Food and drug administration




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UNITED STATES OF AMERICA


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FOOD AND DRUG ADMINISTRATION


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CENTER FOR DRUG EVALUATION AND RESEARCH


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DERMATOLOGIC AND OPHTHALMIC DRUGS

ADVISORY COMMITTEE


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46TH MEETING


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TUESDAY,

JULY 15, 1997


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BETHESDA, MARYLAND


The Advisory Committee met in the Versailles Room of the Holiday Inn, 8120 Wisconsin Avenue, at 8:30 a.m., Joseph McGuire, Jr., M.D., Chairman, presiding.


PRESENT:


JOSEPH McGUIRE, JR., M.D.

KEN HASHIMOTO, M.D.

EDUARDO TSCHEN, M.D.

SUSAN COHEN, B.S.

JOEL MINDEL, M.D.

E. WILLIAM ROSENBERG

M. ROY WILSON, M.D.

LYNN M. DRAKE, M.D.

TRACY RILEY, Executive Secretary


SPECIAL GOVERNMENT EMPLOYEES, CONSULTANTS, AND GUESTS PRESENT:


WILMA F. BERGFELD, M.D.

O. FRED MILLER, III, M.D.

EVA F. SIMMONS-O'BRIEN, M.D.

PHILIP T. LAVIN, Ph.D.

LAWRENCE B. HARKLESS, D.P.M.

BENJAMIN A. LIPSKY, M.D.

DAVID J. MARGOLIS, M.D.

CLINTON M. MILLER, III, Ph.D.

THOMAS A. MUSTOE, M.D., Ph.D.

DAVID R. THOMAS, M.D.

DIANE COOPER, Ph.D., R.N.


Also Present:


Kurt Stromberg, M.D.

Karen Weiss, M.D.

Libero Marzella, M.D., Ph.D.

David Finbloom, M.D.

William H. Eaglstein, M.D.

Celia Witten, Ph.D., M.D.

Joanne Less, Ph.D.

Jonathan Wilkin

Kathryn O'Connell, M.D., Ph.D.

Ellen Redding

Ruth Bryant

Adrian Barbul

George Cherry

Oscar Alvarez

Diane Krassner

Stephen L. Harlin, M.D.

A-G-E-N-D-A

Introduction, Chairman McGuire 4


Conflict of Interest Statement 8


Public Comment Session


Advanced Tissue Sciences, Ellen Redding 9

Wound Ostomy and Continence Nurses Society, 15

Ruth Bryant


Discussion Objectives, Karen Weiss 20


TOPIC 1: STANDARD OF CARE


Variability of wound management 26

Aspects of wound care 52

Methods for compression load pressure 63

management

Perforator competence and Doppler studies 68

Debridement of venous stasis ulcers 78

Dressings 90

Surgical closure 94

Systemic antimicrobials 96


TOPIC 2: DISCONTINUATION OF STUDY TREATMENT

FOR ADVERSE EFFECTS, BLINDING, AND VEHICLE CONTROLS


Impacts of infection and removal from

trial 107

Third party evaluation 130

Vehicle controlled studies 138


TOPIC 5: ENDPOINTS


Ulcer closure 155

Products defined by the sponsor as wound

healing agents 164

Ulcer recurrence 195

Wound debriding agents 201

Wound deodorizing agents, topical

antimicrobial and topical analgesics 211

Acceptable closure 219


TOPIC 3: ENTRY CRITERIA INDICATIONS 251


TOPIC 4: WOUND ASSESSMENT 270


TOPICE 6: STERILITY OF THE PRODUCT 299

P-R-O-C-E-E-D-I-N-G-S

(8:38 a.m.)

CHAIRMAN McGUIRE: Good morning. This is the day 2 of the 46th meeting of the Dermatologic and Ophthalmic Drugs Advisory Committee meeting.

The meeting today will be structured quite differently than the meeting yesterday. We're doing something that's different, a little bit different, for this committee, and also it's a little bit different for the agency. The agency is generating a guidance document for wound care and wound care products, and it is their purpose that we help them and advise them in assembling this.

