FOOD AND DRUG ADMINISTRATION

P R O C E E D I N G S (8:08 a.m.)

MR. JEHN: I am going to start the meeting with a brief COI statement, and then move on. Again, this meeting today was originally going to have a closed session, but today is totally public. That session has been canceled.

This brief announcement is in addition to the conflict of interest statement read at the beginning of the meeting on November 3, and will be part of the record for the Blood Products Advisory Committee meeting on November 4, 2005.

This announcement addresses conflict of interest for the discussions of topic II, on alpha-1 protease inhibitor products.

In accordance with 18 US Code Section 208(b)(3), waivers have been granted to Drs. Donna Di Michele and Katherine Manno.

Dr. William Duffell, Jr. is serving as industry representative, acting on behalf of all related industry, and is employed by Gambro BCT. Industry representatives are not special government employees and do not vote.

With regard to FDA's guest speakers, the agency has determined that the information provided by these speakers is essential.

The following information is being made public to allow the public to objectively evaluate any presentation and/or comments made by the speakers.

Dr. Mark Brantly is professor of medicine and molecular genetics and microbiology and Alpha-1 research professor at the University of Florida, Gainesville.

Dr. Hans Peter Schwarz is associate professor of medicine, vice president, global pre-clinical research and development, Baxter Bioscience, Vienna, Austria.

As guest speakers, they will not participate in the committee deliberations, nor will they vote. This conflict of interest statement will be available for review at the registration table.

We would like to remind members and consultants that if discussions involve any other products or firms not already on the agenda, for which an FDA participant has a personal or an imputed financial interest, the participants need to exclude themselves from such involvement, and their exclusion will be noted for the record.

FDA encourages all other participants to advise the committee of any financial relationships you have with the sponsors, products, competitors or firms, that could be affected by the discussion. Thank you.

DR. ALLEN: Thank you, Mr. Jehn. We will open the discussion this morning with an information update, serious adverse events following falsely elevated glucose measurements resulting from administration of an IVIG product containing maltose.

Presenters from the FDA will include Anne Gaines, Dr. Gaines, Dr. Pierce, and Ms. Bernhardt.

Agenda Item: Information - Serious Adverse Effects Following Falsely Elevated Glucose Measurements Resulting from Administration of an IGIV Product Containing Maltose.

DR. GAINES: Good morning. The topic of the presentation was just read to you. So, I won't bother reading that again.

I would mention, though, that this presentation has been divided into three segments. The first segment is an adverse event case report summary. The second and third segments will address other regulatory, biochemistry and device aspects of this issue.

Artifactual hyperglycemia -- and I will try to enunciate, perhaps sounding like an affectation, because we are talking about hyperglycemia and hypoglycemia, and obviously the distinction will be important.

Artifactual hyperglycemia, or falsely increased glucose results, may occur in patients who receive parenteral maltose, parenteral galactose, or oral d-xylose- containing biologic and drug products.

This artifactual hyperglycemia would most generally be manifested when blood glucose levels are measured with methodologies that are non-specific for glucose in the presence of maltose, galactose or d-xylose-containing products.

The clinical consequence of artifactual hyperglycemia is that falsely elevated glucose results, due to maltose, galactose or d-xylose, may result in life threatening or fatal hypoglycemia.

This life threatening or fatal hypoglycemia may result in two instances. The first instance would be when insulin is inappropriately administered for artifactual hyperglycemia.

Actual patient data from a patient who was receiving a maltose containing intravenous immune globulin product will serve to illustrate this point.

In a patient who was receiving this maltose containing intravenous immune globulin product, when the blood glucose level was measured using a glucose non-specific methodology, the result was reported as 231 milligrams per deciliter. This represented a falsely increased value, due to the presence of maltose.

When the patient's blood glucose level was measured using a methodology that was specific for glucose, the result reported was 84 milligrams per deciliter, and this value represented the patient's actual blood glucose.

So, had a treatment decision been made on the basis of the first glucose result, the 231 milligrams per deciliter, insulin might have been indicated.

However, based on the glucose result obtained using a glucose specific methodology, which gave the patient's actual glucose level, insulin would not have been indicated.

The second instance which may be associated with life threatening or fatal hypoglycemia is when treatment is not provided for actual hypoglycemia.

Again, data from a patient actually receiving a maltose containing intravenous immune globulin product can serve to illustrate this point.

When the patient's blood glucose level was measured using a glucose non-specific methodology, the result was reported as 167 milligrams per deciliter. Again, this represented a falsely increased glucose value due to the presence of maltose.

