FOOD AND DRUG ADMINISTRATION
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Meeting of:
BLOOD PRODUCTS
ADVISORY COMMITTEE
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.
November 4, 2005
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TABLE
OF CONTENTS
Page
Information:
Serious Adverse Events Following
Falsely
Elevated Glucose Measurements Resulting from
Administration
of an IGIV Product Containing Maltose
- Ann Gaines 3
- Ross Pierce 14
- Patricia Bernhardt 21
- Questions and Discussion 24
- Statement by Octapharma 41
Heterogeneity of Commercial Alpha-1-Proteinase
Inhibitor
(Human) Products - Implications for Long-term
Safety
and Efficacy.
Introduction and Questions to the Committee 46
- Andrew Shrake
Observations on Marketed Alpha-1-Proteinase 52
Inhibitor
Products - Ewa Marszal
Identification and Possible Implications of a 59
Human
Plasma Purified Anodal Variant of
Alpha-1-Antitrypsin
- Mark Brantly
Characterization of Aralast Compared to Other AIFI 75
Preparations
- Hans Peter Schwarz
Safety Reporting for Alpha-1-FI Products 90
-
Tina Khoie
Post-Marketing Study Commitments for Licensed 107
Alpha-1
FI Products - Rationale - Ross Pierce
Licensed Therapeutic Protein Products with Known
Structural
Modifications - Andrew Chang 120
- Kurt Brorson 129
Open Public Hearing 136
- Miriam O'Day 138
- Sarah Everett 140
- Barbara Merrill 142
- Robin Huff 144
- Otto-Erich Girgsdies 145
- Val Romberg 149
Committee Discussion 150
COMMITTEE
MEMBERS:
JAMES
ALLEN, MD, MPH, Chair. President and CEO, American Social Health Administration,
Research Triangle Park, NC
DONNA
M. DI MICHELE, MD. Associate Professor of Pediatrics and Public
Health, Weill Medical College and Graduate School of Medical Science, Cornell
University, New York, New York
MATTHEW
KUEHNERT, MD, CDR,
U.S. Public Health Service, Assistant Director for Blood Safety, Division of
Viral and Rickettsial Diseases, CDC, Atlanta, Georgia
CATHERINE
S. MANNO, MD, Professor
of Pediatrics, The Children's Hospital of Philadelphia, University of
Pennsylvania School of Medicine, Philadelphia, Pennsylvania
KEITH
QUIROLO, MD, Hemoglobinopathy
Pediatrician, Clinician Director, Apheresis, Transfusion Medical Director,
Sibling Donor Cord Blood Program, Department of Hematology, Children's Hospital
and Research Center, Oakland, California
GEORGE
C. SCHREIBER, ScD, Vice
President, Health Studies, Westat, Rockville, Maryland
DONNA
S. WHITTAKER, PhD, Director,
Robertson Blood Center, Fort Hood, Texas
CONSUMER
REPRESENTATIVE:
JUDITH
BAKER, MHSA, Regional
Coordinator, Federal Hemophilia Treatment Centers, Children Hospital, Los
Angeles, CA
NON-VOTING
INDUSTRY REPRESENTATIVE
LOUIS
KATZ, MD, Executive
Vice President, Medical Affairs, Mississippi Valley Regional Blood Center,
Davenport, Iowa
ACTING
NON-VOTING INDUSTRY REPRESENTATIVE
WILLIAM
H. DUFFELL, PhD, Director
of Government Affairs, Regulatory Affairs Quality Systems, Gambro BCT Lakewood,
CO
TEMPORARY
VOTING MEMBERS:
HENRY
M. CRYER, III, MD, PhD, Chief, Trauma and Critical Care, Division of General Surgery,
University of California, Los Angeles, California
ADRIAN
M. DI BISCEGLIE, MR, Professor
of Medicine, Chief of Hepatology, St. Louis University School of Medicine, St.
Louis, Missouri
SAMUEL
H. DOPPELT, MD, Chief,
Department of Orthopedic Surgery, The Cambridge Hospital, Cambridge,
Massachusetts
HARVEY
KLEIN, MD,
Chief, Department of Transfusion Medicine, National Institutes of Health,
Warren G. Magnuson Clinical Center, Bethesda, Maryland
ROSHNI
KULKARNI, MD, Professor
and Chief, Pediatric and Adolescent Hematology/Oncology, Michigan State
University, East Lansing, Michigan
SAMAN
LAAL, PhD, Assistant
Professor, Department of Pathology, New York University School of Medicine, New
York, New York
KENRAD
NELSON, MD, Professor,
Department of Epidemiology, Johns Hopkins University School of Hygiene and
Public Health, Baltimore, Maryland
THOMAS
QUINN, MD, Professor
of Medicine and Deputy Director, Infectious Disease Division, The Johns Hopkins
University, Baltimore, Maryland
FREDERICK
SIEGAL, MD, Medical
Director, Comprehensive HIV Center, St. Vincent's Catholic Medical Center, St.
Vincent's Manhattan, New York, New York
GORDON
SNIDER, MD, Towson,
Maryland
IRMA
O.V. SZYMANSKI, MD, Professor
of Pathology, Emeritus, University of Massachusetts Medical Center, Department
of Pathology, Worcester, Massachusetts
EXECUTIVE
SECRETARY:
DONALD
JEHN, Executive
Secretary, Blood Products Advisory Committee, Division of Scientific Advisors
and Consultants, CBER, FDA
COMMITTEE
MANAGEMENT SPECIALIST:
PEARLINE
MUCKELVENE, Division
of Scientific Advisors and Consultants, CBER, FDA
STAFF:
SUSAN
ZULLO, PhD, Acting
Associate Director for Policy, Office for Blood Research and Review, CBER, FDA
RHONDA
DAWSON, Policy
Analyst, Office for Blood Research and Review, CBER, FDA
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.
I do it in my own ICU, but I am not sure whether they use
the values by the lab or a glucometer at the bedside. Do you have any information, across the country, what ICUs are
doing to use those protocols?
DR. PIERCE: I
don't, but there is obviously a great temptation to want to use the point of
care device, because of its virtually instantaneous feedback. It obviously
takes a longer period of time to get a stat glucose back from the clinical lab.
So, there is pressure to move in that direction, but people
have to be cognizant of the potential down sides from interfering medicines.
Also, in sepsis, there is a difference between the
capillary blood glucose level and the venous blood glucose level. So, the venous blood glucose level can be
significantly lower than that of the capillary blood glucose level that is
measured typically with the point of care devices. This needs to be taken into
account in these protocols as well.
DR. KULKARNI: I was
wondering, if there a dose dependent effect?
We use IVIGs for all different doses for ITP indications.
DR. PIERCE: We
believe that the lowest recommended dose in the labeling of any IVIG product
that contains maltose is capable of producing this false elevation of glucose
measurements using the GDH PQQ method.
DR. SIEGAL: The
dose that was given in the U.S. case was something on the order of 60 grams
over the time that he was given gammaglobulin?
DR. GAINES: he
received three different doses, or three different administrations. The first
one was a 10 gram dose, the second was a 70 gram dose. The third one, which
actually was after the fact, so to speak, was a 35 gram dose. This was a 63 kilogram patient.
DR. SIEGAL: So,
about 1,000 milligrams per kilo would be the dose roughly that he got. I mean,
you wonder about hyperozmolarity in this setting. Obviously, it is pretty short lived, and people use huge doses of
gammaglobulin and ITP in other settings that may really create problems for
patients that are real, not just fictitious in the sense that there is a lot of
disaccharide floating around for the time being. Has that ever been considered
an issue?
DR. PIERCE: The
osmolarity of IVIG products has been considered when evaluating the potential
for adverse events, and it is something that we always consider when looking at
new products that are coming to use for investigation.
DR. KLEIN: I just
want to make sure that I understand correctly. Is there no point of care test
that is specific for glucose, or is it that the specific ones with glucose
oxidase have other disadvantages, such as sensitivity to low PO2?
DR. PIERCE: Maybe
Dr. Bernhardt can respond to that.
MS. BERNHARDT: Yes,
there are several that use the NAD version, and there are many that use the
glucose oxidase version.
It is the hospital's choice which one they choose to buy.
My personal opinion is that the people responsible for purchasing the equipment
to be used in these point of care settings should be more aware of these
limitations for these devices in their particular settings, based on the types
of medications and treatments that are used for the patients.
DR. KLEIN: At the
risk of sounding simplistic, is the licensure of something that is non-specific
at point of care, is this historical?
Is it much cheaper to buy and, therefore, a better thing to do, or is
there some reason maybe to think about not having something that is
non-specific that is on the market?
These are just a couple of the drugs that contain
interfering substances, and clearly there will be more in the future.
MS. BERNHARDT: The
main purpose for these devices is not for point of care use. It is for home testing by diabetics to
monitor their individual glucoses, and the hospitals choose to sometimes use
these in point of care settings, as Dr. Pierce said. It is probably quicker
than waiting for a stat result from a laboratory, but that is not the real
intent of the devices.
DR. KLEIN: Are they
cheaper? Is there only one manufacturer
of specific ones?
MS. BERNHARDT: No,
I don't believe so.
DR. ALLEN: That is
a very interesting issue in terms of devices developed and intended for one use
not being restricted in any other way.
DR. NELSON: I can
give a personal account that it is not only the ICU, but post-surgery patients
also have glucose monitored insulin given, and it is a rapid device. It
happened to me six months ago.
DR. KUEHNERT: I had
some questions about surveillance. You mentioned the passive surveillance
aspect. Was the U.S. case detected through Medwatch? I am just curious how it came to attention by the hospital.
DR. GAINES: It is a
long complicated story, and I am not good at telling short stories, but I will
do my best. We became aware of this particular case initially because of a list
serv.
I am not enough of a computer person to really understand
what list servs are, but it was a specialized medical specialty e mail list
serv, where this case was reported.
The queries were, has anyone seen a case like this. The
physician and pharmacist had actually worked up the case reasonably thoroughly
to know what the problem was.
The report has since been reported to Medwatch, after I
investigated the case along with the hospital personnel as a pro forma matter.
It is in Medwatch, but that is not how we became aware of this one.
DR. KUEHNERT: There
are a lot of ways that these things come to attention, and Medwatch is only
one. So, I would just encourage you to think creatively about how to improve
surveillance on this.
I don't know how many hospitals look when there is an
adverse event associated with someone who is on insulin, if they look to see
what other products they received, but that would be a good idea to maybe track
that.
Just along the comments by Dr. Klein, I don't know how many
other products contain these sugars to know if there are other events that are
occurring to those products as well. That would be something certainly of
importance.
In trying to get the message out, you mentioned the list
servs and other ways to do that, but I was wondering, when you were talking
about labeling of the strips, I saw this letter. Is there also a plan to put a
warning on these products, and also, looking at these other products that have
these sugars as well?
DR. GAINES: Are you
referring to the test strips or the intravenous solutions?
DR. KUEHNERT: The
intravenous solutions. I think it mentioned the test strips, but I wondered
what about the solutions?
DR. PIERCE: The
IGIV products, the labeling of all of them is in the process of being revised,
to reflect something in the warning section as well as a subsection of
precautions on drug laboratory test interactions.
We are continuing to work with CDER and other parts of the
agency to try to identify other products which might interfere with the GDH PQQ
testing method, and we are hopeful that the other centers that have purview
over those products will take appropriate action.
DR. KUEHNERT: Just
a last question. When something like this happens, is there some sort of
pharmacy action that occurs, that when you have insulin and a product like
this, that there is some sort of warning generated? Do you know if that is something that happens in hospitals?
DR. PIERCE: It is
an excellent question. I think it should happen in this type of case, and pharmacies
do, as you point out, now more and more, particularly with the electronic sort
of ordering systems, it is very easy for these automatic potential drug drug
interaction warnings to come up. So, this is certainly something that would be
good to consider instituting.
DR. ALLEN: I think
to answer your question from a different perspective, if you have been or
worked in one hospital, you have worked in one hospital.
There is no any degree of uniformity. It would depend on
the awareness of the hospital pharmacy system and the working committees, the
medical care structure within the hospital.
We have got such a complex -- I don't want to use the word
system. We have got such a complex structure in our country that there isn't
any single way to do that.
The issue of surveillance or reporting, you have to
appreciate or recognize the adverse event for what it is before it can be
adequately reported.
Then people have to know that the reporting system is in
place. As you pointed out, the degree of under-reporting with the existing
mechanisms is probably fairly significant.
I think many hospitals today, certainly when I was in
training, which was a number of years ago, we had regular mortality review
conferences. A high percentage of
patients in hospital were sent for autopsy, we had lots of adverse review settings.
I think that is much less common today, even in university
settings, and certainly at the community level hospital setting. I don't think there is nearly as much
post-event review as would be very helpful.
DR. KUEHNERT: Just
to make a follow up comment to that, other than in Medwatch, I am not aware of
product surveillance for adverse events for IVIG or other products. So, that is
something I guess we can think about in the larger picture along with
transfusion adverse event surveillance, but it is just lacking in the United
States.
I don't know, in other countries that have hema-vigilance
programs, whether they include other products, but it is certainly something
that will be of interest in the future.
DR. KLEIN: The U.S.
Pharmacopoeia has a system, but I don't know whether it would cover all
hospitals.
DR. CRYER: Just one
other comments about a solution. In fact, the data that was provided indicated
that the hospital at least was collecting the right information.
So, I guess if you are going to use point of care testing,
the advantage of that is efficiency. You know right away rather than having to
wait for the lab test to come back.
Then you probably ought to have duplicate laboratory tests
with some sort of warning system as soon as the lab knows that you have a value
outside the range, which almost all hospitals have.
You would think that there would be some warning in some
reasonable lag time that this was occurring. It seems to me that a solution is
just to make sure that that duplicate testing is being done when doing point of
care testing.
DR. PIERCE: That is
certainly one approach. In this case, it was obvious form a review of the data
that the hospital personnel were relying primarily on the point of care glucose
meter.
The frequency with which laboratory-based glucose
measurements were being obtained dropped off dramatically in the last day
before the patient really deteriorated in terms of his neurological status.
If that blood sugar of 12, if that had been obtained six or
12 hours later than that, that could also have affected the timing, the
recognition of the problem.
DR. ALLEn; Dr.
Cryer's point, however, might be something that could be included in the
discussion section of the article. I
think that is a very important warning.
DR. STEFANO: If I
could address one of the concerns that was just raised, next week in Chicago,
we are actually just starting to find out, through the ICH -- the International
Conference for Harmonization -- how many different systems that are in place in
terms of notifications.
So, next week, on the table for discussion, is to hear what
the EU and the Japanese and so on, all the members, are doing in terms of
notification, so that we understand what everyone is doing around the world,
and try to find a point at which we can harmonize, if that is even remotely
possible. So, that might answer some of your concerns.
DR. KUEHNERT:
Great, thanks.
DR. DI MICHELE: I
just wanted to add that, certainly among blood product derivatives and clotting
factors, I think there has been a move lately to encourage post-licensure
pharmacosurveillance in a much more organized way, whether it is industry based
or non-industry based.
I would like to add my vote for that as well, because
almost everything we learn about products, we learn post-licensure.
DR. QUINN: Jim, you
may know more about this, but would this be construed as medical error? The American Association of Accreditation of
Hospitals is trying to standardize and get a reporting system in.
Now, a lot of hospitals would probably not want, for the
points that you issued, they would not want a lot of this, because it becomes
public information.
Nevertheless, that is somewhere where FDA could interface
with the American Association for the Accreditation of Hospitals, for this type
of reporting system.
I think physicians, health care providers, need to be made
more aware of this interaction. For us working on wards, we give massive
amounts of intravenous gammaglobulin for ITP for many of our patients, and this
kind of information is not as readily available.
Pharmacies need to alert it if you are using this. When a
patient is diabetic, you need to be aware of what to use to monitor it and so
forth.
DR. ALLEN: You ask,
do I know, and I don't, but I think it is a very good point and one that is
worthy of additional follow through.
DR. SIEGAL: Both as
a user of a glucometer and also as a purveyor of IV gammaglobulin a fair amount
of time, I was sort of vaguely aware of the hyperglycemia issue because I have
seen it actually, and I assumed that it was not real.
In fact, I think people in medicine and nursing probably
are blissfully unaware of the shortcomings of glucose monitoring.
I am sure that most people who actually use these things
have no idea that PO2 and other medications could interfere or, if they are
aware, it is only subliminally.
It ought to be stated, and maybe directed at the people who
are likely to do this -- intensivists and hematologists and immunologists and
people who use these products a lot.
DR. ALLEN: I
certainly think that the steps that have been taken are the right ones, but
clearly a lot of information, disseminated broadly to different groups within
the medical and hospital care setting needs to be done as part of this.
DR. KULKARNI: I
just wanted to know, how long does the hyperglycemia last? The immunoglobulin lasts for a long time in
the body.
I am just wondering, once these patients go home, do they
continue to be aware of this glucose monitoring and the problems with it?
DR. PIERCE: The
duration of this is going to be dependent on a lot of different factors and is
going to vary form patient to patient.
The position that we have taken is that, if these products
are used -- the maltose containing products, for example, in a particular
individual, that they just should be using an alternative method for the
determination of glucose.
We are not in a position to say, well, you can go back to
using the GDH PQQ method after X number of hours or days.
MS. BAKER: Has the
American Diabetic Association or any other patient advocacy organizations been
engaged in discussions about this?
DR.PIERCE: The
important drug warning letter issued by Octapharma was sent to the diabetologists
from the mailing list of the Endocrine Society. We have not had direct discussions with the organization that you
mentioned, however.
DR. DUFFELL:
Judith's question actually picks up on the thought that I had. We were
talking yesterday about labeling and putting a lot of things in labeling.
This is another case where, since really the intended
audience for most of these devices is home use -- it is not really point of
care -- I am wondering if we have done a good study of that warning and the impact
it is going to have on the end user, whether it is going to cause undue
concern, and whether or not it even means anything to them, as it is worded
here.
I don't know if most patients would understand what the
significance of this is. So, coming back to Judith's remark, it may be a good
idea to try to test pilot, with the appropriate organizations, how most end
users actually perceive this type of warning. Is it achieving the effect, or is
it even appropriate for them.
If it is point of care where this is occurring, maybe you
are going at it the wrong way to put something into the device labeling, and it
should be some other means of communication.
MS. BERNHARDT:
These warnings have been in the device labeling for quite some
time. For over-the-counter products,
which these glucose meters and strips are primarily considered to be, we do
consumer testing of the labeling to ensure that it can be understood at a
seventh grade level.
The labeling regs that we are under require certain other
information to be in the labeling, information that a typical lay user may not
understand, but it is required by the regs to be in there.
Some manufacturers choose to have a completely separate
labeling for professional users versus lay users. Most of them, however, just
have the one labeling, and this information is usually in a separate section
that is addressed to health care professionals.
I think the diabetes nurse educators, that do work with a
lot of the diabetics, they are very aware of the limitations for these devices,
but the hospital personnel may not be as aware.
DR. DUFFELL: So,
the warning that was put up in that slide already exists. This is not a fix.
This is something that is already being done.
MS. BERNHARDT: That is actually from a label. That was an
example from a label that we consider to be a complete warning for this
particular interference, and that is what we are going to aim to try to get all
the manufacturers to conform to that.
DR. DUFFELL: So, it
is in one, but you are going to get all of them to use it.
