Guidance for Resorbable Adhesion 
Barrier Devices for Use in 
Abdominal and/or Pelvic Surgery; 
Guidance for Industry 
 
 
 
Document issued on:  June 18, 2002 
 
 
 
This document supersedes Guidance for Resorbable Adhesion Barrier Devices for 
Use in Abdominal and/or Pelvic Surgery, published on December 16, 1999.  
 
 
 
 
 
 
 
 
 
U.S. Department Of Health and Human Services 
Food and Drug Administration 
Center for Devices and Radiological Health 
  Office of Device Evaluation 
 
Plastic and Reconstructive Surgery Devices Branch 
Division of General, Restorative and Neurological Devices 
and 
Obstetrics and Gynecology Devices Branch 
Division of Reproductive, Abdominal and Radiological Devices 
 
    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 Docket No. 
99D-5199 and 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 Elaine Blyskun at 
301-796-6533 or by email at elaine.blyskun@fda.hhs.gov
. 
 
Additional Copies 
 
Additional copies are available from the Internet at:  
http://www.fda.gov/cdrh/ode/guidance/1356.pdf, 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 (1356) followed by the pound sign (#).  Follow the remaining voice prompts to 
complete your request. 
 
 
 
 
 
    Table of Contents 
 
BACKGROUND ............................................................................................................................ 1 
GENERAL IDE REQUIREMENTS FOR ADHESION BARRIERS (21 CFR 812) .................... 2 
GENERAL PMA REQUIREMENTS FOR ADHESION BARRIERS (21 CFR 814) .................. 3 
PRECLINICAL DATA .................................................................................................................. 4 
I.  DEVICE DESCRIPTION................................................................................................... 4 
II.  CHEMISTRY...................................................................................................................... 4 
III.  ANIMAL TESTING........................................................................................................... 5 
A.  Toxicology/Biocompatibility Studies.............................................................................5 
B.  Pharmacokinetics Studies...............................................................................................7 
C.  Effectiveness Studies......................................................................................................7 
IV.  PHYSICAL AND MECHANICAL TESTING.................................................................. 8 
V.  MANUFACTURING......................................................................................................... 8 
A.  Product Characterization.................................................................................................8 
B.  Final Product Specification.............................................................................................8 
C.  Product Expiration Dating..............................................................................................9 
D.  Device Applicator...........................................................................................................9 
E.  Sterilization.....................................................................................................................9 
F.  Pyrogenicity Testing.....................................................................................................11 
CLINICAL INVESTIGATIONAL PLAN ................................................................................... 11 
I.  INTRODUCTION ............................................................................................................ 11 
II.  INTENDED USE.............................................................................................................. 12 
III.  FEASIBILITY STUDIES ................................................................................................. 12 
IV.  PIVOTAL STUDIES ........................................................................................................ 13 
A.  Purpose of Study...........................................................................................................13 
B.  Study Hypothesis ..........................................................................................................13 
C.  Endpoints......................................................................................................................14 
D.  Assessment Tools..........................................................................................................15 
E.  Important Assessment Considerations..........................................................................16 
F.  Study Design.................................................................................................................17 
G.  Statistical Methods........................................................................................................18 
    H.  Case Report Forms........................................................................................................21 
I.  Device Applicators........................................................................................................21 
J.  Informed Consent..........................................................................................................22 
K.  Post approval Studies....................................................................................................22 
L.  Special Considerations..................................................................................................22 
V.  RISK/BENEFIT ANALYSIS ........................................................................................... 23 
VI.  LABELING....................................................................................................................... 23 
A.  Indications for Use........................................................................................................24 
B.  Contraindications..........................................................................................................24 
C.  Warnings/Precautions ...................................................................................................24 
D.  Adverse Events.............................................................................................................24 
E.  Clinical Studies.............................................................................................................25 
F.  Instructions for Use.......................................................................................................25 
REFERENCES ............................................................................................................................. 25 
     
Guidance for Resorbable Adhesion Barrier 
Devices for Use in  Abdominal and/or Pelvic 
Surgery; Guidance for Industry 
 
This document is intended to provide guidance.  It represents the Agencys current 
thinking on this topic.  It does not create or confer any rights for or on any person and 
does not operate to bind the Food and Drug Administration (FDA) or the public.  An 
alternative approach may be used if such approach satisfies the requirements of the 
applicable statute and regulations. 
 
BACKGROUND 
This guidance document discusses the development of preclinical and clinical information for an 
Investigational Device Exemption (IDE), Premarket Approval (PMA), or Product Development 
Protocol (PDP) application for a resorbable adhesion barrier product for use in the abdominal 
and/or pelvic cavity.  This document provides guidance for the preparation of an IDE application 
and for the development of valid scientific evidence to support PMA applications for adhesion 
barriers that are resorbed within 30 days of placement into the peritoneal/pelvic cavity.   
 
FDA has determined that the resorbable adhesion barrier is a significant risk device as defined in 
21 CFR 812.3(m)(4).  The resorbable adhesion barrier is a class III device which is subject to 
premarket approval in accordance with section 515 of the Federal Food, Drug, and Cosmetics 
(FD&C) Act.  
 
This guidance document is based upon FDAs analysis of published scientific information, 
interaction with manufacturers, and input from FDAs Medical Device Advisory Committees 
(General and Plastic Surgery Devices Panel and the Obstetrics and Gynecologic Devices Panel).  
It is the product of a collaborative effort between the Plastic and Reconstructive Surgery Devices 
Branch (PRSB) in the Division of General Restorative and Neurological Devices (DGRND), and 
the Obstetrics and Gynecology Devices Branch (OGDB) in the Division of Reproductive, 
Abdominal, and Radiological Devices (DRARD).  We encourage you to submit comments at any 
time.  Please see the Preface of this document for instructions on submitting your comments.  
 
Applications with primarily gynecologic indication(s) will be reviewed primarily by OGDB.  
Applications with more general abdominal indication(s) will be reviewed primarily by PRSB.  
Regardless which branch takes the lead role, there will be collaboration and consultation between 
the two branches.  Appropriate reviewers from the Office of Device Evaluation (ODE), Office of 
Science and Technology (OST), Office of Surveillance and Biometrics (OSB), and Office of 
Compliance (OC) will participate in the review.  Consultation from the Center for Drug 
Evaluation and Research (CDER) and/or the Center for Biologics Evaluation and Research 
(CBER) and appropriate device advisory panel members may be necessary depending on the 
product, indication(s) for use, conditions of use, and surgical models. 
 
This guidance document provides a framework specific to the development of preclinical and 
clinical information for these devices.  It is designed to be used in conjunction with other FDA 
    1   
publications on IDE, PMA, and PDP applications.  We cannot anticipate all of the issues related 
to individual products in a guidance document.  Therefore, we encourage you to consult with 
FDA as early as possible in planning your product development.   
 
