Guidance for the Content of
Investigational Device
Exemptions for Solutions for
Hypothermic Flushing, Transport
and Storage of Organs for
Transplantation; Guidance for
Industry and FDA Reviewers
Document issued on January 16, 2001
U.S. Department Of Health and Human Services
Food and Drug Administration
Center for Devices and Radiological Health
Gastroenterology and Renal Devices Branch
Division of Reproductive Abdominal and Radiological Devices
Office of Device Evaluation Preface
Public Comment
Comments and suggestions may be submitted at any time for Agency consideration to
Dockets Management Branch, Division of Management Systems and Policy, Office of
Human Resources and Management Services, Food and Drug Administration, 5630
Fishers Lane, Room 1061, (HFA-305), Rockville, MD, 20852.    When submitting
comments, please refer to the exact title of this guidance document.  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 Kathy Olvey, 
Gastroenterology and Renal Devices Branch, 9200 Corporate Boulevard, HFZ-470, 
Rockville, MD, 20850 or by email at kathleen.olvey@fda.hhs.gov.
Comments may not be acted upon by the Agency until the document is next revised or
updated.
Additional Copies
Additional copies are available from the Internet at:
http://www.fda.gov/cdrh/ode/guidance/1164.html, or CDRH Facts-On-Demand.  In
order to receive this document via your fax machine, call the CDRH Facts-On-Demand
system at 800-899-0381 or 301-827-0111 from a touch-tone telephone.  Press 1 to
enter the system.  At the second voice prompt, press 1 to order a document.  Enter the
document number 1164 followed by the pound sign (#).  Follow the remaining voice
prompts to complete your request. Guidance for the Content of
Investigational Device Exemptions for
Solutions for Hypothermic Flushing,
Transport and Storage of Organs for
Transplantation; Guidance for Industry
and FDA Reviewers
This document is intended to provide guidance.  It represents the Agencys current
thinking on the above.  It does not create or confer any 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 and regulations.
INTRODUCTION
This guidance is based on 1) current scientific knowledge, 2) clinical experience, 3) previous
submissions by manufacturers to the FDA, 4) the Safe Medical Devices Act of 1990, 5) the
FDA Modernization Act of 1997 and FDA regulations in the Code of Federal Regulations
(CFR).  As advances are made in science and medicine, and as changes occur in
implementation of congressional legislation, these review criteria will be re-evaluated and revised
as necessary.
General information regarding IDEs is provided in 21 CFR Part 812 as well as in the FDA
Investigational Device Exemptions Manual, and in a guidance document titled, Guidance of
IDE Policies and Procedures.  These documents are available from the Division of Small
Manufacturers Assistance (DSMA) at (800) 638-2041 or on the internet at
http://www.fda.gov/cdrh/manual/idemanul.html and http://www.fda.gov/cdrh/ode/idepolcy.html,
respectively.
This document addresses solutions designed for flushing, transport and preservations of whole
organs, including the kidney, liver, pancreas, heart and lung.  It does not address solutions for
preservation of the cornea, nor does it address the preservation of tissues (e.g., bone, cartilage,
bone marrow, etc.) or cells (including pancreatic islet cells). It does not address machines
designed for perfusion of donor organs. Further guidance may be obtained through pre-IDE submission or meetings with the FDA.  The
FDA encourages all sponsors to arrange a pre-IDE meeting or teleconference whenever
possible.
LEAST BURDENSOME APPROACH
The issues identified in this guidance document represent those that we believe need to be
addressed before your device can be approved/cleared for marketing.  In developing the
guidance, we carefully considered the relevant statutory criteria for Agency decision-making.
We also considered the burden that may be incurred in your attempt to comply with the
guidance and address the issues we have identified.  We believe that we have considered the
least burdensome approach to resolving the issues presented in the guidance document.  If,
however, you believe that information is being requested that is not relevant to the regulatory
decision for your pending application or that there is a less burdensome way to address the
issues, you should follow the procedures outlined in the A Suggested Approach to Resolving
Least Burdensome Issues document.  It is available on our Center webpage at:
http://www.fda.gov/cdrh/modact/leastburdensome.html
In addition to the information described in the general IDE guidance documents listed above, the
FDA recommends that all IDEs for these products contain the information described on the
following pages.
I.  DEVICE DESCRIPTION
A complete description of the solution should be provided.  The description should
address each of the following issues.
A.  A listing of the chemical composition of the solution (including supplier and
amounts) should be provided.  All chemical components should be United
States Pharmacopoeia (USP) grade. If not, adequate justification should be
provided to demonstrate that the chemicals possess sufficient purity for use in
this product.
B.  An explanation of the purpose of each chemical component, (e.g., prevention of
swelling, metabolic support, etc.) should be given.
C.  The description should explain how the solution is to be used (e.g., for perfusion
or static storage), highlighting any unusual features.
D.  A description of the manufacturing process, including the method of sterilization,
should be provided.  The sterility assurance level and the results of sterility (i.e.,
endotoxin and bacteria) testing for at least one batch of product should be
submitted.
2 E.  A complete description of the packaging material should be provided.  The
packaging material should be appropriate for this intended use (i.e., blood or
tissue contacting) therefore, biocompatibility testing as described in CDRH Blue
Book memorandum G95-1, Use of International Standard ISO-10993-1,
Biological Evaluation of Medical Devices Part-1:  Evaluation and Testing
should be provided.  In lieu of biocompatibility testing, the sponsor may identify
a legally marketed product that uses the exact material for a similar intended
use.