When the patient's blood glucose level was measured, however, with a glucose specific methodology, which reflected the patient's actual blood glucose level, the result was reported as 41 milligrams per deciliter.

Had the patient been assessed on the basis of the first blood glucose level, or the 167 milligram per deciliter level, no action would seemingly have been indicated.

However, if the patient was assessed on the basis of the second blood glucose level, which reflected the patient's actual blood glucose level, the patient would, as a minimum, needed to have been monitored, if not treated, for hypoglycemia.

CBER is aware of six case reports involving maltose containing intravenous immune globulin products that were associated with falsely elevated blood glucose measurements.

The first two case reports listed there were associated with fatal outcomes. The only case for which we have an appreciable amount of information is the first case. However, the other cases will also be summarized on the basis of what information was available.

The first case occurred in the United States and was reported to us in July of 2005. This case involved an 86-year-old male patient with a complicated medical history, including medical history of diabetes melitis.

He was admitted to the hospital with a four day history of cellulitis of his right foot, which rapidly progressed in a necrotizing fascitis and sepsis.

He received Octagam for treatment of septic shock. Octagam is an intravenous immune globulin product that was licensed by CBER in May of 2004.

It was initially licensed in 1993 in Europe, and is currently distributed worldwide. Octagam contains 10 percent maltose.

Septic shock represents an off label use of Octagam. The patient experienced a very complicated hospital course, including amputation of his right leg above the knee, renal dialysis, transfusion with various blood components and blood derivatives, among other medical interventions.

The patient's blood glucose levels were monitored with a glucose meter, a point of care device, that used a glucose non-specific methodology.

Similarly, his insulin doses were adjusted on the basis of the glucose meter levels which, again, were glucose non-specific methodology.

The patient became hypoglycemic, became comatose, was diagnosed with irreversible neurological damage, and expired following removal of life support measures.

This chart shows the patient's blood glucose levels in conjunction with octagam administration during hospital days three through five.

I will point out that the X axis represents the patient's sequential blood glucose measurements during this time frame, and it represents not an interval time line. It just is sequential data points. So, it is an ordinal time.

The blue horizontal line represents when octagam was administered. Octagam was administered as a five percent solution in three doses, as you can see, 10 grams, 70 grams, 35 grams respectively, that was infused at approximately 150 mls per hour.

The pink data points represent the patient's blood glucose levels that were obtained using a glucose specific methodology.

These pink data points represent the patient's actual blood glucose, regardless of whether or when octagam was administered.

The yellow data points represent the patient's blood glucose levels that were obtained using a glucose non-specific methodology.

Prior to the administration of octagam, these yellow data points would also reflect the patient's actual blood glucose level.

However, following the administration of octagam with increasing maltose concentrations in the patient's blood, these yellow data points would represent increasingly falsely increased glucose levels.

This graph is identical to the previous graph, with the exception that this shows a patient's blood glucose levels in conjunction with insulin administration.

The horizontal orange lines represent when the patient received regular insulin that was administered subcutaneously in doses ranging from two to 20 units.

The horizontal green line represents when the patient was administered IV drip insulin, and that was administered in doses ranging from 12 to 24 units per hour.

We can see that, as the octagam infusion began, the patient's blood glucose level started to rise. To appreciate the magnitude and the clinical consequence of these falsely increased values, I will just point out that the pink data points and the yellow data points representing the glucose specific and glucose non-specific values originally, initially, show a one to one correspondence.

For example, these represent values that may have either been simultaneously obtained, or obtained close enough in time that they can be reliably compared. You can see that the two values essentially reflect the same number of milligrams per deciliter. However, as the octagam infusion continued, you can see the pink and yellow data points diverge.

Here, and here in particular, you can see there is a marked divergence and, at the extreme, the difference between the patient's blood glucose values measured, using glucose specific and glucose non-specific methodology, showed a discrepancy of 270 milligrams per deciliter.

At the beginning of the octagam infusion, the patient was able to respond to verbal stimuli. As the falsely increased glucose levels were used to monitor his insulin doses, additional insulin was given and, by the time his blood glucose level began to decrease, his responsiveness to verbal stimuli also decreased accordingly.

At this point in time, indicated by the arrow, the patient was noted to be non-responsive. A blood glucose level obtained at this point in time, using the glucose non-specific methodology, revealed a blood glucose level of 115 milligrams per deciliter.

The corresponding pink data point, representing the blood glucose level using the specific methodology, was 12 milligrams per deciliter.

The patient's responsiveness never changed throughout the remainder of his hospitalization, up until the time of his death.

The second case report involves a case that was reported to the medicines and health care products regulatory agency in the United Kingdom in 2002.