The Least Burdensome Approach 
 
The issues identified in this guidance document represent those issues that we believe need to be 
addressed before your device can be marketed.  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 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 web page at: 
http://www.fda.fgov/cdrh/modact/leastburdensome.html.  You may send your written comments to 
the contact person listed in the preface to this guidance or to the CDRH Ombudsman.  
Comprehensive information on CDRH's Ombudsman, including ways to contact him, can be found 
on the Internet at:  http://www.fda.gov/cdrh/resolvingdisputes/ombudsman.html. 
 
GENERAL IDE REQUIREMENTS FOR ADHESION BARRIERS (21 CFR 812) 
FDA has determined this device is a significant risk device as defined in 21 CFR 812.3(m)(4) 
and, therefore, studies involving these devices do not qualify for the abbreviated IDE 
requirements of 21 CFR 812.2(b).  In addition to the requirement of having an FDA-approved 
IDE, sponsors of such trials must comply with the regulations governing institutional review 
boards (21 CFR 56) and informed consent (21 CFR 50). 
 
Clinical evaluation of significant risk devices requires an approved Investigational Device 
Exemption (IDE) application in addition to IRB approval.  The FD&C Act authorizes the FDA to 
exempt these devices from certain requirements of the Act that would apply to devices in 
commercial distribution.  The exemption allows devices intended solely for investigational use to 
be shipped for use on human subjects during a clinical study. 
 
An IDE application must, at a minimum, include the following elements:  
 
  name of the device 
  device description 
  intended use 
  report of prior investigations 
  preclinical safety and effectiveness information 
  chemistry 
  animal testing for safety and effectiveness 
  physical, mechanical, and reliability testing 
  manufacturing 
  clinical plan 
  purpose and objectives 
  study hypothesis 
    2   
  protocol 
  patient population 
  statistical considerations 
  risk/benefit analysis 
  product handling and storage information 
  investigator information 
  institutional review board (IRB) information 
  sales information 
  informed consent 
  environmental impact 
  other, e.g., case report forms 
  labeling. 
 
See 21 CFR 812 for these and additional IDE requirements. 
 
GENERAL PMA REQUIREMENTS FOR ADHESION BARRIERS (21 CFR 814) 
A PMA application must contain the following basic elements: 
 
  name and address of applicant 
  table of contents 
  summary of safety and effectiveness: 
  indications for use 
  device description 
  alternative practices 
  marketing history 
  summary of studies (non-clinical and clinical) 
  conclusions drawn from studies 
  complete description of: 
  device 
  components 
  properties relevant to adhesion prevention 
  principles of operation 
  manufacturing 
  conformity to any applicable standards 
  data 
  non-clinical 
  clinical 
  bibliography 
  labeling 
  environmental assessment, unless the device qualifies for an exemption 
  financial disclosure. 
 
See also CFR 814.20 for additional information on these and other PMA requirements. 
 
    3   
PRECLINICAL DATA 
I.  DEVICE DESCRIPTION 
This section should identify the essential physical characteristic of the subject device, e.g., film, 
gel, solution.  You should provide a detailed description of all features of the device, including 
the name of the device; physical dimensions (describe all sizes if applicable); all components; 
physical, chemical, and biologic properties; the mechanism(s) of action; and information 
regarding resorption and/or metabolism.  You should also include a discussion of the scientific 
basis (physical/biologic plausibility), which supports the development of this product for this 
indication, with relevant scientific literature. 
 
II. CHEMISTRY 
 
A.  You should describe all material components of the device.  Such information should 
identify the source and purity of each component.  You may supply the information 
by reference to a Master File(s), if you include the appropriate letter of cross-
reference.  Submission of a Certificate(s) of Analysis and/or a Materials Safety Data 
Sheet(s) (MSDS) can also greatly simplify review of components not commonly used 
in medical devices.   
 
B.  If collagen or other animal material is a device component, the application should 
identify the species and tissue from which the animal material was derived and the 
specific type of collagen or other material.  See also the sterilization section below, on 
materials from animal sources, and the guidance document Medical Devices 
Containing Materials Derived from Animal Sources (Except for In Vitro Diagnostic 
Devices) at:  http://www.fda.gov/cdrh/ode/88.html. 
 
C.  You should submit the following information for each material/component in the 
device:   
 
  chemical name, chemical abstracts service number 
  trade name 
  structural formula and molecular weight 
  if the material is polymeric, you should provide the molecular formula, a 
measure of the average molecular weight, and the molecular weight distribution.  
FDA recommends measurement by gel permeation chromatography, but other 
techniques may be used 
  if the product is solid, you should provide weight and dimensions per product 
unit 
  if the product is liquid, you should provide weight, viscosity, color, and pH. 
 
D. You should perform chemical characterization of each material to assess incoming 
material characteristics.  The quality of the materials should be monitored for 
appearance, viscosity, average molecular weight, pH, organic volatile impurities, and 
    4   
particulate matter as appropriate.  You should list the incoming raw material 
specifications along with the test methods and appropriate limits of acceptance.   
 
E.  You should present the chemical formulation and manufacturing information in a 
step-by-step process, from the starting materials to final products.  This should 
include all non-reactants and reactants (including catalysts, curing agents, and 
intermediate precursors) for all device components.  You should include analyses of 
the copolymer content, when applicable, to establish the consistency of the product. 
 
F.  You should describe the finished sterilized device including the components and 
composition.  You should document analytical tests and acceptance specifications 
with data from at least three lots compared and reported to demonstrate control over 
the manufacturing process.   
 
G. Residual chemicals are a concern whether they are present as raw materials, as 
processed products of raw materials, or are introduced in any way during the 
manufacturing process.  To address this concern, you should extract the final 
formulated sterilized product in both polar and non-polar solvents.  You should 
measure potential toxic contaminants by a sufficiently sensitive method, such as High 
Performance Liquid Chromatography.  You should also measure volatile and non-
volatile residuals. 
 
H. You should describe any unique characteristics of the device in sufficient detail using 
objective (quantitative) measures that will allow the reviewer a clear understanding of 
these unique characteristics.   
 
III.   ANIMAL TESTING 
A.  Toxicology/Biocompatibility Studies 
 
The preclinical toxicology/biocompatibility studies should follow the ISO 10993-1: 
1992 Guidelines, Biological Evaluation of Medical Devices- Part 1:  Evaluation and 
Testing, that recommends the six standard tests listed below for implanted devices that 
contact tissue for 24 h to 30 days with blood contact. 
 
1.  cytotoxicity 
2.  sensitization 
3.  irritation or intracutaneous reactivity 
4.  systemic toxicity 
5.  genotoxicity (ames reverse mutation, chromosomal aberration, and mouse 
lymphoma forward mutation) 
6.  subchronic implantation and toxicity 
 
The subchronic implantation study duration should mimic the proposed use of the material. 
You should design the study with the characteristics of the product in mind; i.e., studies 
    5   
should be carried out beyond the point of detectable levels of the product in the body.  The 
test material should be implanted at or near the proposed site of use and should be assessed 
until after the material has been resorbed by the body.  You should monitor the animals for 
systemic toxicity, as well as for local effects at the implantation site.  You should also 
include macroscopic pathology and histopathology. 
 
