1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR DRUG EVALUATION AND
RESEARCH
DRUG SAFETY AND RISK MANAGEMENT
ADVISORY COMMITTEE
(DSaRM)
COMMITTEE MEETING
CDER Advisory Committee Conference
Room.
2
P A R T I C I P A N T S
DSaRM Committee Members:
Peter A. Gross, M.D., Chair
Michael R. Cohen, R.Ph., M.S., D.Sc.
Stephanie Y. Crawford, Ph.D., M.P.H.
Curt D. Furberg, M.D., Ph.D.
Jacqueline S. Gardner, Ph.D. M.P.H.
Arthur A. Levin, M.P.H.
Henri R. Manasse, Jr.,
Ph.D.
Robyn S. Shapiro, J.D.
Annette Stemhagen, Dr.PH
Brian L. Strom, M.D., M.P.H.
GI Advisory Committee Members:
Alexander H. Krist, M.D.
Maria
H. Sjogren, M.D.
Consultant:
Leslie
Hendeles, Pharm.D.
FDA
Participants:
Carol
Holquist, R.Ph.
Marci
Lee, Pharm.D.
Paul Seligman, M.D., M.P.H.
[a.m. and p.m.]
Vibhakar Shah, Ph.D.
Eugene Sullivan, M.D.
Mark Avigan, M.D., C.M.
Julie Beitz, M.D.
Robert Justice, M.D., M.S.
Ann Marie Trentacosti,
M.D.
3
C O N T E N T S
AGENDA ITEM
PAGE
Call to Order and Opening Remarks,
Introduction of
Committee - Peter Gross, M.D., Chair,
DSaRM 5
Conflict of Interest Statement - Shalini
Jain,
PA-C, M.B.A., Executive Secretary,
DSaRM 8
Opening Remarks - Paul Seligman, M.D.,
M.P.H.,
Director, Office of Pharmacoepidemiology
&
Statistical Science (OPSS) and Acting
Director,
Office of Drug Safety (ODS) 11
FDA Presentations
- Permeability of LDPE Vials: A Clinical
Perspective - Eugene Sullivan, M.D.,
Deputy
Director, Division of Pulmonary Drug
Products. 13
- Medication Errors and Low-Density
Polyethylene
(LDPE) Plastic Vials -
Marci Lee, Pharm.D.,
Safety Evaluator, Division
of Medication Errors
and Technical Support 23
- LDPE Vials for Inhalation Drug
Products: A
Chemistry, Manufacturing, and Controls
(CMC)
Perspective - Vibhakar Shah, Ph.D.,
Chemist,
Division of New Drug Chemistry II 36
Questions from Committee 55
Industry Presentations
- Container Labeling Options using
rommelag Blow-
Fill-Seal Technology - Mohammad
Sadeghi, V.P.,
Research/Development, Holopack
International
Corp.
65
- Labeling of LDPE Containers: Options for
Improving Identification for Prevention
of
Medication Errors - Rick Schindewolf,
V.P. & GM,
Biotechnology & Sterile Life
Sciences, and
Patrick Poisson, Director of Technical
Services,
Biotechnology & Sterile Life Sciences, Cardinal
Health
90
- American Association of Respiratory
Therapy
Care - Karen Stewart, M.S., R.R.T. 93
Questions from Committee 94
4
C O N T E N T S
(Continued)
Open Public Hearing 106
Introduction of LDPE Issues
Paul Seligman, M.D.,
M.P.H. 118
Committee Discussion 118
Committee Discussion (Continued) 182
Opening Remarks and Reintroduction of
Advisory
Committee - Peter Gross, M.D., Chair 182
Conflict of Interest Statement - Shalini
Jain,
PA-C., M.B.A. 185
Introduction of Lotronex Issue - Paul
Seligman,
M.D., M.P.H.
187
Open Public Hearing 189
Sponsor Presentation
Risk Management Program for Lotronex -
Craig Metz,
Ph.D., V.P., U.S. Regulatory Affairs,
GlaxoSmithKline 206
FDA Presentation
Lotronex Update - Robert Justice, M.D.,
M.S.,
Director, Division of Gastrointestinal
and
Coagulation Drug Products 241
Questions from Committee 248
Adjourn
298
5
1 P R O C E E D I N G S
2
DR. GROSS: Good morning. I'm Peter
3
Gross. I'm Chair of the Drug
Safety and Risk
4
Management Committee, and starting with the person
5 at
my left with that famous laugh, Brian Strom,
6
would you please introduce yourself?
7
DR. STROM: Thank you. I'm Brian Strom
8
from the University of Pennsylvania.
9
MS. JAIN: You know what? Before we go
10 on,
Brian, Peter and the rest of the committee as
11
well as the division wanted to say a warm thank-you
12 for
serving on our committee. You've been a
great
13
asset for a year and a half, and we realize that
14
you're going to continue as consultant, and we just
15
wanted to say thanks.
16
DR. STROM: It's been a real
pleasure, and
17 it
was a hard decision to let the rotation happen.
18
I've enjoyed it, but given other commitments back
19
home--but it's been fun.
20
MS. JAIN: Thank you.
21
DR. GROSS: You've been great,
Brian. We
22
will continue to take advantage of your skills.
6
1
DR. MANASSE: My name is Henri
Manasse.
2 I'm
chief executive officer and executive vice
3
president of the American Society of Health-System
4
Pharmacists, a membership organization that
5
represents about 32,000 pharmacists practicing in
6
hospitals and organized health systems.
7
MS. SHAPIRO: Robyn Shapiro. I'm a
8
professor and director of the Center for the Study
9 of
Bioethics at the Medical College of Wisconsin.
10
DR. STEMHAGEN: I'm Annette
Stemhagen.
11 I'm
Vice President of Strategic Development at
12 Covance,
a contract research organization, and I
13
serve as an industry representative to this
14
committee.
15
DR. GARDNER: Jacqueline Gardner,
16
University of Washington, Department of Pharmacy.
17
MR. LEVIN: Art Levin, Center for
Medical
18
Consumers, and I serve as the consumer
19
representative.
20
DR. FURBERG: Curt Furberg,
professor of
21
public health sciences at the Wake Forest
22
University.
7
1
DR. HENDELES: I'm Leslie
Hendeles. I'm a
2
clinical pharmacist at the University of Florida,
3 and
I've done research on the bronchospastic
4
effects of preservatives in nebulizer solutions.
5
DR. CRAWFORD: Good morning. Stephanie
6
Crawford, associate professor, College of Pharmacy,
7
University of Illinois at Chicago.
8
DR. COHEN: Mike Cohen, Institute
for Safe
9
Medication Practices.
10 DR. SELIGMAN: Paul Seligman, Director,
11
Office of Pharmacoepidemiology and Statistical
12
Science, Center for Drug Evaluation and Research,
13
FDA.
14
DR. SULLVAN: My name is Gene
Sullivan.
15 I'm
the Deputy Director of the Division of
16
Pulmonary and Allergy Drug Products here at FDA.
17
MS. HOLQUIST: I'm Carol
Holquist. I'm
18 the
Director of the Division of Medication Errors
19 and
Technical Support in the Office of Drug Safety,
20
Center for Drug Evaluation and Research.
21
DR. LEE: Marci Lee, a pharmacist
and
22
safety evaluator in the Division of Medication
8
1
Errors and Technical Support.
2
MS. JAIN: Thank you,
everyone. My name
3 is
Shalini Jain. I'm the Executive
Secretary for
4 the
Drug Safety and Risk Management Advisory
5
Committee. I'll now read the
conflict of interest
6
statement for the meeting today.
The meeting issue
7 is
low-density polyethylene vials.
8
The following announcement addresses the
9
issue of conflict of interest with respect to this
10
meeting and is made a part of the record to
11
preclude even the appearance of such at this
12
meeting.
13
Based on the agenda, it has been
14
determined that the topics of today's meeting are
15
issues of broad applicability, and there are no
16
products being approved at this meeting.
Unlike
17
issues before a committee in which a particular
18
product is discussed, issues of broader
19
applicability involve many industrial sponsors and
20
academic institutions.
21
All special government employees have been
22
screened for their financial interests as they may
9
1
apply to the general topics at hand.
To determine
2 if
any conflict of interest existed, the agency has
3
reviewed the agenda and all relevant financial
4
interests reported by the meeting participants.
5 The
Food and Drug Administration has granted
6
general matters waivers to the special government
7
employees participating in this meeting who require
8 a
waiver under Title 18, United States Code,
9
Section 208.
10
A copy of the waiver statements may be
11
obtained by submitting a written request to the
12
agency's Freedom of Information Office, Room 12A-30
13 of
the Parklawn Building.
14
Because general topics impact so many
15
entities, it is not prudent to recite all potential
16
conflicts of interest as they apply to each member,
17
consultants, and guest speaker.
18
FDA acknowledges that there may be
19
potential conflicts of interest, but because of the
20
general nature of the discussion before the
21
committee, these potential conflicts are mitigated.
22
With respect to FDA's invited industry
10
1
representative, we would like to disclose that Dr.
2
Annette Stemhagen is participating in this meeting
3 as
an industry representative, acting on behalf of
4
regulated industry. Dr. Stemhagen
is employed by
5
Covance Periapproval Services, Incorporated.
6
In addition, we would like to note that
7
Karen Stewart, FDA's invited guest speaker, is
8
participating as a representative of the
9
respiratory therapists in the United States through
10 the
American Association for Respiratory Care.
She
11 has
no financial interest in or professional
12
relationship with any of the products or firms that
13 could
be affected by the committee's discussions.
14
With respect to the three invited industry
15
guest speakers, we would like to disclose that
16
Mohammad Sadeghi is employed by Holopack
17
International, Richard
Schindewolf is employed by
18
Cardinal Health and is vice president and general
19
manager of Biotechnology and Sterile Life Sciences.
20
Patrick Poisson is employed by Cardinal Health, and
21 he
serves as Director of Technical Services at the
22
Biotechnology and Sterile Life Sciences division.
11
1
In the event that the discussions involve
2 any
other products or firms not already on the
3
agenda for which FDA participants have a financial
4
interest, the participants' involvement and their
5
exclusion will be noted for the record.
6
With respect to all other participants, we
7 ask
in the interest of fairness that they address
8 any
current or previous financial involvement with
9 any
firm whose product they may wish to comment
10
upon.
11
Thank you.
x DR. SELIGMAN: Good morning.
On behalf of
12
13 the
Center for Drug Evaluation and Research, it is
14 my
pleasure to welcome members of the Drug Safety
15 and
Risk Management Advisory Committee and members
16 of
the public to today's meeting. As
always, we
17
greatly appreciate the time and efforts devoted by
18 the
committee members and all participants in
19
providing advice to the FDA on important public
20
health issues.
21
We have two topics on the agenda for
22
discussion today--the first related to the
12
1
prevention of medication errors and the second
2
providing an update on a risk management program
3
that was considered by this committee two years ago
4 and
was implemented in 2002.
5
The first topic will focus primarily on
6
minimizing the incidence of medication errors with
7
drug products packages in low-density polyethylene,
8 or
LDPE, containers. The package is
intended to
9
preserve drug product purity and quality. However,
10
current techniques used to label the product create
11
problems related to legibility of the product name
12 and
strength. Additionally, various products
are
13
packaged in containers that look similar. We've
14
found that these difficult-to-read labels and
15
look-alike containers have contributed to
16
medication errors involving the administration of
17
wrong dosage strength or wrong drug product to the
18
patient.
19 Today, we would like to discuss what
other
20
solutions or alternative packaging designs exist
21
that could improve the legibility of the label,
22
prevent ingress of chemical contaminants, and in
13
1 the
process reduce or eliminate medication errors.
2
Then later this afternoon, we will receive an
3
update on the Lotronex risk management program.
4
With that brief introduction, I look
5
forward to our discussions today and, again, I also
6
want to personally thank Dr. Strom for his service
7 on
this committee.
8
With that, I guess we may proceed with the
9
first speaker. Dr. Gross?
10
DR. GROSS: Dr. Sullivan will be
the first
11
speaker on the Permeability of LDPE Vials: A
12
Clinical Perspective.
13
DR. SULLIVAN: Good morning. As I
14
mentioned, my name is Gene Sullivan.
By training
15 I'm
a pulmonologist, and I'm the Deputy Director of
16 the
Division of Pulmonary and Allergy Drug Products
17 in
the Center for Drug Evaluation and Research here
18 at
FDA.
19
This morning, I'm going to spend about 15
20
minutes or so providing some background for the
21
discussions today. I'll be
conveying some clinical
22
observations regarding issues raised by the use of
14
1
LDPE vials in the packaging of inhalation drug
2
products, particularly as it relates to the
3
permeability of the vials.