MS. BERNHARDT: Yes,
some of the other devices have warnings for just maltose, some of them will
have a warning for maltose and galactose, but that particular one that I
provided the example for is a complete one that addresses all those sugars, and
that is what we would like to see in the future.
DR. ALLEN:
Although, as was noted in the discussion yesterday, labels sometimes
aren't read or followed.
I think the other part of that, that you raised, in terms
of the point of care use for an instrument that wasn't designed for that, one
wonders whether or not CLIA should be involved in looking at how point of care
lab tests are done in hospital settings, which I assume would include certainly
emergency departments, intensive care centers, perhaps surgical suites
themselves a wide variety of settings in the hospital, where they may be used
in ways that they weren't designed for or intended.
MS. BERNHARDT:
Glucose meters on test strips are automatically waived by CLIA.
DR. ALLEN: I
understand that, but maybe within a hospital setting, that waiver is not
appropriate. That was the point I was trying to make.
All right, further discussion or questions from the FDA on
this issue? That was a fascinating
discussion. I am going to take the chairman's prerogative now.
Octapharma has asked to be able to make a statement on this
topic. Normally this would occur during an open public hearing. We do not have
an open public hearing scheduled at this time
It is later in the morning toward the end of our discussion of topic
two.
Given that the Octapharma statement is pertinent to this
discussion, I will allow the Octapharma people to make a five-minute
presentation at this time if you wish, or you may be invited to speak during
the open public hearing. It is your discretion. Would you introduce yourself, please, and then you have got five
minutes for your statement?
Agenda Item:
Statement by Octapharma.
MR. SCHLEISS:
First, I would like to thank the board for allowing us to give this
presentation. Obviously, we have been actively involved in this process.
My name is Tom Schleiss(?). I am the medical affairs manager for Octapharma. Also, with me in
the front row, is my esteemed colleague, Dr. Stephan Haag, who is the
international business manager for Octapharma.
This interaction is a known characteristic of certain
point-of-use glucose monitoring systems. As you have already heard, it is the
GDH PQQ system that is being used that is non-specific for glucose.
This involves about 25 percent of the meters that are
currently on the market. That is one statistic. The other statistic is, in the hospital setting, approximately 60
percent of the hospitals that use these point of use meters use a meter that
does have this interaction. So, it is
certainly a high percentage in the hospital, but in overall point of use
systems, it is only about 25 percent of them.
Maltose, maltatriose and, to a lesser extent, maltotetrose,
are misinterpreted by these test systems as glucose, and this results in this
elevated glucose reading.
As we have seen in this one particular case, the falsely
elevated glucose readings can result in the inappropriate administration of
insulin, which can cause life threatening hypoglycemia.
The flip side of the coin is, a patient may be hypoglycemic
but, because of the elevated reading, they may look to be in a normal state
and, as a result, the hypoglycemic state may go untreated because of the
falsely elevated glucose readings.
Maltose itself is not a dangerous drug. It has been used in
a variety of products for years. It has been used in IVIG solutions, as is the
case in ours. A similar type of maltose
is used in peritoneal dialysis fluid, and that is where this interaction first
became known, was in peritoneal dialysis solutions, and the interaction with
the glucose monitoring systems which had the GDH PQQ systems. This was approximately 2003 that this came
to light.
As a result, our product, and other products, have this
labeling regarding this interaction in their package inserts. There is also at least one oncology drug
that has maltose as part of its preparation.
The warning statements regarding this non-glucose
specificity are normally present in the package inserts, specifically the test
strips that are used with these glucometers.
Information is present in there.
Warning statements regarding the potential for falsely
elevated glucose readings with certain glucometers are normally present in the
prescribing information of maltose, and icodextrin containing drugs, icodextrin
being the peritoneal dialysis solutions.
Icodextrin is converted to maltose, and then this interaction takes
place.
Octapharma has had information regarding this interaction
in our package insert since the introduction of our products into this country.
We have been in the U.S. market for about two years. We have been in other markets throughout the
world for a significantly longer time.
We worked in collaboration, and under the guidance of the
FDA and, as you saw there, we made changes not only to our warning but also to
our precaution statements and our package insert.
We have also sent a dear doctor warning letter to the
parties that were agreed upon between Octapharma and the FDA. I think you have already seen the language
that we have added to our package inserts.
I also worked very closely with the Institute for Safe
Medical Practices. They are another sort of a Medwatch type of an agency.
I personally worked very closely with them regarding this
interaction and what happened with this patient and, as a result, they were
really the first to post a very balanced piece of -- a summary piece which
identified the interaction, looked at ways to avoid the interaction. It was a
very, very helpful publication that went out to all pharmacists, and a fair
amount of nurses also subscribed to this.
Dr. Haag and I have also worked very closely with Roche,
who makes the Accucheck blood glucose monitoring system, which is the system
that was involved in this particular case.
They are as eager as we are to help strengthen the language
in their package insert, and help identify their hospital systems and their
patients who are using these systems, of this potential interaction. Are there
any questions?
DR. SNIDER: Have you spoken to nurses organizations
about the interaction? In hospital use,
nurses are really the people who most frequently use these tests, with respect
to the physicians or the pharmacists?
MR. SCHLEISS: The
information has gone out to practically any practitioner who would be involved
on this. We focused specifically, in terms of pharmacists and nurses, on our
clients, which would include everyone involved in their agencies.
We only use two distributors. Both of them received the information to pass along to their
customers. So, our intent was, knowing that pharmacists and nurses are
involved, our intent was to notify everyone.
Even from day one, this was an interaction which our sales
force was instructed to inform all of our customers that this was present. This was nothing that we ever tried to hide.
In this particular case, it was a pharmacist who had not
actually seen any of our representatives.
So, he wasn't aware of it.
DR. ALLEN: Other
questions or comments? Okay, thank you very much. We will move now into
presentations and then discussion of topic two, the heterogeneity of commercial
alpha-1 proteinase inhibitor products, human, the implications for longer-term
safety and efficacy.
The first presentation, by Dr. Andrew Shrake of the FDA,
will be the introduction and questions to the committee.
Before we proceed, I just wanted to acknowledge that Dr.
Snider is sitting at the table as a temporary voting member for the topic two
discussion. Welcome.
Agenda Item:
Heterogeneity of Commercial Alpha-1-Proteinase Inhibitor (Human)
Products - Implications for Longer-Term Safety and Efficacy. Introduction and Questions to the Committee.
DR. SHRAKE: Good
morning. Topic two today is heterogeneity of commercial alpha-1 proteinase
inhibitor products, implications for longer-term safety and efficacy.
Before starting our discussion of the heterogeneity of
licensed alpha-1 PI products, I would like to briefly summarize the role that
alpha-1 PI plays physically, ramifications of alpha-1 PI deficiency, and
treatment of alpha-1 PI deficiency.
Individuals who are homozygous for mutant alpha-1 PI -- and
the most common mutant is the Z mutant -- these individuals have low circulating
levels of alpha-1 PI due to the tendency of Z mutant to fold more slowly during
translation, giving rise to the formation of polymer which, in turn, gives rise
to the formation of inclusion bodies within hepatocytes, which are, in fact,
the major site of synthesis of alpha-1 PI.
Alpha-1 PI deficient individuals have chronic obstructive
pulmonary disease, and usually present with progressive, ultimately fatal,
emphysema, due to the action of uninhibited elastase in the lower lung,
particularly on elastin, and some of these individuals manifest chronic liver
disease, including hepatocellular carcinoma.
Such deficient patients receive alpha-1 PI augmentation
therapy to slow the rate of progression of the emphysema.
At present, there are three plasma derived alpha-1 PI
products for augmentation therapy of patients with congenital alpha-1 PI
deficiency.
Prolastin was licensed by Bayer Corporation in 1987, and I
believe just this past year Talecris bought the license.
Aralast was originally licensed by Alpha Therapeutic
Corporation in 2002, and shortly thereafter Baxter purchased the license. Zemaira was licensed by Behring in 2003.
Augmentation therapy involves weekly intravenous
administration of a licensed product at a dose of 60 milligrams of functionally
active alpha-1 PI per kilogram of body mass, in order to maintain circulating
levels of alpha-1 PI at 11 micromolar or greater, as measured antigenically.
For a 75 kilogram person, this corresponds to infusion of
4.5 grams of alpha-1 PI per week, throughout the lifetime of the patient. That
is a lot of protein.
I would like to give a brief overview of the events that
gave rise to the issues that are under consideration this morning.
On September 16, 2004, Dr. Mark Brantly from the University
of Florida Medical School, contacted our laboratory concerning an atypical
isoelectric focusing pattern that he had observed in analyzing sera of patients
who were on augmentation therapy with aralast.
Then, on September 24, CBER initially contacted Baxter to
request lots of aralast for isoelectric focusing analysis, both by CBER and by
Baxter.
Then, on October 14, 2004, the Alpha-1 Foundation contacted
the CBER center director's office reporting the same observation -- that is,
the atypical IEF pattern for aralast, but the report was from a different
laboratory.
On October 15, CBER contacted Baxter again and, at that
time, requested pharmacovigilance data, and inventory samples of both the
product and patient serum samples from clinical studies, Baxter isoelectric
focusing results, and at the same time also requested that Baxter initiate an
investigation into the root cause of the atypical IEF pattern for aralast.
During a telecon on October 20, 2004, Baxter speculated to
the FDA that the additional isoelectric focusing bound is, in fact, a rare
glycoform that becomes highly enriched during the purification of aralast.
In contrast, during that same telecon, CBER contended that
there was an anodic shift by a whole negative charge of most of the major BADs.
At least at that point we felt that was a very reasonable explanation.
We also communicated to Baxter during that telecon was that
our IEF results also demonstrated consistency of manufacturing back to the
conformance lots that were used for the licensure of aralast.
During November 2004, CBER continued the investigation by
comparing isoelectric focusing properties of all three products with those of
alpha-1 PI in plasma, and then reported the results to CBER management on
December 7, 2004.
Shortly after that report, CBER confirmed the consistency
of the atypical IEF properties of aralast during the phase III clinical trial
which was used for licensure of aralast.
These involved data that I believe Dr. Brantly is going to talk about
later.
On January 11 of this year, the Alpha-1 Foundation sent
patients undergoing therapy for alpha-1 PI deficiency a letter notifying them
of the atypical IEF pattern of aralast.
The letter mentioned potential concerns which needed to be
evaluated. These concerns included potential altered in vivo half life, altered
biodistribution, increased antigenicity, and organ toxicity.
Then, on June 9 of this year, Baxter came to the FDA and presented
results of a biochemical analysis of aralast, and I believe it is these data
that Dr. Schwarz is going to talk about later.
These are the presentations that are going to follow. Dr.
Marshall will present results from an expanded isoelectric focusing study of
all three licensed products, as well as alpha-1 PI in plasma, and Dr. Brantly
will discuss the detection of, and implications of, a modified alpha-1 PI in
aralast and, as I just mentioned, Dr. Schwarz will present the results of
Baxter's biochemical analysis of aralast.
Dr. Khoie from CBER will discuss results of a detailed
consideration of safety reporting for all three licensed products.
Dr. Pierce will summarize proposed safety monitoring
programs for al products, and post-marketing study commitments for two of the
licensed products, and the rationale for the design of these studies.
Drs, Chang and Brorson will describe therapeutic proteins,
both plasma derived and recombinant, that have known structural modifications
and that have been licensed by FDA.
It is important to add here that, even though one product
with a specific, well defined modification, is demonstrated to meet FDA
criteria for approval -- that is, safety, efficacy, potency and purity, each
product is considered on a case by case basis.
In other words, a specific modification may allow approval of one
product but not necessarily of another.
Even though we have yet to hear the presentations, let's
keep in mind the following issues, since the committee will be asked to respond
to these questions this afternoon.
Based on the differences in primary structure of alpha-1
PI, and the concentrations of alpha-1 PI polymers in these products, does the
committee have any comments and/or recommendations regarding:
One, the adequacy of the requested or planned postmarketig
commitment studies to evaluate the longer term safety and efficacy of alpha-1
PI products as measured by specified clinically meaningful end points;
Two, the adequacy of the proposed safety monitoring
programs;
Three, any other suggested actions, for example,
communications through labeling or other venues. Thank you.
DR. ALLEN: Thank
you, Dr. Shrake, for the overview. Our next presentation is by Dr. Ewa Marszal,
who will tell us about observations on marketed alpha-1-proteinase inhibitor
products.
Agenda Item:
Observations on Marketed alpha-1-Proteinase Inhibitor Products.
DR. MARSZAL: Good
morning. I will be talking about
differences among alpha-1 PI products, and the consistency of their
manufacturing.
All alpha-1 PI licensed products are manufactured from
human plasma, and that is why they contain contaminating plasma proteins.
In addition, they contain inactive alpha-1 PI species, such
as polymers in latent form, and they have different kinds and different levels
of modifications of the primary structure.
This slide shows protein composition of alpha-1 PI
products. The analysis, denaturing, reducing polyacrylamic gel electrophoresis,
staining with komase blue, and the intensity of the bands corresponds to the
active amounts of the protein species.
Here I show analysis of three lots for each of the
products, and the lots were randomly selected from 2003-2004 manufacturing.
Alpha-1 PI is the major component of all these products,
and this analysis does not discriminate between the active and inactive forms.
The major impurity is albumen, and there are also minor
other impurities. However, there is only one impurity -- IGA -- that we know
that is causing serious adverse events.
All these products have IGA warning on the label.
The specific activity of the products expressed in
milligrams of active alpha-1 PI per milligram of total protein can be as low as
.35 for prolastin, .55 for aralast, and .7 for zemaira, and this information is
from the package insert.
This slide shows a molecular weight distribution of the
species present in the products, and this analysis is size exclusion, high
performance liquid chromatograph.
The area under the curve corresponds to the relative
amounts of the species present in the product, and the elution profile is shown
for one randomly selected lot for each product.
The major peak corresponds to the monomeric form of alpha-1
PI active and inactive, plus albumen. Albumen does not result from alpha-1 PI
under these analysis conditions.
In zemaira, we can see the presence of alpha-1 PI
dimer. in aralast and prolastin, we can
see higher molecular weight species, which include polymers of alpha-1 PI and
probably albumen, and also protein impurities contribute to this pattern.
Now, I would like to introduce isolectric focusing. It is
an electrophoretic method. The proteins are applied to a gel and migrate
through the gel in the electric field.
In isoelectric focusing, there is pH gradient. Alpha-1 PI is a negatively charged protein
at physiological pH. It is applied in the cathode area, and it migrates toward
the positively charged anode.
On the way, it is encountering an increasing concentration
of protons, which neutralize its charge, and the protein stops at pH, where the
next charge on the protein is a zero, and the protein focuses at this pH.
Alpha-1 PI, when analyzed by isoelectric focusing, shows
high heterogeneity, and it is due to the presence of three polysaccharide
chains, each of which can have two or three antennae.
Each antennae is capped with a sialic acid molecule, which
carries a negative charge, as shown here in red.
So, different alpha-1 PI molecules with different numbers
of branches have different charges, and they focus at different pH.
Heterogeneities, also caused by the presence or absence of
N-terminal pentapeptide, which has two negative residues, and heterogeneities
are also caused by natural alpha-1 PI polymorphism.
However, the effect of polymorphism is not seen in old
plasma samples, and is not seen in the product. It is because dominating
variants have the same charge.
These are dominant alpha-1 PI isoforms in plasma, M6 and M4
and M2. Although it is present in smaller amounts, it is also clearly visible
on the gels.
All these forms have full length polypeptide chains, and
the only difference is the number of sugar branches. M4 has one more negative charge converted to M6, and M2 has one
additional negative charge compared to M4.
So, they are present on the gels as three separate bands.
So, now let's look at isoelectric focusing analysis of
plasma and the products. On the left-hand side you can see analysis of samples
that were not manipulated in any way.
On the right-hand side, you can see samples that were desyalyated(?).
In the plasma, we can see clearly isoforms M6 and M4, and
also most likely M2, and the staining of this gel was with komase blue. So, above the bands, the staining shows the
presence of other proteins that focus in this pH range.
The most similar pattern to that of alpha-1 PI in plasma is
in prolastin, also two major bands, and they focus at the same pH as M6 and M4
isoforms in plasma.
In Zemaira, there are also two major bands, but they are
shifted slightly toward down, which suggests certain modification.
In aralast, there are also two major bands. However, they
focus at M4 and M2 positions. The simplest interpretation of such a result
would be that actually in aralast, all alpha-1 PI is normal. However, the
product is enriched in isoform M4 and M2.
However, a closer look at the gel suggests that actually
these two bands correspond to isoform M6 and M4, creating an additional
negative charge. So, they are shifted by one negative charge toward the anode.
In addition, we can see also the presence of normal M6
isoforms. This suggested that, in aralast, there are two forms of alpha-1 PI,
normal and carrying an additional negative charge.
To test this hypothesis, we desyalyated the protein. In this case, we would expect to see two
different kinds of polypeptide strains.
On the other hand, since this heterogeneity is only caused
by the presence of the sialic acid after desyalyation, we should see only one
band.
This is what we essentially see after the desyalyation. So,
this is a western blot of plasma, and western blot was performed to be able to
visualize alpha-1 PI, since it focuses in this region where there are many
other proteins present.
On the other hand, for the products, we used komase blue
stained gel. So, in plasma, there is a major band, but we also see minor other
bands.
The band on the top most likely corresponds to polypeptides
missing their N terminal peptide. However, there are also other faint bands here,
which suggest that a small population of alpha-1 PI in plasma is also modified.
Now, the most similar pattern among the products is seen in
the prolastin, and the major band focuses at the same pH as the major band in
the plasma.
In Zemaira, the major band is shifted slightly toward down,
which confirms that there is some modification of this protein.
In aralast, the major band is shifted by one negative
charge toward the anode, suggesting that there is a modification.
Also, in aralast, we see a smaller amount of normal alpha-1
PI. In addition, we can see that, in
zemaira and in prolastin, there is also a population of proteins carrying an
additional negative charge, which suggests that there is modified protein
present there.
However, the modifications here can be different, and there
may be more than one modification, resulting in an extra negative charge, and
the modifications in the product can be different from the modification that is
observed in plasma.
Baxter carried out an extensive investigation to identify
the cause of the atypical isoelectric focusing pattern of their product, and
they will provide their data shortly.
One of the most important questions that we wanted to
address when we learned about the atypical isoelectric focusing pattern of
aralast was, if aralast tested in clinical trial had the same atypical pattern
as it is showing right now.
To answer this question, we collaborated with Dr. Mark
Brantly, from the University of Florida. He tested patients plasma samples from
the clinical trial and provided us with the results. We were able to unblind the patients and analyze the data.
We found that, at the time of the clinical trial, aralast
consistently was showing the atypical isoelectric focusing pattern that it is
showing right now.
In addition, we analyzed a number of current lots for all
the products, and historical lots for all the products. We found that each of the products shows the
same isoelectric focusing pattern over time.
So, in summary, I would like to emphasize that alpha-1 PI
products contain different levels of contaminating plasma proteins.
They contain different amounts of inactive alpha-1 PI
species, such as dimers or polymers.
They contain different levels of primary structure modifications.
Alpha-1 PI, in each product, differs somewhat from alpha-1
PI in plasma, or in terms of isoelectric focusing patterns, all because it
contains polymers. Manufacturing of
each alpha-1 PI product appears to be consistent over time, when judged by
isoelectric focusing. Thank you.
