The following information astounded me and left me speechless. I've read the clinical trial discussed in this rejection statement and have a great deal to say about the lack of a professional and scientific approach which came from the members of the NIH subcommittee who reviewed and rejected this trial.

Furthermore, it is my understanding that it is the directive of the NIH to support research on alternative treatments to hysterectomy -- not maintain that the status quo is adequate and therefore further research is unnecessary. Recommendations from Vivian Pinn, the Director of the Office of Research on Women's Health, were very specific in this regard. (See: www4.od.nih.gov/orwh/report.pdf Agenda for Research on Women's Health for the 21st Century.) Apparently the individual divisions of the NIH feel less than compulsory in regards to compliance. Apparently they view the research agenda recommendations as nothing more than rhetoric. It would appear, from statements made throughout this rejection, that members of this subcommittee were puzzled by the need to research alternative treatments to hysterectomy at all. It would also appear that they are in dire need of guidance regarding the desires and directives of women suffering from uterine fibroids.

I don't intend to let this issue simply slide away. Researching alternative treatment options to hysterectomy for symptomatic uterine fibroids is crucial to the long-term health and well-being of millions of women. This division of the NIH and this subcommittee needs to be held accountable for their statements and their actions. Write to me if you agree or want more information on how you can take a stand on this issue.

Tell me what you think of the following NIH rejection summary!

Estella Parrott, M.D., M.P.H.
Program Director
Reproductive Medicine
Gynecology Program
Reproductive Sciences Branch
Center for Population Research
National Institute of Child Health and Human Development
NIH
6100 Executive Blvd., Rm. 8B-01
Bethesda, MD 20892-7510
Tel: (301) 496-6515
Fax: (301) 496-0962
ep6lh@nih.gov

SUMMARY STATEMENT

Application Number: 1 R01 HD38374-O1A1

Review Group: POPULATION RESEARCH SUBCOMMITTEE

UNIVERSITY OF CALIFORNIA
DEPT OF RADIOLOGICAL SCIENCES 10833 LE CONTE AVE, BL-423 CHS
LOS ANGELES, CA 90095-1721

Project Title: MULTICENTER PROSPECTIVE TRIAL COMPARING UTERINE FIBROID EMBOLIZATION TO MYOMECTOMY

RESUME
This revised Multicenter Clinical Trial grant application, presented by Scott C. Goodwin, M.D., is a large, randomized, prospective clinical trial to compare myomectomy and uterine artery embolization to treat women with uterine bleeding due to leiomyomata. The lack of scientific hypotheses, the concern regarding the ultimate importance of the question, and safety issues limit enthusiasm for this project.

DESCRIPTION
(Adapted from applicant's description): The proposed study is a prospective randomized multi-institutional clinical trial comparing the effectiveness and quality-of-life outcomes of uterine artery embolization and abdominal myomectomy in women with abnormal uterine bleeding, pelvic pain and/or bulk symptoms related to uterine leiomyomata. The primary specific aim of the study is to evaluate the effectiveness of UAE and myomectomy in alleviating abnormal uterine bleeding. Secondary aims include evaluation of the relative effectiveness of UAE and myomectomy on (1) pain and/or bulk symptoms, (2) the patient's quality of life, and (3) ovarian function. Subjects will be chosen from a clinic population at the participating institutions. Eligible patients must have failed or refused medical treatment for leiomyoma, and must have abnormal uterine bleeding for at least 3 months. For this study, abnormal uterine bleeding is defined as more than 8 days of menstrual flow per month, menstrual cycle less than 21 days, bleeding score of >100 on the pictorial blood loss assessment chart or anemia (hemoglobin less than 12 g/di). Other inclusion criteria include an imaging study showing the presence of leiomyoma either by ultrasound or MRI, and an endometrial Sampling within 6 months to exclude pelvic malignancy. Criteria for: exclusion include pedunculated uterine leiomyoma with a base less than 2 cm, 2 or less submucosal leiomyoma without significant intramural component in the absence of other leiomyomas, gynecological malignancy, pregnancy coagulopathy, severe systemic disease, long-term steroid use, acute vasculitis, or inability to comply with the study regime or follow the study protocol. The study duration is 5 years including 6 months for planning, training and implementation, 30 months for recruitment, 18 months for follow-up beyond the end of the recruitment, and 6 months for data analysis and manuscript preparation. Subject follow-up and data collection will occur before treatment (baseline) and at 1, 3, 6, 12 and 18 months after the initiation of treatment according to the assigned arm. Medical and physical exams will be performed. Monitored laboratory data will include serum hemoglobin and follicle-stimulating hormone level. Radiographic studies will include pelvic MRI or pelvic ultrasound. Patients will also complete a self-assessed blood loss chart, visual analog scale, bulk symptom scale, and the SF-36 questionnaire. The first analysis of the primary and secondary endpoints will be done 12 months after the procedure.