4
This slide provides an overview of my
5
presentation. I'll begin with
some introductory
6
remarks which will put my presentation into the
7
context of today's discussions and will serve to
8
introduce the remainder of the talk.
Next I will
9
discuss the inhalation drug products that are
10
involved, providing some examples and a brief
11
description of the nature of these drugs.
12
Following this, I will discuss the patient
13
populations for which these drugs are used,
14
emphasizing aspects of these populations that put
15
them at risk for adverse effects of chemical
16
contaminants. Then I will discuss
the potential
17
sources of chemical contaminants, their potential
18
adverse effects, and the difficulties that exist in
19
terms of adequately monitoring for them.
Finally,
20 I
will summarize the issue and current state of
21
affairs in order to set the stage for the remainder
22 of
today's discussion regarding minimizing the
15
1
potential for medication errors.
2
The topic for discussion for today's
3
Advisory Committee meeting is how best to minimize
4 the
potential for medication errors associated with
5
LDPE containers, particularly given the clinical
6
concerns related to their permeability and the
7 resulting
move away from the paper labels that have
8
previously been used to identify the products. My
9
presentation is intended to review the nature of
10
these clinical concerns in order to provide
11
background for the remainder of the discussions
12
today.
13
This slide summarizes the clinical
14
concerns that I mentioned. Many
inhalation drug
15
products are packaged in LDPE containers. LDPE is
16 a
material that is permeable to volatile chemicals,
17 and
there are numerous volatile chemicals that
18
exist in the immediate packaging environment.
19
Volatile chemicals that find their way into
20
inhalation solutions may have a number of adverse
21
effects on the airways, and because these adverse
22
effects may be poorly tolerated by patients,
16
1
efforts should be made to minimize the potential
2 for
contamination of inhalation drug products.
3 Such
efforts have included minimizing the content
4 of
volatile chemicals in the immediate packaging
5
environment.
6
For instance, the practice of using paper
7
labels, which are applied directly to the LDPE
8
containers and which contain numerous volatile
9
chemicals, is not recommended.
However, as you
10
will see in subsequent presentations, the use of
11
alternative labeling approaches has raised the
12
issue of medication errors.
13
Now, I also want to point out that my
14
presentation is focused on the clinical concerns
15
related to chemical contamination of these
16
products. In the next
presentation, Dr. Shah will
17
also talk about product quality concerns. For
18 instance, ingress of volatile chemicals might
19
adversely affect the stability of the active drug
20
substance in a particular drug product.
21
This slide provides some examples of
22
inhalation drug products that are packaged in LDPE
17
1
containers. They include
bronchodilators, such as
2
Albuterol, Ipatropium, Metaproterenol, and
3
Levalbuterol; also a mass cell stabilizer, cromolyn
4
sodium; an inhaled steroid, Budesonide; and an
5
antibiotic, Tobramycin.
6
These products are inhalation solutions,
7 or
sometimes suspensions, that are intended for
8
oral inhalation using a nebulizer.
One thing to
9
keep in mind is that the manufacturing processes
10 and
materials for inhalation products are very
11
carefully controlled in order to maintain a very
12
high standard of product purity.
That is, a
13
significant amount of attention is paid to the
14
manufacturing processes and the materials used so
15
that the content of contaminants is minimized.
16
This would include contaminants that arise during
17 the
manufacturing processes, so-called process of
18
synthetic impurities; contaminants that arise due
19 to
degradation of components of the formulation; or
20 the
subject of today's concern, contaminants that
21
enter the formulation from the packaging materials,
22
so-called leachables.
18
1
These drugs may be used in a regular
2
dosing schedule or may be used as an as-needed
3
basis, and the bronchodilator products in
4
particular are common used in the inpatient and
5
acute-care settings, including emergency
6
departments and intensive care units.
7
These inhalation products are used by
8
patients with a variety of pulmonary disorders,
9
most commonly patients with asthma, COPD--which is
10
chronic obstructive pulmonary disease, a category
11 of
lung disease comprised of chronic bronchitis and
12
emphysema--and cystic fibrosis.
Although these
13
diseases are distinct, in general they are
14
characterized by fixed or variable obstruction to
15
airflow and a variety of patterns of histologic
16
abnormalities, including various patterns of airway
17
inflammation. In addition, asthma
in particular is
18
associated with an underlying propensity for
19
allergic responses. And most of
the diseases are
20
associated with a sensitivity to nonspecific
21
irritants which result in acute bronchospasm, a
22
feature known as airway hyperresponsiveness.
19
1
To focus specifically on asthmatics for a
2
moment, asthmatics may react adversely to both
3
nonspecific chemical irritants and to allergens to
4
which they have developed specific immunity.
5
Irritant reactions are characterized by symptoms of
6
wheezing and shortness of breath.
It is well known
7
that patients with severe asthma may react to very
8 low
levels of exposure to irritants.
Clinically,
9
this is often related to perfumes, cleaning agents,
10 or
smoke in the environment. In fact, we
commonly
11
make use of this feature of asthma to help
12
establish the diagnosis using methacholine
13
challenge testing. In the
methacholine challenge
14 test,
patients with suspect asthma are exposed to
15
successively higher concentrations of this irritant
16 in
order to elicit bronchospasm.
17
In addition to the nonspecific irritant
18
reactions, asthmatics may also develop bronchospasm
19
from inhaled allergens. This
allergic reaction is
20
associated with both an acute early-phase broncho-
21
constriction and a delayed late-phase response
22
characterized by airway inflammation and airflow
20
1
limitation.
2
So what are the potential sources of
3
contaminants in inhalation drug products packaged
4 in
LDPE? In general, these are from
volatile
5
chemicals found in the labels and secondary bulk
6
packaging. These chemicals may be
found in the
7
various glues, inks, and lacquers that are used.
8 One
thing to point out is that the specific
9
chemical nature of these inks, glues, et cetera,
10 may,
in fact, change after approval due to changes
11 in
the sources of these packaging materials.
12
The FDA conducted an analytical survey of
13
approved inhalation solutions marketed in LDPE
14
containers and found that 29 of the 37 samples
15
tested positive for various volatile chemicals that
16
were presumed to have originated in the packaging
17
materials. Dr. Shah will describe
this analysis in
18
much more detail in his presentation later this
19
morning.
20
Chemical contaminants in inhalation drug
21
products may be associated with a variety of
22
adverse effects, including irritant and immunologic
21
1
effects, leading to acute bronchospasm and airway
2
inflammation and hyperresponsiveness, other toxicologic
3
injury, or even potentially carcinogenicity.
4
In terms of monitoring for adverse effects
5
that might be attributed to chemical contaminants
6 in
these products, it is important to note that
7
appropriate attribution may be very difficult
8
because the expected adverse effects--bronchospasm
9 and
airway hyperresponsiveness--mimic the symptoms
10 for
which the drugs are being used. This is
a very
11
difficult circumstance and makes it quite likely
12
that adverse effects would not be recognized and
13
reported. For instance, modest
bronchospasm
14
related to chemical contaminants might lead to
15
reduced efficacy of the drug, but this would likely
16 not
be identified. Even if the adverse
effect were
17
more significant, the findings would likely be
18
attributed to refractory underlying disease.
19
So, to summarize, many inhalation drug
20
products are packaged in low-density polyethylene
21
containers. This material is
permeable to volatile
22
chemicals. Numerous volatile
chemicals exist in
22
1 the
immediate packaging environment.
2
Various volatile chemicals have, in fact,
3
been identified in these products.
These volatile
4
chemicals may have irritant as well as other
5
toxicologic effects. And because
these effects may
6 be
particularly poorly tolerated by patients,
7
efforts should be made to minimize the potential
8 for
contamination of inhalation drug products.
9
It was this line of reasoning that in part
10 led
to the development of the Draft Guidance
11
entitled "Inhalation Drug Products Packaged in
12
Semipermeable Container Closure Systems." Among
13
other things, the Draft Guidance recommends that
14
measures be taken to limit chemical contamination
15 of
these products. One such measure would
be the
16 use
of alternative approaches to paper labels, such
17 as
direct embossing or debossing of the containers.
18
However, as will be discussed in
19
subsequent presentations, the move away from paper
20
labels has introduced a new concern, that of
21
medication errors due to difficult-to-read and
22
look-alike packaging. The issue
of how best to
23
1
minimize the potential for medication errors will
2 be
the topic for today's discussion.
3
DR. GROSS: Thank you, Dr.
Sullivan.
4
The next speaker will be Shah.
5
MS. JAIN: He is not here.
6
DR. GROSS: Okay. Later for Dr. Shah.
7
Dr. Marci Lee will now talk about
8
medication errors and low-density polyethylene
9
plastic vials.
10
DR. LEE: Good morning. My name is Marci
11
Lee. I am a pharmacist and safety
evaluator in the
12
Division of Medication Errors and Technical Support
13 in
the Office of Drug Safety.
14
The purpose of this presentation is to
15
describe medication error reports and feedback from
16
patients and practitioners involving products
17
packaged in LDPE containers. I
will focus on some
18
factors we identified that may contribute to
19
confusion and errors with these products. Finally,
20 I
will describe packaging and labeling approaches
21 for
your consideration.
22
Our error analysis included in your
24
1
background package was from 87 relevant reports.
2 These
came from patients, caregivers, and
3
practitioners, such as respiratory therapists and
4
pharmacists, who reported to the programs listed.
5
These reports were received between January 1993
6 and
August 2002. Many reports involved difficulty
7
reading embossed product containers.
Some reports
8
were actual errors where the wrong medication or
9 the
wrong dosage strengths were dispensed.
10
Although some of these were detected before the
11
medication was administered to the patient, some
12
were not. The outcomes of these
reports ranged
13
from no harm to difficulty breathing, which can be
14
life-threatening. The remainder
of the reports
15
described the potential for confusion and errors
16
with these products.
Subsequently, as of April
17
2004, 51 additional relevant medication error
18
reports were identified for a total of 138 reports.
19
In addition to our analysis, FDA received
20
correspondence from ISMP, USP, and Senator Harkin
21
regarding the safe use of products packaged in LDPE
22
containers.
25
1
Several themes emerged from the narratives
2 of
the medication error reports as factors that can
3
contribute to errors. They
include
4
difficult-to-read containers, look-alike packaging,
5 and
routine handling of LDPE by patients and health
6
care practitioners.
7
Some of the slides for this portion of the
8
presentation will include direct quotes from the
9
error reporters. The first
contributing factor to
10
consider is the difficult-to-read labeling.
11
Concern was expressed in a medication error report
12 because it is difficult to see the name of
the drug
13 and
its ingredients. Another person noted
that if
14 the
lot and expiration date are on opposite sides
15 of
the same area of plastic, it is even more
16
difficult to read. In addition,
practitioners
17
described how the vials needed to be angled in the
18
light to read them. For some, the
text is
19
difficult or impossible to read.
20
In addition to difficult-to-read
21
containers, another concern from the medication
22
error perspective is the issue of look-alike
26
1
packaging. Often there is very
little on the
2
container itself to help people distinguish these
3 products.
4
This photo accompanied one medication
5
error report. It highlights the
potential for
6
confusion from look-alike vials from just a few of
7 the
products available in these containers.
Almost
8 all
of these vials contain a different drug
9
product. The paper labels and the
unique round
10
vial shape help to differentiate three of the vials
11
from the rest. However, these two
can be difficult
12 to
read.
13
In addition, this problem spans various
14
drug classes and routes of administration. This
15
complicates the picture for practitioners and
16
creates the opportunity for errors to occur among
17
inhalation, injection, ophthalmic, and oral
18
products.
19
In this case, heparin is an injectable
20
medication. This photo was
included with the
21
report of potential for confusion between heparin
22 and
Tobramycin due to look-alike containers.
27
1
Pharmacies may store a variety of these products,
2 and
the potential for confusion will likely
3
increase as we see more products other than
4
inhalation solutions packaged in the LDPE
5
containers. This increases the
likelihood for
6
administration of the wrong drug product by the
7
wrong route of administration.
8
Another example of an injectable drug
9
product with similar packaging is Naropin. These
10
ampules are specially design to fit both Luer lock
11 and
Luer slip syringes. Although this
feature may
12
minimize the likelihood for confusion with the
13
other LDPE containers, there is still potential for
14
confusion between the dosage strengths within the
15
Naropin product line. This vial
includes black
16
type on a clear background.
Again, for some this
17 may
be difficult to read.
18
Timoptic OCUDOSE is an example of an
19
ophthalmic solution packaged in an LDPE container.
20
This image shows that the tip of the container has
21
been extended to allow for a label.
