Guidance for Resorbable Adhesion Barrier Devices for Use in Abdominal and/or Pelvic Surgery - Guidance for Industry
Published: 2002-06-17
Status: Final Type: Guidance Document Category: Premarket (510(k) / PMA / De Novo / IDE) Topics: Premarket Docket: FDA-2020-D-0957
Official Source
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-resorbable-adhesion-barrier-devices-use-abdominal-andor-pelvic-surgery-guidance-industry PDF: https://www.fda.gov/media/71607/download
Official Full Text
Guidance for Resorbable Adhesion Barrier Devices for Use in Abdominal and/or Pelvic Surgery;
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 device’s 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 • 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 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. • 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. 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.
- 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 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.
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.
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.
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); • 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
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, peerreviewed literature.
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.
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 (prepivotal) phase of development.
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: • age • sex • 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.
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.
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
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.
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.
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 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.
A clinical assessment of the way the trials were done at the study sites. Clinically meaningful differences here may preclude pooling.
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.
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.
- 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 Ringer’s 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. 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.
- 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 Center’s 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 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
- 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.
- 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 FDA’s 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 • 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.
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
Adhesion Scoring Group. 1994. Improvement of inter-observer reproducibility of adhesion scoring systems. Fertility and Sterility 62: 984-988.
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.
American Society for Reproductive Medicine. 1997. Revised ASRM classification of endometriosis: 1996. Fertility and Sterility 67(5): 817-821.
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.
Gomel V and Erenus M. 1990. The American Fertility Society, 16th Annual Meeting. Program Supplements (Abstracts) P-097, S-106.
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.
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.
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.
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.
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
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.
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.
Operative Laparoscopy Study Group. 1991. Postoperative adhesion development after operative laparoscopy: evaluation of early second-look procedures. Fertility and Sterility 55(4): 700-704.
Stout AL and Steege JF. 1991. Resolution of chronic pelvic pain after laparoscopic lysis of adhesions. Am. J. Obstet. Gynecol. 165(2): 278-283.