIBILITY STUDIES


INTRODUCTION

On November 21, 1984, the American Society for Artificial Internal 
Organs (ASARIO) submitted a citizen petition requesting FDA to amend 
the investigational device exemptions (IDE) regulation to allow 
limited clinical investigations of significant risk devices to be 
subject to less than the full IDE requirements.  FDA may not be able 
to accept the petition in its entirety but recognizes the importance 
of providing flexibility in the review of IDE applications for 
feasibility studies, as long as the subjects' safety and welfare are 
ensured.  While CDRH has been exercising its discretion in the review 
and approval of feasibility studies, it has become apparent that this 
procedure needs to be formalized in order to be consistently applied 
by the reviewing divisions and to advise the research clinical 
community of these procedures.

It is relatively easy for a sponsor to identify a feasibility study by 
merely pointing out that the study involves a new device or a new 
technology and will involve only a few human subjects.  It is much 
more difficult to establish the criteria for relief from specific 
requirements of IDE regulation while assuring that patients are not 
placed at unreasonable risk.  Relief can only be granted on a 
case-by-case basis, and continual assessment and analysis of the 
review of feasibility studies is essential to developing more concise 
guidance.  This guidance document outlines principles which should be 
considered when reviewing IDE applications for feasibility studies.  
It is expected that application of these principles will facilitate 
the review and approval of feasibility studies, to the extent 
consistent with research subjects' safety and welfare and within 
ethical standards.

THE CONCEPT OF FEASIBILITY STUDIES

In a developmental process, a device is designed to meet a clinical 
need and testing begins in the laboratory using animal and/or bench 
methodology.  Once the design and operating parameters have been 
subject to adequate preclinical tests, the developer may wish to 
conduct an initial limited study in humans to confirm the design and 
operating specifications before beginning an extensive clinical trial.  
The initial study may indicate that minor or major changes in the 
device or its manufacture are necessary before proceeding.  It may 
also indicate that the device does not meet expectations and it will 
be terminated.  The performance of the device in the limited study 
serves to establish the parameters for the larger clinical study, such 
as sample size and indices of measurement. 

Inherent in the utility of the limited study is the importance of 
maintaining sufficient flexibility for the researcher to make 
adjustments in the device, its manufacture or the investigational plan 
in the early stages of clinical testing without the need for repeated 
prior FDA approval.

REVIEWER GUIDANCE

1.  APPLICABILITY

This guidance applies to limited clinical investigations of 
significant risk medical devices which are intended to provide data on 
the device's feasibility for diagnostic or therapeutic clinical use.  
IDE applications subject to the guidance are those which are 
identified by the sponsor as feasibility studies and which demonstrate 
that they meet the general considerations applicable to such studies 
as note below.  A feasibility study may also be identified as phase 1 
studies, pilot studies, prototype studies, introductory trials or 
feasibility studies, or which is characterized as a feasibility study 
from the objectives of the investigational plan.

2.  INTERACTIONS WITH SPONSORS

FDA encourages early and continued interactions with device innovators 
and potential IDE sponsor to establish a rapport which will expedite 
the review process.  Device technology is advancing rapidly and FDA 
must develop and nurture lines of communication in order to anticipate 
problems, training needs and other resources necessary to review 
applications.  The sponsor or researcher gains by being able to plan 
an acceptable preclinical and clinical approach to product 
development.  The sponsor and reviewer should also explore possible 
waivers that could be granted.

3.  GENERAL CONSIDERATION FOR ORIGINAL AND SUPPLEMENTAL IDEs

Original IDEs:  IDE applications for feasibility studies will vary in 
scope but typically will include one investigator at one site with a 
limited number of subjects, usually ten or less.  Data from the 
feasibility study will not be considered as pivotal evidence of safety 
and effectiveness but rather as a basis to finalize and confirm the 
device design and determine its potential for further development.  
FDA will continue to require that an IDE application for a feasibility 
study address all the elements of an IDE application unless a waiver 
is approved.

Generally, reviewers should focus their attention upon the device's 
potential risk to subjects.  Additional concerns, e.g., a rigorous 
examination of the investigational plan, may be delayed until the next 
phase of development where the study is designed to determine the 
device's safety and effectiveness.  The IDE regulation provides that 
an application may include anticipated changes to a device during
the course of an investigation.  For a feasibility study, FDA and the 
sponsor may employ this provision to qualify a range of device changes 
and testing parameters that can be undertaken by the sponsor without 
the need for further FDA approval.