However, there
22 may
be potential for contamination despite the
28
1
placement of this label.
2
Gastrocom is an example of a product for
3
oral administration that is packaged in an LDPE
4
container. This image illustrates
the instructions
5 for
use.
6
In summary, there are least four different
7
routes of administration for products packaged in
8
LDPE containers. Again, this
complicates the
9
picture for practitioners and creates the
10
opportunity for errors to occur among inhalation,
11
injection, ophthalmic, and oral drug products.
12
We have discussed several issues that
13
contribute to medication errors with LDPE
14
containers. We have seen examples
of containers
15
that are difficult to read and difficult to
16 distinguish from one another. We have noted that
17 the
look-alike contains look-alike containers are
18 not
from a single drug product category or
19
associated with a single route of administration.
20 Now
we will explore how routine handling of LDPE
21
containers by patients and practitioners can
22
contribute to errors.
29
1
The foil overwrap serves to protect the
2
containers from light and the environment. It is
3
recommended that the containers are stored in the
4
foil overwrap until time of use.
However, the
5
reality is that the foil overwraps are commonly
6
discarded. Once discarded, the
clearly labeled
7 portion
of the packaging is often eliminated.
8
One reason noted in our analysis for the
9
overwrap to be removed is an effort to fit the
10
products into a medication cart.
The foil overwrap
11 and
carton for many inhalation solutions use color
12 to
differentiate the dosage strength. Most
foil
13
overwraps contain multiple unit dose LDPE vials.
14 For
example, the foil overwrap for Xopenex contains
15 12
vials.
16
Carol, if you'll pass the sample?
17
This image includes the 12 vials which are
18
contents of a single foil pouch of Xopenex. All of
19 the
vials in this image are the same dosage
20
strength. However, Xopenex is
available in three
21
different dosage strengths. The
vials for all
22
three strengths look alike when they are removed
30
1
from the foil. Although the foil
helps to
2
differentiate them, it is possible that these vials
3 may
not remain in the foil pouch until their time
4 of
use. These individual LDPE containers
can be
5
stored in a variety of places once removed from the
6
foil overwrap.
7
It is a common practice for LDPE
8 containers
to be stored in the pockets or pouches
9 of
the practitioners who administer these
10
medications. In summary, while it
is possible for
11
various products to have clearly marked foil
12
overwraps, as long as the containers themselves are
13
poorly marked there is still potential for
14
confusion.
15
Once the container leaves the foil
16
overwraps, it no longer matters how well labeled
17 the
foil pouch is. This is a concern,
regardless
18 of
the number of vials contained in the foil
19
overwrap. However, a single
container in the foil
20
pouch may minimize the likelihood for the vial to
21
become separated from the overwrap.
22
At this point we would like to stimulate
31
1
ideas for discussion about how to address the
2
issues that have been raised so far.
The remainder
3 of
this presentation will include a series of
4
photos. These images will
highlight various
5
packaging and labeling approaches to consider.
6
Remember to keep in mind who will be using the
7
products and how they will be used.
Our goal is to
8
identify packaging that will resolve our concerns
9 but not introduce any new problems for those
who
10
manufacture or use the products.
11
The paper label approach allows for use of
12
color to distinguish look-alike vials.
For some,
13
these may difficult to read due to the small font
14
size of the text. The reports in
our analysis
15
demonstrated that some people may identify these
16
medications by the color of their label alone.
17
Based on the earlier presentation, we learned of
18 the
potential safety and product quality concerns
19
with this approach for inhalation solutions.
20
Although this packaging no longer appears
21 to
be used for Timoptic, this image illustrates
22
another approach with paper labels.
The paper
32
1
label is applied to the tip of the container. The
2
packaging allows for use of color to differentiate
3 the
containers and dosage strengths.
However, it
4 may
not address the potential for ingress.
5
Again, consider the size of the label and
6 the
potential font size issues which may make the
7
text difficult to read.
8
We have a sample of this also going
9
around.
10 Here is an approach that extends the
tip
11 of
the container to allow for the text to be
12
embossed in the flange instead of the body of the
13
vial. This approach allows for
more space for
14
printed text; however, if both sides are embossed,
15
they tend to interfere with the readability of the
16
text.
17
In contrast, this approach includes an
18
embossed container without an extended flange. In
19
addition, the container is topped with the letter
20
V-shaped tip. In this case, V is
for Ventolin.
21
This approach allows for use of the unique vial
22
shape and possibly texture to help differentiate
33
1 the
product.
2
Another approach used to differentiate the
3
various products in LDPE vials is the use of the
4
embossed letters A, I, and R at the tip of the
5
container. In addition to a
visual cue, the vial
6
makes use of texture to distinguish the products.
7 A
is for Albuterol, I is for Ipatropium, and so on.
8
Again, for some this is difficult to read.
9
One approach that has contributed to
10
medication errors with acetylcysteine is the use of
11 a
glass vial. The packaging has led to
medication
12
errors where practitioners inject the product
13
instead of administering the drug via inhalation
14
because the vials look similar to those that
15
contain an injectable product. According
to the
16 May
30, 2001, ISMP newsletter article, these error
17
occur despite warnings on the label that state "Not
18 for
injection" or "For inhalation."
In addition,
19
they have a target area on the rubber stopper
20
similar to the injectable products.
21
Another approach used to distinguish these
22
products includes the use of a uniquely shaped
34
1
container. Although these round
vials distinguish
2
Pulmicort from other drug products, it is difficult
3 to
differentiate between the two dosage strengths
4 of
Pulmicort once they are removed from the foil.
5 The
image on the right illustrates what the
6
containers look like once the foil overwrap is
7
removed.
8
Some products, such as sodium chloride
9
inhalation solution, utilize a tinted vial as a
10
means of differentiation. This
approach allows for
11 the
use of color to help differentiate the
12
containers from other products.
However, this
13
particular packaging has not been evaluated by CDER
14 at
FDA. These vials also include embossed
text.
15
Another approach is the shrink wrap
16
approach which allows for the combination of
17
embossed information on the end of the vial and the
18 use
of black print on a clear background.
Again,
19 for
some this may be difficult to read. The
20
printed portion of this label clings to the vials
21
without adhesives, eliminating one potential source
22 of
packaging contamination. However, there
are
35
1
still sources of volatile chemicals with the shrink
2 wrap
approach.
3
There's also a sample of this going
4
around. The individual foil
overwrap approach was
5
described in the Draft Guidance that Dr. Sullivan
6
referred to in his presentation.
This method will
7
protect the drug product from contamination from
8 the
environment and minimize the opportunity for
9
contamination from the packaging itself.
10
Each foil overwrap contains a single vial.
11
This is thought to increase the likelihood of the
12
pouch staying with the container and minimize the
13
risk for errors. The overwrap
allows for the use
14 of
color and other means of differentiation to help
15
distinguish these products.
16
At this time we are seeking other ideas
17 and
approaches to consider. What other
materials
18
could we use? What has been done
for other
19
products? What will meet the
needs of those using
20 the
products in both the inpatient and outpatient
21
setting? How should FDA evaluate
any proposed
22
changes?
36
1
Also ask yourself, Will it prevent
2
contamination from secondary packaging in the
3
environment? Will it be difficult
to read? Will
4 it
look like other containers? Will it
create new
5
problems? Will it be difficult to
use? And,
6
finally, should inhalation products be handled
7
separately from products with other routes of
8
administration? We look forward
to hearing your
9
ideas and suggestions.
10
DR. GROSS: Okay. To round out the
11
presentations, Dr. Shah will talk about the
12
perspective for chemistry, manufacturing, and
13
controls.
14 DR. SHAH: Good morning.
My name is
15
Vibhakar Shah, and I'm a chemist in the Office of
16 New
Drug Chemistry for Pulmonary and Allergy Drug
17
Products. Before I start, I would
like to
18
apologize for my delay. I was
stuck in traffic for
19
almost one and a half hours. Let
me tell you, it's
20 not
a pleasant experience. But, in any case,
21
that's life. And I'm sure when we
move to White
22 Oak
it's going to get worse.
37
1
[Laughter.]
2
DR. SHAH: You were supposed to
hear this
3
talk before Marci's talk, but, anyway, here it
4
goes.
5
You already heard from Dr. Sullivan the
6
clinical concerns arising due to the permeability
7 of
LDPE vials, especially when used with paper
8
labels for inhalation drug products, and also you
9
heard some of the medication errors which are
10
caused because of legibility issues with the paper
11
labels. And I'm going to talk
about in the next 20
12
minutes regarding the problems and issues with
13
product quality concerns arising due to the use of
14
LDPE containers, with or without paper labels and
15
with or without overwrap, for these drug products.
16
In the context of today's discussion, my
17
presentation will also focus on how best to
18
minimize the potential medication errors given the
19
quality concerns associated with these container
20
closures.
21
With that, this slide gives you the
22
outline of my talk. I'm going to
start with a
38
1
brief introduction to the type of inhalation drug
2
products that are packaged in LDPE containers, and
3
after that I'll be overviewing the current
4
container-closure systems that are used.
Following
5
that, I would like to discuss the results of an
6
analytical survey conducted by the agency for
7
several inhalation drug products under the Drug
8
Product Quality Surveillance Program.
This survey
9
particularly identified the clinical concerns as
10
well as the quality concerns arising from the drug
11 product
contamination by packaging components
12
because of the permeability of LDPE.
13
Following that, I would like to discuss
14
some of the quality concerns arising with the use
15 of
LDPE vials, with or without paper label and foil
16
overwrap. I will discuss the
agency's current
17
approaches to control and minimize the product
18
contamination from packaging components and discuss
19
current recommendations for packaging of inhalation
20
drug products as provided in the Draft Guidance.
21 And
I will end my presentation with summarizing the
22
quality concerns, what I have discussed so far.
39
1
This slide lists the inhalation dosage
2
forms administered by oral inhalation, and these
3
drug products include inhalation solutions,
4
suspensions, spray, inhalation aerosol, and
5
inhalation powder. However, for
today's
6
discussion, the remainder of the talk will focus on
7
inhalation solutions and suspensions as they are
8 the
only two dosage forms that are packaged in LDPE
9
containers.
10
This slide you have already seen in Dr.
11
Sullivan's presentation. It just
shows the type of
12
drug products which are packaged into LDPE
13
containers.
14
Currently, inhalation solutions and
15
suspensions are packaged in LDPE vials, and there
16 are
three components, basically: LDPE vials,
vial
17
labels, and foil overwrap pouch.
Not all the
18
inhalation solutions and suspensions may have foil
19
overwrap pouch or adhesive paper label.
But in any
20
case, the unit-dose vial--that is, the LDPE
21
vial--is made up of low-density polyethylene by
22
blow-fill-seal or form-fill-seal process. The
40
1
labeling information on a vial is conveyed either
2 by
a self-adhesive printed paper label or by
3
embossing or debossing the labeling information on
4 the
LDPE vial itself during the fabrication of the
5
vial.
6
Foil overwrap acts as a protective
7
secondary package and may contain anywhere from one
8 to
12 vials per pouch. The labeling
information
9 may
be conveyed by a self-adhesive paper label on
10 the
foil overwrap, or the foil overwrap may be
11
printed. Furthermore, different
colors for foil
12
pouches may be used to differentiate the multiple
13
strengths of the drug product.
14
Now, let me go over the container-closure
15
components of the LDPE vial, paper label, and
16
foil-laminate. I'll start the
LDPE vial.
17
The unit-dose vial, which is made up of
18
low-density polyethylene, is chemically a
19
polyethylene homo-polymer resin.
The polyethylene
20
resin is made by polymerization process and may
21
contain several chemical additives in addition to
22 the
reactant polymer. They include chain
transfer
41
1
agent, chain initiator, antioxidant, so on and so
2
forth.
3
Furthermore, it is available in different
4
grades for different applications.
That indicates
5
that the composition of the LDPE may change
6
depending upon how it is being used.
There are
7
many manufacturers and suppliers of this LDPE.
T1B This slide lists some of
the 8
9
characteristics and properties offered by LDPE or
10
LDPE vials which probably makes it a material of
11
choice for packaging of inhalation solution and
12
suspensions from a manufacturer's point of view.
13
These include: they are flexible
and malleable;
14
stress crack, impact, and tear resistant; they are
15
considered chemically inert at room temperature; or
16 it
may be used at elevated temperature for extended
17
periods of time; or it can be sterilized. They are
18
used on high-speed production lines and,
19
aesthetically, they can be clear to translucent in
20
appearance.
21
However, it is permeable to volatile
22
chemicals and gases, and because of this
42
1
permeability, there are several quality concerns
2
which I'll be discussing later in my talk.