If the contact is longer than 30 days, we recommend chronic toxicity and carcinogenicity 
studies (i.e., 2-year rat implantation) as well.  
 
General considerations for adhesion barriers 
 
Safety margin -- In all biocompatibility and toxicity testing, the dose of the product 
used should reflect a reasonable safety margin compared to the doses proposed for 
use in humans.  Generally, you should test a range of doses, up to ten times the 
highest dose to be used in humans, or provide a justification for a smaller safety 
margin.  You should justify a human exposure larger than one-tenth of the no adverse 
effect level observed in animals. 
 
Assessing biocompatibility of adhesion barriers -- The tests needed for assessing 
biocompatibility of adhesion barriers varies.  For some materials, some tests may not 
be necessary, if you provide adequate justification.  For other materials, additional 
tests may be necessary due to the nature of the material. 
 
Preclinical testing -- You should complete all preclinical testing, with the possible 
exceptions of the carcinogenicity and reproductive and developmental toxicity 
testing, at the time you submit the IDE, prior to clinical use of the product.  The 
exceptions will depend upon the results of the genotoxicity testing; the likelihood of 
reproductive or developmental effects; and the intended use of the device.  Informed 
consent forms should disclose any safety studies that are pending.  If the intended use 
is to improve fertility, the reproductive toxicology testing should be complete before 
patients are exposed to the barrier.  As with the other aspects of this guidance 
document, you should direct specific questions to the appropriate reviewing division 
and branch. 
 
Special considerations for adhesion barriers 
 
Testing for Delay of or Prevention of Healing -- Inflammation and the replacement 
of soft tissue with fibrous tissue is an expected outcome of the normal healing 
process.  Reducing the formation of adhesions may also delay or prevent healing.  
This should be tested in animal studies.  Adhesion barriers placed at suture lines or at 
anastomotic sites should not reduce tissue-holding strength after suture removal. 
 
Infectivity Testing  You should test enhancement of sepsis following challenge 
with a bacterial inoculum.  This may result, for example, from the stimulation of 
bacterial growth, from the inhibition of antibiotic diffusion to the infection site, from 
a device-related increase in the entrance of infecting organisms into the systemic 
circulation from the surgical site, or from unknown mechanisms.  You should 
challenge animals with a mixture of gut organisms in the presence and absence of the 
    6   
adhesion barrier, and score for mortality and abscess formation.  You should conduct 
studies with the appropriate sample size and design so as to be statistically valid. 
 
Reproductive/Toxicology Studies  You should perform 
reproductive/developmental (teratology) toxicology studies using two species and 
evaluate the potential effects of the device on ovulation/spermiogenesis, conception, 
embryo-fetal toxicity, and teratological effects.  You should design 
reproductive/developmental toxicity studies so that the maximum exposure of the 
product based on its ADME (see pharmacokinetics, below) occurs at the time of 
interest (ovulation/conception, early and late gestation). 
 
Carcinogenesis/Metastasis Effects -- Device materials may have both local or 
systemic effects on the growth and/or metastasis of malignancies.  FDA believes 
special testing is needed if the components of the barrier do not have a well-
established history of implantation in the abdomen and pelvis, or if there is reason to 
suspect that one of the material components may effect the growth or metastasis of 
malignant cells.  If the device is intended to be used in cancer patients, the preclinical 
testing should be followed by an oncology trial.  Otherwise, the device should be 
contraindicated for patients with known or suspected malignancies.      
 
B.  Pharmacokinetics Studies 
 
You should conduct pharmacokinetics studies to determine the absorption, distribution, 
metabolism and excretion (ADME) route(s), mechanism(s), and timeline of excretion of 
the product.  If the product is metabolized or otherwise converted into molecular entities 
that may result in toxicity, the pharmacokinetics studies should address the fate of each 
of the toxic components over time.  The studies should be carried out to time points at 
which there is no detectable level of the product.  The studies should clearly address the 
fate of any toxic components identified in the chemistry section.  Before the device is 
tested in humans, the pharmacokinetics or other data should demonstrate that any 
potential toxins do not pose a safety concern. 
 
C.  Effectiveness Studies 
 
You should conduct effectiveness studies in appropriate animal model(s) to provide 
proof of concept; that is, these studies should suggest that there is a reasonable 
premise for efficacy in the human.  Animal studies may also suggest better designs for 
the clinical studies to follow.  These studies should represent, insofar as possible, the 
surgical approach (laparotomy versus laparoscopy), the specific surgical site(s) (e.g., 
between viscera and body wall, around loops of bowel), the types of adhesions  (e.g., de 
novo adhesion formation versus reformation of existing adhesions), the method of 
adhesion evaluation (e.g., score, incidence, extent, severity), and the method of 
application that will be used in human studies.   
 
They should also be well-designed and controlled to show statistically significant 
differences between group treated with the product and the control group.  You should 
compare doses of the product to those proposed for use in humans.  You should also 
include a brief discussion of the rationale for and the limitations of the animal model 
    7   
used.  
 
IV. PHYSICAL AND MECHANICAL TESTING   
You should conduct bench testing of the physical/mechanical properties of the product and 
submit this information in the IDE application.  The key physical properties of the device 
should be characterized.  The actual testing will depend on the nature of the device.  Solid, gel, 
and liquid barriers might be characterized by tear strength, cohesivity, or viscosity, 
respectively.  At least one physical parameter should be used as a specification for the release 
of product. 
 
V.  MANUFACTURING 
A.  Product Characterization 
 
Information about the product composition and structure is critical in precisely defining 
the device subjected to preclinical and clinical testing.  Therefore you should include a 
full description of the device, including the physical dimensions, materials and properties 
of the product.  Information similar to that discussed above in the chemistry section (i.e., 
reagent source, purity, certificate(s) of analysis, and/or MSDS) may be helpful in 
determining final product specifications.  
 
You should identify each of the manufacturing, processing and packaging steps.  You 
should present them in flow sheet form.  Accompanying text should identify the purpose of 
each step, the components and materials used in each, as well as the quality control 
procedures and facilities used. 
 
B.  Final Product Specification 
 
You should provide information about all in-process and final product tests.  You should 
identify the product release specifications, test methods, sampling plans (including 
definitions of batch or lot), and acceptable quality levels.   
 
You should select the final product release specifications to ensure that the product will 
perform safely and effectively.  You should provide the rationale for the specifications.  
Examples of final product release specifications include the following: 
 
  device dimensions  
  composition of selected components 
  mechanical properties 
  residual levels of manufacturing reagents 
  residual levels of heavy metals 
  pyrogen levels 
  sterility. 
 
    8   
C.  Product Expiration Dating 
 
You should submit data supporting the expiration dating for the product.  Stability studies 
should monitor the critical parameters of a device that are required to ensure the device 
will perform safely and effectively during its entire shelf-life, as described above under 
Final Product Specification (Section V. B.).  You should provide justification for the 
tests selected.  Studies should also demonstrate that sterility can be maintained over the 
shelf life of the device, either through sterility testing or package integrity testing.   
 