II.  REPORTS OF PRIOR INVESTIGATIONS
IDEs for these products will typically require bench and animal testing prior to beginning
a clinical study.  Guidance for these tests is provided below.
A.  Bench testing should address the stability of the product under both proper
storage and worst-case conditions.  A combination of real-time and accelerated
test results may be acceptable for the IDE, however, real-time storage data
should be submitted in any marketing application for these products.  The
stability testing should include analysis of all chemical constituents and any
degradation products, measurement of particulate and assessment of sterility
(bacteria and endotoxin) after storage for specified time periods.  With regard
to particulate, the solutions should meet USP specifications for large volume
parenteral solutions.
B.  Animal testing will normally be necessary to demonstrate the safety of the
solution and, possibly, to establish the appropriateness of surrogate endpoints
that may be used in the clinical trial.  Separate animal studies will normally be
necessary to demonstrate adequate preservation for each type of organ to be
studied in the proposed clinical trial.
A complete description of the animal tests should be provided and should
address the issues below.
1.  A justification for the selected animal model should be provided,
especially with regard to its relevance to the ultimate clinical use of the
product.  Although exploratory studies may be performed using a small
animal model (e.g., mice), it is highly recommended that confirmatory
studies be performed with a larger animal model (e.g., rabbits, pigs or
dogs) to more closely approximate the expected clinical conditions.
2.  Provide an explanation of specific organ performance parameters that
will be evaluated, as well as a justification for their relevance in
determining the safety and effectiveness of the proposed solution.
3 3.  The investigational product should be tested against a control solution.
It is recommended that the control be a solution that is widely used for
preservation of the organ in question.
4.  The results should be summarized in tabular and graphical format, with
statistical analysis as appropriate.
C.  Any clinical data obtained with the product, either in the U.S. or at foreign sites,
should be supplied. If the data are described in literature articles, these should
be provided.  Foreign sites do not require IDE approval and are not required to
be included in the IDE application, except as prior information to support the
safety of the product or the applicability of the statistical analysis plan.
However, clinical data obtained at foreign sites may be submitted in the
marketing application as part of the primary data set.  It is helpful for future
marketing applications if the foreign sites use the same clinical protocol as the
IDE study.
D.  A bibliography of all publications, whether adverse or supportive, that are
relevant to an evaluation of the safety or effectiveness of the device should be
provided along with copies of all published or unpublished adverse information.
III.  INVESTIGATIONAL PLAN
A complete description of the investigational plan should be provided.  As noted above,
general recommendations on the content of IDE submissions is provided in the guidance
documents referenced above.  The following recommendations are provided in addition
to the recommendations given in the general IDE guidance document.
The FDA strongly recommends that organ preservation solutions be studied in a multi-
center, prospective, randomized, controlled trial.  The control solution may be the
solution currently in use at the investigational site (i.e., heterogeneous control) or the
sponsor may select an appropriate control solution for all of the investigational sites
(homogeneous control).
Data from foreign sites will be considered in any marketing application for this product.
However, the data should be complete and should address all of the considerations
outlined below.  The FDA believes that it would be appropriate to include data from at
least one U.S.  investigational site in the marketing application, due to differences in
clinical practice and patient outcomes between the U.S. and foreign transplantation
centers.
In general, the number of patients and the number of sites should be determined using
appropriate statistical analyses.  However, the FDA recommends that the study include
4 at least three sites in order to capture potential differences among transplantation
centers.  The investigational plan should address the following:
A.  Purpose of the Investigation
The purpose of the investigation should be provided.  The sponsor should state
whether they intend to demonstrate equivalence or superiority to the control
solution.  The sponsor should also state whether the organ preservation times
are to be consistent with current clinical practice or if a claim of extended
preservation time is desired.
B.  Clinical Protocol
The clinical protocol should be described in detail, and should address the
number of patients, the number of investigational sites, and the control solution
to be utilized at each site (including the chemical composition).  A complete
listing of the inclusion/exclusion criteria should be provided, as well as the
reasons for removal of the patients from the study or for termination of the
study.
A description of the study endpoints should be given.  The FDA recommends
that the primary endpoint be 7 day patient survival for organ preservation
solutions for the heart, lung and liver (specifically, 7-day ventilator or ECMO-
free survival for lungs).  The primary endpoint should be 7 day graft survival for
solutions intended for preservation of the kidney.
In all cases, 30 day follow-up is strongly recommended, and 30 day survival
should be tabulated and analyzed as a secondary endpoint.  Additional
secondary endpoints should be chosen to appropriately represent target organ
function.  For example, appropriate secondary endpoints for heart preservation
solutions include cardiac index, wedge pressure, need for inotropic drugs,
biopsy results and time in ICU.  Appropriate secondary endpoints for kidney
solutions are post-transplant creatinine and blood urea nitrogen (BUN) levels,
histologic evidence of ATN, as well as need for post-transplant dialysis.
The protocol should address the expected preservation time for the organs.
Studies designed to support claims of extended preservation time raise
additional issues.  Contact FDA to discuss these issues, if appropriate.
Regardless of the intended claim, preservation times should be recorded for all
organs in both the treatment and control groups.
5 C.  Statistical Plan
A complete description of the statistical plan should be provided.  The plan should
address the sample size, proposed randomization scheme, proposed interim
analysis and early stopping procedures (if applicable), poolability of the data and
proposed analytical methods.  Additional guidance on statistical methods for
evaluation of clinical trial data is provided in Statistical Guidance for Clinical
Trials of Non-Diagnostic Medical Devices.  A copy is available from DSMA or
on the CDRH webpage at http://www.fda.gov/cdrh/ode/odeot476.html.
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