3
The next I would like to talk about is the
4
paper label, the components of a self-adhesive
5
paper label and how it may contribute to the
6
quality concerns of inhalation solutions and
7
suspensions.
8
Typically, a paper label consists of a
9
base paper, adhesive, inks, pigments and dyes,
10 varnishes,
over-lacquer, et cetera, and depending
11
upon the application, the base paper may contain or
12 may
be treated with all or many of the chemicals
13
that I have listed here.
14
Adhesive is the layer which comes in
15 immediate contact with the LDPE vial when it
is use
16
with self-adhesive paper labels.
This slide lists
17
typical chemical composition of an adhesive. This
18 is
not an all-inclusive list. There are
many more
19
proprietary chemicals used in the formulation of
20
these adhesives. Depending upon
the physical
21
chemical properties of these chemicals, that is to
22
say, volatility, they may permeate through the LDPE
43
1
vial into the drug product.
2
I have listed here some of the
3
over-lacquer components.
Over-lacquer is an
4
evaporative(?) coating which is typically comprised
5 of
chemicals such as plasticizers, resins, (?)
6
solvents, diluents, surfactants, and many more.
7
Some of these chemicals are proprietary in nature.
8
Over-lacquer, or varnish, may be used for a
9
transparent glassy appearance of the label, also a
10
stabilizer for the print work and art work, or it
11 can
be used as a protective barrier to the moisture
12 and
overall to extend the longevity of the label.
13
Again, in this case also, depending upon the
14
physical chemical properties of some of these
15 chemicals
and their constituents, also the
16
concentration and storage conditions, these
17
chemicals may have a potential to permeate through
18 the
LDPE vials into the drug product.
19
These are typical ink components.
One may
20
think that ink might be just a single-component
21
formulation. However, if you look
at it, there is
22
more than one chemical included into the ink
44
1
formulation. And, again, these
are also propriety
2
formulations.
3
These ink formulations may be
(?)-based
4 or
organic solvent-based, and depending upon the
5
brand of solvents which are used in the
6
formulation, they may have a potential to permeate
7
through the LDPE vials into the drug product.
8
The last I would like to talk about is the
9
foil-laminate. Primarily,
foil-laminate is used as
10 a
protective secondary packaging for the drug
11 formulations
that may be sensitive to light and
12
react to gases such as oxygen.
13
Typically, foil-laminate is a flexible
14
packaging composed of multiple layers of various
15
types of plastic films which are fused together
16 either by heat or pressure-sensitive adhesives
17
applied to one or both sides of an aluminum foil.
18 In
this cartoon, aluminum foil is represented by
19
layer D, and as you can see, the whole foil
20
overwrap surrounds the drug product vial on an
21
automated packaging line.
22
The thickness of aluminum foil, which is
45
1 D,
and the number of pinholes per unit area are
2
crucial for ensuring the consistent barrier to
3
permeability. Furthermore, each
of the composite
4
layers may contain volatility chemicals, organic
5
solvents, as they are used in adhesives, which may
6
permeate through a LDPE vial into the drug product,
7 especially the adhesive layer that is closer
to the
8
drug product. In this case, that
is shown by G.
9 So
the composition of these are very critical.
One
10 has
to really have a knowledge of its composition
11
before they can be selected for the foil overwrap.
12
Alternate approaches to adhesive can be considered,
13
such as fusion of the multiple layers of
14
foil-laminate by heat-set process.
15
In addition to the clinical concerns
16
discussed by Dr. Sullivan, the permeability of LDPE
17
raises several quality concerns, and these are
18
listed on this slide, mainly the drug product
19
contamination through ingress of volatile chemicals
20
which may be originating from the environment that
21 may
be irritant or toxic to the respiratory tract
22 and
may sensitize individuals; drug product
46
1
degradation because of the reactive gases and light
2
that permeate through the LDPE vial and cause
3
degradation of the drug product; and change in
4
product concentration because of the water
5
evaporation through the LDPE vials.
This in turn
6 can
accelerate the drug product degradation because
7 of
the concentration of the drug product.
8
Now, let me share with you the results of
9 an
analytical survey of approved NDA and ANDA
10
inhalation solutions marketed in LDPE vials without
11
protective overwrap. The basis
for this survey was
12 a
large-scale voluntary recall of inhalation
13
solution by a firm due to contamination of the drug
14
product with 1-phenoxypropanol.
This is a known
15
component present in the packaging components.
16 This
recall was conducted with FDA's knowledge and
17
followed by a health hazard evaluation.
It was
18
later found out that the source of this chemical
19 was
the varnish or over-lacquer that was used for a
20
shelf carton.
21
Alarmed by this incident, the
agency was
22
concerned that there may be other inhalation drug
47
1
products with such contamination from packaging
2
components. As a result, it was
decided to conduct
3 a
product quality survey of some of the marketed
4
inhalation solutions.
5
This was initiated by the Office of
6
Generic Drugs in consultation with the Division of
7
Pulmonary and Allergy Drug Products and in
8
coordination with the Office of Compliance, Office
9 of
Regulatory Affairs, field offices, and Pacific
10
Regional Laboratory. Seven ANDAs
and one NDA for
11
inhalation solutions covering five different drug
12 substances
were selected.
13
There were 38 samples representing 37 lots
14 of
various drug products in LDPE vials without a
15
protective overwrap foil pouch.
The samples were
16
screened for potential volatile chemicals which are
17
known to be present in the packaging components,
18
such as vanillin, 2-phenoxyethanol, and
19
1-phenoxy-2-propanol by sensitive analytical
20
techniques such as GCMS and HPLC methods. Let me
21
share the results of this survey.
22
Twenty-nine out of 38 samples tested
48
1
positive for chemical contamination originating
2
from packaging components. Five
known chemical
3
contaminants, as listed below, were detected
4
originating from packaging, such as benzophenone,
5
polyethylene glycol, 2-(2-butoxyethoxy)ethanol,
6
2-(2-ethoxyethoxy) ethanol acetate, and
7
2-hydroxy-2-methylpropriophenone.
8
A health hazard evaluation was conducted
9 at
the levels these components were detected in
10
these drug products. However, it
was indicated
11
that the levels of these components did not raise
12
sufficient safety concern in the intended
13
population to warrant a recall of these drug
14
products. Nonetheless, the
following issues were
15 of
concern:
16
It was indicated that potential for these
17
chemicals to cause bronchospasm at levels detected
18 is
unknown, especially in patients with respiratory
19
diseases.
20
It was also indicated that concentration
21 of
these chemicals might be grater at the end of
22
expiry than what was detected at the time they were
49
1
tested.
2
It also showed that permeation through
3
LDPE vial is a real phenomenon.
4
It was also concluded that additional
5
chemicals may be present, but may not get detected
6
because the analytical techniques which were used
7 may
not be suitable, not knowing what components
8
might be present into those solutions.
9
And, also, future changes in the materials
10
used in labeling and packaging may result in
11
contamination with different chemicals.
12
So, in a nutshell, product contamination
13 can
occur because of the formulation component
14
degradation or by leaching of chemical constituents
15
from packaging components, such as resin components
16 I
have listed, paper label components, foil
17
overwrap components, cartons, and environment.
18
These are the typical extractable or
19
leachable components which have been found in the
20
drug product from packaging components.
Some of
21
them are irganox 129, 2, 2, 6-trimethyloctane,
22
which is coming from resin components.
Some of the
50
1
paper label components that we have seen is benzoic
2
acid, ethyl phthalate, benzophenone, danocur 1173,
3
cyclic phthalates. From the foil
overwrap, we have
4
seen methacrylic acid, 2-phenoxyethanol, and some
5 of
the organic solvents such as acetone,
6
2-butanone, ethylacetate, propylacetate, heptane,
7 and
toluene. And from cartons, methacrylic
acid
8 and
1-phenoxy-2-propanol.
9
So this raises a significant quality
10
concern, and there are several other factors.
11
These are the factors. Because of
the proprietary
12
nature of components and composition of this
13
packaging material, we may not know what is present
14 in
the solution. The composition of these
15
components which are present in the packaging may
16
change without the knowledge of applicant and the
17
agency. And you cannot detect if
you don't know
18
what you are looking for. As a
result, there is no
19 one
analytical procedure to detect unknown chemical
20
contaminants. And there is
incomplete
21
toxicological data or information available for
22
many of these identified chemical contaminants.
51
1 And
as the environmental conditions change, that
2 may
introduce new contaminants.
3
So what are the potential approaches the
4
agency has taken to minimize and control the
5
contamination from packaging components to the
6
extent possible? Our approach has
been and we have
7
recommended that characterize or identify all
8
possible extractables and establish a profile for
9
each packaging component, for resin, vial, paper
10
label, foil-laminate overwrap.
11
What I mean by extractable is
extractable
12 is
a chemical compound, which can be volatile or
13
non-volatile, that gets extracted from a packaging
14
component in a suitable solvent by utilizing
15
optimum extraction conditions, such as time and
16
temperature.
17
Extractable profile for a given packaging
18
component typically can be a chromatogram
19
representing all possible extractables.
20
After that, establish a correlation
21
between extractable and its leachable potential,
22 and
what I mean by leachable is leachable is any
52
1
chemical compound that leaches into the drug
2
product formulation either from a packaging
3
component or a local environment on storage through
4
expiry of the drug product. An
extractable can be
5 a
leachable.
6
And to ensure batch-to-batch consistency
7 of
the drug product, appropriate specification for
8 a
leachable is established based on its
9
qualification and observed levels in the drug
10
product on storage.
11
As a result, the next approach is we asked
12
them to set meaningful acceptance criteria for a
13 given
extractable in corresponding incoming
14
packaging components based on its qualification
15
level and actual observed data.
Once that is
16
accomplished, meaningful acceptance criteria for a
17
given leachable based on actual observed data in
18 the
drug product also be established.
19
These are the recommendations we have
20
provided in the Draft Guidance.
We have
21
recommended that adequate knowledge of composition
22 and
physico-chemical properties of packaging
53
1
components is essential for appropriate selection
2 of
these components. We discourage paper
label
3
directly on the LDPE vial and encourage alternative
4
approaches, including embossing or debossing, in
5
lieu of the paper label on the LDPE vial because of
6 the
reasons I discussed, because of the product
7
contamination. This can be
accomplished by
8
extended bottom flanges to unit-dose vial that can
9
carry essential vial labeling information and can
10
retain the product identity.
11
We have also recommended use of protective
12
overwrap foil pouch for the LDPE unit-dose vial.
13
This in turn can minimize the ingress and leaching
14 of
chemical contaminants from the local environment
15
provided that the components that have been
16
selected for the fabrication of the overwrap foil
17
pouch are appropriately selected.
18
The self-adhesive paper label on a foil
19
pouch or pre-printed foil pouch is also
20
recommended, and different color schemes to
21
differentiate multiple strengths of the drug
22
product is also recommended. This
in turn can
54
1
prevent ingress or leaching of chemical
2
contaminants from paper labels and may improve the
3
legibility issues.
4
The last recommendation we have in our
5
Draft Guidance is to limit the number of unit-dose
6
vials per pouch, ideally to one LDPE vial per foil
7
pouch. This can minimize the risk
of medication
8
error by patients and health care professionals,
9 and
it can prevent unnecessary exposure to local
10
environment when compared to packaging of
11
multi-unit-dose vials in a foil pouch.
12
So, in summary, so far I have presented to
13 you
that volatile chemicals present in the
14
packaging components and local environment have a
15
great potential to permeate through LDPE vials into
16
drug product formulation on storage.
The agency's
17
analytical survey and other supportive data have
18
confirmed ingress and leaching of such volatile
19 chemicals into the drug product formulations.
20
Ingress or leaching of such chemicals into
21
drug product formulation poses a safety concern for
22
patients with respiratory illnesses, such as asthma
55
1 and
COPD. Embossing or debossing of LDPE
vial in
2
lieu of paper label is recognized to have
3
legibility issue. However, paper
labels, although
4
perceived to address legibility issue, overall may
5 not
be the optimum solution because of the safety
6
concerns associated with potential leaching and
7
ingress of paper label components in the drug
8
product through LDPE vial.
9
The agency's current recommendations as
10
stated in the Draft Guidance may serve as a first
11
step in the right direction to address the issues
12
that are being discussed today.
And the agency is
13
seeking other viable approaches to address these
14
issues to promote safe product use without
15
compromising the integrity of the drug product.
16
With that, I will conclude my talk, and
17
thank you for your attention.
18
DR. GROSS: Thank you very much,
Dr. Shah,
19 and
I want to thank the first three speakers who
20
presented a very clear review of the problem.