You should collect the devices used for shelf life testing from at least three successive 
product lots; devices from each product lot should be evenly distributed among the 
groups of devices used for the various tests.  The expiration date supported by the data 
should be the time at which there is at least a 95 percent probability that the selected 
parameter will be within the acceptance limit on the expiration date. 
 
When accelerated aging studies are used to support shelf life, you should provide 
justification for the accelerated stress conditions.  For example, decomposition mechanisms 
may show equivalence at both the standard and elevated temperatures, i.e., the slope of the 
Arrhenius curve is constant with changes in temperature.  In cases where equivalence 
cannot be demonstrated, e.g., device failure occurs by different mechanisms at different 
temperatures, you should submit an additional justification.   
 
You should verify the results of accelerated studies with real time test data. 
 
D.  Device Applicator 
 
If a device applicator is used to apply the device, you should include a description of its 
design, function, and performance.  If the applicator is cleared by 510(k), a brief 
description along with identification of the 510(k) are sufficient.   
 
If the applicator is not cleared by 510(k), but is provided and designed exclusively for 
your adhesion barrier, then a more complete description is needed.  If the applicator is 
reusable, see the guidance document, Labeling Reusable Medical Devices Reprocessing in 
Health Care Facilities:  FDA Reviewer Guidance (April 1996), 
http://www.fda.gov/cdrh/ode/198.pdf.  You may also obtain this guidance from the 
Division of Small Manufacturers, International and Consumer Assistance (DSMICA). 
 
E.  Sterilization 
 
You should include the following information about product sterilization: 
 
  the method of sterilization (e.g., ethylene oxide, irradiation) 
  the validation method for the sterilization cycle 
  the sterility assurance level (SAL) achieved  (In general, a SAL of 10-6 is needed 
for all sterile devices, unless there is substantial justification for not being able to 
achieve this level.) 
    9   
  the method for monitoring the sterility of each production lot 
  a complete description of the packaging including the method of sealing the 
device.  
 
If the method of sterilization is radiation, you should specify the dose.  If the method of 
sterilization is ethylene oxide (EtO), you should identify the maximum levels of ethylene 
oxide and ethylene chlorohydrin residues that remain on the device.  Residual levels of 
ethylene oxide and ethylene chlorohydrin that remain on the device following EtO 
sterilization should conform to the maximum limits for residual materials recommended in 
ANSI/AAMI/ISO 10993-7:1995, Biological Evaluation of Medical Devices - Part 7: 
Ethylene Oxide Sterilization Residuals (Sterility) (revised 8/20 1998) or to comparable 
methodology.  The ANSI/AAMI/ISO document should be used with the accompanying 
AAMI Technical Information Report (TIR) No. 19:1998. 
 
You should describe the aeration conditions and the time necessary for the product to reach 
the specified residual levels.  You should also include a dissipation curve for the residual 
levels of ethylene oxide and ethylene chlorohydrin. 
 
The document should also contain a complete description of the analytical methods that 
were used to qualify and validate the sterilization cycle for a disposable applicator and for 
the adhesion barrier itself.  You should include copies of all protocols and raw data that 
support the validation of the sterilization cycle, including all calculations regarding the 
sterility assurance level. 
 
You should identify the device bioburden and provide data to support the control of this 
bioburden during the production of the device. You should include copies of all protocols 
and raw data including identification of the portion of the device sampled for the testing.  
The application should also contain the results of bioburden resistance testing or a 
justification for why this is unnecessary.  This testing should include devices tested from 
at least three manufacturing lots.  
 
You should identify the time of routine revalidation and the circumstances (bioburden in 
excess of an established limit, or a change to the product, or packaging) that would 
necessitate revalidation of the sterilization cycle. 
 
Materials from Animal Sources 
 
For devices derived from animal material, FDA believes you need to demonstrate that 
the processing methods and sterilization techniques are sufficient to produce a SAL of 
10-6.  The application should identify the species and tissue from which the material 
was derived.  You should consult the CDRH Guidance, Medical Devices 
Containing Materials Derived from Animal Sources (except for in vitro diagnostic 
devices): Guidance for Reviewers and Industry, 
http://www.fda.gov/cdrh/ode/88.html, for applicable information.  For guidance on 
the viral safety of such products, see the International Conference on 
Harmonization; Guidance on the Viral Safety Evaluation of Biotechnology Products 
Derived from Cell Lines of Human or Animal Origin.  This document can be 
    10   
obtained from the Center for Biologics Evaluation and Research (CBER) at 1-888-
CBER-FAX.   
 
F.  Pyrogenicity Testing 
 
Pyrogenicity testing will help define limits to protect patients from the risk of febrile 
reaction.  A febrile reaction to a pyrogenic substance may have the potential to 
increase the rate of adhesions.  Testing by an established USP pyrogenicity assay 
such as the Bacterial Endotoxins Test (Monograph 85) using Limulus Amebocyte 
Lysate (LAL) or Rabbit Pyrogen Assay (Monograph 151) method ensures that the 
adhesion barrier device coming into contact with a patient has been tested for levels 
of gram-negative bacterial endotoxin present in the product.  
 
You should identify the method of pyrogenicity testing, as well as information about 
how the assay was performed and the assay results.  Because there is no "gold 
standard" in the medical community for what the upper limit of acceptability of 
endotoxin levels is for an adhesion barrier, it is important that you establish 
specification limits and manufacturing action levels and perform an established USP 
endotoxin test such as the Bacterial Endotoxin Test by LAL or Rabbit Pyrogen assay 
on any implanted device. 
 
CLINICAL INVESTIGATIONAL PLAN 
 
I.  INTRODUCTION 
This section provides points to consider when designing clinical protocols to support a PMA or 
PDP application for a resorbable adhesion barrier to be used in the peritoneal/pelvic cavity(s).  
While there is no consensus on a standardized clinical trial design for all of these devices, there 
are certain principles that FDA believes are essential for providing the valid scientific evidence 
needed to provide reasonable assurance of safety and effectiveness and bring these products to 
market.  A clinical protocol for an adhesion barrier should include:  
 
  clear statement of devices intended use  
  clinical development plan designed to develop the data needed to support the intended 
use  
  study hypothesis(es) 
  study endpoints for safety and effectiveness 
  plan for assessing safety in which all adverse events are identified and analyzed 
  plan for assessing safety and effectiveness on the basis of an intent to treat population 
as well as an evaluable population  
  assessment tools (e.g., adhesions scoring systems, planned second-look procedure, 
video, functional testing) 
  study design with inclusion and exclusion criteria 
    11   
  case report forms 
  statistical methods  
  risk/benefit analysis 
  informed consent 
  balance of premarket and post-approval data development 
  labeling which accurately presents study data. 
 
Note:  We encourage you to work closely with FDA when developing study plans and protocols 
for these devices.  
 