We have some different people at the table this morning. We still have a pretty big table so I'd like to start at my right and have members of the advisory committee and the FDA introduce themselves, beginning with Doctor Wilkin.

Could we have some sound. Sir, if you could just stay over there for a while, we're going to introduce the people at the table.

Doctor Wilkin.

DOCTOR WILKIN: Jonathan Wilkin, Director, Division of Dermatologic and Dental Drug Products.

DOCTOR LESS: Joanne Less, Director of the Investigation Device Exemption staff.

DOCTOR WITTEN: Celia Witten, Division Director for the Division of General and Restorative Devices in the Office of Device Evaluation.

DOCTOR WEISS: Karen Weiss, the Director of the Division of Clinical Trials in the Center for Biologics.

DOCTOR MARZELLA: Louis Marzella, reviewer in the Division of Clinical Trials.

DOCTOR THOMAS: David Thomas, Geriatric Medicine.

DOCTOR HASHIMOTO: Ken Hashimoto, Department of Dermatology, Wayne State University in Detroit.

DOCTOR MUSTOE: Thomas Mustoe, Division of Plastic Surgery, Northwestern University in Chicago.

DOCTOR FRED MILLER: Fred Miller, dermatologist, Geisinger Division of the Penn State-Geisinger Health System.

DOCTOR DRAKE: Lynn Drake, Department of Dermatology, University of Oklahoma Health Sciences Center.

MS. RILEY: Tracy Riley, Executive Secretary to the committee.

CHAIRMAN McGUIRE: Joseph McGuire, Pediatrics and Dermatology, Stanford, California.

DOCTOR BERGFELD: Wilma Bergfeld, Departments of Dermatology and Pathology, The Cleveland Clinic Foundation.

DOCTOR MINDEL: Joel Mindel, Departments of Ophthalmology and Pharmacology, Mount Sinai Medical Center, New York.

DOCTOR SIMMONS-O'BRIEN: Eva Simmons-O'Brien, Departments of Dermatology and Internal Medicine, Johns Hopkins University Hospital.

DOCTOR ROSENBERG: Bill Rosenberg, Dermatology at the University of Tennessee, College of Medicine.

DOCTOR COOPER: Diane Cooper, Colleges of Nursing and Medicine, University of South Florida, and Institute for Tissue Regeneration, Repair, and Rehabilitation in Bay Pines, Florida.

DOCTOR TSCHEN: Eduardo Tschen, Department of Dermatology, University of New Mexico.

DOCTOR LAVIN: Phil Lavin, Boston Biostatistics and Harvard Medical School.

MS. COHEN: I'm Susan Cohen, I guess I can say Boston, too. And I co-host and produce a radio program on consumer issues.

DOCTOR MARGOLIS: David Margolis, Department of Dermatology and Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine.

DOCTOR HARKLESS: Larry Harkless, podiatrist, Department of Orthopedics, University of Texas Health Sciences Center, San Antonio.

DOCTOR LIPSKY: Benjamin Lipsky, University of Washington, general internal medicine and infectious diseases in the VA Puget Sound.

DOCTOR WILSON: M. Roy Wilson, ophthalmology, Charles Drew University and UCLA.

DOCTOR CLINTON MILLER: Clint Miller, Professor Emeritus, Medical University of South Carolina.

CHAIRMAN McGUIRE: Thanks very much.

Tracy Riley, the Executive Secretary, will a conflict -- Oh, sorry.

DOCTOR O'CONNELL: Kathryn O'Connell, Division of Dermatology and Dental Drug Products, FDA.

CHAIRMAN McGUIRE: You've got to be on time.

Doctor -- Tracy Riley will read the conflict of interest statement.

MS. RILEY: Thank you. Good morning.

This is the conflict of interest statement for the Dermatologic and Ophthalmic Drugs Advisory Committee for July 15th.

