Food and drug administration

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MARCH 15, 2002

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This transcript has not been edited or corrected, but appears as received from the commercial transcribing service. Accordingly, the Food and Drug Administration makes no representation as to its accuracy.

The Committee met at 8:00 a.m. in the Grand Ballroom, the Gaithersburg Holiday Inn, Two Montgomery Village Avenue, Gaithersburg, Maryland, Dr. Kenrad E. Nelson, Chairman, presiding.








ROBERT J. FALLAT, M.D. Consumer Representative

LIANA HARVATH, PhD Temporary Voting Member

F. BLAINE HOLLINGER, M.D. Temporary Voting Member

JEANNE V. LINDEN, M.D. Temporary Voting Member


JUDY F. LEW, M.R. Member



DAVID F. STRONCEK, M.D. Temporary Voting Member



LINDA A. SMALLWOOD, PhD Executive Secretary



III. Review of Data Supporting Extension of

Dating Period for Platelets

A. Introduction and Background 12

Jaro Vostal, M.D., Ph.D.

B. Extension of Platelet Storage 16

Sherrill Slichter, M.D.

C. Safer, Cheaper and Just as Good 56

James AuBuchon, M.D.


D. Committee Discussion 112

IV. Bacterial and Fungal Contamination of

Human Tissue Intended for Transplantation

A. Introduction and Background 140

Ruth Solomon, M.D.

B. Microbial Contamination and Cross 147

Contamination Concerns During Processing

Mary Malarkey

C. Preliminary Findings From 168

Investigation of Allograft-Associated Infections

Marion A. Kainer

D. Reducing the Risk of Tissue 203

Transplant-Transmitted Infections

D. Ted Eastlund, M.D.

E. Adverse Reactions After Corneal 241


Michael A. Lemp, M.D.


F. Committee Discussion



(8:07 a.m.)

DR. SMALLWOOD: May I ask the Committee members to please be seated.

Good morning. Welcome to the second day's session of the 72nd meeting of the Blood Products Advisory Committee. I am Linda Smallwood, the Executive Secretary.

On yesterday I read the conflict of interest statement that pertained to the proceedings of this meeting. If there are any questions concerning that, you may see me at the break, and I will be happy to share that statement with you.

For today's meeting, we will have Dr. Jeanne Linden, who is a consultant and who will be participating with us today. Also, two of our members will be -- that were present yesterday are absent, Dr. Fitzpatrick and Dr. Klein.

I would just like to ask the Committee members, if you need to have arrangements made for taxis, to please see the young ladies at the desk outside during the break.

There will be one deviation from our agenda this morning. We will start out with a presentation from Dr. Richard Lewis who will provide you with a summary of a workshop on medical errors. Other than that, we will proceed with our agenda as printed, and hope to keep on time. Thank you.

DR. LEWIS: Thank you, Dr. Smallwood.

I have a 15 minute summary of the workshop, and Dr. Smallwood told me that I had to do it in seven minutes. That was one of the conditions of being on. So she is serious about keeping on time today, and I'll try to do my best to do that.

In the month of February we helped sponsor a workshop on best practices to reduce transfusion errors, and I think this is a very important subject, and it was a worthwhile workshop, which was sponsored both by FDA and the Agency for Health Care Research and Quality, both HHS agencies.

If I could have the next slide, please.

We looked at various areas of errors that could occur in transfusion services and blood banks. We summarized some of the current safety initiatives within Health and Human Services, looked at what some of the sources are for errors, looked at some systematic errors and how to address them, how reporting could figure in on errors in transfusion, and looked at some of the technology that could address some of those problems, both current technology and future technologies. Next slide.

Within HHS, to summarize some of the Patient Safety Task Force initiatives: The Patient Safety Task Force is an HHS-wide task force which includes members from FDA, CMS, CDC, and AHRQ.

The ARHQ also has some independent work on patient safety. They are funding grants and contracts to address medical errors, and also lead the Patient Safety Network, which is an effort to device a large computer analysis method, not a single database but a method to look at all of the different types of information relating to errors that might be contained within HHS.

We also heard from CMS and discussed their Quality Improvement Organization, which also is an error reporting emphasis. Next slide.

Some of the sources of transfusion error: We heard that there are roughly -- this is data from Kathleen Sazama as well as Jeanne Linden. Roughly, over the last ten years 37 deaths per year occur as a result of transfusion errors. Estimates are that about five percent of -- this represents about five percent reporting.

The majority of those errors are ABO incompatibility, roughly 56-59 percent of fatalities, and these errors generally occur either at sample collection or at the actual transfusion. Twenty-five to 29 percent of those errors occur at the blood bank. Next slide.

So it was confirmed by presentation from Hal Kaplan that the human/system interface is where most of these particular errors occur, and some of the contributing factors are wrist band removal, incorrect labels, and confusion over the name of the patient. Next slide.

We heard form Dr. Michael Busch about infectious disease testing, and he had looked at a large database of discordant results between NAT testing and serology in both HIV and HCV studies. He commented that investigating these particular discrepancies offered an opportunity to see where errors might occur in testing.