NOTE
The sections that follow are, for the most part, unedited, verbatim comments of the reviewers assigned to this application. They are provided to illustrate the range of opinions expressed. The application was discussed and scored by all reviewers present. The attached commentaries may not necessarily reflect the position of the authors at the close of group discussion, nor the final majority opinion of the group. The Resume, however, is the authoritative representation of the outcome of group discussion.

CRITIQUE 1

Significance
Comparison of uterine artery embolization (UAE) and myomectomy in the treatment of myoma-associated abnormal uterine bleeding is an important clinical question with significant public health ramifications, given the number of myomectomies and hysterectomies done for this indication. If UAE can be shown to be equal to myomectomy in efficacy and safety, with roughly equivalent costs, it would represent an attractive, less invasive alternative to myomectomy. In devising a trial comparing UAE to myomectomy, the authors have cogently addressed a major weakness of the first submission. �

Approach
The methodologic approach to be used, that of a multi-center randomized trial, will provide meaningful information on the relative efficacy of the two treatment alternatives. The major outcome measure, Pictorial Blood Loss Assessment Chart (PBAC), is appropriate as it has been validated against menorrhagia, and because it reflects the symptom that brought the patient for treatment to begin with. Although the investigators will collect pre-post data on myoma volume with MRI, this endpoint is not included in the statement of secondary hypotheses (p. 65, in the application) or in the statistical analysis section (p. 78, in the application). Other secondary outcome measures are sensible, well described, and have been considered in the data analytic procedures. Inclusion and exclusion criteria are now clear. The inclusion of women with frequent episodes of uterine bleeding, however, might be reconsidered to the extent that frequent, irregular bleeding might signify anovulation. Myomectomy or UAE might reduce the volume of anovulatory bleeding, but the underlying problem would not be resolved by these procedures.

Dr. Goodwin has published extensively on UAE, and has played a pivotal role in educating radiologists and gynecologists about its potential utility in the management of uterine fibroids. He clearly has the clinical expertise to coordinate the clinical activities of this project. He currently is Principal Investigator on a feasibility study of magnetic targeted carriers under magnetic guidance in the swine and canine models, but is not listed as an investigator in ongoing clinical trials. It does not appear that Dr. Goodwin has previous experience in running a large clinical trial, but he will now have help from Dr. Elashoff, who has extensive clinical trials experience. The experience of investigators in the other centers with regard to participation in clinical trials, and their past performance in recruiting to randomized clinical trials, is not described.

The lack of a data coordinating center in the last application and an incomplete description of proposed data analysis has been corrected by the addition of Dr. Robert Elashoff as a key co-investigator. He will assure appropriate and sophisticated statistical analysis, and will head a Statistical Coordination Unit that will be responsible for randomization, data security, quality control/assurance, auditing and monitoring; all of these functions are well thought out and clearly described, except that it is not clear whether randomization will be blocked by site. Based on the description of the PBAC scoring system, PBAC is an ordinal variable. Description of the analysis of this primary endpoint (p. 80, in the application), however, appears to treat PBAC as a ratio variable. Although based on previous studies using PBAC cited by the authors, PBAC does not appear "to depart importantly from normal distributions," greater justification for treating this ordinal variable as a ratio variable in the analysis is needed. Are there data on the correlation between PBAC scores and the volume of blood loss across the entire range of PBAC values? Does the difference between 60 and 70 in PBAC units mean the same as the difference between 1 0 and 20 in ml of blood loss? The repeated measures model that allows estimation of both fixed and random effects parameters, including the description of both parametric and nonparametric approaches, is a strength of the proposal. The sample size chosen is based on a power analysis designed to detect a difference between treatments of eight PBAC units. What does this mean, approximately, in ml of blood loss, and is this a clinically meaningful difference? Based on previous literature, it would be helpful to know not only the expected difference between groups, but the absolute baseline and post-treatment values that are anticipated, as well as the variability around these values. Also, the power analysis is performed under the assumption of a 1-tailed test. We really do not know, a priori, which of the two treatments will result in a larger PBAC change score; thus, a 2-tailed test would seem appropriate, which would have a major impact on sample size requirements.