DR. ALLEN: Thank
you very much, Dr.Marszal. Questions for clarification? Okay, we will move on, then, to the next
presentation by Dr. Mark Brantly of the alpha-1 Foundation. The topic is identification and possible
implications of a human plasma purified anodal variant of alpha-1 antitrypsin.
Agenda Item:
Identification of Possible Implications of a Human Plasma Purified
Anodal Variant of Alpha-1-Antitrypsin.
DR. BRANTLY: Thank
you very much. Let me just -- you will
know more about alpha-1 A-trypsin by the end of this series of presentations,
but I wanted to review just a little bit more about it.
It is a 394 amino globular protein. This is the protein
structure. What is absent from here is the glycosilated forms, which we really
don't know how they look on here.
This is the reactive site loop. It is under an enormous amount of stress. It sort of acts as bait
for proteases, and the cleavage of this causes a major rearrangement.
It has a single cysteine in it, and it is the isoelectric
point, for all of the variants fall within a pH range of 4.2 to 4.8.
The functions of alpha-1 A-trypsin is, one of the most
traditional and primary ones that we focus on is the ability to inhibit a
number of serine proteases, including neutrophil elastase.
In addition, recently it has been shown that it inhibits
neutrophil defensins, which is a potent antimicrobial and a cytotoxic molecule.
It is now -- there is accumulating evidence that it has
broad anti-inflammatory effects and, indeed, it may be one of nature's
anti-inflammatory molecules. It
inhibits lymphocyte trafficking. It appears, in vitro at least, to prevent LPS
induced stimulation.
One of the names that it is also called is alpha-1
proteinase inhibitor, and that is important as we go through this talk.
Now, again, more isolate refocusing gels, because this is
sort of the center of the story in this matter. One of the things I was noticing as we look at our gels a little
bit differently -- so, I flip mine over a different way.
This is a schematic of what alpha-1 A-trypsin variants look
like. Again, the IEF method is used for separating protein isoforms by
charge. The isoelectric point is on the
pH scale where a protein has no net charge.
Traditionally, it has been used for laboratory diagnosis of
alpha-1 A-trypsin, but it is obviously very potent for understanding isoforms.
Now, in the first lane right here is M1M1, which is the
most common variant seen in the human population. There are some different isoforms, which we will talk about a
little bit more, but the major isoforms are the 4 band and the 6 band.
On the far end right here is the ZZ protein, which has a
single amino acid substitution, which causes basically both a drop in the
function and also the amount that is secreted.
You can see that an MZ individual right here actually has
the combination of both of those isoforms in there.
So, an individual that is being augmented with alpha-1
A-trypsin would normally have an MZ pattern, and that sort of begins the story
here.
This is actually what the isoforms look like. Again, there
are basically five major isoforms. The two most prominent isoforms are actually
the four and the six band, and they constitute approximately 85 percent of all
the alpha-1 A-trypsin that is circulating.
Again, the major differences are basically the carbohydrates.
For the seven and eight band, they are identical to the
four and the six band, with the exception of a five amino terminal clip.
Now, let's just tell the story about how we identified the
anodal drain in Aralast. Individuals
with alpha-1 A-trypsin deficiency have commonly ZZ. So, the pattern on therapy,
as it was expected, would be MZ.
The E region is actually -- we have a known variant for E,
which is a different amino acid substitution. This E region variant was
identified in two different laboratories, my lab, and a lab at Temple
University.
At first, when I saw this, I thought I was looking at a
genetic modification. So, I actually did genotyping and found that the subjects
were ZZ, and then surmised that it was probably some sort of post-translational
modification. As it turns out, after
investigating, we found that all the subjects were on Aralast.
This brought some concerns, in that originally I was very
involved in the Alpha Therapeutic Corporation's development of their API, which
subsequently was licensed to Aralast.
Originally, when I did the analysis of that particular
product, it had an MM pattern to it. So, there was a change in the pattern from
the time that we did initial analysis of the material until now.
So, one of the big questions that the FDA had was, is this
the same material that is used in the pivotal trial, because obviously that
would be a big problem.
So, let me tell you a little bit about the Alpha
Therapeutics Corporation pivotal trial. Again, as I mentioned, this ended up
being the same material that Aralast is.
The clinical trial was run from 1996 to 1999. There were 28
deficient individuals that were enrolled for a six-month study. There were two
early drop outs.
The comparitor was Prolastin. The primary outcome variable was not compared, that is, the total
and the functional amount of atrypsin.
That was the central laboratory for this particular study,
both at the NIH, and subsequently when I moved to the University of Florida.
It was a two-arm cross over study, where the ATC API had 13
individuals, and the Prolastin had 13 individuals. This period right here was 12 weeks and they were crossed over to
ATC API at the end of this thing, and again, it was a 24-week study.
We actually had an opportunity to analyze all the samples
that we had available. We had 11 of the 13 samples. I wanted to select just a
specific time prior to cross over, because I think this is illustrative as far
as looking at this.
This is a lot of Aralast, where you can see the major bands
here. Here is an individual with some prolastin, and here is an individual that
is on Aralast, with very little of the M bands sort of being visually picked
up. You can actually very easily -- you don't have to have the key to figure
out which patients are on prolastin and which ones are on Aralast. Again, here are the Z bands running down
here and a standard.
We used these bands, actually -- I did then some metric
studies on the banding patterns, and looked at the proportion of the E as
compared to the N, and the results are here on the right-hand side.
A densitometry was done at the six week point, and I am
just showing the data on the ATC API patients, rather than the prolastin patients.
What we found was that approximately 76 percent of the
total nadir alpha-1 A-trypsin -- this was done right before the next dose --
was the modified form, that you can see right here.
This was consistent with our observations, and also,
importantly, consistent with what we anticipated that Aralast had, which the
vast majority of the material was the modified form.
Now, the pivotal results, the ATC pivotal result was in a
publication, and I just want to go over them briefly.
It demonstrated that the antigenic and the functional
amount of alpha-1 A-trypsin, based on the antiprotease activity, was similar to
comparator prolastin.
There were no serious safety signals in this small, short
study and, following six weeks of the ATC API, the modified material was about
76 percent of the materials total.
The half lives were similar between ATC and API. There was
a statistical difference between them, suggesting that there was a longer half
life for the ATC API, but the confidence bands definitely overlapped each
other.
Now, Baxter did a great deal of elegant work in trying to
figure out the cause of this anodal variant.
As it turns out, the anodal variance is secondary to the loss of the C
terminal positively charged lysine, which is located here in the structure. That loss is presumably secondary to carboxy
peptidase activity, which is a contaminant.
Now, the question is whether the loss of this terminal
lysine is important or not, and I think that is sort of the central issue of
all the presentations here.
So, let me show you some structural studies that sort of
look at what the lysine 394 is before and after protease cleavage, because that
is sort of a key component.
One of the things you can see is, even after cleavage and
the significant rearrangement of the molecule, the 394 amino acid does not
move. It basically is located -- this is two different crystal structure
salts. So, we know this actually is
probably a fixed position rather than a non-fixed position, in that a non-fixed
position, actually you can't get x-ray coordinates on, because it is moving
around too much.
The other thing is that it appears to be in range of the
serine 292 as far as hydrogen bonding. I didn't bring some cartoons to show you
rotation, because I thought it was a little bit too much to go over here, but
it is quite important.
One of the things I want to focus in on is this molecule
right here, which is the cleavage product, which is also called the C36
peptide.
There are now a number of studies that are coming out suggesting
that this is a biologically active molecule that may actually be a weak agonist
on the TLR-4 receptor, suggesting that it may actually block LPS mediated
events.
So, we don't know whether this may cause it to lose more of
this peptide, in other words, to be freed up, or whether it changes its
biology.
One of the other things that I had the opportunity, because
my lab does a lot of this, and we do a lot of work for the industry is, I have
had the opportunity to basically test a number of products, even some of the
products that the FDA doesn't have access to yet.
This is an isoelective focusing gel looking at five
different forms of alpha-1 antitrypsin. There is Acommida(?), which is an
Israeli company, that is developing alpha-1 A-trypsin, and Prolastin, Zemaira,
Aralast, and Trypsone, which is made by Griffels(?).
On the far sides here are M-1 standards. In other words,
this is plasma from a normal individual. You can see, here are the major bands.
That is the 2 band right here, the 4 band, the 6 band, the 7 band and the 8
band, that you see.
You can see that the Acommida material has a similar band
dependence, but has this material right here, which is not seen in the plasma.
You can also see that Zemaira is also. So, this group of
three are very similar. If you look at both Aralast and Trypsone, they have a
similar banding pattern, where a majority of the alpha-1 A-trypsin is actually
this anodal variant here.
These are high resolution scans. So, we can actually see a
little bit better this distinct difference, and that these are definitely
different.
So, again, none of these products are exactly the same as
native alpha-1 A-trypsin, but more than 65 percent of the trypsin in Aralast is
the modified form, presumably.
We also know, from studies, that both prolastin and zemaira
have some of the modified forms. It is in the range of two to six percent, and
there are other known modifications in these products.
So, is there reason for concern using a modified form of
alpha-1 A-trypsin for augmentation therapy?
number one, i would like to remind you that this study -- in fact, all
the studies involving this, were very small clinical studies that were done to
establish the safety profile.
The modified form is 30 percent more in aralast than it is
in prolastin, and I think that is an important thing to remember.
There is the potential of antigenicity because of the loss
of the surface amino acid, and we know that is for sure.
Now, alpha-1 A-trypsin, there are other variants that don't
cause antigenicity. So, i think that we are comforted by the fact that other
molecules may not cause antigenicity.
The charge difference may make a significant difference,
though, in sort of the biodistribution of the molecule.
Obviously, a highly positive charge may be really cleared.
.We just don't know at this point. Again, this dimension, the cleavage of the
modified form creates a modified C terminus, which may end up being important.
One of the things we clearly know is that alpha-1 A-trypsin
has many functions that we haven't quite figured out. I would also remind you that it is the second-most abundant
plasma protein.
There is reason to believe -- and unfortunately there is
reason to believe that ATC did their animal studies, their animal tox studies,
probably using the other form of alpha-1 A-trypsin, not the form that went into
the clinicals.
So, in summary, the anodal variant is a modified form of
alpha-1 A-trypsin. It is a truncated C
terminus, which occurs probably during purification.
At least 65 percent of the aralast is the modified form.
Then, truncation could potentially modify antigenicity tissue distribution,
clearance and stability.
This modified form of alpha-1 A-trypsin may or may not have
all the functional properties of native alpha-1 A-trypsin.
I think that careful monitoring of patients taking this
group of products is really warranted. Thank you very much.
DR. ALLEN: Thank
you, Dr. Brantly. Questions of clarification of Dr. Brantly on his
presentation?
DR. EPSTEIN: One
question, Mark. You pointed out that
the Griffolds product has essentially the same protein modifications as the
aralast. Are there any safety data in Europe on the Griffolds product?
DR. BRANTLY: I
haven't had access to it. So, it is just unknown. The commonality between --
and I think the Baxter folks can tell you more -- they are basically
essentially the same product, and they had the same protocol and that kind of
stuff. So, we don't know.
They have a much smaller core and, if I recall, all the
Griffolds product is being used in either South America or in Spain.
DR. DI BISCEGLIE:
My question is, what is the significance of, or how important, is
measurement of the activity in trying to assess differences or clinical
utility, or comparisons between products?
DR. BRANTLY:
Actually, we have taken a molecule that is a highly conserved molecule,
and we picked out, in our puny human terms, picked out one function that we
think is the critical function in this particular molecule, which is an
antiprotease activity.
Do I think it is important? I think it is important. Do I think that it is the whole
story? Absolutely not.
I think that we have chosen this one function -- and
indeed, a very important function -- to sort of focus in on.
Quite frankly, it is very difficult to measure many of the
other properties that this molecule may have at the present time.
DR. DI BISCEGLIE:
In the improved indication, we are trying to prevent emphysema. Is this activity not thought to be the
pivotal activity in causing that disease?
Yes, the molecule might have other activities, but in this disease,
isn't that the most important activity?
DR. BRANTLY: That
is the hypothesis. I think that, as a scientist, I have to say that we may be
wrong. Again, this is based on a
hypothesis of the anti-protease homeostasis hypothesis, and that is that it is
inhibition of neutrophil elastase that causes the problem.
We know that these molecules have potent anti-inflammatory
effects. So, it may be a chicken and the egg process also, in that the
recruitment of neutrophils into the lung may be a major key step in going
through this.
So, the anti-inflammatory properties may be more important.
It is just a matter of how you look at the molecule and its major process. I have been humbled enough time in my
hypothesis that I am a little more circumspect now.
DR. LAAL: Does the
structural change lead to an immune response that would eventually alter the
function of your molecule?
DR. BRANTLY: We
know, from the ATC study, that the amount of alpha-1 A-trypsin is similar to
what it was with prolastin.
That suggests that there are not neutralizing antibodies.
So, its function specifically for its anti-protease effect, and actually the
amount of it, is not altered, suggesting that at least in that study, that
there was antibody formation.
I did do a crude antibody test during this study, but
unfortunately, one of the things is there is not -- you can't get a positive
control for this. So, I don't know how
specific it was and how sensitive the assay was for antibodies. I feel pretty strongly, from the data, that
there is no evidence of neutralizing antibodies.
DR. SZYMANSKI: I
might have missed in your presentation, but how many polymers did you find in
there?
DR. BRANTLY: You
know, isoelective focusing is not very good for polymers, because they don't
tend to migrate out into the gel.
Better ways to look at polymers, actually, are other
methodologies, either HPLC or actually non-denaturing gels.
DR. SZYMANSKI:
Would the polymers be considered dangerous?
DR. BRANTLY: It is
not known. There is a body of literature to suggest that polymers are
pro-inflammatory. There are some suggestions from other parts of the literature
that suggest they may not be pro-inflammatory. .So, I think that the process --
I mean, I think the jury is a little bit out on that aspect of the polymers.
One thing I would remind you is that in general our RE
system hates aggregates and polymers. So, usually they are cleared by first
pass. I don't believe anybody has been able to detect increases of polymers in
people who have been augmented.
I also want to remind you that polymers naturally form,
actually, in normal sera, too. Particularly, you can get polymer formation for
Z individuals that occur.
DR. DOPPELT: I
think you said that, in the initial toxicity studies, that the product was
different from this current product. Is there something different in the
manufacturing?
DR. BRANTLY: This
is the part that I can't stitch together for you because there is sort of a
black box. I don't believe that Baxter can stitch that together either.
In 1995, when ATC came to me to help them with the analysis
of their drug, I did isoelectric focusing on that drug, and actually did
denaturing gradient gels, and did an extensive characterization of that
particular molecule. It was very similar
to prolastin at that point.
Between 1995 and 1996, my understanding is a number of
manufacturing changes were made, and I did not analyze -- I was not asked to
analyze those samples, and went forward with the clinical trial at that point,
not realizing that there had probably been a change in the molecule.
From the timing, I would guess that the molecule used for
the animal studies was not the same as it was for the clinical study. Actually, when I was given the material, the
animal studies had already been done.
DR. SZYMANSKI: I would
just like to know how much is this alpha-1 antitrypsin concentrated in the
products versus the normal plasma.
DR. BRANTLY: Many,
many, many-fold. Example, it depends on the manufacturer, quite frankly, but
usually there -- it is re-suspended and then fused in a range from, let's see,
50 milligrams per ml, and normally in the human sera it is about 150 milligrams
per deciliter. So, it is substantially concentrated. The typical dose is about
4.5 grams for a 60 kilogram individual.
DR. ALLEN: Thank you
very much. We will move on to our next speaker at this point, Dr. Hans Peter
Schwarz from Baxter Health Care, characterization of Aralast compared to other
alpha-1 proteinase inhibitor preparations.
Agenda Item:
Characterization of Aralast Compared to Other AIPI Preparations.
DR. SCHWARZ: Good
morning, members and guests. I would like to address, in the next 15 minutes or
so, modifications to primary structure on alpha-1 Antitrypsin in all commercial
products, the potential cause of the micro heterogeneity of alpha-1 A-trypsin
in Aralast, and I will close with an elucidation on the potential implications
of the microheterogeneity found on alpha-1 antitrypsin molecule in Aralast.
Now, this is a two dimensional IF gel, what I would call
the united colors of alpha-1 antitrypsin. Here, aralast and prolastin were
labeled with a specific dye, which enters co-linked bounding with epsilon amino
group of lysine, and you nicely see aralast in green, and prolastin in red, and
the slight anodal shift of all the isoforms.
At the same time, this technique allows you to identify different
contaminating proteins.
These 2D IF gels confirm what you saw presented by the
previous speakers, that there is an anodal shift of the alpha-1 PI molecule in
aralast. This is just a magnification
of the mobility of the alpha-1 antitrypsin protein in aralast toward the anode,
compared to prolastin in red.
Now, what are the modifications which have a potential
impact on the protein charge, secondary structure modifications based on the
glycosylation differences, and primary structure modifications such as
deamidation, cysteine modification, and removal of terminally located charged
amino acids.
This is a summary of data comparing the N glycan structures
on the three commercially available products, aralast, prolastin and zemaira,
by an HPLC analysis, and you will appreciate that there is no difference
between the products. This is also
confirmed by mydetov(?) analysis.
So, there is no
difference in N-glycan profile between aralast, prolastin and zemaira, and the
pattern is similar to that found for antitrypsin in plasma also, although I am
not showing you the data..
So, the first message I would like to convey to you is that
the N glycan pattern of all three antitrypsin products used for the treatment
of hereditary emphysema is similar to that of plasma and, therefore, ethanol
fractionation and downstream purification has no impact on any glycan
differences.
Now, this is a high resolution IF gel, and it shows you two
things. Number one, the consistency of the IF pattern of aralast over the
years.
This is a lot made in 1996, and then this is a lot of 2001,
2004, 2003 and 2002. Second, the
purpose of this slide is to correlate the N glycan pattern to IF bands.
Prolastin in plasma, N6, as we heard just now before, has
three B antennaric glycan structures attached and, in four, two B antennary and
one 3-antennary structure. This is both in prolastin and aralast, and we
actually did analysis of this gel by cutting out the gel and subjecting them to
MS.
Now, what is the situation in the banding pattern of
aralast? This band, which co-migrates
at the level of M-4 in plasma and prolastin, consists or has the three B
antennary glycan structures attached, similar and identical to M6, while this
band, in aralast, has the two B-antennary and one 3-antennary structure
attached.
So, this band corresponds to M6, present in plasma and
prolastin, and this band corresponds to M4. Then there is a shift toward the
anodes, and the N-glycans are therefore not responsible for the IF pattern
characteristics of aralast.
Therefore, we started the investigations to look into
potential changes on the protein backbone. First, deamidation.
Deamidation potentially results in an additional negative
charge. it is the non-enzymatic conversion of asparagine 116, or asparagine 314
to aspartic or isoaspartic acid.
This slide shows the data for aralast, zemaira and
prolastin, both by a quantitative assessment, which was then confirmed by MS
analysis.
In aralast, six percent of the molecule is deamidated to
one isoaspartate, in zemaira seven percent and, in prolastin, 10 percent of the
molecules are deamidated.
So, deamidation is one of the primary sequence
modifications which are present in all commercial products. What about cysteine
modification? This is the attachment of
another molecule, 0-cysteine to cysteine 232.