II.  INTENDED USE 
You should identify, as clearly and precisely as possible, the intended use of the adhesion 
barrier.  The specific indications should include the following: 
 
  adhesion type, i.e., de novo, reformed, surgical site, non-surgical site 
  target population 
  conditions for use  
  anatomical site(s) of application 
  expected outcomes.  
These indications are commonly refined, as clinical experience from feasibility studies is 
analyzed.  At the pivotal trial stage of product development, intended use, and indications 
should be in reasonably sharp focus.  
 
The intended use determines the objectives of the clinical trial, which are generally to 
demonstrate the safety (i.e., associated morbidity and mortality) and effectiveness (i.e., 
associated patient benefit) of the device for a defined clinical benefit in a target population, 
under specific conditions of use. 
 
The intended use should be clearly supported by data and be presented in the proposed labeling.  
Labeling in the clinical protocol should accurately present the data that have been collected on 
the device.  One of the most difficult issues for adhesion barrier devices is how broad or narrow 
the indications should be, i.e., how much can the data from the clinical trials be extrapolated to 
broader or related uses.  Part of the answer to this question depends on the selection of the 
surgical model(s) used in the trial and the ability of the sponsor or applicant to provide a sound 
scientific justification that the data support clinical benefit and safety in broader applications. 
 
III.  FEASIBILITY STUDIES 
The purpose of feasibility (pre-pivotal) studies is to test the study methodology and to obtain 
preliminary clinical assessments of the safety and effectiveness of the device.  These small, 
usually non-randomized, one or two center studies are intended to evaluate the procedures 
    12   
that you will use in the pivotal study, refine the design of the device, refine the instructions 
for use, and provide initial experience to potential investigators.  The data derived from 
feasibility studies are used to design the pivotal trial, estimating the treatment effect and 
sample size for the pivotal safety and effectiveness study.  
 
Specific adhesion barrier device-related issues that you should address in pre-pivotal studies 
include: 
 
  method of delivery and placement 
  resorption and elimination in humans, if applicable 
  site-to-site variability in the human body, if applicable 
  effectiveness for various types of adhesions 
  handling characteristics of the device 
  target population 
  conditions of use 
  preliminary safety: morbidity and mortality effects; signs of increased infectivity and 
altered wound-healing 
  sensitivity and specificity of assessment tools for detecting study endpoints and 
clinical benefit. 
 
You should analyze the results of feasibility studies in a supplement to the IDE application 
before initiating the pivotal trial.  We encourage you to schedule pre-pivotal meeting(s) with 
the FDA to present and discuss the results of these feasibility studies. 
 
IV.  PIVOTAL STUDIES 
A.  Purpose of Study 
 
The purpose of a pivotal study is to develop the safety and effectiveness data to support 
the intended use, and therefore justify the indication(s) for use.  The study purpose 
should clearly identify elements of the intended use: intent, target population, and 
conditions of use.  Compound (multiple) intended uses should be addressed in separate 
statements for clarity.  The broader the study is, the broader the eventual labeled 
indication for use may be.  
 
B.  Study Hypothesis 
 
While the objective(s) provides a focus for the trial, the hypothesis is the basis for the 
statistical analysis.  An effective and efficient clinical trial will have one or more 
objectives and corresponding hypotheses that are very specific and unambiguous.  These 
objectives will answer a number of detailed questions about why the trial is being 
conducted including the following. 
 
    13   
  Is the trial to show that a new device is as effective as, or better than another 
intervention or treatment?  In other words, is the trial intended to support a claim 
of equivalence (non-inferiority) or superiority?   
 
  How will effectiveness be judged?   
 
  With respect to safety, is the trial intended to show that the new device is safer 
than, or as safe as, another treatment; and how will safety be evaluated?   
 
  For which patients and condition will the device be used?   
 
Answering these questions generally will provide the basis for the entire trial, as well as 
for labeling later.  It is important you base testing of any statistical hypothesis(es) on 
clinically meaningful difference(s).    
 
C.  Endpoints 
 
Based on the definition of effectiveness (21 CFR 860.7), the most direct method of 
providing valid scientific evidence of effectiveness is to select an appropriate clinical 
outcome and design a study to evaluate a statistically significant and clinically 
meaningful effect on a recognized adhesion-related morbidity.  However, some clinical 
outcomes that result from adhesions may be difficult or impractical to evaluate in the 
premarket phase due to, for example, the multi-factorial nature of clinical outcomes such 
as live births or post-operative pain, or the overall low and time-dependent incidence of 
bowel obstruction due to post-operative adhesions.  The clinical outcomes associated 
with adhesions may be reasonably assessed by parameters which are more immediately 
measurable and potentially less confounded.   
 
In any case, clinical study outcomes endpoints should be:  
 
  objective 
  reproducible 
  clinically reasonable/biologically plausible measures of clinical benefit for the 
target population. 
 
Examples of clinically reasonable/biologically plausible measures are:  
 
  validated multi-factorial scoring systems 
  clinically meaningful incidence 
  extent and severity of post-treatment adhesions in patients without adhesions at 
baseline  
  clinically meaningful reduction in adhesion numbers 
  extent and/or severity of post-treatment adhesions in patients with adhesions at 
baseline.  
    14   
 
You may report incidence of observed adhesions in a number of ways, e.g., as the 
percentage of patients with no adhesions, or as the number of pre-designated surgical 
sites with adhesions.  Extent and severity are also scored and reported in a variety of 
ways using a variety of different nomenclatures.  Standardized composite scores of 
adhesions of predetermined grade at predetermined sites are being developed and utilized 
with increased frequency and should lead to greater reproducibility within and between 
studies.1,2,3,6,7,9  For any scoring system, you should clearly define which anatomic sites 
are being scored.  You should also define the following methods, if used in your scoring 
system: 
 
  methods of evaluating extent of adhesions, i.e., direct measure with a centimeter 
marked ruler versus estimation of the percentage of organ covered; 
  methods of evaluating the severity of adhesions; and  
  methods of combining incidence, severity and extent scores into meaningful 
composite scores. 
Currently, there is no consensus on the levels of adhesion reduction that are clinically 
significant.  In addition, there is little information on the clinical significance of 
adhesion reduction at specific anatomical sites, or reduction of adhesion extent or 
severity.4,5,11,12,14  You should carefully consider all of these parameters (level and sites 
of adhesion reduction) when designing a clinical trial.  You should discuss clinical 
relevance of the extent of adhesion reduction indicated by your endpoints. 
 
Post-approval studies are a reasonable method of further understanding the clinical 
relevance of the chosen endpoints.  Post-approval studies are discussed below in section 
K.  
 
D.  Assessment Tools 
 
The following tools for assessing adhesion reduction are being used now or, with 
some further development and testing, may be used in the future.  We recognize that 
various tools have advantages and disadvantages.  When choosing a method, the 
sponsor should discuss why this tool is appropriate for the study.  
 