21
We are now open for discussion.
Perhaps
22
I'll start off with a couple questions.
56
1
We talk about low-density polyethylene.
2
Does high-density polyethylene reduce transmission,
3
number one? Number two, would
increasing the
4
thickness of the container reduce transmission?
5
And, number three, have other plastics been
6
considered? I'm not a chemist so
I don't know, but
7
polypropylene, polystyrene? And
are any of those
8
possibilities?
9
DR. SHAH: So far, traditionally,
LDPE is
10 the
choice of material by the manufacturer because
11 of
some of the properties it can offer. And
I
12
guess one can increase the thickness of the LDPE
13
vial or may use a different polymer.
However, one
14 has
to keep in mind that by nature, when you do the
15
fabrication of the vials, it may have some kind of
16 a
permeability. But that depends on the
degree of
17
permeability. LDPE offers one
side of the
18
spectrum, or other polymers may offer a different
19
type of permeability. But one has
to conduct some
20 of
the studies to show that it does not permeate.
21
DR. GROSS: Michael?
22
DR. COHEN: Dr. Lee mentioned
shrink wrap
57
1 at
one point, and then added that there might still
2 be
some concern about, you know, the volatility, I
3
guess, of the inks in the shrink wrap itself. It
4
does not come in contact with the actual LDPE
5
plastic, though, so I'm trying to figure out why
6
that would be a concern. Do you
think it's still
7
possible for that to leach in?
8
DR. SHAH: Yes, let me answer
that.
9
Shrink wrap, again, it's a plastic and it suffers
10
through the same thing. It comes
in direct contact
11
with the LDPE vial. So depending
upon the chemical
12
components of the ink and how it is being used, in
13 a
shelf carton or anything, it still will have the
14
same unit problems that I discussed.
15
DR. COHEN: Can I ask a follow-up?
16
DR. GROSS: Yes, go ahead,
Michael.
17
DR. COHEN: Have you done
testing--
18
DR. SHAH: No, we--I mean, we have
not
19
even received--or we have not approved a drug
20
product with the shrink wrap.
There is no example
21 of
that, at least to CDER. Maybe in other
22
divisions, another agency, but we haven't received
58
1
any.
2 DR. GROSS: Jackie, next question?
3
DR. GARDNER: I understand the
problem of
4
potentially masking the effect of contamination by
5 the
condition, but I was surprised to see only 87
6
reports of medication errors that you're working
7
from. And given the excellent
presentation and the
8
potential for confusion, I'm surprised that there
9
were so few because it looks like it would happen a
10
lot. I wondered if we could have
some perspective
11 on
why there would be so few, and maybe Mike can
12
help with that.
13
And then the second thing is I wondered
14
whether any of the potential suggested
15
recommendations or the different packaging types
16
have been tested in any way that we could
17
reasonably expect that they might reduce the
18
potential for error if they were implemented,
19
whether the foil wrap or any of these things have
20
been tested among the people who would be using
21
them.
22
DR. GROSS: Next question, Leslie?
59
1
Does anybody have an answer?
Marci?
2
DR. LEE: Thank you. As to the number of
3
reports being few, since the review was done, there
4
have been additional reports submitted to the
5
agency for a total, I think I said, of 138 reports,
6
which may still sound like a small number, but
7
considering the problem is probably very underreported. We
8
also had some reports that were
9
describing errors that had to do with restocking.
10 For
example, a transport team's pouch was supposed
11 to
contain three Albuterol and three Ipatropium
12
vials, and at this one given time it contained one
13
vial of one drug and five of the other.
So, you
14
know, in the report the narrative says, "We suspect
15
that at least one patient has been affected by this
16
problem."
17
The same thing can happen in an inpatient
18
setting where the drugs are getting intermixed in a
19
bin. So it's really an unknown,
the actual impact
20 of
the problem.
21
DR. GROSS: Leslie?
22
DR. HENDELES: I'd like to just
respond to
60
1
Jackie's comment. Mixing these
medicines up is
2
very unlikely to be associated with a visible toxic
3
reaction, so that might be--if anything, the
4
adverse consequences is a lack of therapeutic
5
effect when you're treating a disease that's
6
involving acute bronchospasm. So
the clinician
7
can't distinguish between lack of drug effect from
8
worsening of the disease.
9
But the question I had was: Is
there any
10
evidence that these contaminants in any way
11
interact with the active drugs to either decrease
12
their stability or to in some way inactivate them?
13
DR. SHAH: They may not
inactivate, but
14
they will increase the degradation of the products.
15
They may react with the active, and then you will
16
form an adduct. But you are not
going to, you
17
know, inactivate the drug product.
18
DR. SULLIVAN: The other thing t
keep in
19
mind is that the list of potential contaminants is
20
innumerable. So what may be true
of one chemical
21 may
not be true of the others.
22
DR. GROSS: Curt Furberg?
61
1
DR. FURBERG: I'd like to expand
on that
2
question. What are the health
effects of these
3
contaminants? Are they all
toxants? And if we
4
don't know that these contaminants have adverse
5 health
effects, is this a big issue?
6
DR. SULLIVAN: Well, I think the
unknown
7 is
part of the problem, and being a clinician at
8 the
agency, we've been tasked with addressing the
9
specific risk of specific chemicals that have been
10
found in assays done, particularly--it was
11
discussed in the analytical survey and so forth.
12 So
we get asked this question: What's the
13
toxicologic potential of this chemical?
And we
14
don't know most of the time.
There haven't been
15
toxicologic studies done. We
don't know the
16
carcinogenic potential. We don't
know the extent
17 to
which it acts as an irritant or has other toxic
18
effects. And then we have to
judge, okay, what's
19 the
risk out there, and it's very difficult.
20
DR. FURBERG: Yes, but shouldn't
you add
21
that to your recommendation that we find out?
22
DR. SULLIVAN: Well, I think
that's part
62
1 of
why we're saying it's best to just try to limit
2
potential exposure, because you can't list all of
3
these chemicals. For instance,
the one that was
4
mentioned was found in a drug product, and it was
5
traced back to the fact that the actual carton that
6
these vials were contained in, the manufacturer of
7
that carton, who isn't the drug manufacturer,
8
changed the glue or lacquer in that carton. And so
9 a
chemical that we wouldn't have previously been
10
aware of made its way into the drug.
11
DR. SHAH: Again, the agency does
not
12
control the cartons. We will
control to a point
13 and
look into the things. The carton is
something
14
very--and as a result, I think our approach has
15
been--or we recommend the use of overwrap pouch.
16
That can also limit to a certain extent.
I mean,
17
there is no 100-percent guarantee that it may not
18
permeate or the glues which are used in the
19
foil-laminate itself may get into the drug product.
20
But one needs to study these things
21
before, you know, providing to the agency.
22
DR. GROSS: Okay. Henri, and then we'll
63
1
hold questions after that until later.
2
DR. MANASSE: I have a couple of
3
questions. One is: Do we see the impact of the
4
degradation on all of the active ingredients, that
5 is,
for the Albuterol and the Tobramycin and the
6
cromolyn? Is that pretty much
standard across all
7 of
the ingredients that these volatile substances
8 do
have a degrading impact?
9
The other question I had is: What
10 experiences
can we gain from either the food and/or
11 the
cosmetic industry? Are there experiences
there
12
since so much of this packaging is also with
13
low-density polyethylene containers?
14
And my last question relates to the
15
potential application of the bar code to packages
16
vis-a-vis the incoming rule. To
what extent will
17
symbology printing either exacerbate or lessen this
18
particular issue?
19
DR. SHAH: I kind of lost
you. What was
20 the
first question?
21
DR. MANASSE: The first question,
Is the
22
infusion, leaching of the contaminants equally
64
1
impactful on all the active ingredients in these
2
products?
3
DR. SHAH: I think some of these
will stay
4 as
a degradation product. They may not
impact the
5
active ingredient, but it will be just a product
6
contamination.
7
Now, itself, how it will affect the
8
particular patient population, that is--as Dr.
9
Sullivan said, we don't know the potential of that.
10 So
it may not probably reduce the concentration of
11 the
active into the drug product. However,
that
12 uncertainty
regarding the safety is a concern.
13
The second question was?
14
DR. MANASSE: The second question
relating
15 to
experiences in the food and cosmetic industry
16 and
what may be learned there.
17
DR. SHAH: Okay.
I think by far the
18
most--these packaging components are used also in
19
tablets and other solid oral dosage forms. There
20 the
risk is less because you are taking it orally.
21
Here the problem is because of the patient
22
population, we are more concerned.
And I don't
65
1
know what else can be learned from food and other
2
industries because there is--I don't know that much
3 scrutiny
is there. The only thing that is there
is
4
whether they are adequate in terms of oral dosage
5
use. That's it.
6
Does that answer--
7
DR. MANASSE: And my last question
related
8 to
the upcoming application of the bar coding rule
9 and
the imprinting of symbologies to implement that
10
particular rule.
11
DR. LEE: Actually, LDPE vials was
one of
12 the
products that was exempt from that rule.
It
13
won't be required down to the vial, but any outer
14
packaging it will be on.
15
DR. GROSS: Okay. We'll take a break now
16 and
reconvene at 9:45.
17
[Recess.]
T2A DR. GROSS: The first speaker will be
18
19
Mohammad Sadeghi, who will talk about container
20
labeling options using rommelag blow-fill-seal
21
technology.
22
DR. SADEGHI: Good morning. I'm Mohammad
66
1
Sadeghi with Holopack International.
I'm here to
2
talk about container labeling options using
3
blow-fill-seal technology, and most of all these
4
products you've been hearing today about and
5
packaging and LDPE, low-density polyethylene,
6
they're all manufactured using blow-fill-seal
7
technology.
8
So what I'm going to do is go over what
9 the
blow-fill-seal process is, what container
10
labeling options you have, what are the pros and
11
cons on each, and some examples.
12
Blow-fill-seal technology is an integrated
13
aseptic technology for manufacturing aseptic
14
products. That's an example of a
machine. The way
15 it
works is you feed in raw pellet resins from one
16 end
and the (?) solution from another, and the
17
machine will actually melt the pellet, created the
18
container, fill it aseptically, and seal it.
19
The process consists of four major steps.
20 As
you see, the plastic is molten first and
21
extruded in a cylindrical shape, and the molds are
22
formed into the container, the needle comes in, and
67
1
there is the Class 100 in this
(?) area, fills
2 the
container, and it withdraws, and then the
3
container is sealed and ejected from the machine.
4
Now, labeling options that you can have
5
with this technology consist of embossing, paper
6
label on tab if you do not want to put it directly
7 on
the container, or printing on the tabs.
8
Embossing consists of a mirror--engraving
9
mold with a mirror image of the information. You
10
have small vacuum ports on the mold surface that
11
actually will do this, such into the softened
12
plastic into the engraving embossing, hence
13
embossing the container.
14
This is an example of what a mold cavity
15
looks like, and you see the surface inside the main
16
cavity where the engraving takes place.
17
This is a close-up of what it's like to
18
have as the imprint. What you see
in the bottom
19
would be replaceable magazines that you can change
20 for
lot number and expiration date.
21
Another option of embossing is hot stamp,
22
which in this case instead of molding it during the
68
1
production, as the container is ejected from the
2 BFS
machine, it's actually put into a machine where
3 it
actually is a hot stamp that would actually
4
emboss the container, again, and this is done on
5 the
tabs and not directly on the body of the
6
container.
7
Paper labels on tabs, one of the
reasons
8
this container was developed was to avoid direct
9
contact labels with--paper labels with the actual
10
container body, and the secondary was the
11
small-volume containers that required information
12 and
there was not enough surface area to put the
13
engraving on the container. They
developed a tab.
14
Either it can be on the cap or as a tail, have the
15
embossed information.
16
You can use the same tab, actually,
17
instead of--it's a solid surface, so you can use it
18
either to print or add paper to the label.
19
The pros and cons of each labeling option:
20
Embossing has been discussed here.
The pros are
21
there is no maintenance of label inventories;
22
ensure 100-percent labeling of containers; labels
69
1
cannot be removed; and ensure each unit is
2
traceable and no leachables. The
cons are, which
3 has
been discussed also, it is difficult to read on
4
clear containers.
5
Paper label on tabs is--paper label
6
obviously makes it clearer to read, and you can use
7
colors. It greatly reduces
potential leaching into
8 the
solution because it's not directly applied to
9 the
container body. However, there is still
10
potential leaching of adhesive.