The following announcement addresses the issue of conflict of interest with regard to this meeting and is made a part of the record to preclude even the appearance of such at this meeting. Based on the submitted agenda for the meeting and all financial interests reported by the committee participants, it has been determined that since the issues to be discussed by the committee will not have a unique impact on any particular firm or product, but rather may have widespread implications to all similar products, in according with 18 U.S. Code 208(b)(3), general matters waivers have been granted for today's meeting.

In the event that the discussion involves any other products or firms not already ont he agenda for which an FDA participant has a financial interest, the participants are aware of the need to exclude themselves from such involvement and their exclusion will be noted for the record. With respect to all participants, we ask in the interest of fairness that they address any current or previous financial involvement with any firm whose products they may wish to comment upon.

CHAIRMAN McGUIRE: I think we have speakers for the public session.

Is there anyone here from Advanced Tissue Sciences? This is Ellen Redding.

MS. REDDING: Good morning. My name is Ellen Redding. I'm the Vice President of Regulatory Affairs and Quality Systems for Advanced Tissue Sciences. I welcome the opportunity to work with FDA and with the advisory panel on what I believe is a very important topic of discussion, certainly very timely in this day and age when we are appreciating more fully the importance of conducting chronic wound studies with some novel therapies as well as some unique opportunities for this patient population. I think this is, as I said, a very timely discussion and guidelines for future studies would be greatly welcomed.

Advanced Tissue Sciences has been involved in chronic wound studies for many years now in the field of tissue engineering which has allowed us some very unique opportunities to work with some unique and potentially innovative products in this area. We have worked in the area of venous stasis ulcers, pressure ulcers, and now diabetic foot ulcers.

So, we welcome the opportunity to provide some suggestions, some experiences that we've had, and hopefully what will be a very fruitful discussion this morning and will lead to some guidelines that the entire industry and the entire field of medicine can appreciate over time.

Certainly we believe that pivotal chronic wound healing studies should and can be very well controlled. This is an area where industry is becoming increasingly more involved. These are very large, very expensive trials. There is a great deal of competition for this patient population base and in many, many -- at many, many times, it is very difficult to know whether or not we have a successful therapy until the termination of a very large, very expensive trial. So, we need to take every opportunity that we can to be creative, to reduce costs as must as possible. Ultimately to reduce costs of the therapies to the population.

Unlike active acute wounds, chronic wounds are typically secondary by-products of the underlying disease which offers many, or provides many, variables to these clinic settings. And in order to control as many of these variables as possible and limit the size of the trial, I think we do need to be very sensitive to the patient population that we're dealing with.

In the cases where there are gold standards of care, standard therapies which do exist, I think we need to pay particular attention to these. It is very important, very valuable pieces of information upon which we can design very solid clinic trials. In the case where there are solid and building historic controls, this information can provide us a great deal of insight into the standard adverse reactions expected in this patient population, for instance, or certainly the availability of typical standards of care to this patient population for control purposes. When there are cases where there is not agreement on what a standard of care may exist, then you do have more opportunities for creativity. But certainly where there are large and increasing patient populations, we do have an opportunity to reduce our sample size, perhaps, and look at the possibility of a 2 to 1 or a 3 to 1 clinical study design.

Increasing availabilities of inventive therapies do not always lend themselves to the more desirable double blind studies. In the case of tissue engineered products, for instance, and when we're dealing with tissues such as Dermagraf, a product is frozen and must be thawed at the patient's bedside or in the clinic. And these kinds of situations do not lend themselves to double blind studies.

The study design must insure that the effectiveness of the treatment can be determined. We need to absolutely be able to tell at the end of the study that our treatment had in fact made the difference. And to that end, the control arm needs to be very carefully developed. Both the control arm and the treatment arm to the extent possible, should receive the same treatments so that at the end of the study we certainly can tell that the treatment that is being studied is the one that is making the difference.

We have to take into consideration the issues of practicality in the compliance when you're dealing with design of a control arm or the standard of care. And we must allow the patients to continue an active way of life.