Supplemental IDEs:  The IDE regulation provide that changes affecting 
the scientific soundness or the rights, safety and welfare of subjects 
need to be submitted to FDA for approval prior to implementation.  IRB 
approval is also required when the changes affect the rights, safety 
and welfare of subjects.  FDA and sponsors should use these criteria 
to the maximum extent possible to limit the type of changes needed to 
be submitted as supplements.  It is the sponsor's responsibility to 
determine whether a change meets the criteria.  All changes, whether 
major or minor or whether submitted as a supplement, should be 
described in progress reports, end-of-study reports and in request for 
expansion of the investigation.

4.  SPECIFIC IDE REQUIREMENTS AND CONSIDERATIONS

An IDE application for a feasibility study must address all the 
elements required by the IDE regulation unless a waiver is granted for 
a specific element.  Elements that are not relevant may be indicated 
as "not applicable."  Summary information, in lieu of full reports, is 
acceptable provided that the summary is sufficiently detailed and 
comprehensive to permit knowledgeable evaluation of the data.

Preclinical Studies:  It is the sponsor's, responsibility to define 
and conduct adequate tests to establish the lack of unreasonable risk 
and the expected performance of a device prior to clinical use.  A 
limited trial may represent the initial introduction of a device into 
a human population, therefore, FDA must be assured that a sufficient 
battery of tests have been completed.  It is the prerogative of the 
sponsor to indicate whether some preclinical tests (e.g., chronic 
toxicity) are not essential to early clinical studies and will be 
initiated only if the device will undergo further clinical study.

Investigational Plan:  The sponsor must include a thorough risk 
analysis which describes the risks to the subject, how they will be 
minimized and a justification that they are reasonable in relation to 
the expected benefits.  The scope and duration of limited studies will 
vary, but in general, are less ambitious than full clinical studies 
which provide the pivotal evidence of safety and effectiveness.  The 
investigational plan should have a valid scientific objective and 
reasonable study protocol.  Disapprovals should be limited to 
situations where there are critical safety-related concerns.  Other 
deficiencies can be corrected or clarified under a conditional 
approval decision.

Manufacturing and Control Data:  In some developmental programs which 
lead to feasibility studies, FDA recognizes that traditional 
manufacturing information may not exist.  As noted above, often 
devices do not proceed to further development if the early studies do 
not prove satisfactory and so only pilot manufacturing processes may 
be used. It is incumbent upon the sponsor to establish a reasonable 
process of design, manufacture, quality control and testing and to 
indicate to FDA in an IDE application where other standard procedures 
are unnecessary or premature.  FDA should tailor its deficiencies to 
the circumstances that exist and the stage of development.  Expanded 
clinical studies that may follow early studies may require additional 
assurances regarding manufacture and quality control as the numbers of 
devices to be distributed increase.  The conditional approval decision 
should be employed as much as possible.

Informed Consent:  Attention should be paid to the informed consent's 
description of the nature of the study, i.e., explanation of the 
purpose of the research, and indication that the subject is one of the 
first exposed to the device.

Other IDE Application Requirements:  All other aspects of IDE 
application for feasibility studies, including investigator agreement, 
IRB information, sales information, environmental impact statements 
and labeling should be evaluated under a conditional approval decision 
unless there are extentuating circumstances.

ANALYSIS OF FEASIBILITY STUDIES

ODE will conduct an analysis of the types of IDE applications being 
submitted for feasibility studies.  The purpose of this analysis is to 
determine whether the guidance is providing sufficient direction to 
reviewers and flexibility to researchers.  It will also further 
establish the nature and extent of feasibility studies.  The IDE Staff 
will collect the following information in their analysis: device type; 
objectives of the study; study design; number of investigators and 
sites; study sample size; duration of study; conclusions of the study; 
use of the data; percent of device types progressing to expanded 
trials; time to approval of studies and percent of approvals; percent 
of applications accepted without additional information; and waivers 
granted.

SUMMARY

The reviewer should remain cognizant of the following principles when 
examining IDE applications for feasibility studies:

    o    Focus the review on the risk/benefit ratio and place less emphasis 
         on the scientific thoroughness

    o    Open and maintain lines of communication with researchers 
         and sponsors to forestall problems

    o    Employ maximum flexibility, where appropriate

    o    Use conditional approval decisions to the fullest extent 
         when deficiencies exist

    o    Consult with the Program Operation Staff (POS) on 
         application of the guidance when necessary