This case involved a 50-year-old diabetic male with a failing pancreas renal transplant, who received octagam as an anti-rejection agent. This represents an off label use of octagam.

Based on artificial hyperglycemia, as a result of the maltose contained in the octagam, the patient had inappropriate insulin administered.

He became severely hypoglycemic, became comatose, was diagnosed with severe nervous system depression, and expired. No further information was provided.

The third and fourth cases represent cases that were reported to the French health product safety agency in 2003. Both of these cases involved three-week-old male, non-diabetic patients, who received octagam for unknown indications.

Both of these patients developed artifactual hyperglycemia, although this was apparently recognized and resolved without the need for medical intervention. However, we don't have any additional details on these cases.

The fifth and sixth cases were reported in the Medical Journal of Australia in 2004. Both of these cases involved an intravenous immune globulin product by the name of Intergam, which is not licensed in the United States. Intergam-P, though, does contain 10 percent maltose.

The first patient was a 64-year-old diabetic female on dialysis, who received intergam-P for ITP, or immune thrombocytopenic purpura. This represents a labeled indication for this product.

The patient subsequently developed artifactual hyperglycemia, for which insulin was administered in increased doses.

The patient then developed hypoglycemia, which resolved without apparent sequelae. Again, no further details were really provided.

The second case was a 35-year-old non-diabetic female on parenteral nutrition who, likewise, received intergam-P for ITP.

She, likewise, developed artifactual hyperglycemia, which was recognized and apparently resolved without the need for medical intervention. Again, there is limited information that was provided on this case.

We, unfortunately, do not know how frequently artifactual hyperglycemia occurs. We, more important, have no idea how often it occurs associated with serious adverse events.

The reason why we don't have answers to any indications of frequency are that FDA's adverse events surveillance for licensed products uses primarily passive surveillance.

There are numerous limitations to passive surveillance, and FDA's medwatch or adverse event reporting system is an example of a passive surveillance system which serves as our primary source of data for adverse events.

Among the various limitations of passive surveillance systems, including medwatch, is the reliance on voluntary reporting of adverse events by physicians, other health care professionals, patients, and others.

It also requires that someone suspecting that there is a possible causal relationship between a product and an adverse event, there are various other factors that influence this.

Newly licensed products tend to have more reports submitted than older products. Publicity, whether it is in the newspaper or some sort of presentation, may prompt what we call stimulated reporting.

Whatever the limitations are, though, the net result is that we are confident that we have a significant amount of under-reporting.

However, the extent of the under-reporting is unknown. It probably varies from product to product. .So, there is no way we can correct our data, so to speak, to reflect some sort of frequency estimate.

So, even incidence rates or estimated reporting rates, under normal circumstances, without additional data sources, cannot be calculated from our data.

The limitations of passive surveillance, specifically the Medwatch adverse event reporting system notwithstanding, Medwatch has enabled us to detect, investigate and act upon numerous adverse events.

For those reasons, we encourage physicians, other health care professionals, patients and others, to report adverse events, particularly serious adverse events, to FDA for any FDA improved product, including the maltose-containing intravenous immune globulin products.

Adverse event reports can be submitted directly to FDA by internet, by telephone, by fax or by mail. Instructions and forms for submitting adverse event reports to FDA are listed at the cited Medwatch web site.

Alternatively, adverse event reports can be submitted to FDA through manufacturers or distributors, and I say to FDA, because manufacturers and distributors, in turn, are required to submit reports to us that they receive about adverse events.

Contact information for reporting adverse events to manufacturer or distributors is generally available in professional package inserts, or on their sponsored web sites. I thank you for your attention.

DR. ALLEN; Thank you very much. We will move on to the other presentations, and then have time for questions for all the speakers at the end. Dr. Ross Pierce?

Agenda Item: Information.

DR. PIERCE: Good morning. I am going to talk a little bit about the different point of care glucose testing systems, and also the CBER response to this problem that you just heard about.

So, since their introduction, point of care glucose meter devices have become widely used, not only for home blood glucose monitoring, but also in hospitals and clinics.

The test strips that use the glucose d-hydrogenase pyroloquinoline quinone, or GDH-PQQ method, are not specific in every case for glucose, in that maltose can be falsely read as glucose by that enzyme.

At this time, we believe that all of the test strips that use the GDH-PQQ test method are, in fact, labeled with some type of precaution regarding the potential for maltose in the patient's blood to cause falsely high readings of blood glucose.

Non-specific glucose test methods, as you have just heard, are unfortunately, from time to time, still inappropriately used in patients who have received maltose-containing products, as reflected in the horrific case that we heard about from Dr. Gaines.