For a multi-center trial of this size, pilot data on the ability to recruit subjects into the randomization protocol, or some other assurance about recruitment, would be expected. For twelve sites, assuming approximately equal recruitment, each site would have to recruit two patients per month over 30 months to reach the study-wide goals for sample size. Although each site may perform more than two UAEs and/or myomectomies per month, the willingness of gynecologists to refer to the trial, and the willingness of patients to be randomized, is uncertain. The application does not contain any data along these lines, nor does it contain letters of support from the team at each site detailing the number of myomectomies/UAEs performed annually, support from gynecologists for referral to the trial, the planned methods for recruitment, and previous experience with randomized trials. With the increased sample size that might be needed under a 2-tailed test for power estimates, assurance about recruitment becomes even more important.

CRITIQUE 2

OVERALL CLINICAL TRIAL
Uterine fibroids are the most common gynecologic tumors in women. The tumors, arising from a single smooth muscle cell rarely become malignant, but account for the primary diagnosis of women receiving hysterectomy as a surgical treatment modality. Symptoms of fibroids most frequently include abnormal uterine bleeding, particularly menorrhagia and hypermenorrhea, but also include pelvic pain and pelvic pressure, bloating, increased urinary frequency, and constipation. To date, hysterectomy is the only definitive cure for myomas, and the American College of Obstetricians and Gynecologists (ACOG) has recommended surgical therapy for both symptomatic and asymptomatic fibroids when uterine size exceeds that of a 12-week pregnancy. Given that hysterectomy fails to provide any preservation of fertility, has significant emotional and occasional sexual consequences to women and represents an expensive treatment, the proposal of Dr. Goodwin and associates is both timely as a potentially more positive clinical treatment for uterine fibroids.

Technical and scientific merit of the research approach and method
Medical treatment of fibroids has essentially involved treating the bleeding and pain with steroids and antiinfammatory agents or removing steroid support to the disease via the administration of GNRH agonists. Although several effective products are currently approved for fibroid treatment, GNRH agonists do not represent a permanent solution to the disease since significant bone loss and other quality of life issues can accompany treatments after 4-6 months of therapy. Since adequate blood flow to fibroids is known to be an essential element in the pathophysiology of this disease, a sound treatment strategy has involved the reduction in arterial blood flow. Transcatheter Arterial Embolization (TAE) would appear to be a clinically sound, relatively safe and minimally invasive (compared to other surgical modalities), and effective treatment for the basic clinical symptoms of fibroids. Myomectomy represents the most commonly used surgical alternative to TAE among U.S. health practitioners, which is clearly more invasive and has significant quality of life issues.

Technical and scientific merit of the statistical approach
The investigators appear to have incorporated the assistance of a number of professional statisticians in order to propose reasonable statistical analysis approaches for each of the specific aims of the proposed multi-institutional trial and no overwhelming problem in obtaining statistical power for the primary comparison of TAE to myomectomy would be anticipated. The blood loss analysis would appear to be a reasonably valid endpoint. The secondary pain, bulk, quality of life and ovarian function hypotheses can probably be compared among the various centers involved. Certainly, the investigators have given a lot of thought to asking specific questions that will allow them to address long-term outcomes of TAE versus myomectomy. The inclusion of reproductive gynecologists to the application have strengthened the overall clinical perspectives necessary to fully analyze the endocrine-related outcomes of the treatment modalities.

Technical and scientific merit of logistical factors
Each institution will function independently in terms of patient recruitment and clinical procedures, a necessity for a multi-institutionally trial. Unavoidable differences in the skill level of various investigators will contribute to variances in the outcome data among multi-centers. However, the investigator has clearly tried to strengthen the power of the comparison of TAE to myomectomy, the most common surgical approach. The application is stronger for this more simplified approach.

Evidence of pilot phase experience
The Principal Investigator is a leader in the utilization of TAE for the treatment of fibroids in the United States and the collective experience of other involved investigators at the various centers would indicate a reasonable expectation of continued success clinically with the TAE procedure, though there will certainly be skill variability issues.

Working plan and operations manual
The investigators have a generally good working plan and have sought the advice and �consultation of leaders in the reproductive medicine field. The issues of patient selection seem to have been clarified. Some concern exists in regard to the issue of individual skill levels among the investigators involved.

Availability of patients/subjects for the trial
As noted previously, the locations of multiple medical centers, many within dense urban environments will likely provide the suggested number of patients, for the proposed trial.

Overall feasibility and likelihood of achieving trial goals and cost/benefit of failure
Given the population of patients available to the investigators, the likelihood of completing the study as outlined is good. The cost/benefit of success significantly outweighs the cost/benefit of failure.