11
Direct printing on the tab, it's clearer
12
than embossing on the tab to be read; it eliminates
13
potential leaching from paper, adhesive, varnish
14 and
stuff that goes with the paper label; and it
15
greatly reduces potential leaching into the
16
solution, again, because it's on the tab, on a
17
separate space on the container, not directly on
18 the
container body; and, lastly, allows for bar
19
code printing on line as well.
However, you still
20
have the ink, which potentially can leach into the
21
solution.
22
Now, examples of these various things,
70
1
there's a container with embossed labeling. The
2
containers can be also embossed and color-coded
3
because the same container can be used for
4 different
concentrations of products, or you can
5
have color-coded and embossed to represent the same
6
product in different concentrations or doses.
7
You can apply the paper on the tab, both
8
removing the paper from direct exposure to the
9
solution, but also it is readable.
Or having
10
direct printing on the tab for bar code
11
information.
12
Also, you have traditional paper on the
13
container, which is...
14
Now, the other thing is the issue of--one
15 of
the things that comes to mind is the size of the
16
containers, is eliminating paper containers--paper
17
labels from all outside containers or is it
18
dependent--it is a size-dependent solution.
19
Obviously, if you have a liter container such as
20
viewed here and you have a paper label, is that
21
also going to be--it's something that has to be
22
removed, and considered this is--it should be in
71
1
relation to the size of the container.
If it is a
2
three- (?) container, you have the same treatment
3 as
one-liter container.
4
Another example of various container
5
sizes.
6
Thank you.
7
DR. GROSS: Okay. Now we'll hear from the
8
Cardinal Health team, Rick Schindewolf and Patrick
9
Poisson.
x MR. POISSON: Good morning.
My name is
10
11
Patrick Poisson. I'm the Director
of Technical
12
Services at Cardinal Health Woodstock.
With me
13
today is Mr. Rick Schindewolf, who's the general
14
manager of the Woodstock, Illinois, facility.
15
Just a little bit about our role in the
16 industry.
Cardinal is a diversified health care
17
company with operations in distribution, manufacturing,
18
research, and management solutions.
The
19
Cardinal Health Woodstock facility is a
20
blow-fill-seal facility that produces approximately
21 1
billion units annually. Our product
portfolio
22
involves NDA, ANDA, 510(k), and USP Monograph
72
1
products.
2
Some of the advantages of why people
3
select low-density polyethylene in blow-fill-seal
4 is
blow-fill-seal is recognized as an advanced
5
aseptic process. There's also an
immense
6
flexibility in container design that allows various
7
applications of the container and its use. It's
8
also a very cost-effective approach to producing
9
pharmaceutical products.
10
Now, some of the limitations: As
11
previously mentioned, LDPE is a semipermeable
12
material. The technology also uses
heat to form
13 the
container, and there may be issues with
14
heat-sensitive products. And
based on the focus of
15
this meeting today, there are obviously some
16
labeling issues as well.
17
Now, the general industry approach has
18
been to emboss and deboss the containers to display
19 the
necessary information, which includes product
20
name, concentration, manufacturer, lot number, et
21
cetera. Typically, respiratory
products are
22
packaged in a secondary overwrap in multiple units
73
1 or
single units, and that provides the additional
2
protection necessary to prevent chemical
3
contamination.
4
This has already been touched upon, but
5
these are the main highlights of the Draft
6
Guidance, and I won't spend any time on this since
7
this has been discussed already.
8
Now, what are some of the advantages to
9 the
embossing/debossing approach? It
provides an
10
immediate tamper-evident identification of the
11
product. It eliminates the
potential for
12
contamination from labels. And it
provides ease of
13
label copy control.
14
Some of the limitations associated with
15
that: It can be difficult to read
on clear
16
containers. It does not provide a
very readily bar
17
code-readable print. And the vial
size affects
18
legibility of the print that's embossed and
19 debossed. We cannot emboss or deboss down to a
20
very small font size that's readable that could
21
compete with a paper label.
22
Now, we believe there are some
74
1
possibilities for enhancing product identification
2 in
the low-density polyethylene container, and
3
these are listed here: reduce the
content
4
requirement to allow an increased text size;
5
addition of physical/tactile identifiers for
6
generic product groups; alternative label
7
approaches such as a sleeve label; color coding
8
unit-dose vials for generic product groups; and
9
individual secondary overwrap.
10
Increased text size. There's a limited
11
surface area on the container that is available for
12
embossing/debossing. Due to the
technology, we
13
cannot emboss or deboss on the sides of the vial.
14 We
can only emboss and deboss on the front.
The
15
text size can be significantly increased; however,
16 we
would have to remove some of the information
17
that's normally provided. This
approach would not
18
change any of the materials involved in the
19
process, so there would be no impact on the current
20
product chemistry. This could
also be implemented
21
fairly quickly, eight to ten weeks.
And there
22
would be a one-time cost for the manufacturer to
75
1 buy
the appropriate equipment.
2
This is a drawing of what that concept
3
would look like.
4
In addition to that, physical/tactile
5
identifiers could be added to the container. This
6
would provide an easily recognizable/legible symbol
7 on
the container that would represent a product
8
type, for instance, A for Albuterol sulfate, I for
9
Ipatropium bromide, et cetera.
This is already
10
currently being implemented on products
11
manufactured at Cardinal Health.
This also does
12 not
change any of the container materials or
13
process, so, again, no impact on the current
14
product chemistry. This also
could be implemented
15 in
eight to ten weeks, depending on the regulatory
16
approval of this label change, possibly as a CBE
17
30. Again, there would be a
one-time minimal cost
18 to
buy the necessary equipment to do such a change.
19
This is a drawing of what that concept
20
could look like. And we have some
samples which
21
we'll pass around for the committee to see. And
22
those can also be provided in clear plastic. And
76
1
here are some photos of the same vials.
2
This is a picture contrasted with one of
3 the
current formats that is out on the market, so
4 you
can see that there's a definite increase in the
5
identification of the products resulting from this
6
type of change.
7
The sleeve label concept would involve a
8
redesign of the extended tab to make that area
9
amenable for application of a non-paper label.
10
Cardinal has designed such a vial that has a patent
11
pending that would be capable of receiving a shrink
12
wrap sleeve.
13
This label provides a contrasted
14
background for enhanced legibility and also provide
15 a
bar code-readable print. This would
involve no
16
changes to the product contacting surfaces of the
17
container. The shrink of pressure
sensitive label
18
would be applied to an appendage of the container,
19 not
in direct contact with the product.
20
This would also involve an increased
21
manufacturing cost for equipment, labor, and
22
materials, and we believe it could be implemented
77
1 in
12 to 14 months following regulatory approval
2
with associated stability testing data.
3
This is a picture of what that concept
4
looks like, and we have some samples that we'll
5
pass around. This particular
product was mentioned
6 in
an earlier presentation as the catheter flush
7
saline and heparin.
8
Color coding. Products could be
9
color-coded to aid in identification.
That would
10 be
a similar approach to the AAO recommendations
11 for
cap color for ophthalmic products. It
provides
12 a
contrasting background to aid the legibility.
A
13
colored vial is easier to read.
However, it could
14
impact the product chemistry with leachables and
15
extractables. There would be a
slight increase in
16
manufacturing costs for raw materials.
Again,
17 implementation
time would be based on stability
18
data and regulatory approval of such a change.
19
This is a picture of what that concept
20
would look like.
21
Individual secondary overwrap, that has
22
been touched upon. It provides
enhanced labeling
78
1
opportunities, bar code-readable print for a
2
single-dose vial. However, the
overwrap can and
3
will be separated from that unit at some point in
4
time during its use, and we don't control that, so
5 we
cannot predict when that will happen. So
there
6
could be legibility/identification issues still at
7 the
time of use. There's a significant
8
manufacturing cost increase with the raw materials,
9
equipment necessary, and labor.
If that was done
10
with the current process, that change, the
11
implementation time would be 12 to 14 months
12
following regulatory approval of the packaging
13
change with associated stability data.
14
In summary, we believe there are
15
opportunities for improvement of the labeling of
16
low-density polyethylene containers.
Each
17
alternative is a viable alternative, we believe,
18 and
it should be assessed based on impact to the
19
product, speed of implementation, ease of
20
regulatory approval, and cost to the patient.
21
Thank you--oh, sorry. Our
recommendations
22 are
to increase label information font size on
79
1
individual vials. Add a tactile
symbol for generic
2
identification based on the following advantages:
3
quick approach, no impact on product chemistry or
4
stability, and no impact on patient cost. For
5
hospital-dispensed unit-dose vials, add a sleeve
6
label to accommodate bar coding.
7
Thank you.
8
DR. GROSS: Thank you very much.
9
Our next speaker is Karen Stewart of the
10
American Association of Respiratory Care.
x MS. STEWART: Good morning.
Thank you for
11
12
giving me the opportunity to present today. I
13
think in your packets you have my written
14
statement, and I have a couple of slides here that
15 I
want to share with you.
16
I've been a registered respiratory
17
therapist since 1971, and I am here as the
18
spokesperson for the American Association for
19
Respiratory Care representing respiratory
20
therapists both nationwide and internationally.
21
Respiratory therapists, like all other
22
health care professionals, are very concerned about
80
1
medication errors. In recent
years, since the
2
elimination of most paper labels on unit-dose vials
3 of
medication, it has become increasingly difficult
4 to
determine the content of the unit-dose vial.
5 I'm
going to share with you some pictures of what
6 the
therapist typically has on their person as
7
they're making rounds.
8
Not only is the print on the vial
9
difficult to read, the size and the shape of the
10
vial contributes to this difficulty.
11
In 2001, the American Association for
12
Respiratory Care completed a human resource survey,
13 and
at that time the average age of a respiratory
14
therapist was 44. This is another
contributing
15
factor to the difficulty of reading the content of
16 the
medication vial. While I may have just
17
emphasized that the current relative age of the
18
respiratory therapist and the difficulty the older
19
therapist experiences in reading the labels, I want
20 to
clarify to you that deciphering respiratory care
21
medication labels is a problem that cuts across all
22 age
groups of respiratory therapists. The
problem
81
1 is
how the medication is labeled or not labeled
2
appropriately.
3
The work flow of the respiratory therapist
4 I
think is probably most important for you to
5
understand. The therapist
typically includes
6
delivering medications and treatments to a number
7 of
patients for a local geographic region in a
8
hospital. The patients that are
assigned have a
9
very wide variety of medications that are being
10
delivered to them. Once the
medication is checked
11 by
the pharmacist for drug interactions, the
12
therapist typically carries medication with them as
13
they begin rounds. It would not
be unusual for a
14
therapist to carry between 14 and 15 different
15
vials of medication. The
medications must be under
16
control so that therapists either carry the
17
medication in a fanny pack or they carry the
18
medication in a locked draw on a cart they carry
19
with them.
20 In some institutions, medications are
in a
21
Pyxsis system. In this situation,
the medication
22 can
either be placed in a single patient medication
82
1
labeled drawer or they come from stock supply. So,
2
again, multiple vials in a stock drawer.
3
I just wanted to give you a view of what's
4 in
somebody's pocket typically.
5
Another concern that faces the respiratory
6 therapist
is the lack of bar coding on the vial.
7
Many hospitals are moving toward the scanning of
8
medication bar codes. The driving
force for this
9 use
of technology is to identify the correct
10
patient, identify the correct medication, confirm
11 the
correct dose of medication, confirm the correct
12
route of medication, and record the time of the
13
medication delivery.
14
I want to share with you a few comments
15
that I picked up from some respiratory therapists
16 in
just the most recent weeks.
17
Staff have complained about the inability
18 to
see clearly the medication information.
For
19
this reason, we switched to a different product
20
that is individually wrapped in clearly labeled,
21
color-coded foil packaging. The
current situation
22
with the raised-letter labeling is an accident
83
1
waiting to happen. I know you
talked earlier about
2
underreporting. It's because
we've given the dose
3 and
never know we gave the wrong one in some cases.
4
This is a second therapist: I
complained
5
bitterly when the look-alike vials came out. We
6 did
not leave them for any nurses to confuse.
We
7 do
not know of any medication errors beck of the
8
look-alikes. Doesn't mean it
didn't happen. We
9
just don't know.
10
So, again, a little bit more emphasis on
11 the
fact that we are seeing probably underreporting.
12
This is a third one: We have had
problems
13
with the unit-doze Xopenex and Atrovent looking
14
alike and labeled in the same clear package. We
15 use
Pyxsis and it's still a problem.
16 So even moving the medication into
a more
17
controlled environment continues to be a problem
18 for
the therapist who's on the floor.
19
This is a fourth therapist: One
20
encouraging thing that I have seen is differing
21
shapes and sizes on a very few of the medications.