1.  Second look surgery 
Second look via laparotomy or laparoscopy is currently the primary modality for 
assessing adhesion formation/reduction in the abdomen and pelvis.  It has the 
advantage of direct visual inspection; surgical manipulation to fully explore the 
cavity(s) and assess severity, e.g., filmy, firm, concrete; and provides an  
    15   
opportunity for simultaneous therapeutic intervention.  Issues that need to be 
addressed when second look is used include the following:  
  the potential morbidity of a second surgical procedure unless planned in 
standard care; 
 
  ethical issues regarding the potential benefit (or lack thereof) of such 
procedures to individual subjects;  
 
  masking issues; and  
 
  issues related to investigator bias.  
 
2.  Video recording 
Video recording is frequently added to the second look assessment to provide a 
permanent record of the procedures and to provide a mechanism for masking by 
allowing for independent third party reviews.  As with other technological 
advances, the utility of this methodology is highly dependent on the quality and 
reliability of the recording.  Recordings should be complete and of sufficient 
optical quality to allow for accurate assessment of the quantity and quality of 
adhesions as well as an assessment of how those adhesions may be affected by 
the surgical exploration, itself.  An important consideration when using video 
recording is that the method of evaluating the abdomen be consistent among 
patients (e.g., assessing surgical sites in the same order and for the same amount 
of time), in order to reduce potential bias.  
 
3.  Imaging studies 
With additional technology development, imaging studies might be used in the 
assessment of adhesion barriers.  Thus far, they do not provide enough detail to 
be used effectively in the abdomino-pelvic cavity. 
 
4.  Functional testing 
Functional testing has shown great potential for assessing the impact of adhesion 
reduction in musculoskeletal applications; however, the present utility is less 
apparent for abdomino-pelvic applications.  Newer methods for measuring 
intestinal motility and other methods of testing the function of gastrointestinal 
and gynecologic organ systems may be developed in the future to provide a 
useful, non-invasive alternative to surgically mediated anatomic assessment.  
These methods will require further research and validation.   
 
E.  Important Assessment Considerations 
 
Because a consistent method of assessing adhesion reduction has not been established, 
you should include detailed information about the following in your clinical protocol: 
 
  anatomic sites to be evaluated; 
  the time during surgical procedure at which adhesion scoring will be done 
(beginning or end or both in case of partial or selective adhesiolysis); 
    16   
  adhesion characteristics to be measured (incidence, severity, extent) and methods 
of grading or measuring each characteristic; 
  method of assessing each component of the score at each anatomic site, e.g., 
laparoscopic, open laparotomy, videotaping;  
  method of counting an anatomic site that is to be evaluated but is anatomically not 
present or not assessable in a specific patient; 
  methods of combining the adhesion characteristics per anatomic site, per patient, 
or per treatment group; and  
  methods for establishing that the composite score (when used) is a valid and 
reliable tool for assessing adhesions or the morbidity resulting from adhesions. 
 
F.  Study Design 
 
1.  Control 
FDA recommends randomized, concurrently-controlled, pivotal trials, given the 
absence of well-defined historical controls or other appropriate control methods. 
You should justify your choice of control with the most recently available, peer-
reviewed literature. 
 
2.  Randomization 
Randomization should occur immediately prior to device application, after a patient 
has been evaluated and found to satisfy pre-operative, as well as intra-operative 
inclusion / exclusion criteria.  The time of randomization should be documented on 
the case report form. 
 
3.  Masking 
You should address, to the greatest extent possible, the potential for investigator 
and, to a lesser degree, patient bias.  Investigator masking is problematic for 
adhesion barrier trials that use either placebo or active controls, since differences 
between the test and control subjects are usually readily apparent and it is normally 
preferable, from a patient care perspective for the same surgeon to perform the 
initial and second look procedures.  You may use one of several alternative methods 
for controlling bias including video recording with masked independent review or 
application of the device/control by an assistant who will not participate in adhesion 
scoring.  You should assess these or other methodologies during the feasibility (pre-
pivotal) phase of development. 
 
4.  Patient Selection Criteria 
The target population should consist of patients who are expected to benefit from 
device use under specified conditions of use.  The inclusion and exclusion criteria 
for the clinical study should identify significant patient variables that characterize 
the target population, such as: 
 
    17   
  age 
  gender 
  fertility status 
  pregnancy history 
  history of abdomino-pelvic disease due to adhesions, e.g., recurrent bowel 
obstruction, infertility, pain 
  adhesion burden at baseline, e.g., none, mild, moderate, severe with objective 
and definition of mild, moderate, severe 
  surgical history 
  history of inflammatory disease 
  history of major organ dysfunction 
  surgical wound classification10: clean, clean-contaminated, contaminated, or 
dirty. 
 
You should identify intraoperative inclusion/exclusion criteria prospectively.  Some 
exclusions, such as active pelvic infection, fecal contamination, unexpected 
malignancy, and extent of adhesions, may not be known until the time of surgery. 
You should consider excluding patients undergoing certain unanticipated surgical 
procedures, such as the removal of a fallopian tube or ovary, because such 
procedures may complicate the adhesion count.  Randomization should not occur 
until the time the device or control is placed.    
 
5.  Procedure 
You should include information about the following in your description of the 
clinical procedure in which the adhesion barrier device is used:  
 
  when, where, and how the device is used 
  minimum and maximum dosage per patient 
  length of procedure 
  method of lysis 
  possible covariates, e.g., blood loss, glove use. 
 
6.  Follow-up 
You should prospectively define the period of follow-up and frequency/content of 
evaluations.  These should be appropriate for the device, procedure, and the endpoint 
you are evaluating.  Please see the discussion of post-approval studies in section K, 
below for further information. 
 
G.  Statistical Methods 
 
    18   
You should provide a comprehensive statistical plan.  It should include prospectively 
defined methods of addressing each of the following: 
 
  study hypothesis 
  sample size calculation 
  number of study centers 
  success/failure criteria 
  effectiveness patient populations (intent-to-treat, evaluable, etc.) 
  pooling of data 
  covariates 
  stratification 
  protocol deviations 
  drop-outs 
  analysis plan and statistical methods  
  data auditing. 
 
1.  Analysis Cohorts 
The Intent-to-Treat population, which is defined to be the cohort of all enrolled 
and treated patients, is the preferred population for study outcome analysis.  Intent to 
Treat analysis allows for the evaluation of all patients who enroll in the study, even 
though some may not complete the study, e.g., patients who are, for any reason, lost 
to follow-up, drop-outs, or terminated by investigator.  You should prospectively 
specify the analysis plans that will account for patients who do not complete the 
study.  You should also present analysis of the Evaluable patient cohort, i.e., 
patients who enter and complete the study, recognizing such analyses are subject to 
bias.  Comparison of outcomes on the basis of Intent to Treat and Evaluable patients 
allows assessment of outcome robustness.  Analysis details should be prospectively 
agreed upon by the sponsor and FDA.   
 
2.  Data Poolability 
Most clinical trials are conducted at more than one study site, but the sample size for 
the study assumes that results from all the study sites may be combined or pooled.  
Many times, this assumption is warranted.  However, sometimes it is not.  Thus, 
investigating whether study results may be pooled across study sites will be a key 
element of the analysis.  
 