We came across this because here we did another high
resolution IF gel, and using zemaira, prolastin and aralast under reducing and
non-reducing conditions.
You will see that, in prolastin, under reducing conditions,
there is a slightly anodal shift, which suggests that the cysteine is too
stimulated in prolastin and in aralast.
We confirmed this by MS analysis. Aralast and prolastin
have another cysteine attached to the cysteine 232, while this is absence in
zemaira, and this is probably due to the purification process of zemaira, which
includes denaturing agents.
So, aralast and prolastin, as well as alpha-1 antitrypsin
in plasma, exhibit cysteinylation at 232, and this is not detected in zemaira.
What about the C terminal truncation, which would result in
the loss of a positively charged lysine, and the des-lys isoform of antitrypsin,
which we have identified.
Here is, again, an electrospray analysis showing the lack
of the C terminal lys in aralast, as well as in prolastin, as well as in
zemaira, and here are some peptides with the presence of the lysine. Using an HPLA analysis, you can easily
quantify the lack of lys on these products.
Our analysis resulted in the following conclusion: The
des-lys antitrypsin is present in aralast at the level of six to seven percent,
in zemaira around six percent, and in prolastin about two percent.
Now, this summarizes the primary and secondary structural
changes we have identified on the alpha-1 antitrypsin molecule in all the
commercial products.
There is no difference in the glycoisoforms when you
compare aralast, prolastin and zemaira in plasma. However, I would like to point out that, in the course of this
investigation, we identified, in plasma, novel site specific N glycan patterns.
For example, for the first time, tetra antennary structures
were attached to antitrypsin, as well as Lewis X structures in plasma alpha-1
antitrypsin.
Deamidation is present in alpha-1 antitrypsin in all the
products available. It is not possible to assess this in plasma.
We are currently working on identifying the lack of the C
terminal lys in normal plasma, but I will show you later data which suggests
that in other tissues, in other body fluids, such as BL, actually the C
terminal lys is removed.
The cysteine, decysteinylation at position 233 is present
in aralast and prolastin, absent in zemaira and present in plasma.
So, all antitrypsin molecules in the different commercially
available products show some differences as compared to alpha-1 antitrypsin
from plasma.
What about the potential cause of this particular micro
heterogeneity, especially expressed in aralast? There is a group of enzymes, a family of enzymes, the so-called
carboxy peptidases, which cleave C terminal basic amino acids, such as lysine
and arginine from all kinds of proteins and peptides involved in hormone
maturation and complement activation.
I just want to mention three carboxy peptidase M. This is a
membrane bound carboxy peptidase, which is highly expressed in lung tissue, but
also present in the BL fluid. Carboxy peptidase N, which is active in plasma,
and found at the concentration of 30 micrograms per ml, and carboxy peptidase
U, which is also known as TAFI.
Now, this slide shows and outlines the presence and
concentrations of two main carboxypeptidases in plasma, as well as in different
fractions of the fractionation, plasma starting material and then, in blue,
carboxy peptidase and, in red, TAFI.
I just would like to point to fraction IV-1, which is used
for the manufacturing of alpha-1 antitrypsin.
So, relatively high concentrations.
I would like also to mention that carboxy peptidases are
below the limit of detection in final containers of all products available.
Now, this slide shows the ethanol dependence of the C
terminal lys cleavage induced by CPN. Here we used a specific assay which can
measure the lys removed by the action of CPN, and increasing amounts of ethanol
will facilitate and accelerate removal of the lysine, in pink, in prolastin,
and in blue, aralast. So, there is more
lysine removed from prolastin because it has more to be released.
Now, this is an important slide because it shows actually
that CPN can remove the C terminal lysine also in absence of ethanol, but the
reaction is highly stimulated in the presence of ethanol.
Interestingly, recombinant yeast derived alpha-1
antitrypsin seems to be more susceptible to the action of CPN.
This is a time course of the removal of the lysine from
recombinant alpha-1 antitrypsin. So, in
five minutes, more than half of the lysine is removed.
This high resolution IEF shows the generation of anodal
isoforms of alpha-1 antitrypsin by the treatment of recombinant membrane bound
CPN.
This lane is aralast, and in lane zero is an experimental
lot similar to prolastin, and increasing concentrations of carboxy peptidase M
applied.
So, you see a shift of the M6 band, you see a shift of the
M4 band, interestingly also a shift of M7 to M7* and a shift from M8 to
M8*. So, carboxy peptidase M is very
potent in generating these specific isoforms which lack C terminal lysine.
Here is a quantitative assessment of the conversion of M4
to M2* and M6 to M4*, upon the action of carboxy peptidase M.
Now, this is very new data, and you have not this in the
package. This is alpha-1 antitrypsin
isoform peptin obtained from human PL samples.
Here a highly sensitive IF gel was used to detect alpha-1
antitrypsin in bowel samples from subjects not on replacement therapy, and
alpha-1 antitrypsin was detected in all bowel samples.
Interestingly, the IF pattern resembles the alpha-1
antitrypsin shift observed in aralast here in lane two, and here are the
patient samples.
This suggests that an isoform shift with the removal of C
terminal lysine may occur naturally, and is possibly induced by the action, or
the presence, of membrane bound carboxy peptidase M.
So, in summary, all basic carboxy peptidases can cleave to
C terminal lysine from alpha-1 antitrypsin. The cleavage of C terminal lysine
occurs also in absence of ethanol.
Ethanol enhances the reaction of CPN, approximately 24, and
if it is 15 percent ethanol, there is a 20-fold effect on both KCAT and KM in
the presence of 15 percent ethanol.
CPN is the most likely candidate causing the C terminal
lyse cleavage in plasma, and I have no time to give you the reason for this
statement.
I would like to refer also to an interesting paper
published in the JBC, 1962, where they describe effects of ethanol both on KCAT
and KM, regarding the activity of carboxy peptidase B.
Now, potential implications of the micro heterogeneity of
alpha-1 antitrypsin observed in aralast, we did extensive preclinical in vivo
and in vitro investigations to rule out concerns regarding the additional extra
negative charge.
This is just a summary of a very extensive bioinformatic
investigation. Actually, the investigations were performed in two different
institutions, and they came to the same results. Let me walk through this.
There is no conservation between species of the C terminal
lys in alpha-1 antitrypsin. Therefore, the lys 394 is unlikely to play a major
structural or functional role.
3-D analysis of available structures for alpha-1
antitrypsin, and its complex with protease do not support a major structural
role of lys 394.
The C terminal loop region is stabilized by a hydrogen bond
network, in which lys 394 is not involved.
So, the conclusion is that lys 394 plays no major structural role in
alpha-1 antitrypsin, when uncleaved and cleaved, as well as when forming
complexes with its proteases.
This slide summarizes the functional relevance of the C
terminal truncation. It shows the alpha-1 antitrypsin dependent inhibition of
porcine elastase, so the inhibition of the porcine elastase as a function of
the concentration of alpha-1 antitrypsin.
You will appreciate that, for prolastin, zemaira, aralast
and an experimental lot we performed with it, that has 100 percent des-lys
truncation, the curves are superimposable.
So, lys, terminal lys, has no effect in any way on the capacity of
alpha-1 antitrypsin to neutralize porcine elastase.
Now, thus, the high degree of C terminal truncation, and
introduction of an additional negative charge has an impact on metabolic
clearance in rats. There is comparison
of different alpha-1 preparations which had a different degree of C terminal lys
truncations.
Distribution of the lung, we did rat BL studies. There was
a clear comparability of alpha-1 preparations with different degrees of C
terminal lys truncation, including the 100 percent des-lys alpha-1 PI in rat
BAL studies.
Diffusion from vasculature into the interstitium, it is an
interesting model which is called the skin blister suction model, comparability
of alpha-1 antitrypsin preparation with different degrees of C terminal lys
truncation, including the 100 percent des-lys form in guinea pig suction
blister models.
Finally, we did confocal studies to assess the diffusion of
these different forms of alpha-1 antitrypsin from the vasculature into the lung
tissue, and also here, there was no difference observed.
So, if I may include, alpha-1 antitrypsin in all products
approved for augmentation therapy demonstrate at least one primary structure
modification.
The des-lys alpha-1 antitrypsin is induced by the action of
carboxy peptidases, and the ubiquitous presence of these enzymes in plasma, as
well as in lung tissue will likely result in exposure and, hence, tolerance to
the des-lys alpha-1 antitrypsin form.
The des-lys is one of many known isoforms of alpha-1
antitrypsin that does not affect inhibitory activity, immunogenicity or
essential functions of alpha-1 antitrypsin. Thank you very much for your
attention.
DR. ALLEN: Thank
you, Dr. Schwarz. We will entertain clarification questions.
DR. DI MICHELE:
Thank you, Dr. Schwarz. As usual, it is beautiful, elegant biochemistry,
and it takes me a while to catch up, but I actually have a couple of clarifying
questions.
Based on what you presented, and the fact that the same
isoform sort of shift occurs naturally in alpha-1 patients, antitrypsin
deficiency patients, does it appear to be an inherent molar imbalance between
the carboxy peptidase and the amount of protein substrate that you think might
be causing the shift?
In one case, in your manufacturing, you seemed to be
enhancing the carobxy peptidase end, and in the other case, naturally
occurring, there seems to be just naturally less protein. Is that what might be going on here?
DR. SCHWARZ: That
is a very good question, like always.
It might be a combination of different effects. As I demonstrated, there is a clear effect
of ethanol by decreasing TTN and increase TKCAT.
On the other hand, the removal of the C terminal lys is
time dependent. So, the obvious question is, you know, how long is the alpha-1
antitrypsin in the fractionation intermediates, exposed in the presence of
ethanol to the carobxy peptidases.
Obviously, manufacturing procedures and ethanol are almost
generic, but there are slight differences in ethanol fractionation between the
manufacturers.
Regarding the naturally occurring isoform or truncation of
lysine, you know, it might well be that there is a conformational change when
the alpha-1 antitrypsin molecule travels from the vasculature through the lung
tissue into the alveolar space, which allows exposure of the C terminal lys in
a way that makes it more accessible to the action of membrane bound carboxy
peptidase, but this is speculative.
DR. DI MICHELE:
Thank you. The other question I have is, in addition to there being this
anodal shift, there appears to be, of course, also a shift in the relative
concentrations of the M6 and the M2 isoforms, and a shift toward an increase in
the M2, a decrease in the M6.
You showed a lot of physical chemical properties that
haven't been altered by that shift, but the question is functionally, is there
any reason to believe that an M2 isoform might have increased immunogenicity
when present in higher concentrations, let's say, relative to the native
molecule.
Secondly, have you done any studies on the sort of
inhibitory activity on, for instance, neutrophil elastase, and the relative
effect on that functional activity from a change in isomer in the product.
DR. SCHWARZ: I will
answer your second question first. We used the porcine elastase assay, and here
we compared, as you remember, different products, as well as the one that lacks
totally des-lys. So, here there is no
difference, but we have not done neutrophil elastase.
Regarding the immunogenicity of specific isoforms -- if
this is your question -- if at M2 it would be more immunogenic than at M6, I
cannot answer this.
All that I can say is that we are not satisfied, as you
know. What we did were classic antigenicity studies, where we immunized rabbits
with prolastin or aralast and then did both IF gels as well as page, and both
antibodies recognized the same banding pattern. That partially answers your question, because we did IF also. So,
they recognized the --
DR. DI MICHELE: You
did some animal immunogenicity studies. The only question, though is that, I
know from some of the materials that we were given, that fraction -- you didn't
initially use fraction four as your starting material, and I was just wondering
why that change was made.
DR. SCHWARZ: The
starting material, prolastin is made of fraction IV-I, and aralast is made of a
combination of IV-I plus IV-IV. That is
the difference.
DR. KLEIN: Just so
I am clear, the animal immunogenicity studies were done with the material that
was used in the phase III trial?
DR. SCHWARZ: It is
retail material, it is commercially available material. If I may just clarify something, these gels
are extremely high resolution.
So, the charge difference, from a biological relevance, is
negligible. While one sialic acid gives a PI change of .06, the lys truncation
PI difference is .05.
DR. ALLEN: Thank
you, Dr. Schwarz. We will move on, safety reporting for alpha-1 proteinase
inhibitor products, Dr. Tina Khoie, Food and Drug Administration.
Agenda Item:
Safety Reporting for Alpha-1-FI Products.
MS. KHOIE: Good
morning. My name is Tina Khoie, and I am a fellow within the office of biostatistics
and epidemiology within CBER. My
presentation today will focus on the alpha-1 proteinase inhibitor product
safety reporting.
Before I begin, I would just like to acknowledge my
colleagues in the OBE office, Catherine O'Connell, Craig Zinderman and Robert
Wise, who were all invaluable resources as I was preparing this presentation.
My primary objective for today is to present and summarize
and describe all of the spontaneously reported adverse events from alpha-1
proteinase inhibitor post-licensure safety surveillance.
To start off with, in the next three slides, I will be
giving some definitions of some important terms that I will be referring to.
I will also review the information in the alpha-1
proteinase inhibitor safety labeling, and I will review the error surveillance
system.
First, I would like to make sure everyone is familiar with
some of these important terms. First, an adverse event is any unwanted outcome
which is associated with an alpha-1 proteinase inhibitor product, irrespective
of causality.
A report is one adverse experience, and it excludes
duplicate and follow up reports.
A serious adverse event is one that results in death, a life
threatening experience, hospitalization or prolongation of hospitalization,
disability or incapacity, a congenital or birth defect, or other important
medical events, based on clinical judgement.
Finally, an unlabeled event is one that is ont listed in
the professional package insert.
So, what adverse events are currently listed in the package
inserts of the alpha-1 proteinase inhibitor products?
This table provides an overview and, therefore, does not
list all the adverse events in each of the package inserts.
Although there are differences in the contents of the
package inserts, I will review seven of the adverse events which are listed in
each of the product package inserts for prolastin, aralast and zemaira.
They include allergic-like reactions, chest pain, dyspnea,
or shortness of breath, dizziness, fever, rash or pruritus, and viral
transmission.
I am going to give a brief overview of AERS, the adverse
event reporting system, for those who may not be familiar with it.
AERS is the FDA's passive, post-marketing safety
surveillance system, and by passive I mean that, for the most part, reports are
submitted on a voluntary basis.
The AERS data base contains adverse event reports for all
drugs and therapeutic biologics dating back to 1969. The reports that it contains all direct reports, which originate
from consumers and health care professionals, all manufacturer reports through
October 1997, and all serious manufacturer reports since November 1997.
Since November 1997, non-serious reports submitted by
manufacturers in period reports have no longer been entered into the AERS data
base. However, we can retrieve those reports by going back to the original
submissions.
So, safety reporting in terms of our methodology was
obtained by querying the AERS data base for all adverse event reports in which
an alpha-1 proteinase inhibitor was listed as a suspect product. No other restrictions were place in this
query.
As I mentioned previously, ARES no longer contains the
non-serious adverse event reports submitted in periodic submissions since
November 1997.
Although prolastin has been on the market for a
significantly longer period of time, I was able to retrieve the non-serious
periodic reports for a time period in which all three products were licensed,
and that was between January 2003 and July 2005.
The data that I retrieved from the reports included
demographics, adverse reaction MEDRA PTs, and lot numbers. MEDRA PTs stand for medical dictionary for
regulatory activities preferred terms, and these are an internationally
recognized set of medical terms that were instituted in November 1997, and
really helped to form a standardized way of classifying and communicating about
medical information throughout the medical product regulatory cycle.
The results of the AERS query and the periodic report
search resulted in the identification of 806 prolastin reports since
prolastin's approval in 1987, 38 aralast reports since its approval in December
2002, and six zemaira reports since its approval in July 2003.
Ninety percent of all the alpha-1 proteinase inhibitor
reports are domestic, 10 percent foreign, and prolastin was the only product
which had foreign reports.
From this point on, I will be focusing primarily on the
domestic reports. In terms of demographics, 12 percent of domestic reports were
classified as serious, 67 percent as non-serious, and 21 percent of reports had
this information missing.
Fifty-one percent of all reports involved patients between
30 and 69 years of age, one percent of reports involved patients less than 30,
and one percent greater than 70 years of age, with 47 percent of reports having
age data missing.
Forty percent of reports involved females, 35 percent
males, 25 percent of reports had missing data for gender.
So, this table shows the actual number of domestic reports
that were received by the FDA between January 2003 and July 2005, the time
period in which all three products, at some point, were licensed during these
three years.
The reports are broken down in terms of the ones that were
serious and non-serious. I would just like to point out that the date that we
went by was the date on which the FDA received the reports.
A large number of these reports came in as periodic submissions,
and prolastin's periodic submissions are submitted on an annual basis, and
aralast and zemaira at this point are submitted on a quarterly basis.
So, the data from 2005, the year 2005, includes the
periodic reports that we received, the annual periodic report that we received
from prolastin already for 2005, and about three quarters of the periodic
reports for aralast and zemaira, which were received also in 2005.
Although these three products are listed on the same table,
I would just like to stress that we must not compare the numbers between these
three products.
These numbers have not been adjusted for differences in
market share, and so we can take a look to see how many reports we are dealing
with, but we should not be comparing numbers between the three products.
Now, we will review what adverse events were reported. The
first two tables will review the most commonly reported adverse events, and
some of the more medically important adverse events but, again, will not
represent all adverse event MEDRA PTs that were listed in all of the adverse
event reports, and these are domestic reports.
There were over 250 different MEDRA PTs listed amongst all
of the domestic alpha-1 proteinase inhibitor adverse event reports. This table just lists the 10 most commonly
identified MEDRA PTs since product approval.
The number of reports that you see represent the number of
reports that identified each of these MEDRA PTs. Keep in mind that reports
generally listed more than one MEDRA PT.
The most common adverse MEDRA PTs included, from this list,
dyspnea, headache, and fever. Once again, we must not compare the numbers
between these three products, because we have not made adjustments for
differences in market share, nor in the length of time that the product was on
the market.
This table, rather than listing the most common adverse
events, lists some of the events which were judged medically to be more
important, based on the level of severity commonly associated with these types
of events.
It is important, once again, to note that we must not
compare the numbers between these three products, for the fact that we did not
take into account the differences in market share, nor in the differences in
time on the market.
Finally, I would just like to conclude by emphasizing some
of the limitations of passive surveillance and spontaneous reporting, some of
which were nicely reviewed by Dr. Gaines.
First, there is significant under-reporting, most likely
greatly underestimating the actual incidence of these events in patients who
were on these products.
Secondly, there are reporting biases involved. Newer
products, that are newly licensed, there is generally a greater enthusiasm for
reporting for these products.
In addition, if there are clinical studies underway, AERS
tends to capture more of these reports, since clinical study adverse events are
required to be reported.
Finally, reporting biases involved the fact that reports
that are sent into the FDA may differ in some characteristics compared to those
that are not sent in to us, perhaps in severity of the event.
Another limitation is the fact that reported events are
unverified and often they are incomplete. For example, we received several
chest pain reports, but many of the reports lack some important background
clinical information, such as if EKGs were done, lab tests, and what those
results were, information on the temporal onset of the event, physical exam
result, past medical history, concurrent medications, and so forth.
So, without that kind of important background, it is hard
to determine the type of chest pain that was involved in the report.
Another limitation involves the fact that reported events
may be related to confounding factors such as underlying medical conditions and
concurrent medications.
Finally, causal inferences are not usually possible when
using passive surveillance data, because a direct link between the event and
the product is not always possible.