Control of all the variables or as many variables as possible is certainly desirable but flexibility is required. You cannot always measure the compliance of the patients. When you're dealing with issues such as weight bearing or the possibility that bed rest may be the optimal method of healing of certain ulcer types, you should always try to take into consideration what the patient will or will not bear, what the patient population expects or cannot comply with. Certainly we have heard that in certain cases bed rest is the optimal method of treating certain types of ulcers but when you're dealing with a patient population that may include patients in the work force or may include individuals who are primary care givers, this is not a practical source of a healing methodology. So, this needs to be taken into account in the patient population that you're dealing with.

And of course, objective endpoints need to be established for complete healing but we need to avoid, whenever possible, the need for a third party blinded assessment. This is not always practical in the clinical setting and it also adds to the cost of the study. We do need to develop objective endpoints or definitions of endpoints that take the guess work out of the final assessment for the investigator and take out that bias. But that is certainly possible. We can use when cases of wound healing studies or ulcer studies, we can use tracings for computer analysis. We can use photographs. Certainly start out with some very definitive definitions of complete healing such as epithelial layer, presence of epithelial layer, lack of drainage, and then we can also add patient follow up to confirm the next week, for instance, that total healing has in fact taken place.

When you're dealing with issues of complete wound healing in chronic ulcers, frequently the discussion of the need for wound biopsies or the value of wound biopsies come up. And this is not always, again, a practical measure of complete healing or even an assessment, or an opportunity for an assessment, of the type of healing that has taken place. In many cases, once these very chronic long term ulcers have healed, patients are not going to want to, and physicians are not going to want to, rebiopsy that wound, inflicting additional trauma to that wound when we finally had success in this case. We certainly have seen in the literature where these types of insults cause recurrence of the ulcers and in many cases the IRBs and physicians consider this to be unethical. So, we need to consider the value of these kinds of measures.

So, in conclusion, certainly chronic wound healing studies can be well controlled but the definition of that good control really must remain flexible enough. We need to -- it's very important to separate out what is essential information from non-essential information, in light of the fact that we're dealing with a very specific patient population who have had these wounds for a very long period of time and to have actually very active lives to conduct under the circumstances.

Thank you very much.

CHAIRMAN McGUIRE: Thank you.

We have a representative this morning from the Wound Ostomy Continence Nurses Society, Ms. Ruth Bryant.

MS. BRYANT: Good morning. My name is Ruth Bryant. I am a clinical nurse specialist in wound care. I've been a clinical specialist for the past 15 years. I'm also the past president of the Wound Ostomy and Continence Nurses Society which is an organization of 4,200 members dedicated to the care of patients with wounds, ostomies, and incontinence. And in 1998, we'll be celebrating our 30th anniversary, so we've been around of ra while.

The committee members already have a copy of our response to questions for consideration concerning clinical trial designs for chronic cutaneous ulcers. And on behalf of the WOCN, what I'd like to do is just take a few minutes to add some comments addressing clinical care specifically that would ultimately relate to clinical trial design and to adoption of clinical trial results and to clinical practice.

I represent an organization of nurses who have championed chronic wound care before it was in vogue, when the only wound care product available was gauze, before moist wound healing itself was even widely accepted or considered standard care. Nurses have played a key role in the introduction and acceptance of transparent dressings, hydrogels, hydrocolloids, and the many other wound care products that we enjoy today. So, we are thrilled with the advent of interactive products that combine modalities that are demonstrated to be efficacious and we are concerned about how clinical trial designs will occur in wound care.

We've also played a key role in educating nurses and physicians in comprehensive wound management, stressing the need to manage the disease process while optimizing the topical wound environment. The clinical reality is that nurses provide much of the wound care in the United States. Our involvement can range from identification of ulcer etiology, wound assessment, treatment selection, and conservative sharp debridement to simply application of prescribed treatment. The generalist health care provider, be that a nurse or a physician, will be prescribing and applying products and there is a strong potential for misdiagnosis of ulcer types, for over utilization of products, and this has already been demonstrated through some of the things that have happened with HCFA and claims that have been made for products, because we all know more is better for wounds, or we think they are. And inadequate attention to critical comprehensive patient care issues such as offloading, management of shared forces, and adequate glucose control.