84
1
Since the death of the multi-dose vial of
2
Albuterol, we have a supplier who sends us
3
unit-dose vials of Albuterol that have a very
4
distinctive teardrop shape and a
much smaller size
5 for
medication. I give that a Bravo. A similar
6
thing has happened with the octagonal unit-dose
7
vials of Pulmicort.
8
And I think if you look at the very end of
9
this, that small round is the Pulmicort.
But this
10 is
what's in the pocket of the therapist, and all
11
they have to read on most of those are just that
12
clear lettering.
13
I was at a program, I did a program in
14
Cincinnati last week, and I mentioned this in a
15
patient safety presentation that I did to
16
therapists. About 600 were there,
and what was
17
interesting about it is several of them came up to
18 me
afterward and said, Can you imagine what the
19
night shift therapist goes through trying to read
20
these?
21
Now, low light--it's bad enough, you know,
22
with the age, but the low light.
85
1
There's a couple more comments from
2
therapists in there. I think that
you've probably
3 got
those. You get the gist of what we're
trying
4 to
say. So on behalf of the American
Association
5 of
Respiratory Care, I really appreciate the
6
opportunity to share the association comments.
7
I have one more slide that I want to share
8
with you, and it's this one. What
you're seeing
9
here are just the different medications.
One of
10
those happens to be Tobramycin.
One of them--two
11 of
them are bronchodilators. Two of them
are
12
exactly the same medication in different doses.
13
Just to really emphasize what the packaging is
14
doing to the therapist at the bedside.
15
Thank you.
x DR. GROSS: Okay.
Thank you very much.
16
17 We
will not have the committee ask some questions
18 of
the speakers, and you can ask questions of any
19 of
the speakers that have presented this morning.
20
Leslie?
21
DR. HENDELES: I have two
questions for
22
Karen. First, is there any Joint
Commission
86
1
requirements in terms of how respiratory therapists
2 are
supposed to handle medication?
3
MS. STEWART: There's been--
4
DR. HENDELES: And I have a second
5
question, which is: Would
respiratory therapists
6
mind carrying these single-unit dose vials wrapped
7 in
foil in their pockets?
8
MS. STEWART: There are
recommendations
9
around the delivery of medications from JCAHO, and
10
most of that is surrounding the control. It is
11
first the pharmacist's review of that medication to
12 see
if there are any other interactions, and the
13
second being that that medication is always under
14
control. And you'll see as you go
across the
15
country a number of different ways that hospitals
16 are
handling the medication control issue.
Some of
17
them--the folks that I talked to last week, some of
18
them have a cart where they carry all their
19
plastics and other things that they need with a
20
locked drawer, and their medications are in that
21
drawer. Other ones are using
Pyxsis, and some are
22
still carrying it physically on their person in a
87
1
side pocket or a fanny pack.
2
Your second question is, if they were
3
individually wrapped, I think that therapists would
4 use
those either in any of those devices under
5
control. The problem is that they
open, for
6
example, a packet of Xopenex with 12 vials in it.
7
That's just too much for them to carry when they've
8 got
so many different types to carry.
9
DR. HENDELES: If it's just one,
they
10
would be able to?
11
MS. STEWART: I think they would
be able
12 to
carry it, yes.
13
DR. GROSS: Yes, Stephanie?
14
DR. CRAWFORD: Thank you. This question
15 is
for Patrick Poisson, but, Ms. Stewart, don't go
16 too
far just in case you want to add to it.
I
17
thank each of the speakers for their presentations.
18
Mr. Poisson, with respect to your
19
presentation, the sixth slide was talking about the
20
advantages and disadvantages--I'm sorry, the
21
advantages and limitations. Each
of the advantages
22
from my interpretation were in the manufacturing
88
1
process. As you presented, each
of the limitations
2 was
from the clinical use. So my question
is:
3
From the recommendation--potential alternatives
4
that you suggested, have you conducted, your
5
company, or performed any studies using clinical
6
groups such as the respiratory therapists to see
7
acceptability of each of these options?
8
MR. POISSON: One thing I probably
failed
9 to
mention is that Cardinal Health is a contract
10
manufacturer, and the products that we manufacture
11 are
distributed by our customers. And it's
12
difficult for us to step in front of them and ask
13 for
this type of work to be done.
14
Now, we have done some work with the
15
shrink wrap sleeve label, and the feedback from
16
that was very positive. However,
that was a very
17
unique opportunity for us to get involved with
18
that.
19
In regards to the recommendations, yes,
20
some of them are manufacturing--are good for the
21
manufacturing process. However,
one that maybe
22
wasn't explained as well is the sterility of the
89
1
product. Using a blow-fill-seal
technology to
2
manufacture products is recognized as providing a
3
better microbiological quality of product out to
4 the
market versus a conventional process.
5
DR. GROSS: Michael? I'm sorry.
6
Stephanie, another question?
7
DR. CRAWFORD: Thank you. Just one quick
8
follow-up. One of your recommendations
was
9
increase text size. You mentioned
that, of course,
10
something would have to come off if that were
11
happening--would come off if--
12
MR. POISSON: I think we'd have to
13
undertake those discussions with the agency as to
14
what could come off.
15
DR. GROSS: Michael?
16
DR. COHEN: I've been looking at
these
17
LDPE plastics for several years, actually, and
18
trying to come up with solutions.
And actually the
19 best
thing I've ever seen is that shrink wrap, that
20
overwrap, or sleeve, or whatever you want to call
21
it. Is that a proprietary system,
or is that
22
available to any manufacturer?
And can you foresee
90
1 the
actual use across the entire spectrum of LDPE
2
containers, even the parenterals?
3
MR. POISSON: Well, we're very
pleased
4
with the progress we've made on the sleeve label.
5 It did
involve some development that we regard as
6
intellectual property. So
regarding availability
7 to
the whole industry, I really can't speak on
8
that.
9
There will be potentially some leachable
10
extractables even from that system.
There is ink
11 on
that label. So that has to be evaluated
for
12
each product that it's used for.
It still may not
13
work for every product.
14
MR. SCHINDEWOLF: If I could just
make a
15
comment on the proprietary nature, what's
16
proprietary about that vial is the rounded end. A
17 lot
of the vials that you'll see and I think some
18
that were presented earlier can be on a flat end as
19
well. And we found that the
rounded end helped the
20
legibility. As the sleeve
shrinks, there tends to
21 be
some--what's the word I'm looking for?
The
22
print can be--
91
1
MR. POISSON: It can be distorted.
2
MR. SCHINDEWOLF: Yes,
"distortion,"
3
that's the word. So this was to
help the
4
readability of the bar code label itself, so that's
5
what's proprietary in that particular design.
6
DR. GROSS: Yes, Henri?
7
DR. MANASSE: In terms of patient
safety,
8 one
of the biggest issues that I think most
9
practitioners confront is the kind of work-arounds
10
that people utilize to make things convenient for
11
them, and this notion of carrying drugs around in
12
your pocket is a very good example.
But it seems
13
that the sleeve is a pretty critical issue with
14
respect to the capacity of adding more information
15
coupled with bar codes, symbologies, et cetera.
16
Have you all thought about how you can
17
eliminate the dissociation of the sleeve from the
18
package itself? Because the
work-around, people
19 are
tearing off the sleeves and then carrying the
20
package by themselves. And is
there a way that you
21 can
avoid that other than at the direct point of
22
care?
92
1
MR. POISSON: I'll try and address
that.
2 One
of the ways that these are used is that the cap
3 is
actually twisted off of the vial. And
one of
4 the
problems I see with individually foil
5
overwrapping is the removal of that foil could
6
potentially damage the vial in that process. So
7
it's a difficult thing to overcome.
We could
8
tighten the foil potentially around the vial, but
9 it
just opens it up for damage in the transfer
10
process from the location within the hospital to
11 its
use point.
12
You know, there are a lot of advancements
13
going on in packaging. Certainly
five years ago I
14
don't think we would have all the options that we
15
have now. Maybe at some point in
time we can get
16 to
a better alternative with the foil.
17 DR. GROSS: Robyn?
18
MS. SHAPIRO: I have two
questions. One
19 is
actually Henri's. And this is to the
agency.
20
What factors, if any, are considered currently in
21 the
approval process with respect to these
22 problems?
93
1
And the second question is: It
seems to
2 me
that this morning we have much more information
3
about the potential error, problem, than the
4 leachability
and contamination problem, and much
5
more potential risk. Has there
been--maybe this is
6 for
Karen. Has there been litigation over
this?
7
And, if so, what has happened?
8
MS. STEWART: I can't speak to any
9
litigation, and I think one of the concerns that we
10
have as therapists is that this probably goes underreported.
11 The
therapist delivers that care
12 and
leaves the bedside to treat the next patient.
13 So
they may not see an adverse effect or, as stated
14
earlier by Dr. Sullivan, I believe, the patient
15
does not get the potential relief of the
16
medication.
17
In other words, if you have Tobramycin and
18 a
bronchodilator in your pocket, they both look
19
alike, you give the Tobramycin to the patient who
20
needs the bronchodilator, you may not see the
21
effect. So it becomes
underreported.
22
MS. SHAPIRO: And the patient may
not
94
1
either. I mean, they may not
realize--the patient
2 or
the family or whomever, the error may not be
3
disclosed to anyone.
4
MS. STEWART: Except the patient's
5
therapeutic treatment regime is going to be longer
6
with a longer length of stay because they didn't
7 get
the proper--
8
MS. SHAPIRO: Sure, but they may
not know
9
why.
10
MS. STEWART: Right.
11
DR. GROSS: Are there any other
questions?
12
MS. SHAPIRO: Can I have the first
13
question answered by Paul or somebody about what
14
currently is considered?
15
DR. SHAH: You are talking about
in terms
16 of
the quality controls?
17 MS. SHAPIRO: In the approval process for
18 any
new drugs, what, if any, is considered with
19
respect to safety relating to this possibility for
20
error?
21
DR. SHAH: Let me just try to
briefly
22
summarize.
95
1
When we get an application and we have
2
these kind of packaging components, then usually
3 the
applicant may provide this information for all
4 the
components of each and every packaging
5
component into the NDA, or they may choose to
6
provide that information, if it proprietary,
7
through a Drug Master File. Then
we review the
8
chemical composition of each and very packaging
9
component in a Drug Master File, but we cannot
10
relay that information to the applicant.
11
Once we know from the composition that
12
there is a potential for volatile chemicals to be
13
present in the component and they may permeate
14
through the LDPE vials, then we ask the applicant
15
indirectly, without revealing the other
16
information, Have you studied any legibility or
17
extractable--have you found any extractable, what
18
kind of solvent conditions you have used to extract
19
this leachable? And we encourage
them to contact
20 the
DMF supplier, work with them, and develop some
21
procedures to find out what can be present and
22
establish a profile. Once you
establish a profile,
96
1
then you may identify, okay, these are the typical
2
components present into a component, packaging
3
component, and we are going to use that as a basis
4 for
screening the incoming packaging material.
And
5
then you may have some kind of acceptance criteria.
6
That may be a GC profile. Or if
you have
7
identified a particular component by its chemical
8
structure, then you may say, okay, it is extracted
9 at,
say, one milligram per ml or something like
10
that, okay? So then you will
conduct some kind of
11 a
study for the shelf life, over the shelf life,
12
whether that particular extractable gets into the
13
drug product or not. If it does
not, then at least
14 you
have established that if I control the amount
15 of
incoming acceptance criteria, I have established
16
incoming packaging material, then I do not see the
17
leachable into the drug product.
So then you don't
18
have to have a test for leachable into the drug
19
product, but you have to establish that
20
relationship.
21
So we go through a series of steps to
22
establish that, and once we are satisfied, then we
97
1 may
decide, okay, you are going to control or
2
minimize this particular component at acceptance
3
level in incoming packaging material.
Or you will
4
have to carry out the leachable testing.
5
MS. SHAPIRO: What about the
analysis with
6
respect to the possible safety problems on account
7 of
the error issues?
8
DR. SHAH: Okay. Once we get that, we see
9
that, okay, it is present into the drug product at
10 a
certain level. And if we know the
identity of
11
that chemical, then we ask our pharmacology and
12
toxicology person to review that data and decide
13
whether that will have any safety issue.
And if
14 they
decide that it may have a safety issue, then
15
they may ask the applicant to qualify that
16
particular material or chemical at that level.
17
MS. SHAPIRO: Okay. And all that has to
18 do
with the leachability question. But what
about
19 the
question having to do with the confusion
20
problems on account of the labeling and its impact
21 on
safety?
22
DR. SELIGMAN: For all drug
products that
98
1 are
approved by the agency, we look at the accuracy
2 of
the label, whether it's misleading or not,
3
whether it's nonpromotional in nature.