So, the consequence of all of these limitations, the bottom
line is really that numerical differences amongst these three products require
very cautious interpretation.
I would just like to thank my colleagues within OBEE and
ORRR, and I will take any questions or comments. Thank you.
DR. ALLEN: Thank
you, Dr. Khoie, and I think you have summarized very nicely the problems with
passive surveillance.
Clarification questions only, please? The next presentation is post-marketing
study commitments. I would assume that we will get into some of this other.
DR. QUINN: Two
questions, very briefly. One, why do all the package inserts say that there is
an increased risk of viral transmission with this product, yet it never came up
in any of the adverse event reporting. That is part one.
Part two is, if you looked at it historically, even with
passive reporting -- you did the last three years, but if you went back
further, was there a shift or an increase in reporting? Is that because passive reporting is getting
better or is it because the product is actually having increased side effects?
DR. KHOIE:
Regarding your first question, the viral transmission being on each of
the product package inserts was related to the section of the label that
provides caution and warnings of potential transmissions, and not necessarily
that they had actual cases of viral transmission from pre-licensure studies.
DR. QUINN: Do you
know why?
DR. KHOIE: I would
have to defer to OBRR.
MS. STEFANO:
Basically, there are very often times when, to exercise -- to err on the
side of caution, we will have class labeling statements.
In other words, if you are a member within this class and
you are using human based products, or animal based products, depending, there
is this class labeling.
DR. KHOIE: The
second question, the trend in the number of reports prior to 2003, I do have
the numbers of the adverse events combined for each of the products.
I did take a look at the number of events for each of the
products individually. Prolastin, having been on the market for a substantially
longer period of time, I can actually show you that graph. I have a reserve
slide.
This actually just shows the distribution of all the
adverse event reports for all the products.
It breaks it down into foreign and domestic, but the majority of these are
prolastin, especially prior to 2003, and we see that -- I just also have to say
that these do not include the periodic reports that I had mentioned I had
retrieved.
More recently, since the late 1990s, there has been no
significant increase. We see a blip in 1995, and that can be partly explained
because we know there was an ongoing clinical trial at that time. So, errors
would have been captured in more reports, because those reports were required
to be submitted.
DR. KLEIN: I was
just wondering if there are additives, stabilizers, incipients, that are
different in the three products that you described that might account for some
of the adverse events that are reported, like headaches and dizziness.
DR. KHOIE: In terms
of the additives, I would have to defer that question to someone from OBRR.
DR. SHRAKE: With
regard to the excipients, there certainly is some difference, but there is no
reason to believe that the excipients are the source of the adverse events,
actually.
DR. DI MICHELE: I
was just wondering, I can imagine that some of these adverse events are sort of
contaminated by the IGA contamination and some of them may be IGA related.
I suspect that, if you don't have sex, age and seriousness
of event data, there is no discussion in the serious adverse event reporting of
whether these patients are IGA deficient or not. I know that is one other potential confounding issue.
My question related to the fact that, if you look at your
last slide on the adverse event reporting, a lot of it was chest pain and
dyspnea.
They also seemed to be even with the prolastin products, a
lot of them were more common among the adverse events that are reported.
I was just wondering if anybody had any insight -- this is
not specifically maybe to you or to anyone who might have any insight into what
those are directly related to.
Are they considered to be allergic reaction? Does it have anything to do with the
diffusion of the product into the alveolar space, or is there anything in
particular about this product that causes this side effect? I was just wondering.
DR. KHOIE: I am
sorry, is your question suggesting that these adverse events are more common in
the product prolastin?
DR. DI MICHELE: I
was saying, just in general -- Mike made a comment first that it is often
difficult to distinguish -- it sort of is a different question than the
excipient question, but since there is IGA in all of these products, and there
is the potential for some sort of allergic type reactions from the IGA in some
patients, that sometimes it is difficult to distinguish product from IGA kinds
of events.
Then I was specifically asking about chest pain and
dyspnea, as to whether that represented something particular with this product,
since we know that this compound basically diffuses into the lung tissue. I
just wondered if anybody had any insight as to what those side effects were due
to, or what those adverse events were due to. It is a general question.
DR. KHOIE: There is
the confounding factor that the indication for the product is clinical
emphysema in patients. So, these patients have severe underlying lung disease.
They do also include in their labels the fact that there is
the potential for volume overload. That is one potential explanation.
Reading through these reports, unfortunately, i can't
summarize all of them for you and say what most of them were likely
attributable to.
DR. PIERCE: If I
could give a brief follow up to that question, we did look specifically at the
chest pain events, to evaluate whether ischemia appeared to be responsible for
a proportion of those.
That did not appear to be a worrisome concern, but we did
ask the manufacturer to do a specific analysis also in parallel with us, of the
chest pain events.
Many, although not necessarily the majority, of the dyspnea
cases appeared to be compatible with acute hypersensitivity reaction.
DR. EPSTEIN: Dr.
Khoie, thank you for this summary of the FDA data. You very carefully gave us all the limitations and caveats, but
didn't actually draw any conclusions.
As I scanned the data, it seems that the relative number
and frequency of the report of adverse events in aralast seemed to mirror the
relative proportions in prolastin. Is that, or is that not a fair conclusion?
In other words, if you scan the prolastin column and you
just ask, what are the predominantly reported findings, you discover that those
are the ones where you show early signals with aralast.
Is it the conclusion of the group that there was no
apparent difference in the type and profile of reports, given the limitation of
the number of reports?
DR. KHOIE: We
really felt that we couldn't make a firm conclusion in terms of being able to
compare the safety profile of these three products, just based on the surveillance
data. It certainly is possible, but I
just wouldn't feel comfortable making that conclusive statement.
DR. KUEHNERT: I
would just agree with you. I think you mentioned that it wasn't possible to get
denominator data.
I know that EARS and Medwatch is sentinel reporting for
numerators but, without denominator data, you just can't make much of anything,
not just about rates, but also about underlying demographics and patient
conditions for people getting these different products.
I would say that, as per Dr. Epstein's question, it would
be very difficult to try to make those comparisons without that information.
DR. SZYMANSKI:
About the instructions of infusing these products, are you supposed to
give them antihistamines, and are these reactions related to the fact after
being treated prior to infusion or what?
DR. KHOIE: In terms
of the symptoms?
DR. SZYMANSKI: Like
people, when they give plasma, they usually give them antihistamines and
tylenol and stuff. Do you give that kind of premedication in these products?
DR. KHOIE: I will
let my colleague in OBRR answer that question.
DR. PIERCE: I think
some of the pulmonologists here might answer that question also, but I can tell
you that in the package insert there is no recommendation for premedication for
any of the alpha-1 PI products.
DR. DUFFELL: You
mentioned before that we don't have a lot of information about other
co-morbidities or medications that these patients were on.
It looks like, just given that, it is kind of hard to draw
some firm conclusions on this, although the data suggested that there is a
correlation here.
As part of the clinical trials, was there any challenge,
re-challenge testing done of these adverse events, or did they just occur by
happenstance in the clinic, that were ever reported on any of the specific
events?
DR. KHOIE: I only
have data from the actual surveillance. Regarding the clinical trials, I would
also have to defer that to OBRR.
DR. PIERCE: I do
not recall any challenge to better ascertain the causality relationship between
adverse events reported during clinical trials of these products. If the manufacturers recall any such events,
they would be free to also comment.
DR. DI BISCEGLIE:
You said you were going to tell us about serious adverse events, but I
didn't see any listed or broken out. Were there serious adverse events, and
could you give us some idea of what those were?
DR. KHOIE: Yes,
there were -- the serious adverse events that I had on the table, I do have a
list of them broken down.
Again, I wasn't able to make any nice summarizing comments
on them. I could tell you -- I could go through them with you. I would just
have to go through the slides. I have the details if you would like that.
DR. DI BISCEGLIE:
Not if there is no clear pattern.
DR. ALLEN: It is
five minutes after 11:00 by my watch, which is about two minutes fast. We are half an hour behind. At this point,
we have been sitting for three hours. We have got three more presentations
which adds up to, if everyone is on time, another 30 minutes of
presentations. I am going to call a
10-minute break right now, and please be back in 10 minutes, and ready to start
talking again.
[Brief recess.]
DR. ALLEN: Dr.
Pierce, would you go ahead with your presentation, please?
Agenda Item:
Post-Marketing Study Commitments for Licensed Alpha-1 PI Products -
Rationale.
DR. PIERCE: I am
going to make a brief announcement with relation to the first topic on the
agenda earlier today.
Just very briefly, I just wanted to let people know that I
was informed that this morning FDA posted a health alert on the CBER web site
regarding this product device interaction with maltose and galactose containing
products, and xylose interfering with the GDHPQQ glucose testing methods.
I wanted to mention that, on that health alert on the FDA
web site, there is a complete list of the GDHPQQ testing method products, as
well as a preliminary list of those products we have been able to identify to
date that contain the sugars that can interfere with the measurement of glucose
by that test system.
So, let me now proceed to the topic at hand. I am going to
be talking about the post-marketing clinical studies of alpha-1 PI products.
It will be useful for the committee to keep in mind two of
the three questions that they are charged with today. I will again read the
first one.
Based on the differences in primary structure of alpha-1
PI, does the committee have comments or recommendations regarding the adequacy
of requested and planned post-marketing commitment studies, to evaluate the
longer-term safety and efficacy of alpha-1 PI products, as measured by
specified clinically meaningful end points.
Second, will the committee have comments on the adequacy of the proposed
safety monitoring programs.
So, you have heard a little bit about, from
Dr. Brantly, the pivotal trial for aralast. In considering the newer
alpha-1 PI products, the pivotal trials employed 14 to 30 subjects, randomized
to the test article. There was one drop out in the case of the aralast study.
In the cast of zemaira, there were additional non-pivotal
trials done, so that the total patient exposure was larger than 30.
These trials were based on the biochemical surrogate end
points, antigenic alpha-1 PI or AAT, and neutrophil elastase inhibitory
capacity, which is a functional measure.
There needed to be a maintenance of the trough steady state
serum levels greater than an arbitrary threshold, and not inferior to that of
prolastin.
Levels in bronchopulmonary lavage fluid were expected to be
significantly greater than at pre-treatment, and we also had six months or
greater safety data, including a measurement of alpha-1 PI antibodies.
So, the sponsors of all three licensed alpha-1 PI products
were asked to conduct post-marketing studies to help evaluate efficacy, not
just of biochemical end points, but clinically meaningful end points directly
related to emphysema.
Now, the first study that was conducted was that with
prolastin, and that was an epidemiology study. In contrast, the manufacturers
of the newer products have been asked to conduct placebo controlled or parallel
controlled, randomized controlled trials.
In the case of zemaira, the manufacturer has agreed to
conduct a placebo controlled randomized controlled trial, and there is an approved
protocol for that study.
In the case of aralast, the company has agreed to conduct a
randomized controlled trial, and the final protocol is pending.
Let me turn back the clock to the completed NIH registry
study, the epidemiology study. At the time that prolastin was approved and that
this study was conceived, it was considered that a randomized controlled trial
was unfeasible.
However, due to its non-randomized nature, the design was
not capable of validating or confirming that the PK surrogate end point
translated into a clinical benefit.
There was no testing in that study of alpha-1 PI blood
levels, and there were large numerical imbalances between the groups of subjects
or patients that were receiving augmentation therapy with prolastin, and those
that were not. This study was reported in 1998.
The mean findings of the study were that there was a
decreased mortality observed among those who received alpha-1 PI compared to
those that did not, with a relative risk of .64 and the confidence intervals
that you see. That was significant at
the .02 level.
For the overall study population, there was no difference
in the rate of FVE-1 decline between those on prolastin and those who had never
taken prolastin during the trial, except in a post hoc subgroup of individuals
with moderate emphysema.
So, several experts have recommended randomized controlled
trials to establish the efficacy of alpha-1 PI augmentation, not just biochemical
efficacy, but clinical efficacy.
The group that did the NHLBI registry study with prolastin
said that definitive conclusion will require a randomized controlled trial.
This was repeated in another publication in the year
2000. A European group of Luisetti said
that there was an urgent need to conduct these trials in 2002.
One of the principal authors in the NHLBI registry study
wrote also, in 2002, that randomized trials of this were needed to evaluate
efficacy, in view of the costly and inconvenient nature of augmentation
therapy.
Well, there has been a single randomized controlled,
placebo controlled, double blind trial, that was published in 1999 by Dirksen,
et al.
This trial employed 56 subjects, and it had the findings --
it used a French alpha-1 PI. The
findings were, at the end of the study period, there was a non-significant
trend for the alpha-1 PI randomization group to be worse than the placebo group
by FEV-1, with a p value of the trend of .2.
So, that turned out an opposite of what one would have hoped.
However, they also looked at efficacy in a different way,
by CT, which studies have indicated is a more sensitive measure.
There, by one way of looking at the CT outcome, they
obtained borderline significance of a p value of .07. By another way of looking at the CT, they had a p value of .2,
the same magnitude as the p value of the adverse trend, when looking at FEV-1.
Now, they did a retrospective power analysis and suggested
that, with 130 subjects, you could do a CT end point randomized controlled
trial and, if the magnitude of the treatment benefit was the same as what they
saw in this trial, that would achieve statistical significance, and this looked
to be something feasible.
So, the sponsors of all three U.S. licensed studies have
either conducted, or agreed to conduct, these post-marketing studies.
What we have asked the manufacturers of the newer products
to do is to conduct their investigations in two stages.
The first stage I will get into in a moment, but the end points
that we suggested they consider looking at were serial end density changes of
ICT, pulmonary exacerbations of COPD -- and there is the suggestion that this
therapy may be effective in reducing those, but there are no good hard data in
that regard, an important question -- serial pulmonary function testing, and
mortality would also be appropriate to examine.
Now, the first stage objective, of the first stage of the
investigation, would be to estimate a magnitude of the treatment effect, and to
assist in sample size determination for an adequately powered stage two follow
up study.
The objective of the second stage would be to actually
answer the question, is there substantial evidence of safety, clinical evidence
of efficacy -- rather -- and to also gather additional longer-term safety data.
Details with respect to the stage one that we asked
companies to consider were to use a randomized controlled parallel masked
design, to have a minimum of 60 subjects -- they could, of course, choose more
-- that would be 30 per group.
We wanted to be flexible in terms of certain aspects of the
design, recognizing the difficulties of employing a placebo control here in the
United States, although we believed that a placebo control was feasible in the
many countries where alpha PI, to this date, has never been licensed.
So, we indicated that a sponsor could choose a dose
controlled design, where they would look at the efficacy of a standard dose in
comparison to a higher dose, and there is some theoretical reason to believe
that higher doses might be more effective.
Also, the placebo control option.
We recommended that the stage one of the investigation be a
minimum of one year duration to avoid seasonal bias when looking at the
pulmonary exacerbations, which we thought was an important end point.
We also believed it important to measure baseline and
steady state antigenic and functional alpha-1 PI blood levels, and we
anticipated that such a trial could also have a longer term follow up.
With respect to the conduct of the stage II investigation,
we recognized that this could be contingent on the outcome of the stage one.
A strongly positive outcome in stage one might obviate the
need for stage II study, also depending on if the size of the stage one study
had been boosted from the minimum that we requested.
The performance of
the stage II study could be dependent on the amount of products available and
earlier, before there were three products on the market, there were
intermittent shortages of prolastin, we were told.
It might be dependent on the availability of subjects, the
number of subject follow up years needed and, in the event that manufacturers
got together and conducted a factorial design study, there might be a
contingency on the willingness of other manufacturers to participate.
So, now I will turn to the four post-marketing studies, or
phase IV studies, or phase III-IV studies that Baxter has committed to conduct
for their Aralast product.
The first one is a stage I efficacy randomized control
trial. This will use an investigational version of the alpha-1 PI product, as
opposed to the version that has been discussed today.
They have committed to conduct a stage II efficacy,
randomized control trial with the same investigational version of the alpha-1
PI intravenous product, notwithstanding those contingencies that I alluded to
earlier.
They have agreed to conduct a repeat bronchial alveolar
lavage study to answer some residual questions with respect to the data from
their study for licensure. This also
will involve an investigational version of the alpha-1 PI.
The fourth study is an uncontrolled safety study that is
actually an amendment to an ongoing non-FDA regulated post-marketing study, if
you will.
This will use a current version of the alpha-1 PI, the one
you heard about today, with that C terminal lysine truncation in the majority
of the molecules in the vial.
This will be a minimum of 60 subjects. It will last two
years, and Baxter will be looking at alpha-1 PI antibody formation, hepatic and
renal function, adverse events, and quality of life measures.
Now I am going to talk about the post-marketing studies
that ZLB Behring is conducting with their Zemaira product.
They have an approved protocol to conduct a two-year,
100-subject placebo controlled, multi-national, parallel group stage one study,
whose primary objective is to look at the effect of Zemaira on the progression
of emphysema, assessed by a decline in lung density as measured by CT.
Because this is a stage one investigation, this study is
powered to only detect a trend of at least a p value of .2.
The secondary objectives are to assess the effect of the
treatment of alpha-1 PI on the number and duration of pulmonary exacerbations,
also on FAV-1, diffusion capacity of carbon monoxide, alpha-1 PI levels,
exercise capacity, mortality, BMI, safety, quality of life, and anti-alpha-1 PI
antibodies.
So, in conclusion, I can say that definitive clinical
efficacy data are still lacking for alpha-1 PI products.
Newer data suggests that clinical efficacy studies now are
feasible, which was not the thought at the time that the innovator product was
licensed in the late 1980s.
Sponsors of all newer intravenous alpha-1 PI products are
asked to conduct, or have been asked to conduct, two-stage post-marketing
investigations of one or more clinically meaningful end points.
Longer term, two-year safety data are being collected for
both Aralast and Zemaira, the two newer products, in 50 to 60 subjects, to
include alpha-1 PI antibodies.
Again, I hope that my remarks have been useful to the
committee in wrestling with these two questions that we posted earlier, and any
advice that the committee has with respect to recommendations we should be
making, in addition to the companies, regarding the design aspects of their
trial or any safety parameters that should be looked at in addition to those
that I have outlined would certainly be appreciated. Thank you.
DR. ALLEN: Thank
you, Dr. Pierce. We have got two more FDA presentations. I would really like to
limit the questioning now to just clarification or direct referral to the
slides, where you want them back up, because we will have a chance for
discussion later.
DR. KUEHNERT: Just
a clarification. You mentioned limited studies, but did you mention anywhere --
maybe I missed it -- ongoing collection of safety data that would be asked of
the companies? That has no time limit,
for ongoing data.
DR. PIERCE: That is
a difficult question to answer, in some sense. We have an approved protocol in
the case of the zemaira product. To my understanding, that trial has not yet
initiated, but may shortly.
We have the agreement in principle to conduct the
clinically meaningful end point study with additional safety data from the
manufacturer of aralast.
In the case of both products, there is ongoing active
surveillance, not just passive surveillance, with respect to adverse
events. I believe that more information
may be available in this regard.
In terms of the formalized post-marketing commitment to
obtain information on aralast, on adverse events over a two-year period and 60
subjects, we are awaiting a finalization of the protocol for that, but that is
really an amendment to an ongoing study that was voluntarily initiated by the
firm, and their contractors. I hope that answers your question.
DR. SCHREIBER: Does
prolastin not have to do a clinical trial?