There are actually two IGIV products licensed in the United States that contain maltose and have this potential.

The difference in the various test kit systems include different enzymes as well as different glucose d-hydrogenase enzymes.

There are two of those that are used in test strips for glucose marketed in the United States, and the GDH-PQQ test method does not use nicotinic acid adenine dinucleotide, NAD, as the enzyme cofactor. It uses PQQ as the co-factor.

This enzyme uses either glucose or maltose as a substrate. Many test systems employ this GDH-PQQ method that is subject to maltose interference.

In contrast, another glucose d-hydrogenase, the NAD dependent glucose d-hydrogenase, uses glucose but not maltose as a substrate. So, maltose will not interfere. This is used in at least one glucose meter test strip system licensed in the United States.

This slide depicts the biochemical, chemical and electrochemical reactions that occur during the assays that are GDH-PQQ based.

As you can see, there is a redox reduction and maltose or glucose is converted into the corresponding lactone by the action of the GDH-PQQ enzyme, and the change in the redox state of the co-factor translates into an electrical signal.

There are other GDH-PQQ test methods, where the readout signal is a calorimetric method, but the enzyme is still subject to maltose interference, because it uses the GDH-PQQ form of glucose d-hydrogenase.

This shows that the co-factor PQQ is structurally distinct from the co-factor used by the other enzyme that is not subject to maltose interference, NAD.

Here you see that the reactive center in glucose is the same structurally as the reactive center in maltose, in terms of the action by the GDH-PQQ enzyme.

So, if we divide these various test strip systems into those that are subject to maltose interference on the left, and those that are not subject to interference by maltose on the right, on the left, we only have DGH-PQQ at the present time.

Now, most of the point of care test strips that are used with glucose meters, that use this enzyme, name the enzyme as PDH-PQQ, but there is at least one point of care calorimetric system that terms this same enzyme a glucose di-oxidoreductase, which is really a translation of the name of this enzyme from the German.

Now, one of the advantages of the GDH-PQQ -- you have already heard about the disadvantage, that it falsely interprets maltose as glucose -- but it does have an advantage, in that it is not subject to a skewing of the readout by low oxygen tension in the patient's blood.

If we go over onto the right hand side, you can see that the NAD dependent GDH enzyme does not interfere, as I mentioned. This is also not subject to interference in the readout by low oxygen tension.

Other more specific methods are hexokinase, where low oxygen tension can interfere with the glucose reading, and glucose oxidase, which is also subject to a bias by low oxygen tension.

Also, mannitol in extremely high concentrations, can interfere with the glucose oxidase methods, which is one of the popular clinical laboratory based methods for glucose determination.

So, which are the IGG products that contain maltose? Well, in terms of polyclonal IGG products, non-hyperimmune products, we have two in the United States, octagam five percent licensed by Octapharma, and gamimmune-N five percent, which is no longer actively distributed in the United States, once its sponsorship was transferred from Bayer to Talecris. However, we believe there may still be some product bearing the Bayer label still in the market place.

Another maltose containing immunoglobulin that is a hyperimmune globulin is WinRho SDF liquid, marketed by Cangene. However, at the label doses, we do not expect that the maltose concentration will be high enough to interfere with glucose because of the comparatively low dose of that product. Off label use might be a different story at higher doses.

Vaccinia immune globulin was approved this year. The license holder is Cangene. This is the product for complications of vaccinia vaccination. It is only available through the CDC, and interference is expected at label doses of that product.

I should also mention that, while WinRho SDF liquid is an approved product, its marketing launch hasn't yet actually occurred.

So, what are the actions that CBER has taken in response to these adverse events? Well, as soon as we found out about this most recent case, we quickly formed a CBER CDRH working group.

We worked to strengthen the labeling of all the maltose containing IGIV and immunoglobulin products. We asked the sponsors of the IGIV products to issue important drug warning letters to physicians, customers and hospitals, and one such letter has issued as of this time.

There has been coordination between -- extensive coordination between -- CDER and CDRH on health alerts for FDA web sites and Medwatch list serves regarding this problem, and we are in the process of drafting an article to be submitted to one or more widely circulated medical journals.

The work that we have done with the sponsors regarding the package inserts is to add a warning -- none of the products had this in the warning section previously -- and to strengthen the precaution section.

In the sort of class labeling that we have developed for the maltose containing IGIVs, the new labeling will indicate that some types of blood glucose test systems, such as GHPQQ or glucose dioxidoreductase methods falsely interpret maltose as glutose, that this has resulted in inappropriate administration of insulin, resulting in life threatening hypoglycemia and that, when administering maltose containing IGIVs, use a glucose specific method for measuring glucose, and instructs the users and clinicians to carefully review the product information of the glucose test system, including that of the test strips, to determine if the system is appropriate for patients receiving maltose containing parenteral products.