Poolability is both a clinical and a statistical issue.  If there are clinically important 
differences in the way the trial was done at different sites, then instead of a single 
trial at multiple sites, there is actually a series of single center trials that need to be 
assessed and presented separately.  In the same way, statistically significant 
differences in results at study sites indicate that there is an important inconsistency 
    19   
among the study sites that should be investigated, and not lost in an overall finding.  
Differences among sites may be important indicators of critical issues in device 
performance.  For example, exploring the reasons for observed differences may 
uncover training, learning curve issues, or special labeling concerns. 
 
A simple approach to investigating poolability has three steps. 
 
1.  A clinical assessment of the way the trials were done at the study sites.  
Clinically meaningful differences here may preclude pooling. 
 
2.  A statistical/clinical assessment to evaluate the similarity of patient 
characteristics and baseline measurements.  Differences here may indicate 
poolability problems.  At the very least, these differences will indicate the 
need for a more complex statistical analysis. 
 
3.  A statistical analysis testing the consistency of results across study centers.  
Again, differences here may indicate poolability problems or the need for a 
more complex statistical analysis. 
 
When testing for differences among sites, the absence of statististically significant 
differences does not indicate that data can be pooled, because most trials are sized 
for an assessment over all sites.  For this reason, clinically meaningful differences 
(even statistically non-significant ones) should not be ignored, but instead should be 
investigated.   
 
One approach to investigating statistical variation among sites is to use a statistical 
model that includes site, along with other factors.  If the analysis confirms that site is 
important, results should be presented by site.  If a statistically significant interaction 
between site and treatment occurs, it indicates a major inconsistency among the sites, 
which should be investigated. 
 
 
3.  Covariates 
Covariates, or potentially confounding variables, may significantly compromise the 
ability of the sponsor and the agency to adequately analyze the data from clinical 
trials.  You should avoid procedural variations, such as the use of different doses, 
different methods of application, different surgical tools, different gloves, etc., 
whenever possible.  You should accurately record all variables, such as whether 
Lactated Ringers or other instillates were left in the abdomen or completely or 
partially removed. 
 
You should address major differences in surgical approach, such as laparotomy vs. 
laparoscopy and the inclusion of multiple surgical procedures with vastly different 
adhesiogenic potential, in separate studies or by prospectively designed stratification 
plans. 
 
    20   
You should identify and control for co-morbidities that may confound evaluation of 
device effect.  Inclusion/exclusion criteria should address the presence or absence of 
diseases (e.g., active pelvic infection), the severity of the diseases, and historical 
information.  Patients excluded from the study will, in general, also be excluded in 
the labeling for the approved product. 
 
You should control for other variables known or suspected to be confounding, e.g., 
the use of anti-inflammatory medications, by appropriate randomization, 
inclusion/exclusion criteria, by evaluation in separate study arms, by stratification, or 
by a prospectively designed covariate analysis.  
 
4.  Additional Information 
Additional information on study design and statistical analysis issues are  
available from CDRH, in the guidance document entitled, Statistical Guidance for 
Clinical Trials of Non-Diagnostic Medical Devices, 
www.fda.gov/cdrh/ode/ot476.html.  The Centers Division of Biostatistics prepared 
this guidance with input from ODE, academia, and the medical device community. 
 
H.  Case Report Forms 
 
You should design case report forms to capture all pertinent information at each point in 
the study from patient screening, through patient enrollment, the initial treatment period, 
assessment of adhesions, and all other patient follow-up.  You should maintain a 
screening log for both the pilot and pivotal studies to allow assessment of reasons for 
non-enrollment of patients considered for the trial. 
 
For operative procedures the case report forms should record variables (covariates) that 
could potentially confound the endpoints, such as: 
 
  the presence of foreign bodies resulting from powder from unwashed gloves, 
gauze, or paper towels  
  procedure duration  
  estimated blood loss  
  the number and locations of adhesions lysed 
  the types of adhesion, e.g., de novo or reformed  
  Surgical Wound Classification10: clean, clean-contaminated, contaminated, dirty.  
 
I.  Device Applicators 
 
You should describe any device applicator used with the adhesion barrier product in the 
clinical protocol, and provide information about the training investigators and 
practitioners receive.  If the applicator is not cleared by 510(k), and it is provided with 
and designed exclusively for your adhesion barrier, then FDA may consider the 
    21   
applicator part of the device, and include it in evaluating the safety and effectiveness of 
the device. 
 
J.  Informed Consent 
 
The requirements for all patients for informed consent, adequate monitoring, and 
necessary records and reports are given in 21 CFR Parts 50, 56, and 812.  Patients 
should be clearly informed of, among other things, the following: 
 
  the safety and effectiveness of the new device has not been established  
  adhesions may actually worsen with treatment 
  adhesions may cause or worsen morbidity such as female infertility or pain 
  adhesions may prevent or reduce morbidity such as obstructive anastomotic leak 
  the incidence of small bowel obstruction due to post-laparotomy adhesions is 
approximately 5%. 
  
Women who desire fertility, should be excluded from feasiblity studies or warned that 
the effects of the device on fertility have not been defined. 
 
K.  Post-approval Studies 
 
There are several reasons why you may conduct a post-approval study.  In some cases, 
FDA may require you to conduct a post-approval study as a condition of PMA approval.  
FDA might require a post-approval study to follow up on unresolved safety issues, such 
as infection rates, where incidence rates are too low for the pivotal study to accurately 
predict.  Or, FDA might require a post-approval study to provide further understanding of 
a finding from the pivotal study that is not completely explained by the available data. 
 
FDA typically relies on input from the advisory panel when requiring a post-approval 
study. 
 
Moreover, you may choose to conduct additional studies on your approved device in 
order to address limitations in the approved labeling, to provide additional information 
for interested clinical users of the device, or to provide additional information to third 
party payers. 
 
L.  Special Considerations 
 
1.  Laparotomy versus Laparoscopy 
Generally, you should evaluate adhesion barriers separately in laparotomy and 
laparoscopic surgical models.8,13  Data derived from laparotomy studies may not 
accurately predict efficacy when extrapolated to a laparoscopic model, because 
significant quantitative and qualitative differences may occur in adhesion formation 
depending on whether the surgery is done by laparoscopy or laparotomy. 
 
    22   
2.  Malignancy 
For adhesion barrier devices intended to be used in the presence of known or newly 
discovered malignancy, you should anticipate the need for additional preclinical and 
clinical testing focused on the issues of accelerated tumor growth and impact on 
clinical progression of primary and metastatic disease.  You should discuss specific 
protocols with the reviewing division before initiating one of these trials. 
 
V.  RISK/BENEFIT ANALYSIS 
Reasonable assurance of safety and effectiveness is based upon a scientific analysis of 
risk/benefit.  In order to perform such an analysis it is critical, as discussed above, that you 
collect complete, objective, and unbiased data for both safety and effectiveness for FDAs 
review.  FDA and its advisory panels will perform its own independent risk/benefit analyses.  
 