DR. PIERCE:
Prolastin, at the time that it was licensed, there was an agreement to
conduct a phase IV study that would look at lung function.
The thinking at that time was that a randomized control
trial was not feasible in terms of the numbers, that you just wouldn't be able
to recruit enough patients.
So, the sponsor substituted the NHLBI registry study for
the trial that they had agreed to conduct, and FDA accepted the substitution of
that. We have not requested that now
Talecris conduct a randomized trial with prolastin to date.
DR. SCHREIBER: Why
is that?
DR. PIERCE: It has
been something that has been discussed.
DR. SCHREIBER: The other two products are not licensed?
DR. PIERCE: We have
three licensed products. The prolastin was licensed in the late 1980s, and then
the other two products, including the one that we have been emphasizing today
about the isoelectric forms --
DR. SCHREIBER: It
was just surprising to me that three licensed products, you can require two of
them to go back and do clinical trials and the other one gets off scot free.
DR. PIERCE:
Talecris will actually be making a presentation during the open public
session today, and they may wish to comment further on information of a
controlled nature with respect to their product, and the potential for
evaluating some of these more immediately clinically pertinent end points.
DR. ALLEN: Okay,
other questions or comments? All right,
the next FDA presentation has two speakers. it is under one title topic,
however, licensed biological products with structural heterogeneity, with known
structural modifications. Dr. Andrew Chang will be the first presenter.
Agenda Item:
Licensed Therapeutic Protein Products with Known Structural
Modifications.
DR. CHANG: Thank
you, Mr. Chairman, good morning. Before I start my presentation, I just want to
repeat a statement that Dr. Andrew Shrake made in his introductory speech
earlier this morning.
That is, the biological products in the United States, at
least, are licensed on a case by case basis, and based upon the standard
specified in our regulations.
My name is Andrew Chang.
I am associate director in the division of hematology, office of blood,
CBER. As Mr. Chairman pointed out, this
presentation will be divided into two speakers.
Because of the limit of time today, I selected two case
studies that related to plasma derived products, and Dr. Kurt Brorson from the
division of monoclonal antibodies, office of pharmaceutical science, CDER, will
present some of the case studies that are related to recombinant and monoclonal
antibodies.
He also will present some of the strategies that can be
used to maintain the quality of the biological product and some strategies that
can be used to assess the impact of the heterogeneity.
There are at least two major factors that can contribute to
the heterogeneity of the biological products. The first one is biosynthetic
processes used by the living organism.
This factor mainly actually applies to recombinant products
as well as monoclonal antibodies, and has a minimal, but not zero, impact to
plasma derived products, for the fact that plasma derived products, normally
are manufactured from a large plasma pool. So, any effect from living organisms
will dilute it, because of a large plasma pool.
The second major factor contributing to the product
heterogeneity is involved with the manufacturing process, and also the storage
conditions that are used for a drug substance and a drug product.
Now, how to control structural heterogeneity for a
biological product? There are two major
elements that should be considered to control heterogeneity.
First, the sponsor or applicant has to demonstrate the
consistency of the heterogeneity pattern of commercial lots with that of the
lots used in preclinical and clinical studies.
Second, to assure lot to lot consistency, the content and
extent of this heterogeneity should be characterized and controlled.
Here is a list of the potential protein modifications that
can contribute to the heterogeneity of biological products.
This is not meant to be inclusive, but rather, examples of
the protein modifications that can happen to a biological product.
These include the primary sequence heterogeneity, the
post-translational modifications, and the high order of the protein structure.
The first case study I want to present to you today is a
charge analysis of unlinked oligosaccharides from factor VIII standards,
recombinant and plasma derived factor VIII products.
Most of you, I am sure probably all of you know, that
factor VIII, an activated form of factor VIII, is a very important cofactor for
intrinsic coagulation pathways.
Patients with defects in the factor VIII molecule, or
absence of the factor VIII, will have a bleeding disorder, and we call them
hemophilia A patients.
Factor VIII is a multi-domain protein that has estimated 24
unlinked polyglycans, oligosaccharides. It is worth it to point out that the
majority of the polyglycan is located in a domain called the P domain.
Factor VIII undergoes activation in vivo and becomes the
activated form of factor VIII. We have,
in the United States, we have multiple licensed factor VIII products, including
recombinant and plasma derived factor VIII products.
One of the licensed products, so-called P domain deleted
factor VIII, the difference between the P domain deleted and the four lanes(?)
factor VIII is the absence of the P domain.
Dr. Schilow et al from the Port Eric(?) Institute, reported
their study which I presented to you today.
What they did is to look at a compilation of
oligosaccharides among different licensed factor VIII products, including
recombinant and plasma derived factor VIII, as well as some national and
international standards.
What they did is, they isolated the oligosaccharides, and
then separated them according to, in this case, the sialic acid charge.
So, they separated them into mutual glycans, monocytic
glycans, diactyic glycans, triacytic glycans, and a tetracytic glycans.
Then they did analysis on the different products, and what
they found is that, as they reported, there are at least three groups.
You can divide the licensed or some of the standards into
three groups according to the differences in composition of oligosaccharides.
The first group, the group is a group of the factor eight
products that has a high level of the diacytic, triacytic and tetracytic
oligosaccharides, greater than 70 percent of the oligosaccharides containing
the di, tri and tetrascytic glycans.
The second group is a group of products that have greater
than 70 percent of the oligosaccharides containing mono and diacytic glycans.
If you look at the product that is approved, you can find
that not only this grouping applies to -- this grouping applies to not only
recombinant, but also the plasma derived factor VIII.
For instance, in this case, the plasma derived factor VIII,
which is categorized as group two, which has greater than 70 percent of the
mono and diacytic glycans. The last group they identified is a B domain delayed
product, named Refacto, and it has the unique oligosaccharide composition.
In conclusion, the charge analysis demonstrated
heterogeneity of the glycoforms of the tested factor VIII products.
The second case I want to present to you today is a
characterization of five von Willebrand Factor concentrates produced by five
different manufacturing processes.
This is actually part of the international study that we
participated in for establishing the first international standards for von
Willebrand concentrates.
Von Willebrand factor is a complex molecule, and it
undergoes serious post-translational modification intracellularly, and it forms
multi-molecule complexes. We call them
von Willebrand factor multimers.
This protein is rather interesting in a non-sheer stress
situation. This multimer has a sphere shape. If you provide a sheer stress to
this model, they will undergo shape change.
In this case it is really a fiber type of the multimer, and it depends
on how much sheer stress you provide. They have different conformations.
We looked at five candidates which are either factor VIII
concentrate or von Willebrand factor concentrate, as the five candidates for
selection of the first international standard for von Willebrand factor
concentrates.
We looked at a multimer form among these five different
concentrates. As you can see, when you
separate different sizes of multimers by agarose gels, and they are detected by
western blotting, you see a different size of the multimers on the gel.
The first line is the international plasma standard, and
the second line is a plasma by itself. Then the rest of the five candidates.
If you look at a one percent gel, they have, for instance,
the C2 log of the high molecular weight multimers. If you are running the gel
by a high concentration of the agarose, you start to see some differences at
low molecular weight multimer forms.
If you look at the function and compare the specific
activity among different concentrates, you can actually also separate them into
three groups.
For instance, the C-1 candidate has specific activity --
risto setting(?) co-factor versus antigen level close to one, as well as the
collagen binding activity versus antigen level.
C-2 actually behaves quick differently from C1, and the
specific activity is close to, or below, 50 percent. The rest of the three
candidates has specific activity close to 70 percent.
In conclusion, the characteristics -- in this case, a
multimer form -- and the specific activity of von Willebrand factor
concentrates, depends on the manufacturing process.
Now I am going to give the podium to Dr. Kurt Brorson for
his presentation.
Agenda Item:
Licensed Therapeutic Products.
DR. BRORSON: Good
morning, and thank you for your attention. As Andy mentioned, I am in CBER's
sister center, the Center for Drug Evaluation and Research.
In the Center for Drug Evaluation and Research, we
regulate, of course, the small molecule drugs that everyone is familiar with
but also, in addition to that, the majority of the biotechnology products.
All of the CMC reviews are conducted within two offices of
CDER, the Office of Biotechnology Products, and the Office of New Drug
Chemistry.
Within the Office of Biotechnology Products, we have two
divisions, the division of monoclonal antibodies, which obviously reviews
monoclonal antibody applications, as well as the division for therapeutic
proteins, which review many other types of biotechnology products.
I am in the division of monoclonal antibodies, and I am
here to give you my perspective on the types of heterogeneity that we see, both
in monoclonal antibodies and in therapeutic proteins made by recombinant DNA
technology.
The first thing to remember about biophramaceuticals is
that they are quite complex, and they have much more potential heterogeneity
than small molecule drugs.
To really illustrate that, here is a structural model of
basically one third of a monoclonal antibody, just the FAB region, compared to
a statin, a typical small molecule drug.
You can see that even one third of an antibody is much
larger than a small statin molecule.
The source of this heterogeneity comes from -- there are a variety of
different types of heterogeneity, and they can be broken down into two types,
cell culture related heterogeneity and stability related heterogeneity. So, let me first describe cell culture
related heterogeneity.
The first thing to keep in mind is that fermentation of
cell culture in a bioreactor, for example, is really an artificial process.
You have cells growing in a bioreactor, in a media that is
usually a complex mixture of chemicals and nutrients.
Relative to plasma and other natural sources, that
environment is much more artificial. Because of that, some cell culture related
heterogeneity to protein product can result.
In fact, the bioreactor conditions themselves, the pH of
the media, the temperature of the media, how long you run the bioreactor,
whether you run it in batch mode or continuous mode, can impact a variety of
things, including the glycosylation, certain charge variance of the product, as
well as some types of substitutions such as a leucine or norleucine
substitution in the final product.
In addition, there is clonal variation between cell lines,
of course. The cell line that is used to produce the product actually can
impact things like adduct placement, the number of adducts on cysteine
molecules, for example, folding or mis-folding of the product, as well as
cysteine pairing. So, all of these cell
culture related issues can lead to heterogeneity in a biotechnology product.
There are also stability related issues with heterogeneity.
Again, it is important to remember that a pure, high concentration protein
solution is an artificial system compared to, for example, proteins in cells in
bodily fluids. Therefore, you are
stressing the proteins to some extent, just by having a high concentration
formulation.
However, I should note that many of the plasma products
face the same issues as recombinant products. So we actually are not that
different from the products that you regulate here, in terms of stability
related issues.
Typical stability related heterogeneity can include things
like clipping, aggregation, deamidation where asparagine can turn into aspartic
acid, or glutamine can turn into glutamic acid, or the loss of epsilon amino
acids on lysine. That will cause a lot of charge variation.
Finally, another very common stability related form of
heterogeneity is in oxidation, where methianines are turned into methiadine
sulfoxide.
Now, for monoclonal antibodies, there are two major sources
of heterogeneity. The first source is
right here, in the glycosylation or the carbohydrates that are attached to the
FC region.
Essentially the major form of heterogeneity here is the
number of galactose molecules or moieties that are attached to this GLIC
neck(?). So, you can have either zero,
one or two galactoses here.
The second form of heterogeneity that is very common in
monoclonal antibodies will exist right here at the C terminus of the FC region.
Now, keep in mind that antibodies are dimers. So, there are
actually two C termini here. That heterogeneity basically is whether or not
there is a C terminal lysine at the end of either zero, one or two of the
proteins that form the antibody dimer.
This has been our experience with 20 or 25-plus monoclonal
antibodies that we have licensed so far, plus a variety of other antibodies
that are under IND.
So, we have come to expect this type of heterogeneity, and
we have developed strategies to deal with it.
This right here demonstrates the C terminal lysine
heterogeneity. This is not an IEF gel. This is actually a substitute method
called the weak cation exchange HPLC column.
It basically measures the same thing. It measures charge
variance, and this is a chromatogram of such a column.
You can see here that you can distinguish between the
antibodies with zero C terminal lysines from the antibodies with one terminal
lysine, from the antibodies with two of them.
We see this repeatedly with monoclonal antibody products.
The way this is approached is that manufacturers will set acceptable range
either for each species or for the three of them combined.
They can be measured by various techniques, IEF gels, which
you have seen extensively this morning are merely one technique. This is the
weak cation exchange column, which is also an acceptable method to look for
charge heterogeneity.
I would imagine that there are many other methods, for
example, capillary isoelectric focusing, that could do the same thing.
It has been our experience that this pattern that we see
repeatedly doesn't seem to impact the potency or the safety profile of the
product.
Now, of course, we do see unacceptable heterogeneity.
Normally the manufacturers will run a stress study, where you store the
antibodies at perhaps 40 degrees C, 45 degrees C, in order to look for
degradation pathways.
You can see, here are two examples of stress induced
heterogeneity. In this experiment here, the antibody was clipped into an FAB
fragment and FC fragment which, again, could be resolved on this weak cation
exchange column.
In this other stability study, the antibody underwent
deamidation. So, basically the charged variance here became even more acidity
and bound to the column more tightly, and you can see a pattern like this.
These would clearly be unacceptable for a licensed product,
and manufacturers will set stability specifications looking out for this type
of pattern.
If they are out of specification -- and clearly these are
out of specification -- it actually can impact potency of the product.
I believe that this antibody was tested here, and it had
about 50 percent of the potency of the intact antibody.
The safety is a good question. We would never allow an
antibody that looked like this to be infused into a patient, even in a clinical
trial. It just is deamidated too much, and it may actually end up being
immunogenic.
This actually probably would lose some potency, but
probably wouldn't pose a safety issue, merely because these are really not
neoantigens, or neomolecules for the patients. They are just merely half of the
active ingredient in each of the species.
Again, we would not want this to be injected into a patient.
I discussed heterogeneity with our sister division, the
division of therapeutic proteins, and they were able to think of three cases
where they saw significant amino acid variation.
The three cases that they recalled -- when I talked to the
deputy division director there, so this probably constitutes most of what they
have seen in terms of heterogeneity -- only one of the cases actually had an
impact on potency.
They saw one case of protein terminus heterogeneity traced
to a metalloprotease, and one case of product clipping. In both cases it had minimal impact on the
potency of the product.
They did have one case where N terminal glutamine
cyclyzation occurred. Interestingly, the cyclyzed form had a
two-and-a-half-fold greater potency.
Again, this is something that can get picked up in the
potency assay itself, which is a normal part of lot release for all products.
So, what does the office of biotechnology products do to
keep a handle on heterogeneity? First,
obviously, there is testing at lot release and stability.
The strategy for lot release testing is to employ a range
of assays to look at as many product quality attributes as possible at the
given time.
Obviously, we will look for charge variance using IEF or
weak cation exchange chromatography. The sponsors will also look for amino acid
sequence variation, oxidation, using internal mapping or C terminal or N
terminal mapping, that can be used to look for clipping or aggregate formation.
Mass spectrometry is highly sensitive to molecular weight
changes. It is not always used in lot release because the equipment is
expensive, but it can be used for that purpose.
Then there is a whole variety of specialized assays that
will look for either carbohydrate changes or, in the case of isoquant, it looks
for deamidation.
Acceptable ranges for the heterogeneity is based set on
basically a combination of clinical experience and manufacturing experience.
It is a combination of what is acceptable in the clinic, as
demonstrated by the clinical trials, compared to what is a manufacturing
process capable of.
The second strategy is formulation. You can formulate your
proteins to minimize heterogeneity, and if heterogeneity cannot be avoided, the
goal is to control it and answer three questions.
First, does the heterogeneity impact the active ingredient
potency. Does it impact bioavailability and, finally, does it impact
immunogenicity.
This can be addressed by a variety of approaches, including
careful examination of data from the potency assay, TK studies and, in extreme
cases, sometimes immunogenicity studies might be warranted. Thank you.
DR. ALLEN: Thank
you. At this point, unfortunately, we are almost an hour behind. I want to make
sure that we have got adequate time for committee discussion. Are there burning
questions for either Dr.Chang or Dr. Brorson from their presentations?
If not, we will move to the open public hearing. Again, I
would like to remind the speakers that have asked to speak to please appreciate
the time constraints on the committee. Give us your presentation very
succinctly, make your important points, and we will then move on.
Agenda Item:
Open Public Hearing.
DR. ALLEN: Let me
read the open public hearing announcement for considered matters meeting. Both the Food and Drug Administration and
the public believe in a transparent process for information gathering and
decision making.
To ensure such transparency at the open public hearing
session of the advisory committee meeting, FDA believes that it is important to
understand the context of an individual's presentation.
For this reason, FDA encourages you, the open public
hearing speaker, at the beginning of your written or oral statement, to advise
the committee of any financial relationships that you may have with the
sponsors and, if known, its direct competitors.
For example, this financial information may include the
sponsor's payment of your travel, lodging or other expenses in connection with
your attendance at the meeting.
Likewise, FDA encourages you, at the beginning of your
statement, to advise the committee if you do not have any such financial
relationships.
If you do not choose to address this issue of financial
relationships at the beginning of your statement, it will not preclude you from
speaking.
The first speaker who has asked to speak is Miriam O'Day
with the Alpha-1 Association, Annapolis, Maryland.
Agenda Item: Remarks by Miriam O'Day.
MS. O'DAY: Thank
you very much I am Miriam O'Day and I am a contract consultant for the Alpha-1
Association and also for the Alpha-1 Foundation, and my statement today is on
behalf of the Alpha-1 Association, which represents the community of
individuals with alpha-1 atrypsin deficiency, the majority of whom are frequent
and life-long plasma therapeutic product recipients.
The association remains concerned about the differences in
the three augmentation therapies that are currently available for the lung
disease associated with alpha-1.
The association contacted the FDA via telephone in October
of 2004, and Dr. Shrake mentioned that on his slide. He had that noted as the
Alpha-1 Foundation. It was actually the
association.
Then we also contacted -- the association again - in January
2005, in writing, when these issues were brought to our attention once again by
concerned physicians.
We continue to hear some concerns expressed, and mainly
that there remain a lot of unanswered questions, and we stated some of those
questions in our correspondence in January.
The primary ones are, is the variance an indication that
the product may not be functioning as anticipated, or otherwise causing harm.
Have physicians been contacted, so that they are aware that
they should be watching for adverse events that should be reported to the FDA,
and has comprehensive patient follow up been conducted on individuals receiving
Baxter's aralast, to determine the clinical significance of these variances.
We remain concerned about the lack of information being
given to patients and health care providers about these products, that may
leave these variances and adverse events unreported and undiagnosed.
We have entered an era when the blood supply is
significantly safer than it has been in the past. In fact, manufacturers frequently use safety as a marketing tool
when talking or interacting with consumers.
As individuals become much more educated about blood safety
and certain methods of viral inactivation, they have also become more savvy
about the impact of infusing blood products on a regular basis.
The FDA should be working with the manufacturer to
establish clear protocols for post-market surveillance that will be shared with
the consumer community.
The current passive system of adverse event reporting is
not a viable evaluation method of product safety, as we heard this morning.
We remain keenly interested in the details of additional
ways that the FDA will measure the clinical implications of the variances in
aralast.
We thank you for the opportunity to address the committee,
and we would like to leave you with the following three recommendations.
One, a dear doctor letter should be issued by the FDA to
clinicians treating individuals with alpha-1 a-trypsin deficiency.
Baxter should be required to conduct comprehensive
post-market surveillance to determine the long-term clinical effects of said
augmentation irregularities, and make such information available to the public.