In many health care settings it will be the nurse who discovers the foot ulcers, who rolls the patient over and finds the pressure ulcer, and then who relays that information to the physicians and obtains the order for topical care, often times, actually, requesting a specific product or a specific intervention. Wound care nurses have long advocated for extensive debridement of neuropathic ulcers, adequate debridement of pressure ulcers, and encouraged appropriate management of venous ulcers. However, every day we encounter reluctance to debride. We encounter reluctance to moist wound healing techniques. And we encounter impediments to appropriate comprehensive care.

As new products become available, as new clinical trials unfold, extensive education programs as essential and it should include nurses. And it should address comprehensive wound management in addition to adequate debridement. Ideally, the WOCN would love to see the incorporation of phrases such as "this product is intended for use in conjunction with a comprehensive management approach under the direction of a physician or a wound care specialist." We support the extensive investigation of safety of new products. We think there's a lot of room for improvement in that area. And we appreciate the specific direction on the appropriate size of ulcer application for these products because all too often these wounds are huge and there's a lot of opportunity for absorption. We also appreciate the labeling of products to be specific so that the products actually address whether they're indicated for a Stage 2, Stage 3, or the extent of the ulcer that they're appropriate for, so that they will curtail inappropriate use of products on extremely shallow wounds.

Must has been said about education in the past. The assumption is that education will approve aggressive debridement, compliance, offloading, et cetera. The fact that there are many other factors that influence compliance such as access to offloading devices, diabetes monitoring equipment, lymphedema control. Much research is needed looking into these other issues because the topical management or whatever we identify will not be sufficient in and of itself. Topical care cannot be seen as a panacea, otherwise we will see anyone who breaks down with an ulcer again recur with the ulcer because they have not treated the underlying pathology.

Topical care is a short term fix. All of us would love to see the long term pay offs. We love to see the wound heal. But we cannot lose sight of a need to assure access to products and resources so that patients can actually manage their underlying disease. We applaud the activities by FDA to look at chronic wound management and appropriate clinical trial design. We also applaud actions by HCFA which include providing diabetes management supplies and studying the efficacy of support services and lymphedema devices because we believe these activities actually dovetail very nicely with the current topic of wound care.

In closing, as wound care specialists, the WOCN is eager to support advancement of clinical practice based on scientific evidence and we are eager to work with participants here in future endeavors involving the care of patients with chronic or acute wounds.

Thank you.

CHAIRMAN McGUIRE: Thank you, Ms. Bryant. That was a very thoughtful statement.

I think now we work. Would, Doctor Weiss, would you like to make an introductory statement?

I think many of you have the document we will be working from. If not, these have been distributed to industry. There are also copies in the foyer. And we will be following the document fairly-- Well, I don't know. We intend to follow it fairly carefully.

DOCTOR WEISS: Good morning. If I can get the first slide. I just have a few overheads just to give the committee and the audience a little bit of a background on how we got to where we are today.

First of all, as hopefully many people are aware but maybe not everybody, there are, of course, three centers within the Food and Drug Administration that are involved in reviewing products for medical use. And all three of these centers have the jurisdiction to review products that are being used for wound healing, the Center for Biologics, the Center for Devices, and the Center for Drugs. And on the overhead are just examples of some of the different types of products that are under the purview of each of the different centers.

(SLIDE CHANGE)

Now, in addition to this division, there is also a inter-center wound healing clinical focus group. And this focus group is, I think, somewhat unique within the agency because it has members that are reviewers from all three centers that are involved in the review of products for wound healing. The mission of this focus group is to expedite development of products for wound healing. The functions of this group are to enhance consistency of the reviews across the centers, to share information from all parts of the agency, to provide a forum for clinical problem solving, and to act as a direct tri-center liaison from the FDA to academia and to industry and other types of organizations.

Now, there have been opportunities already where members of the focus group have been able to comment and serve as a representative of the agency to various organizations. Back in March of 1993, the FDA sponsored a wound healing workshop. This was held at Masur Auditorium on the NIH campus. Subsequently, members of this group published an article,
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