We encourage you to provide, both in the IDE and PMA, risk/benefit analyses that accurately 
characterizes your product in a way that would allow prospective users to make an informed 
decision regarding its use.  The risk/benefit analysis for the PMA will be more definitive, 
because it will include the results of the clinical trial(s).  The risk/benefit analysis should be 
based on your in-depth knowledge of your device, data, and the science of adhesion 
formation and prevention.  It is important that this analysis be as data-based and objective as 
possible. 
 
The risk analysis should identify all of the known and potential risks of the use of the device.  
It should include risks attendant to the procedure(s) involved in the trials, as well those risks 
directly attributable to the use of the product.  These risks should be analyzed separately and 
in combination.  You should also describe your plans to recognize, understand, and minimize 
the risks. 
 
The benefits analysis should identify potential benefits to the patient.  It should include any 
information available about likely differences in benefits to different patient populations. 
 
VI.  LABELING 
Investigational devices must be labeled in accordance with 21 CFR 812.5 and in accordance 
with 21 CFR 812.5, they must state: CAUTION  Investigational Device.  Limited by 
Federal (or United States) law to investigational use. 
 
In the PMA, the final marketing labeling should contain the following basic elements: 
 
  brief device description 
  indications for use 
  contraindications 
  warnings/precautions 
  adverse events 
  clinical studies 
    23   
  patient information (as needed) 
  instructions for use. 
 
A.  Indications for Use 
 
Labeling should accurately represent the data that has been collected on the device.  The 
label indication should be based on the studies conducted to support that indication.  
You should prospectively define the expected indications as clearly and specifically as 
possible.  The indications will depend upon the selection of the surgical model(s) used in 
the trial.  See also the section entitled Clinical Investigational Plan, II. Intended Use. 
 
B.  Contraindications 
 
This section should list those circumstances under which the device should never be 
used.  For example, if an adhesion barrier was known, based on animal or human data, 
to increase infectivity, it would be contraindicated in the presence of active infection or 
enteral contamination. 
 
C.  Warnings/Precautions  
 
When increased risk or decreased benefit is anticipated based on available information 
or not adequately evaluated based on study design (inclusion/exclusion criteria), such 
factors should be listed in this section.  Examples include: 
 
  Decreased effectiveness should be expected in the presence of less than 
meticulous hemostasis. 
 
  The safety and effectiveness of this product has not been evaluated during 
pregnancy. 
 
  The safety and effectiveness of this product with respect to its effect on the ability 
to conceive has not been evaluated. 
 
D.  Adverse Events 
 
You should clearly present all adverse events recorded in the clinical trials in tabular 
form, including numbers and percents.  You should list adverse events in a meaningful 
sequence based upon incidence rates, severity, or another relevant paradigm.  You 
should describe deaths and other significant adverse events in both text and tabular form.  
    24   
 
E.  Clinical Studies 
 
Clinical studies on which safety and effectiveness are based should be summarized in 
tables of data that include the following: 
 
  patient accountability 
  demographics 
  procedure variables 
  baseline evaluation of effectiveness endpoints 
  follow-up evaluation of effectiveness endpoints 
  follow-up evaluation of safety endpoints 
Conclusions and interpretations should be objective.   
 
F.  Instructions for Use 
 
You should provide detailed instructions that reflect the experience gained in preclinical 
and clinical studies.  These instructions should include: 
 
  device preparation 
  patient preparation 
  device delivery 
  device application 
  dosing recommendations 
  operative technique 
  post-operative care 
  retreatment (if applicable). 
REFERENCES 
 
1.  Adhesion Scoring Group.  1994.  Improvement of inter-observer reproducibility of adhesion 
scoring systems.  Fertility and Sterility 62: 984-988. 
 
2.  American Fertility Society.  1988.  The American Fertility Society classifications of adnexal 
adhesion, distal tubal occlusion secondary to tubal ligation, tubal pregnancies, Mullerian 
anomalies and intrauterine adhesion.  Fertility and Sterility 49: 944-955. 
 
3.  American Society for Reproductive Medicine.  1997.  Revised ASRM classification of 
endometriosis: 1996.  Fertility and Sterility 67(5):  817-821. 
 
    25   
4.  Corson SL, Batzer FR, Gocial B, Kelly M, Gutmann JN, and Maislin G. 1995.  Intra-
observer and inter-observer variability in scoring laparoscopic diagnosis of pelvic adhesions.  
Human Reproduction 19(1): 161-164. 
 
5.  Gomel V and Erenus M.  1990.  The American Fertility Society, 16th Annual Meeting.  
Program Supplements (Abstracts) P-097, S-106. 
 
6.  Hulka JF.  1982.  Adnexal adhesion:  a prognostic staging and classification system based 
on a five year survey of fertility surgery results at Chapel Hill, North Carolina.  Am. J. 
Obstet. Gynecol.  144(2): 141-148. 
 
7.  Hulka JF, Omran K and Berger GS.  1978.  Classification of adnexal adhesions:  a proposal 
and evaluation of its prognostic significance.  Fertility and Sterility 30: 661-665. 
 
8.  Lundorff P, Halin M, Kallfelt B, Thorburn J and Lindblom B.  1991.  Adhesion formation 
after laparoscopic surgery in tubal pregnancy: a randomized trial versus laparotomy.  
Fertility and Sterility 55(5):  911-915. 
 
9.  Mage G, Pouly JL, Bouquet de Jolinere J, Chabrand S, Riouallon A, Bruhat MA. 1986.  A 
preoperative classification to predict the intrauterine and ectopic pregnancy rates after distal 
tubal microsurgery.  Fertility and Sterility 46(5): 807-810. 
 
10.  Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR.  1999.  Guideline for 
Prevention of Surgical Site Infection, 1999.  Infection Control and Hospital Epidemiology 
20(4): 247-278. (page 259) http://www.cdc.gov/ncidod/hip/SSI/SSI.pdf 
 
11.  Nagata Y, Honjo K, Shindio M, Tamura M, Kurashima M, Shirakawa K.  1997.  Effects of 
periovarian adhesions on the results of IVF-ET treatment.  Journal of the Japanese 
Fertilization and Implantation Society 14: 54-57. 
 
12.  Nagata Y, Honjou K, Sonoda M, Makino I, Tamura R and Kawarabayashi T.  1998.  
Periovarian adhesions interfere with the diffusion of gonadotropin into the follicular fluid.  
Human Reproduction 13(8): 2072-2076. 
 
13.  Operative Laparoscopy Study Group.  1991.  Postoperative adhesion development after 
operative laparoscopy:  evaluation of early second-look procedures.  Fertility and Sterility 
55(4): 700-704. 
 
14.  Stout AL and Steege JF.  1991.  Resolution of chronic pelvic pain after laparoscopic lysis of 
adhesions.  Am. J. Obstet. Gynecol.  165(2): 278-283.     
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