Number three, that the comprehensive post-market data
should be collected and analyzed prior to granting authority for Baxter to
increase production of aralast. Thank you very much for your time today.
DR. ALLEN: Thank
you, Ms. O'Day. Next, Ms. Sally Everett
also with the Alpha-1 Association.
Agenda Item:
Remarks by Sarah Everett.
MS. EVERETT:
Actually, I am with the Alpha-1 Foundation, and I have no financial
relationships to report. My name is
Sarah Everett. I am an alpha. That is,
I am a person with alpha-1 antitrypsin deficiency.
I was diagnosed in February 1993, and I am here
representing the Alpha-1 Foundation. I became a board member of the Alpha-1
Foundation in January 1997.
The Alpha-1 Foundation is dedicated to improving the
health, quality of life, and finding a cure for those with alpha-1 deficiency.
To that end, the Alpha-1 Foundation participated both in
the recruitment of patients for alpha-1 replacement therapy trials, and the
fast tracking of licensure.
For that reason, we have a heightened responsibility to
assure both the efficacy and the long-term safety of these drugs.
In February 1993, I joined the seven-year long NIH
longitudinal study of prolastin, the first alpha-1 antitrypsin replacement
therapy. To this day, I continue weekly
prolastin with no side effects.
When diagnosed, I had moderate emphysema. Today, almost 13
years later, I have severe emphysema. I strongly believe, however, that
prolastin has slowed my decline, as evidenced by an objective reading of my
FEV-1 over time, as well as my ability to travel here to speak to you today.
For those of us with alpha-1 antitrypsin deficiency, by the
time of diagnosis, our lungs are already compromised and, in some cases,
severely compromised. Alpha-1
antitrypsin replacement therapy is our only lifeline. It is also a lifetime
commitment.
On the other hand, since alpha-1 antitrypsin replacement
therapy can only be given intravenously, it exposes us to great risk.
When taken together with the already compromised state of
our lungs, if something goes wrong, whether lack of efficacy or an adverse
event, it can mean life or death.
For that reason, the efficacy and especially the safety of
all new alpha-1 antitrypsin replacement therapies is critical. Since this is a life time therapy, detection
of potential adverse events in a long-term study is essential.
To that end, the scientific leadership of the Alpha-1
Foundation has strongly recommended long-term post-marketing safety study of
all new alpha-1 antitrypsin replacement therapies.
I believe that a copy of a suggested protocol, entitled,
continuous safety surveillance study for all alpha-1 patients, has already been
provided to you.
On behalf of the Alpha-1 Foundation, I thank you. On behalf
of myself and other alphas, our lives are in your hands. Thank you.
DR. ALLEN: Thank
you, Ms. Everett, for a very important statement from the foundation and on
behalf of yourself personally.
Our next speakers, we have two presentations from industry.
I have got Talecris Biotherpeutics, either Dr. Robin Huff or Dr. Barbara
Merrill.
Agenda Item:
Remarks by Barbara Merrill.
DR. MERRILL: I have
a single slide. I am Dr. Barbara Merrill from Talecris, as you stated, and
we have seen a lot of IEF profiles this morning.
Obviously, we didn't see all the presentations when we
submitted our -- basically, what we are showing you here is a bit of a twist on
what previous speakers have presented.
This is actually a western blot. So, it is isoelectric focusing which you have already heard a
great deal about.
After we did the isoelectric focusing, the proteins are
transferred to a membrane, and then probed with antibodies that are specific to
alpha-1 PI.
So, all that you see is a signal to alpha-1 PI. We do this
in part because we know there are other proteins in prolastin, and we wanted to
just do a specific comparison of alpha-1 PI content between our product,
prolastin, and a plasma pool.
So, the second point I want to make about this slide is,
unlike Dr. Brantly, who was showing comparison t an M1 standard, which is a
single allele, this is comparison to a plasma pool. So, it represents the lower
level variance that you might see in a normal human population, which is also
what prolastin is derived from.
The key point to note here is that the profiles of
prolastin and normal human plasma are extremely similar. I just want to make
that point. My colleague will address the clinical question.
Agenda Item:
Remarks by Robin Huff.
MS. HUFF: I am
Robin Huff, also from Talecris Biotherapeutics, and I wanted to address the
question that came up earlier as to whether a randomized controlled trial would
be requested for prolastin.
I did want to inform the committee, as well as FDA, that
Talecris has voluntarily initiated such a study. It is ongoing. It goes by the
name of Exactly, and in fact, it is looking at many of the end points that were
previously described by FDA as suggested end points. So, all three manufacturers, it would appear, are on the road to,
in fact, exploring these end points.
In addition, I would like to make the note that, unlike the
two more recently approved products, because we were approved in 1987, of
course we enjoy a greater than 17 year history of safety data that has been
collected, that supports the safety of the product, which goes to address the
point that, therein lies part of the difference for why, perhaps, the study was
not actually mandated, but nevertheless, we are voluntarily initiating such a
study.
DR. ALLEN: Can you
tell us how many patients you intend to enroll in the trial?
MS. HUFF: I think
we are looking somewhere on the order of 70-ish, if I can pus an ish behind it,
because I don't want to commit to the specific number. I don't have it handy
with me. It is on that magnitude.
DR. ALLEN: Thank
you very much.
MS. HUFF: That
would be a number to be enrolled. That wouldn't be an established, already
enrolled number.
DR. ALLEN: Our
final listed speaker is from ZLB Behring, Dr. Otto-Erich Girgsdies.
Agenda Item:
Remarks by Otto-Erich Girgsdies.
DR. GIRGSDIES: My
name is Otto Girgsdies. I am from ZLB Behring from the clinical research
department, located in Marburg, Germany.
I first would like to thank CBER for inviting us to give
this presentation. I can make it very short, because most of the points were
already mentioned by Dr. Pierce.
We got our approval for Zemaira in July 2003, on the basis
of the efficacy and safety data assessed in four clinical studies, and we have
included in these studies 90 percents.
This clinical study demonstrated that Zemaira augmented
maintains the serum level of API above the threshold of 11 micromolar, and it
was also shown that API reaches the epithelial lining fluid, where it has to do
its work, and zemaira has been shown to have a similar PK profile as prolastin,
which at that time was the only other product on the market.
We got the approval with a post-licensure commitment, and
we agreed to perform a randomized, placebo controlled, double blind multicenter
study, and we compared 60 milligrams per kilogram body weight of zemaira
weekly, IV administration with placebo, and we will include 100 patients in
that study.
The observation period for this study is thought to be at
least two years, and we also committed to try to extend this study.
The main inclusion criteria is the age between 18 and 60,
but probably most of the patients are starting with 35 or 40.
They have to have a for sure diagnosis of alpha-1
deficiency, and they have to have clinical signs of emphysema and FEV-1 between
35 and 70 percent of predictive.
Our primary end point is lung density, and it will be
measured by computer tomography, and we asked to perform CT scans at five time
points before start of the treatment, and then after three months of the 12
months, 21 and 24 months.
We have chosen end points.
Within the last three to five years, CT scanning has improved very much
in these patients, and we are thinking tha tit is a most robust end point to
show efficacy in such a clinical trial.
Secondary end points, exacerbations, lung function,
exercise capacity -- we are thinking of including a shuttle walk test -- body
mass index, tolerability, mortality were included, and quality of life. We will use the St. George questionnaire for
that.
Pulmonary emphysema is characterized by destruction of the
lung tissue, increased area of trapped area, and decreased blood circulation,
and this results in a decrease of x-ray attenuation, and I will give you an
example of a shift of histogram in a patient and in a normal subject.
Here you can see this is a histogram of a normal subject,
and this is the histogram of a patient with emphysema.
Here, on the left side, here is -1000 houndsfield units,
which means air, and here is water. In the patients with emphysema, you will
get a shift toward the minus thousand parts, and the 15 percentile points we
have chosen as effect variable for the whole lung, because it has shown in
previous studies the lowest variation.
We have an optimized protocol for that, and it is optimized
for density resolutions. We don't have nice pictures, and we have thick slices
of five millimeters, and we use low energy for that, and this brings the
radiation exposure to the down to 1.0 to .7 mSv effective dose. A normal background radiation per year is
about 2 mSv.
We have a validated protocol available for these CT scans,
and the same scanner must be used throughout the study. Hopefully it is
possible, that it does not break down, and all scans must be acquired according
to the final protocol, and this was published very recently by the group of
Stoel and colleagues.
We also will perform duplicate CT scans, because it has
been shown that repeated scans make it possible to individually correct the
volume changes, because this is a major point for making mistakes, and we will
have two CT scans, one at full inspiration level and one at functional residual
capacity, and this has been shown to reduce the sample size requirement by a
factor of about four, irrespective of effect size and power, and the
publication is prepared by right now by the group of Stoel, and an abstract has
been shown very recently, in September, in Copenhagen, that this works.
Of course, each site will be provided with a density
resolution phantom to check for scanner stability with such a phantom, and all
CT scans will be analyzed using a validated software package, and a CT Core Lab
standardizes and controls the quality of our images, and also evaluates the
scans from all the centers. I will hand over now to my colleague, Val Romberg,
saying a few words about the residues.
Agenda Item:
Remarks by Val Romberg.
MR. ROMBERG:
Basically, we have reproduced what Dr. Schwarz talked about for aralast,
for zemaira, prolastin and aralast, and found his same results. So, there are
really no differences there
I did want to mention, though, that it is important to
recognize that, while the cysteine group in alpha-1 exists -- here is kind of a
stylized portion -- in vivo, it exists in two forms.
One is the free form or the reduced form, in this case, and
the other is the oxidized form where you have a disulfide bond with cysteine.
So, in vivo you have these two forms. Zemaira does consist
of strictly this form. However, when it is infused, the expectation is that it
then reacts with circulating cysteine and glutathione, and it goes back into
equilibrium as per the natural product.
The other thing I wanted to mention is just from a
manufacturer's perspective. I know you are considering what to do about
potential differences in the structural characteristics of API from different
manufacturers.
I think it is important to remember that this is a rare
disease. It seems pretty easy to say, let's do another clinical trial, but I
can tell you our company has closed two plants in the last two years.
We laid off half the staff at our Zemaira manufacturing
site recently, and this is not big pharma. This is the plasma industry, and I
would say that financially, and I would ask you to consider that as you are
thinking about what your action should be.
DR. ALLEN: Thank
you very much. Is there anybody else
who wishes to speak during this open public hearing segment?
All right, the open public hearing segment is closed. We
now move into the final phase, which is committee discussion and consideration
of the questions.
Agenda Item:
Committee Discussion.
DR. ALLEN: Why
don't we go ahead. Dr. Shrake, will you be putting the questions up for us
again, so we have got them on the screen, and then we can have general
discussion and address the questions, or it is really parts A, B and C of one
question.
The question is:
Based on the differences in primary structure of alpha-1 PI, and the
concentrations of polymers in the alpha-1 PI products, does the committee have
any comments or recommendations concerning, first, the adequacy of the
requested and planned post-marketing commitment studies to evaluate the
longer-term safety and efficacy of the alpha-1 PI products as measured by
specified clinically meaningful end points, second, the adequacy of the
proposed safety monitoring programs and, third, any other suggested actions,
for example, additional communications through labeling or other venues. These
are open for discussion.
DR. NELSON: On that
list of adverse reactions, I had real trouble figuring out what was due to the
drug and what was due to the underlying condition.
Sometimes, when adverse events are reported, they are
reported in three categories, definitely related, probably, or possibly.
I don't know if that is the way these events are reported.
Things like dyspnea and hepatitis, that is part of the syndrome.
One way with dyspnea, I guess, is the temporal relationship
to the infusion. I had real difficulty
interpreting that list, as to what it really meant.
DR. ALLEN: The
passive surveillance or adverse event reporting system is not very helpful in
this kind of a situation, and clearly it needs to be looked at.
DR. NELSON: I wonder if it was reported in categories,
definitely, probably, possibly?
FDA STAFF:
Generally, the categories you refer to are in Medwatch reports that come
from post-marketing studies, where the investigator is required, under the
regs, what they think the assessment of causality is.
Usually, in true spontaneous reports, which the vast, vast
majority of these were, it is not explicitly stated.
I can tell you, from reading all of these reports, that in
most of them it is not possible to figure out if it is confounding by
indication, or if it is some reaction to the product.
In a number of them, the reporter did actually state that
they think this is an exacerbation of the underlying disease, and not separately
related to the product.
In the case of the reports that were more suggestive of
hypersensitivity -- let's say, swollen eyes, shortness of breath, things like
that -- it was a little easier to figure out, but you are right, it is a
serious limitation.
DR. KULKARNI: I was
wondering if there was any data on product switching, when people switch from
one type to another one. Is there an increase in adverse event or any impact on
its reactivity.
DR. ALLEN: Does
anyone have information on product switching?
DR. KULKARNI: I am
sure this probably happens all the time.
DR. PIERCE: The
design of some of the trials of the newer products include an initial
randomization period in parallel, and then the group that was randomized to
prolastin would then cross over to gain additional experience with the newer
product. Again, nothing stuck out like
a sore thumb in terms of that switch point necessarily.
DR. SNIDER: The one
suggestion I have is that the surveillance for large numbers of patients for
long periods of time -- clinical surveillance, I mean, which is highly
standardized in the questions that are asked, seems not to have been listed on
the presentation that Dr. Pierce gave us.
The chemical and other analyses are fine, but I think we need careful
clinical surveillance.
DR. ALLEN: Thank you, and I think that really needs to be
done through these prospective studies that the FDA would like to see in place
now.
DR. KUEHNERT: Could
I just add a comment to that? I brought
that up before because it looked like those were time limited. I think what seems to be coming up is
continuous surveillance.
DR. CRYER: I think
that, in answering question A, that the three companies are doing three different
studies, all of which are going to add significant information.
However, it seems to me that the one thing that could be
improved upon would be some cooperation among them to design the studies so
that they can be compared, that the patients within their own products could be
compared.
There is a small number of patients out there. They are all
being treated by three different products. Some way to compare the outcomes of
those three products would be beneficial, it seems to me. I recognize the
economic and political problems of accomplishing that, however.
DR. ALLEN: I think
the FDA can take that statement under advisement.
DR. DUFFELL: I was
just thinking along the lines of one of the earlier panel members that, given
the noise in the data that we do have, and the complexities of these
treatments, that I really wonder if we have jumped the gun in requiring a
prospective type trial, and whether or not surveillance alone, in some sort of
an organized fashion, would accomplish the type of data that we need to
determine whether or not a true randomized controlled study is needed.
That is just my comment. It looks to me like it might be
premature to even require the study. Surveillance alone, in an organized
fashion, might accomplish what we needed.
DR. ALLEN: Could
you explain a little bit what your concept of surveillance in this is, whether
it involves tracking of selected patients in a trial sort of environment, or
what exactly would you include in it?
DR. DUFFELL: Kind
of a quasi-trial, but really more of a post-market adverse event reporting type
schema that was thought out in a prospective way, that we elicited the
information that we think may be underlying here.
I mentioned before the idea of a challenge re-challenge
type opportunity. I think that would also, under controlled circumstances,
especially in a clinical setting, could be done safely to determine whether or
not there is a real causal relationship here.
DR. NELSON: That
wouldn't give you efficacy data.
DR. DUFFELL: I am
presuming efficacy has to have been established in order for these products to
have originally been cleared to the market.
DR. NELSON: One of
the presentations suggested that it hasn't or, at least depending on the end
point, that it is still questionable.
DR. KLEIN: In
reading the first question, after listening to all these elegant biochemical
presentations this morning, I didn't see any evidence that these minimal
changes in primary structure or concentration of polymers was related to
anything clinically at all.
I guess the good news to me is that, over the course of
some 18 years and several manufacturers, the safety data of these infusions,
given that they are infusions of large concentrations of proteins, seems to be
pretty good.
The bad news, I think, is that, despite the fact that we
have seen 18 years, I don't see a shred of evidence that there is any efficacy
here at all, unless I have been missing something.
I think really, at this point in time, we need some
efficacy data. The phase IV studies, I think, need to be designed in order to
get us more than the surrogate markers of circulating protein or the presence
of protein in BAL. It really has to do something with the function of the lung
and the function of the human being.
DR. SZYMANSKI: I
agree with Dr. Klein's opinions, and I think we really should have efficacy
data. However, I think this might be difficult, because if this protein is
needed from very early on to protect the lungs, and if you do not give therapy
until you have reached emphysema of a certain degree, how can it get cured?
You can't really make new lung tissue. So, therefore, I
think that the studies might be disappointing. An ideal study would be to start
treating very early on before emphysema has developed.
DR. BISCEGLIE:
Actually, Dr. Klein said very elegantly what I wanted to say. I really
have not seen anything to be too concerned about in this micro heterogeneity in
terms of an impact on patient safety.
I would like to see a little more data on immunogenicity.
We heard just a statement that it hadn't altered it, but we didn't see any
data.
I think the big issue in my mind is, there is no evidence
of efficacy. We have heard a very passionate plea from patient advocates to
reassure them of safety, and I think we should do that.
The horse is kind of out of the barn, these things are
licensed. What are we going to do, if we do these studies and can't prove any
efficacy.
I think we have to do it. I think we have to try to show
that these things work and then, if they don't work, then we are going to be
stuck.
DR. ALLEN: I think the point was made earlier in the
presentations about the need for an adequate population sample in order to do
the efficacy studies.
DR. LAAL: It is not
clear to me if the different lots are being standardized on the basis of
protein concentration or on the basis of enzyme activity, catalytic activity.
That could be one of the reasons why we are not seeing a
lot of efficacy, because we are monitoring for the wrong thing. We are not
monitoring for the function. I didn't see that data at all today.
DR. DI MICHELE: I
just wanted to say that I agree with a lot of what has been said with respect
to the potential relative importance of safety and efficacy data that has to be
gathered.
I also would like to say that the issue that was brought up
by one of the industry representatives was the fact that this was a rare
disorder, and that approaches to rare disorders really have to be considered
separately.
I know that we are discussing this a lot in terms of the
rare plasma protein disorders for coagulation, the rare coagulation
deficiencies.
In many cases, the issue of surrogate markers to get
proteins licensed followed by post-marketing surveillance to really look at
other markers of efficacy and safety I think is an important way to go, and I
think I would certainly endorse that as a way of proceeding.
With respect to the clinical trial design, which is what we
have been asked to comment on, some of the literature that we were given to
read in advance of this suggested, however, that looking at clinical markers
such as pulmonary function, statistically, based on -- I would agree with what
Dr. Szymanski said.
Depending on when the initial treatment is begun, we may or
may not see that much in terms of change in pulmonary function or, worse,
continue to see deterioration, but there was some suggestion from these studies
that pulmonary function and the study thereof would take 500 or so subjects in
a prospective randomized trial, whereas the marker of the CT scan would
certainly say less.
Again, that was certainly strongly stated in the Dirksen
paper, and the point made in some of the other supporting literature.
I would just be a bit concerned about FDA's requirement to
have industry show an effect on pulmonary function as a way of conducting
post-marketing surveillance with respect to efficacy as opposed to the CT scan
model, not knowing too much about this disease, just based on what we were
given to read.
MS. BAKER: I would
also agree with some of the prior comments about collaboration, that the
patient groups have so eloquently stated.
Given that this a rare disorder, there must be a finite
number of centers that have developed the expertise and a decent number of
patients that they care for.