He put forth a rather large number. If you consider the errors in testing as well as prevalence, the chances of getting an infectious disease from a unit of blood were about one in one billion. Next slide.

We discussed systematic errors, and errors in a particular system and how one operates come from both the organizational level, physical contact with the patient, the environment that the individual -- in which they work, as well as the social attitudes in the particular establishment. It was pointed out that it is important to identify points in a process where errors are most likely to occur. Next.

One presentation addressed some of the inexpensive devices that are used in other areas. That was referred to as Poka-Yoke. It's a Japanese system, and some of the examples that they gave were, as you enter a parking garage, for instance, there is a wooden bar that hangs down that stops vehicles that are too large from going in. We saw how doors would have a handle on it to pull and a plate to push, and we were encouraged to look at some simple, inexpensive devices that prompt us technically to do the right thing and void errors. Next slide.

In evaluating the donor history questionnaire, Susan Wilkinson presented some work that she and some of her collaborators have done using an objective structured clinical examination. They had trained donors and tested the interviewers for their competency, and used this as a system of evaluating the actual donor history, the individuals taking the history as well as their interpretation of the responses. Next.

We looked at a number of reporting systems which changes the focus from identification -- In a hospital setting, it encourages changing the focus from identification of a liability situation to one in which you are constantly self-examining your system to determine where there might be particular errors. Next.

We heard form Sharon O'Callaghan, who discussed the FDA Biological Product Deviation Reporting in manufacturing. Most of those reports come in the areas of quality control, labeling or routine testing.

This particular system also includes a root cause analysis, and some of the major identification of causes for errors were that the individuals were too busy, that there were clerical errors or handwritten, as well as additional needs in the particular environment. Next slide.

MERS-TM is a system that I would hope that everyone has at least heard of, a reporting system that focuses on systems and training rather than individual liabilities, again. We heard an example of its implementation at a large facility and their event recognition and system correction methods. Next slide.

Barcoding today has a focus of HHS, and the Secretary Thompson has encouraged the development of a regulation that would require all drugs and biologics to have barcoding. The overall scope of that rule is yet to be decided, but look for this spring a large workshop to discuss both the scope as well as the type of barcoding.

We should all be familiar with ISBT 128, and we heard about the regulations and implementation of new rules to remove barriers to implementation of ISBT 128. Next slide.

We heard other technology trends. The automated donor interview was presented, and some information on how that facilitates the donor history. Dr. AuBuchon presented patient identification system, the blood lock, and his estimates were that it saved, in his facility roughly $200,000 quality adjusted life years, and he pointed out that, although this is very high for other implementation of medical procedures, however, in the context of some of the things that we do to reduce the incidence of infectious diseases in blood, this was rather small.

We also looked at laboratory instrumentation and some of the testing equipment, and how that particular equipment incorporates systems so to reduce interactions with humans and automate the process as much as possible to reduce errors in testing, as well as some patient identification systems, barcoding on wrist bands as well as on blood banks, and how that could reduce numbers of errors. Next slide.

In terms of future technologies, we heard some interesting presentations from the International Biometrics Association. They talked about identifying the actual biological unit through things such as voice scans, facial scans, and fingerprint analysis. I thought it was very interesting, in terms of fingerprint analysis, that there were devices as small as an inch in diameter that one could place their thumbprint on and read the individual immediately. It seemed to me that that could be very applicable to the patient setting where you could find an individual's fingerprint, whether they are conscious or unconscious, and identify the appropriate unit.

Software to identify an individual is available, and rapid -- Actually, it's faster to verify that an individual is who you think that it is than it is faster to identify an individual. I think this verification would be something that would be applicable in the hospital setting.

Thank you very much. I don't know how I did for time. I hope that I stayed within my boundaries. I appreciate the opportunity to present this. I thought it was an important topic and, hopefully, we will address it again at the AABB convention this fall. Thank you

CHAIRMAN NELSON: Any questions or comments? Yes, James?

DR. ALLEN: In one of your early slides where you showed 37 deaths per year and estimated that was about five percent reporting, given that the event is a death, I'm surprised at the degree of underreporting. Is there any explanation for that or ways to correct that?

DR. LEWIS: These were data from Dr. Sazama from M.D. Anderson, and she didn't cite, and I didn't follow up, what her actual sources were. She said that it had been reported. I was surprised, too, and it isn't in our regulations that it is mandatory reporting for all deaths that are associated with transfusion.


DR. LEWIS: Thank you.

CHAIRMAN NELSON: The first topic today on the agenda is review of data supporting extension of dating period for platelets, and this will be introduced by Dr. Vostal from the FDA.

DR. VOSTAL: Good morning, and thank you for the opportunity to introduce this session. Today we are going to talk about the extension of platelet shelf life from five days to seven days and about the quality of platelets that have been stored out to seven days.

Just as an introduction, I would like to direct your attention to the slide over here that covers the platelet storage milestones that we have had over the history of. Starting in 1981, back then platelets were stored out to three days, but improved plastics and bags allowed random donor platelet storage to increase from the three days to five days.