Some of the products only contain the information about maltose interference in the test strips, and not in the package insert of the glucose meter itself. Contact the manufacturer of the test strip if there is any uncertainty.

So, we would like to acknowledge the tremendous amount of cooperation that we received from the hospital pharmacist and the physician who cared for the patient that you heard about from Dr. Gaines this morning.

The case that she described was recently published in an ISMP safety alert on September 8 with an erratum in the next issue. Thank you.

DR. ALLEN: Thank you very much. The third speaker from the FDA will be Ms. Patricia Bernhardt.

Agenda Item: Information.

MS. BERNHARDT: Good morning. I am going to present the CDRH perspective on this issue. CDRH regulates the test strips that are involved in this.

The manufacturers of these test strips, as part of their evaluation of the devices, prior to marketing, evaluate many types of possible interferences, and sugars are one of the interferences that they do look at.

The types of sugars that have been evaluated by the manufacturers are maltose, galactose, xylose, lactose, and sorbitol.

Maltose has been evaluated. I don't have the concentrations -- the highest concentrations -- that the manufacturers have evaluated.

What they have found is that, at concentrations greater than 13 milligrams per deciliter, the interference begins to be seen.

For galactose, the interference is seen at greater than 10 milligrams per deciliter. For d-xylose, the interference is at greater than nine milligrams per deciliter, and d-xylose is typically administered during a xylose malabsorption test and, during that test, the blood xylose concentration reaches approximately 30 milligrams per deciliter.

Because of that, the xylose interference, the warnings in the labeling are that these glucose test strips should not be used during the course of a xylose malabsorption test.

Sorbitol, there is no interference up to 70 milligrams in the blood, and lactose, there is no interference up to five milligrams, and that is 10 times the normal concentration in the blood, which is 0.5 milligrams per deciliter.

CDRH has been working extensively with CBER, as Dr. Pierce mentioned. We are working to post a reminder on the OIVD web site, and the FDA diabetes web page about this interference with these sugars.

These interferences are listed in the warnings in the test strip inserts for the glucose d-hydrogenase PQQ enzyme. We are working with the manufacturers to strengthen those warnings, and to make them more consistent. There is not much consistency between the different labeling for these products.

We are also developing an upcoming patient safety news item, which will talk about this interference. As I have mentioned, we have requested labeling modifications to include the maltose, galactose and the xylose interference, and we are requesting it to be in a more consistent fashion.

An example of a warning from the GDH PQQ test strip label is up on the screen. That is basically the format that we are going to be hoping to see this warning in the labeling in the future.

In addition to the labeling warnings, which have been in the labeling for quite some time, there is a Clinical Laboratory Standards Institute document on glucose monitoring settings without laboratory support, that does mention this maltose interference.

It does not mention galactose or xylose, but it does mention maltose. It lists maltose as a cause of falsely elevated results with some glucose d-hydrogenase systems.

So, the information is out there. We hope that we can increase the health care provider's awareness of this interference so that, when they use these glucose testing methods on their patients, and are administering some of these products that contain some of these sugars, there will be heightened awareness of the potential interference that can be caused. Thank you.

DR. ALLEN: Does that end the FDA presentations? You are well under your allotted time for that. Questions from the committee rom any of the speakers? This is just an informational item. We are not being asked for any advice.

Agenda Item: Questions from the Committee.

DR. DUFFELL: When the medications were being used, were they used on label or off label?

DR. PIERCE: In the two cases that resulted in fatalities, or were associated with fatalities, those were off label uses of the IVIG products.

DR. DUFFELL: In the other cases, you don't know, then?

DR. GAINES: The first two cases, as Dr. Pierce mentioned, were off label use. The third and fourth cases, the French cases, the indication for use was not specified, was not provided, so we don't know.

The fifth and sixth cases, which were from the Australian journal article, were for on-label use for treatment of ITP. Those latter two cases involved an IVIG that was not licensed in the United States, although it was a 10 percent maltose containing intravenous immune globulin product.

DR. CRYER: It is now very commonplace in intensive care units, particularly septic patients or severely injured patients, to be monitoring glucose in a very narrow range using an algorithm between 80 and 110 millimolar.

Obviously a nurse, without a physician, is using an algorithm to give insulin to keep it in that very narrow range.

It seems to me that the important thing to find out would be how are they measuring the glucose in those protocols. I honestly don't know.