With the increasing costs for clinical trials, three
separate IRBs as opposed to one, hiring data managers, hiring research nurses,
I know there are a lot of political implications, but it would be more cost
effective to the clinicians also if there was more collaboration in the design
and the implementation of studies. So, I would recommend that.
DR. QUINN: Just a
couple of comments to follow up on that. One would be having the common
protocol go from the FDA to the three different companies, and it sounds like
that is what is being posed to us. Is
there a common protocol that would be acceptable to the companies, to the FDA
and so forth?
The second is, besides myself, if there is anyone else here
from the NIH, what about NHLBI? Are they involved in research on this disease,
and are they interested in supporting a clinical trial on this, again, coming
back to help the companies.
This is a rare disease. It is going to need federal
support. If these products are clinically efficacious, the numbers are just so
small we will never get to it, unless there is a massive undertaking to reach
out to as many as possible.
The third issue is, in the design of the study, the best is
going to be a placebo controlled trial, randomized.
The horse is out of the barn. Everyone is using these
products, it sounds like, with established disease, or a lot are. Is it going to be difficult to get people to
be randomized into a placebo arm, to really get you your best data.
I raise that. I don't have an answer for it, but it is the
best clinical design. Maybe someone can address that who has thought about
doing these trials.
DR. ALLEN: I
thoroughly agree with your statement about the need for NIH involvement. It was
something that was very apparent to me.
Also, normally, we have as a sitting member a person from
the blood component of NHLBI. I would hope that the FDA would assure that the
lung division at NHLBI is given a transcript of this committee hearing, and
perhaps invited to participate further in the discussions of study design, and
perhaps supporting it.
I agree with you, this really does need a coordinated
approach and it really, it seems to me, is going to need a long-term approach
where we are looking at very early diagnosis before onset of any clinically
apparent lung damage, and consideration of, at what point early on might
therapy be appropriate, in an attempt to prevent early damage, rather than
mid-point.
DR. SZYMANSKI: A
very simple question. What is the gene frequency?
DR. DI BISCEGLIE:
One in 50 for Z among Caucasians.
DR. SZYMANSKI: One
in 50,000?
DR. DI BISCEGLIE:
One in 50.
DR. SZYMANSKI: That
is not so very rare.
DR. BRANTLY: One in
100.
DR. SZYMANSKI: And the homozygosity frequency?
DR. BRANTLY: One in
2,500.
DR. ALLEN: Please
use the microphone, because we are recording. Do you want to stand up and make
a brief clarification of the statements you just made?
DR. BRANTLY; I just
wanted to go back to the frequency. So, the frequency of the Z allele in the
Caucasian population, Northern European is somewhere between 50 and 100. In the
United States, it is closer to one in 100 individuals, and the frequency of the
ZZ allele among the general population is actually about one in 2,500.
However, among the COPD population, approximately one in 10
individuals is either MZ, SZ or ZZ. So, it is a highly enriched population.
DR. MANNO: Back to
the idea of a randomized controlled trial, the one that was presented to us
from ZLB, one of the inclusion criteria was an FEV-1 of between 35 and 70,
which seems to me significant impairment of function.
So, if we are going to do something randomized and
controlled, it is clear we need to be able to identify patients to include
early on.
DR. NELSON: Is this
clinically possible? The time that
patients come to see physicians is when they have symptoms. Isn't that true?
I mean, you would have to screen huge populations in order
to do it, and it seems to me that that is not readily feasible without a
Katrina type of a budget.
DR. SIEGAL: You
ought to be able to collect patients quicker if you enlist the foundations that
are interested in this disease and their family members, screen those. You
could probably find a larger population to look at early.
DR. ALLEN:
Absolutely, I think especially given where the human genome project is
now. The issue of developing family cohorts and being able to screen much more
easily is something that isn't too far down the line.
DR. PIERCE: Just a
real quick comment about the screening issue and the early treatment. Certainly
that would be the best outcome, would be to prevent the disease in those who
are destined to get it.
One of the little complications of that is that, if you do
identify family members, for example, of an index case early, and you follow
them, there is a certain percentage of people with a severe deficiency who
never in their lifetime, even living into old age, develop emphysema. So, that
complicates the picture slightly.
DR. SCHREIBER: I
think that the design that ZLB put up is a very feasible one, and I think it
has a lot of scientific merit.
Using the CT scan to look at lung function seems to be a
very reasonable outcome, compared to the FEV-1. When you look over the data that we got, you have to have a
tremendous rate of functionality decline in the FEV to be able to see any kind
of statistical difference, something to the tune of 50 percent per year.
If we had 50 percent per year, there wouldn't be any women
around like the lady that addressed us. So, that is very, very rapidly
advancing disease, and I think what we see is that there seems to be anecdotal
evidence, evidence by the ability of people with the condition to have function
for a good number of years, that we do have an effective treatment.
Now what we are looking at is our clinical trial to justify
that there is an efficacy of the treatment. One of the things that I think
would be good is if the companies are designing clinical trials, and they are
going to do something like an end point of CT, at least they design them, not
that they have to be combined, but at least that you could look at them with
some kind of combined analysis, a meta analysis.
Two is too small for meta analysis, but at least you can compare
some kind of an outcome based on that type of functionality.
The same we see is that the other end points are very hard
to get to, unless we have huge sample sizes, probably more than the patients
available, and it would be good to enroll early on patients, because then I
think that you might be able to see the change in the functionality at an
earlier stage, which would give us more evidence that we would be happy with.
The other European data bordered on significance. If it had
just crept over a couple of tenths, a couple of hundredths of a p value, we
probably wouldn't be sitting here now, except to discuss whether the three
compounds were similar or not, and whether the side effects were similar.
DR. DI MICHELE: I certainly agree, and maybe, Dr. Schreiber,
you can comment on this further with your experience in clinical trial design.
The only issue with the ZLB study is, I did not see,
certainly in the presentation, what the criteria are going to be for efficacy.
I understand the trial design, and what the primary end
point was, but I didn't think I saw the exact measure of rate of increase in
lung density or whatever it was going to be that they were going to use as a
measure of efficacy, or just slight improvement in one group over the other.
I think the issue is that, because this is a plasma derived
protein, and because it is a plasma derivative, it does have certain safety
considerations, as was mentioned before, in terms of viral safety issues, and
emerging pathogens, et cetera.
I think it is important for this population to actually
prove efficacy. I think given, however, the clinical heterogeneity, it sounds
like in the clinical course, and the actual clinical phenotype and the clinical
progression, how much of a parameter change will it take to give this
population or the drugs enough benefit of the doubt to say, yes, it looks like
there is some efficacy here.
I think, from a statistical standpoint, I don't exactly
know how rigorous the trial design is going to have to be, I think, to prove
efficacy.
It sounds like, with few patients, clinical heterogeneity,
I don't now. I think even the estimate of 130 in the Dirksen paper, you may
actually require more than that. I don't know if you had any comments on that.
DR. SCHREIBER: I
wasn't clear what their end point was. I thought it was a 15 percent shift,
which seems to be a very reasonable end point marker.
DR. GIRGSDIES: May
I comment? You are right. We are not
knowing yet what is really clinically meaningful, which loss of line density,
but we are thinking that we can create these data, and this is just the pilot
study, and we are committed to it, and we will also have, after 50 patients, we
will have an interim analysis to look whether we should include more than 100
patients. You are right. We are creating data right now.
The other comment I would like to give to you, it is really
hard to find patients for a placebo controlled trial where products are on the
market.
I had a hard time, I still have a hard time to look all
over the world to get centers where no product is approved. So, it is in
Australia, it is in Ireland, it is in South Africa. So, it is a hard time for
me.
DR. ALLEN: I would suggest that probably, in this day and
age and where we are with these products, that a placebo controlled trial is
not ethical.
There need to be alternative ways of looking at it, whether
it be comparison of different products, comparison of different dosages, or
other comparative issues in there. It
is almost 1:00 o'clock. We need to quickly address B and C. Dr. Nelson?
DR. NELSON: I just
wondered how the clinical trials are going to deal with important co-factors
like cigarette smoking in this population.
I don't know. It is at least additive. It may be
synergistic. It certainly complicates it. The genetic defect is not the only
thing that causes emphysema.
DR. ALLEN: And
certainly those confounding factors need to be looked at very, very carefully.
Comments on the adequacy of the proposed safety monitoring program or other
suggested actions for the FDA?
DR. KUEHNERT: I
think it would call for reinstituting the registry that NIH had had. I think
you can get an awful lot of really good information about treatment and side
effects and everything else from the registry.
NHLBI just funded a MARFANS registry, and I would think
that a condition like this, a registry is an excellent way to go to answer many
of these questions that we are looking at, particularly given that the centers
that would enroll people in a federally funded research registry would have the
capabilities to do some of these more esoteric testings, like CAT scans.
It certainly would have made the adverse event data that
was reported much more meaningful, had we had some context like that to weight
it against, and to be able to track back to individual patients.
DR. KLEIN: It seems
to me that the discussions about efficacy are a different study set than about
safety, particularly on an ongoing basis.
I mean, the way this came to attention is that something
changed in the product, and who knows what is going to change down the road.
So, you do a six-month efficacy study, fine, you look at
efficacy, but that does not address the long-term safety issues.
I don't know what the solution. I saw this nice handout from the Alpha-1 Foundation, which I
thought was very well thought out, but I am wondering, how is this going to be
supported, who is going to pay for this.
These are the same issues that, frankly, exist for other
plasma products. I don't have an answer, but I think it is something that we
need to think about in a broader way, because these needs are here, not only
for these patients, but for others as well.
I mean, I think there needs to be some lowest common
denominator for surveillance for safety, and I just think that Medwatch isn't
enough.
DR. ALLEN: I
certainly agree with you on that. I think some of the proposed ways to address
it was outlined. I thought it was a very good first start. Other comments or questions?
DR. KLEIN: Just two
comments. A registry would serve the kind of purpose you have in mind, or do
you think that would be insufficient?
DR. KUEHNERT: I
guess I don't know enough about it to know exactly how things get reported, and
is this in any sense of real time, or is it reviewed every year? How often do
people look at the data?
DR. KLEIN: I guess you were talking about long-term effects
of chronic treatment or chronic disease.
I guess those things could be worked out, but you certainly wouldn't
need something real time to look at that.
DR. KUEHNERT: No,
but I mean, probably more often than once a year or something, but it wouldn't
need to be daily but maybe once a month or something.
DR. KLEIN: Finally,
I would just like to go on record, if I may, I rarely disagree with our esteemed
chairman, but I think that maybe in the United States it would be
extraordinarily difficult to do a randomized trial with placebo, but in many
areas of the world where the drugs are not available, it is not all that
difficult to do, although I sympathize with your problems of recruitment.
I think it is absolutely crucial. Here we have a treatment,
an intravenous treatment for life, where we are really not convinced that we
are doing anything to help patients.
I think that, before you commit human beings to that, you
really need to know that you have some evidence that you are going to do them
some good.
So, in areas where it won't be quite as difficult, perhaps,
to recruit subjects, where drug perhaps is not available, I would encourage the
company to do so.
DR. DI MICHELE:
With respect to safety, I agree with a lot of what has been said. There
may need to be sort of more long-term comprehensive collection of data in the
registry format, and I wouldn't disagree with that.
I think that the important issues of safety, to a certain
extent, are going to be tied in a little to efficacy.
I mean, should the efficacy trials, for instance, show
deterioration in pulmonary function if they continue to do that, or certainly
an acceleration of CT changes with product.
Obviously, that may end up being a safety issue in and of itself.
The other issues, though, that have been brought up are
impact of what has been presented to us today on bioavailability, and for
instance, immunogenicity.
I think there probably does need to be some element of
design in safety studies that look at immunogenicity and that look at
bioavailability in terms of whatever can be monitored in terms of pulmonary
function.
That could be a subset of a larger group of patients that
are just followed prospectively on a more passive basis in terms of passive
reporting, but prospectively with respect to adverse events in general, where
issues can be picked up and then looked at in a more organized fashion in terms
of potential etiology.
DR. CRYER: I just
mention that the beauty of having a system where the three trials have similar
end points in time in their design would make it so that only one company had
to do a placebo group, because the others could compare to that one. It sounds like one already has to committed
to it. So, I think that is crucial.
DR. EPSTEIN: I wonder if I could ask a technical question
of the representative from ZLB. Dr.
Pierce pointed out to us that, In the Dirksen study, alpha-1 PI was better than
placebo on CT with a trend of significance of a p of .07, but under a different
analysis of the CT, p was only equal to .2.
That seems to raise a fundamental methodological question
about whether we know the correct way to interpret the CT data. I just wonder if I could get a comment on
that from the ZLB representative.
DR. GREGSDIES: I am
not a statistician. So, I can't really answer your question. Sorry for that.
DR. ALLEN: Other
important comments? Dr. Epstein, have
you received the information that you need?
Do you have specific points you would like to have clarified by the
committee?
DR. EPSTEIN: Yes, I
think we have had a very good discussion by the committee, and that a lot of
the comments will prove very useful to us.
DR. SCHWARZ: I
would like to clarify something, because it came up by one of the committee
members, how products are released, controlled, lot to lot.
Clearly, there are a lot of specifications which must be
met, and one of those is specific activity and the elastic activity, of course.
DR. DI BISCEGLIE: I
am sorry, I had to leave the room for a minute, but I did want to make a
comment about safety monitoring related to liver disease. As a hepatologist, I would be remiss in
leaving that out.
We know that this product would not be expected to have any
efficacy in the treatment of the liver disease, but I wonder if there is any
evidence that it might make the liver disease worse.
The liver injuries caused by accumulation of the protein
within hepatocytes, is it possible that if you raise the serum levels, you
inhibit the secretion of the protein from hepatocytes, and might exacerbate
underlying liver disease that occurs.
So, I would encourage monitoring of liver function.
DR. ALLEN: I think
that is a very important statement. Thank you.
DR. DOPPELT: I just
wanted to add one point .I think everybody -- rightfully -- is focusing on the
efficacy, but if the FEV-I is a difficult parameter to measure, and
theoretically you would like to get people into the studies earlier, but that
may not happen, and you are not quite sure how to evaluate CTs -- there may be
different methodologies -- then the number that you need to get an answer may
be unreachable.
DR. EPSTEIN: I may
have spoken a little bit too quickly. It has been pointed out that we would
like some discussion about the issue of communications at this point in time,
either through modifications of product labeling or a dear doctor letter, as
has been suggested by the Alpha-1 Foundation or Association, I am not sure
which.
DR. DI MICHELE: I
agree. In fact, I was just about to say that, that I think that, with respect
to the issues that were brought up, certainly safety surveillance, which was
the first issue that was brought up here today, I think you could get a jump
start on certainly voluntary reporting, by making sure that both patients and
their doctors, and potentially even ERs, have this information and, you know,
really ask for diligence in reporting.
I would agree with certainly the dear doctor letter, as suggested by the
Alpha-1 Association.
DR. SCHREIBER: I
guess I have to just take the opposite. I saw nothing at all that convinced me
that the small shifts on electrophoresis constitutes any health effect, and the
data that we saw on the health effects was not convincing that these new
products were any different than the one on the market. So, I would not put out a dear doctor letter
at all. I think that there is just no evidence to go on.
DR. DI MICHELE: I
guess what I would say is, it doesn't need to be an alarming letter. I think
just a request for information, if that is what was being raised here today.
It sounds like the companies have gone back and done some
considerable work to try to look at the reasons for this heterogeneity.
I mean, it certainly seems to be enough of a concern, I
mean, within the FDA in terms of product quality, et cetera, that it would seem
to me that what you are calling for is just saying, what are you seeing out
there in the community.
I am not sure it needs to be an alarmist letter saying we
think that there are going to be some problems here. Just, please, you know, examine or be aware of these issues, and
that we would like to know if you see anything of any concern, and these are
the adverse events that we are interested in.
DR. ALLEN: I
certainly would support that position. In particular, given the broader
discussions that were presented by FDA staff on biological products, the issues
of manufacturing, storage and so on, and the whole issue of heterogeneity, my
guess would be that most physicians in practice don't have a significant
appreciation of that, and they presume that what is presented is the ideal,
when in fact it isn't.
So, I would think a letter that certainly points out some
of these issues with a reasonable degree of brevity and clarity for the average
practitioner would be important, and it then raises the need for collection of
further data, the adverse event reporting system.
Again, I think developing a registry with cohort
monitoring, if we can get the NIH to support some of these studies, would be
extremely important for long-term follow up.
DR. KLEIN: I guess
the question is, what do you put in a dear doctor letter. This is already a hot
issue in the community. I don't have to tell any of the alpha-1 people about
that.
I have seen letters to the editor submitted that are going
to be published. So, they are already aware that there is a potential problem.
We have sat through, as I said, several elegant
presentations that suggest to me, at least, one, that there has been no change
in the one product from the time of the phase III study.
There has been an observation, but it turns out that it is
not a change in the product since the data that were used to license the
product.
The second thing that I think I learned is that there is
probably no evidence that any of the small changes in the protein have been
related to anything that relates to either safety or efficacy of this product.
I suppose, if I were trying to write a dear doctor letter,
I guess that is what I would say, that this has been an issue, and right now
there is literally nothing that we can say to suggest that there is either a
threat to the safety of the patient or a decrease in the potential efficacy of
the product, and I don't know what to say beyond that. If there are other
ideas, I would like to hear them.
DR. DI MICHELE:
Historically, you know, several years ago we had a somewhat similar
situation where -- you know, think outside of the box in terms of a dear doctor
letter.
We crafted a letter that was informative, in terms of, here
are the issues on the table, here, you as the physician, are things that you
can do with your patient, and then report back to the company, and then the
company can take that information and, in turn, provide it to us in some sort
of form that we could, in fact, turn it into something more useful.
DR. KLEIN: I thin
the problem, as I see it, is that the patients are being taken care of by
probably physicians who are really experts in lung disease, but probably have
no biochemical expertise, I might say, than I do.
So, sending them data and western blots is not going to be
helpful, unless you can interpret those data for them. I would, again, stress a
cautious interpretation from what we have heard today.
DR. DI MICHELE: I
agree. It is a little bit of a difficult issue, and that is exactly what I
would think that you might be able to send out, is something like, look, this
is an issue that we are grappling with. We don't know if it is an issue. We
would like you, the care takers in the community, to help us by, number one,
thinking about potential adverse events and, number two, reporting them in such
a way that they are interpretable.
For instance, you might want to give age and sex and, God
forbid, IGA status and a few other things like that, that might help both
industry and the FDA really begin to get a handle on exactly -- well, on this
issue, and just to put this issue to rest. I don't see anything wrong with
that, without causing major alarm in the community.
DR. SNIDER: I think
a voluntary reporting system of health effects will not work. There has to be a
system that is prospective, that is carefully designed, and preferably is used
by the three companies.
That probably can't be physician based, but nurse or IV
therapist based, because these people are getting weekly infusions, and with
the development of such techniques, I think we would be much further ahead than
we are now.
DR. DI MICHELE: If
I can just say, I absolutely agree with you, and I think what was just asked
was an interim measure while everything is getting started. Otherwise, I
couldn't agree with you more.
DR. ALLEN: I am
going to call this session closed. I want to thank everybody, all of the
temporary and permanent committee members and the guests.
I think Donna and I both have enjoyed working with you over
the last two days. Some of you will be leaving the committee and, again, thanks
very much, and I look forward to working with you in the future in some other
capacity.
[Whereupon, at 1:14 p.m., the meeting was adjourned.]