Things were going pretty well. So in 1984 this was further increased to seven days. However, about a year and a half later, in 1986, there was a BPAC Committee meeting very similar to this one. That discussed the incidence -- an increased incidence of bacterial contamination associated -- or bacterial contamination and substance -- transfusion substance reactions associated with platelet transfusions.

Based on this data, the dating period for platelet storage was moved back to five days. Now we fast forward to 2002, and we are coming to a point where we think we may have methods of controlling bacterial contamination of the platelet. This could be either by detection or decontamination.

So the question comes up again: When we have the bacterial contamination problem under control, whether we can extend the shelf life of platelets back out to seven days.

Could I have the next slide, please?

We have some reservations about directly extending the shelf life, and that is because there are major differences between platelets that were stored out to seven days in 1984 and the platelets that we are using today.

For example, if you look at the differences in the products that were used, in 1984 it was only random donor platelets that were stored out to seven days, but today we like to do random donor platelets as well as single donor apheresis platelets. Leukoreduction wasn't carried out back then. So there are plenty of leukocytes in these products. However, today leukoreduction is almost universal. So there is a big difference in terms of number of white cells present in these platelet products.

The storage conditions themselves have changed. The plastic bags that were used in 1984 have been improved with different plastics, and some of the apheresis instruments also have different plasma to platelet ratios. So all these things put together make for a different condition for storing platelets out to seven days.

If I could have the next slide. Now this slide -- This is a cartoon modified from Scott Murphy's review in Transfusion Medicine Reviews in 1999. It kind of focuses on the different factors that play a role in storing platelets.

Of course, there is the plastic bag that's gas permeable to oxygen and carbon dioxide. The platelets are themselves stored at room temperature in plasma, and they have the presence of leukocytes. The biochemical events that take place in these cells is that free fatty acids are metabolized by oxidative metabolism to ATP, and glucose is metabolized by glycolysis to lactate and lactic acid.

Now the ratio of these -- or the predominance of these pathways is determined by the availability of oxygen that is diffusing through the outside -- through the bag.

In the lack of oxygen, the predominant pathway is glycolysis and produces lactic acid, leads to generation of acid in plasma. This is usually buffered by bicarbonate that can convert -- that can combine with the acid and generate CO2 which can then diffuse out of the bag.

If there is -- So in cases where there is low oxygen present, you can have a lot of acid generation. And if it overcomes the bicarbonate present in plasma, you can have a drop in acid or drop in pH. You can also have a rise in pH if the number of platelets present is decreased or if the number of leukocytes that also contribute to the cycle is decreased.

So the pH at the end of storage of the platelet product sort of indicates the conditions that the platelet went through when it was stored out.

Just to show you that we think these conditions are changes, I would like to show you the next slide. This is data that is collected by the FDA from platelet products that are submitted to FDA for licensure, and we measure pH at outdate of these platelet products.

You can see that in 1995 pH was close to 7. By '96-97 and up to '99, there is a rise in pH. This may not seem that much, but if you look at the next slide, here we show the percent of the products tested that have a pH greater than 7.4.

As you are going from '95 to '99, you can see that by 1999 more than 40 percent of the products have a pH greater than 7.4.

Now it's not clear whether this has any detrimental effects on platelets when they are transfused, but I think it demonstrates that the conditions for platelet storage are changing over time. That is why we are actually interested to see whether the platelets that are stored out to seven days under the current conditions will still work when transfused today.

So with that brief introduction, I would like to welcome Dr. Slichter, who is the Executive Vice President of Research at Puget Sound Blood Center. She is going to continue with the clinical aspects of seven-day platelet storage.

DR. SLICHTER: Thank you. Could I have the first slide, please. As Dr. Vostal has mentioned, in 1986 over 15 years ago now, the dating time of platelets was shortened from seven days to five days, because of bacterial concerns, you know, as this -- let's see, have we got a pointer? There.

Because of this difference in growth rate of bacterial in platelets, which as everyone knows, are stored at room temperature, versus growth rate in red cells which are stored at four degrees Centigrade. So that's why the dating period of platelets was, in fact, reduced.

If you look at the data -- and this is a literature review done by Mo Blajchman, reported in 2000 -- bacterial contamination of a platelet component is not insignificant, .3 to 1.6 percent. Transfusion associated sepsis is one in 50,000 transfusions with a 20 percent fatality rate, and would suggest that there are 50 to 100 deaths per year associated with bacterial contamination.

Now the causes of bacterial contamination are pretty well understood. Probably the biggest reason for bacterial contamination is inadequate skin preparation prior to the venipuncture. One way to potentially avoid this complication is to remove the first aliquot of blood, which is considered to reduce the risk by taking either the skin plug out of the system and diverting it prior to drawing the rest of the blood into a bag.

The real advance, I think, in terms of whether there is a possibility for extending platelet storage is in the last two areas. There are -- and Dr. AuBuchon who follows me will discuss this. There are a variety of systems now that may be able to be used to detect the presence of bacteria prior to release of the product from the blood center that will allow us to prevent bacterial transfusion, and extend platelet storage.

The other process that is moving along is a decontamination process. So that there are techniques now available for pathogen inactivation of platelets prior to their storage.

Now what I am going to talk to you about today, because I have a limited amount of time, is I am going to concentrate on the
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