The experience and qualifications of the investigators in scientific area of trial and in successfully completing trials
The investigators have good experience in the TAE procedure, given the recent advent of this technology. In terms of successfully running clinical trials, the investigators appear to have incorporated more experienced individuals in developing, implementing or reporting the results of the rather extensive clinical trial proposed in this application.

Competence and experience of the technical and administrative staff
The technical and administrative staff as outlined in the current proposal represents more seasoned individuals with appropriate experience in clinical trials.

Effectiveness of organization
The exact organizational structure of the trial group has been outlined in reasonable detail. Dr. Goodwin assumes full responsibility for completion of the trial and reporting of outcomes, he does not completely outline the delegation of specific authority, meetings and time lines necessary to accomplish his trial goals.

Resources and Environment
The collection of academic institutions involved have excellent resources, scientific and clinical environments. No concern exist regarding resources and environment.

Inclusion of women and minorities
This trial will exclusively be done in women and, between the multiple centers, inclusion of minorities represents a significant strength of this proposal for a clinical trial.

INDIVIDUAL INSTITUTIONAL PROPOSALS

Qualifications and experience of investigators
As noted above, the Principal Investigator has primarily experience in the TAE procedure and has incorporated the assistance of other appropriate professionals in clinical outcomes and statistical analyses.

Availability of technical and scientific resources
Both the technical and scientific resources necessary for a successful trial are extant with each individual institution.

Local organization and administration
No concerns noted.

Commitment of institution to and relative staff to clinical trial
Specific institutional commitments have been included with the application.

Availability of patients/subjects
As noted above, the patient availability at each site location is excellent. The likelihood of their participation is probably good.

Commitment of investigators to joint protocols
There is little tangible evidence of significant past interactions among the Principal Investigator and others; however, the individuals have clearly worked well together during preparation of this much improved application.

CRITIQUE 3

This is a prospective, randomized multicenter trial to examine the effectiveness and quality of life outcomes of uterine artery embolization versus abdominal myomectomy in women with abnormal uterine bleeding due to leiomyomata. The primary outcome is the effectiveness of the techniques in reducing uterine bleeding. Secondary outcomes include evaluation of the procedures on pain or bulk symptoms, quality of life, and ovarian function.

OVERALL CLINICAL TRIAL
It is not clear to this reviewer that the question to be addressed is of significant importance to justify this study. There are no scientific or mechanistic questions to be addressed by the clinical trial. The use of myomectomy versus hysterectomy for abnormal uterine bleeding are available to women and it is unclear why women would chose a similarly invasive and apparently much more painful procedure with an increased risk of premature ovarian failure that is also more costly based on their estimates. If funded, the study should be restricted to women who do not wish to conceive because of the risk of premature ovarian failure. Little information is provided concerning the validity and reliability of the questionnaires. Little discussion is made about the issue of pain control after the embolization (listed as 1-60 days) or the febrile episodes. No data are provided about the feasibility of recruiting strategy to the two arms of the study. Another concern is the cohesiveness of the sites enrolled in the trial. In the revision, the investigators have included staff gynecologists as well as radiologists, but many of the investigators, including the Principal Investigator, are not previously experienced in clinical trials. Thus, how can such a complex multicenter trial be completed effectively? It is not clear what the institutional commitment of each of the institutions is to the project.

Budget
The requested budget is recommended.

ADMINISTRATIVE NOTE A sum of $1,745 will be paid to the field center for each patient recruited, not counting patient recruitment. More detail should be provided about how this is allocated between study coordinator, investigator effort, and other costs. They estimate that only 10% of the patients will be uninsured; yet in many communities (e.g., this reviewer's), the major insurers do not cover UAE for treatment of fibroids because it is thought to be "experimental." Has it been determined in each community that UAE is largely (90%) covered? For the noncovered cases, $6,000 for embolization is much higher than the current reimbursement in many areas for hospital plus physician charges. Does this figure represent prevailing hospital and physician charges, prevailing reimbursements, or the costs of doing the procedure? Since MRis are not normally a part of the standard care for patients undergoing myomectomy (nor probably are they a standard for UAE), can follow-up MRs be billed to insurers as part of routine medical care?

Human Subject
Code 44. Concern regarding pain management issues and discussion of risk of premature ovarian failure are not clearly addressed. # ad hoc or special section application percentiled against "total CSR" base.

Meeting Roster

POPULATION RESEARCH SUBCOMMITTEE
NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT INITIAL REVIEW GROUP
NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT CHHD-G
June 12, 2000 - June 13, 2000

CHAIRMAN
Bartke, Andrzej, Ph.D.
Professor and Chairman
Department of Physiology
Southern Illinois University
School of Medicine
Carbondale, IL 62901
abartke@som.siu.edu

Cameron, Judy L., Ph.D.
Associate Scientist/Professor
Division of Reproductive Biology
Oregon Regional Primate Research Center
Beaverton, OR 97006
http://www.pitt.edu/~neurosci/cameron.html
http://eluviis.ohsu.edu/PhysPharm/ibms/faculty/cameronj/
cameronj@ohsu.edu

Childs, Gwendolyn V., Ph.D.
Vice Chair and Professor
Department of Anatomy and Neurosciences
The University of Texas Medical Branch
Galveston, TX 77555��
http://cellbio.utmb.edu/childs/CV_childs.htm
Department of Anatomy �(effective 4/00)
University of Arkansas for Medical Sciences
4301 W. Markham St; Slot 510
Little Rock, AR, 72205
childsgwenv@exchange.uams.edu
Email to pager: gvchilds@email.skytel.com

Cidlowski, John, Ph.D.
Chief
Laboratory of Signal Transduction
National Institute of Environment Health
National Institutes of Health
Research Triangle Park, NC 27709
http://dir.niehs.nih.gov/dirlst/cidlowski.htm
http://dir.niehs.nih.gov/dirlst/
CIDLOWSKI@niehs.nih.gov

Deleon, Patricia A, PhD
Professor��
Molecular Biology
Department of Biological Sciences
University of Deleware
Neware, DE 19716��
pdeleon@udel.edu

Greene, Paul G, PhD (Temporary Member)
Associate Professor of Medicine
Behavioral Medicine Unit
University of Alabama at Birmingham
BIRMINGHAM, AL 35205
pgreene@bmu.dopm.uab.edu

Guzick, David S., M.D., Ph.D.
Professor and Chair
Department of Obstetrics and Gynecology
School of Medicine and Dentistry
University of Rochester
Rochester, NY 14642
(716)275-5201
http://www.urmc.rochester.edu/stronghealth/ivf/guzick.html
DAVID_GUZICK@URMC.ROCHESTER.EDU

KOPF, Gregory S., Ph.D.
Professor
Department of Obstetrics and Gynecology
School of Medicine
Center for Research on Reproduction and Women's Health
University of Pennsylvania
Philadelphia, PA 19104
(215) 573-4780
http://health.upenn.edu/camb/fac/Kopf.html
kopf@mail.med.upenn.edu

Liu, James H., M.D.
Professor
Department of Obstetrics and Gynecology
College of Medicine
University of Cincinnati
Cincinnati, OH 45267
James.Liu@uc.edu

Matsumoto, Alvin, M.D.
Associate Professor
Department of Medicine
Division of Gerontology and Geriatric Medicine
School of Medicine
University of Washington
Seattle, WA 98198
http://depts.washington.edu/geront/faculty/matsumot.htm
alvin.matsumoto@med.va.gov

Osteen, Kevin G., Ph.D. (02)
Professor
Department of Obstetrics and Gynecology
Division of Reproductive Endocrinology
Vanderbilt University School of Medicine
Nashville, TN 37232
(615) 322-4196
kevin.osteen@mcmail.vanderbilt.edu

Radovick, Sally M, MS
Assistant Professor
Department of Pediatrics
Section on Reproductive Endocrinology
Children's Hospital
Harvard Medical School
Boston, MA 02115
(617) 355-6421
radovick@a1.tch.harvard.edu

Wierman, Margaret E., M.D.
Associate Professor
Department of Endocrinology Medicine
University of Colorado
School of Medicine
Denver, CO 80262��
303-399-8020 x 3137
margaret.wierman@uchsc.edu

Zimmerman, Ralf C., MD (Temporary Member)
Assistant Professor
Department of Obstetrics and Gynecology and Psychiatry
Divsion of Reproductive Endocrinology
Columbia University
New York, NY 10032
212-305-4665

SCIENTIFIC REVIEW ADMINISTRATOR
Ranhand, Jon M., PhD
Health Scientist Administrator
Division of Scientific Review
National Institute of Child Health and Human Development
Bethesda, MD 20892
(301) 435-6884
ranhandj@csr.nih.gov

GRANTS TECHNICAL ASSISTANT
Coleman, Thanora
Division of Scientific Review
National Institute of Child Health and Human Development
Bethesda, MA 20892