We look at
4 the
name for potential confusion. We look at
the
5
packaging regarding dose and frequency.
And if at
6 the
time we find, either at the time of approval or
7
even subsequent to approval, that there is such a
8
potential for either name confusion, for misleading
9
dose, or any kind of misleading information that
10
might lead to medication error, we make a
11
recommendation to the manufacturers to try to--to
12
alter that.
13
I think the reason we're bringing this
14
particular issue to this committee is that this is
15 a
particularly vexing issue. But for the
vast
16
majority of products that we review, when we find
17
such potential for confusion or potential error, we
18
recommend to the manufacturer that that be
19
addressed prior to approval of the product.
20
MS. SHAPIRO: Have you ever, with
21
containers like this, sent it back and said, no,
22
this doesn't--this won't do given these sorts of
99
1 problems?
T2B DR. SELIGMAN: I'm not aware of any. Some
2
3 of
them go through generics.
4
Carol, did you want to respond to that?
5
MS. HOLQUIST: Yes. Actually, our office
6 in Office of Drug Safety, we only get
whatever--we
7
only see the packaging material that comes in with
8 new
products. A lot of these products have
been on
9 the
market for years and years. So if indeed
one
10 of
these products came in today with this packaging
11
labeling, yes, of course, that would be one of our
12
recommendations in our review that, based on
13
post-marketing reports and evidence, we wouldn't
14
recommend this. But then the
agency's hands are
15 kind of tied because of the ingress
issue. So
16
until we find an alternative packaging, it's a
17
conundrum we're in.
18
DR. GROSS: Gene, did you want to
comment?
19
DR. SULLIVAN: Yes, I just wanted
to
20
follow up on a couple things that have been said so
21
far: one, to just make sure the
categories of harm
22 to
patients are in the right column.
There's the
100
1
harm that the legibility issue brings in, so the
2
harm that a patient suffers if he or she doesn't
3
receive Tobramycin but instead receives Albuterol.
4 And
then what I was trying to touch on and the
5
thing that's hard to get your hands around is the
6
harm from the actual presence of these chemicals,
7 and
that it's well known that a patient may come to
8 the
emergency department and receive a few
9
treatments of Albuterol and recover and be
10
discharged. Another patient may
come in and not
11
seem to respond and end up mechanically ventilated.
12 And
to what extent that could be related to
13
contaminants in the drug product would be anyone's
14
guess and impossible to day. So I
just wanted to
15
make sure we consider those two sort of as they're
16 the
competing harms.
17
The other issue I just wanted to talk
18
about a little bit was the issue of the use of the
19
flange or labeling that's not directly applied to
20 the
actual body of the nebule, be it with a shrink
21
wrap or an applied label and so forth; that there
22 is
some intrinsic appeal because it seems to be
101
1
less in contact with the LDPE, but keep in mind
2
that if these are then put into an overwrap, a foil
3
overwrap, perhaps for other
4
reasons--light-sensitive products and so
5
forth--that then you have sort of a micro
6
environment, you know, like a little humidor with
7
these chemical vapors that could then make their
8
way--even though they're here on the flange, they
9
could easily make their way into the product, and
10
that's sort of evidenced by that case where we had
11 the
cardboard carton and that chemical made its way
12
in. So it's not, you know, a
complete solution.
13 We
have to keep that in mind.
14
DR. GROSS: Arthur, you had a
question?
15
MR. LEVIN: One is just a point of
16 information.
Mike, is that the packaging with that
17
label, that's what you are referencing when you say
18 so
far that's the best--
19
DR. COHEN: Not necessarily.
20
MR. LEVIN: Okay.
21
DR. COHEN: This is certainly
acceptable
22 as
a way to identify a container. But the
ones
102
1
I've seen have actually had a similar type of film,
2 but
it's been around the body of the ampule device.
3 And
there was a tear-off so that you would
4
literally pull the tab and tear off the top part of
5 the
plastic. It was a total overwrap.
6
MR. LEVIN: But it's something
more than
7
that.
8
DR. COHEN: Leaving the identify, even
9
though this was exposed.
10
MR. LEVIN: Okay. So the whole thing is
11
shrink wrapped to something.
12
DR. COHEN: That's correct.
13
MR. LEVIN: Right, okay. I didn't think
14 we
had seen one of those.
15
DR. COHEN: We didn't.
16
MR. LEVIN: Yes, okay. So that clarifies
17
that.
18
The second thing is we seem to be sort of
19
entirely focusing in inpatient and, you know, the
20
issue of outpatient is certainly significant. And
21 I'm
just wondering from, you know, what you've done
22 to
look at how well these kinds of solutions work
103
1 in
the outpatient pharmacy setting as opposed to
2
inpatient settings where it's really--making sure
3
that the respiratory therapist who administers the
4
drug is clear on the right drug and the dosage et
5
cetera. What about an outpatient
pharmacy?
6
MR. POISSON: Well, one of the
reasons
7
why--and someone may question why there's 12 vials
8 in
a pouch or even 28 or up to 60. A lot of
the
9
reason behind that is because of the use period in
10 the
outpatient--outside of the hospital. And
based
11 on
feedback we've received, they view that as an
12
advantage to have that type of packaging in that
13
particular environment. And the
possibility exists
14
that maybe some of these options we've presented
15
today, such as the symbol on the vial would help
16
them in that area from using the wrong product.
17
So I think, you know, there's
18
opportunities for a number of these options to be
19 implemented
based on the setting that they're used
20 in.
21
DR. GROSS: Okay. Henri, you have a
22
question?
104
1
DR. MANASSE: I just want to
follow up on
2
Art's point in terms of outpatient use.
I can't
3
imagine given the size of these containers, given
4 the
unreadability of these containers, and the
5
obvious confusion that is brought to bear to those
6
problems, that outpatients, particularly elderly
7
outpatients, can manage this on their own. I think
8
somehow we've got to contemplate where we go with
9
that because the increasing number of people who
10 are
using these on an outpatient basis and the
11
increasing aging of the population presents us with
12 an
incredible challenge.
13
DR. GROSS: Okay. Marci would like to
14
make a comment.
15
DR. LEE: Thank you. I just wanted to add
16 to
that. Based on the medication error
reports
17
that we have received most recently, there are many
18
comments about the elderly population using these
19
drugs. There are several reports
from a pharmacist
20
saying that his patients are expressing that
21
they're afraid to use the product because they're
22
afraid that they're going to double their dose
105
1
accidentally because they're not sure what is in
2
each ampule.
3
Then, also, the letter in the background
4
package that was sent to Senator Harkin, that also
5
involved a woman who was writing in about her
6
elderly mother that was having the same problem
7
also from a mail-order pharmacy.
So in addition to
8 a
regular outpatient pharmacy where there's direct
9
interaction with the pharmacist, you have people
10 who
are unable to get out of their home and receive
11
their medications by mail having the same
12 experiences.
13
Carol wants to add something.
14
MS. HOLQUIST: Also, just in
relation to
15 the
letters at the top of the vials themselves, we
16
actually have gotten some reports as well where
17
there's a question as to what the actual letter
18
stands for, like A, is it for Albuterol or for
19
Atrovent. So some simple fixes,
sometimes you also
20
have to think beyond, that there's more than one
21
product that begins with that letter.
x
DR. GROSS: Okay.
We are a little bit
22
106
1
ahead of schedule, and we will proceed at this time
2
with the open public hearing. Dr.
Eric Sheinin
3
will present. First I need to--
4
MS. JAIN: We need to read a
statement
5
first.
6
DR. GROSS: Both the Food and Drug
7
Administration and the public believe in a
8
transparent process for information gathering and
9
decisionmaking. To ensure such
transparency at the
10
open public hearing session of this Advisory
11
Committee meeting, the FDA believes that it is
12
important to understand the context of an
13
individual's presentation. For
this reason, FDA
14
encourages you, the open public hearing speaker, at
15 the
beginning of your written or oral statement to
16
advise the committee of any financial relationship
17
that you may have with any company or any group
18
that is likely to be impacted by the topic of this
19
meeting.
20
For example, the financial information may
21
include a company's or a group's payment of your
22
travel, lodging, or other expenses in connection
107
1
with your attendance at the meeting.
Likewise, FDA
2
encourages you at the beginning of your statement
3 to
advise the committee if you do not have any such
4
financial relationships. If you
choose not to
5
address this issue of financial relationships at
6 the
beginning of your statement, it will not
7
preclude you from speaking.
x DR. SHEININ: Thank you, Dr. Gross. I
8
9
have no financial ties or interests in any
10
pharmaceutical company or any other company or
11
organization that would be interested in the
12
proceedings before the committee today, so I think
13 I'm
okay with that.
14 DR. GROSS: Thank you.
15
DR. SHEININ: My name is Eric
Sheinin, and
16 I'm
here today to represent the United States
17
Pharmacopeia. At the UPS, I am
the Vice President
18 for
Information and Standards Development.
We do
19
have an expert committee that deals with safety
20
issues, and much of what I'm going to say today is
21 a
direct result of work that they have done.
But I
22
would like to give you some background about the
108
1 USP
for those of you who may not be familiar with
2 us
and also to have it in the record.
3
The USP is a nongovernmental organization
4
that promotes the public health by establishing
5
state-of-the-art standards to ensure the quality of
6
medicines and other health care technologies.
7
These standards are developed by a unique process
8 of
public involvement and they're accepted
9
worldwide. Many other countries
around the world
10
recognize the USPNF standards as their own
11
standards in terms of regulatory procedures within
12
those countries.
13
USP is a not-for-profit organization that
14
achieves this goal through the scientific
15
contribution of volunteers, and the volunteers
16
represent pharmacy, medicine, and many other health
17
care professions. These
individuals work in
18
academia, they work in government, both U.S. and
19
international. In fact, there are
many FDA
20
scientists who serve as volunteer to USP. They
21
also come from the pharmaceutical industry and
22
consumer organizations. In
addition to standards
109
1
development, USP's has several other public health
2
programs that focus on promoting optimal public
3
health care delivery.
4
In our mission statement, it says the
5
mission is to promote the public health, and I
6
always liken that to the mission of CDER, which is
7
also basically to promote the public health. So I
8
believe we're all interested in the same types of
9
standards.
10
At the USP, the volunteers, many of them
11 serve
on our Council of Experts and its expert
12
committees. The members of these
committees are
13 USP
scientific decisionmakers, and they form our
14
standard-setting body. Council
members are elected
15 by
USP's membership at our five-year convention.
16
They're elected on the basis of their knowledge and
17
expertise, and they serve five-year terms. So even
18
individuals who come from industry, from their
19
companies, when they volunteer to work with USP,
20
they represent themselves. They
do not represent
21
their employer, their organization, or anybody else
22
when they work on our standards.
110
1
The 2000-2005 Council of Experts comprises
2 62
nationally recognized scientists, academicians,
3 and
clinicians. Each one of these
individuals
4
chairs an expert committee, and the expert
5
committees are made up then in turn of
6
distinguished experts.
7
One of the committees is named the USP
8
Safe Medication Use Expert Committee.
This
9
committee is comprised of 18 members representing
10
pharmacy, nursing, and medicine.
It includes an
11 FDA
liaison, Carol Holquist. It includes
Captain
12
Jerry Phillips, who was formerly the Associate
13
Director for Medication Error Prevention in FDA's
14
Office of Drug Safety.
15
For more than 30 years, USP has promoted
16 the
importance of collecting and sharing
17
experiential data from health care professionals.
18 In
the last decade, particular emphasis has focused
19 on
medication error reporting and prevention as a
20 way
for USP to positively affect the public health.
21 The
data collected from two of our programs--the
22
USP-ISMP Medication Error Reporting, or MER,
111
1
Program and MEDMARX--are reviewed and analyzed by
2 USP
staff and USP's Safe Medication Use Expert
3
Committee.
4
In October of 2002, USP sent a letter to
5 the
chief of CDER's Compendial Operations staff,
6
Yanna Mille, to inform her, on behalf of the Safe
7
Medication Use Expert Committee, of the continuing
8
concerns of the committee and of health care
9
professionals and practitioners regarding both the
10
difficulty in identifying drug products packaged in
11
low-density polyethylene ampules and vials and the
12
resultant medication errors from their misuse.
13
Plastic ampule packaging is frequently
14
used for respiratory therapy drugs.
The ampules
15
often do not bear labels but are labeled by
16
debossing or embossing the actual plastic
17 container.
This debossing or embossing is
18
described by health care practitioners who have
19
reported to the USP reporting programs as being
20
unreadable, causing difficulty in identifying the
21
product within. Because this
packaging is now
22
being used not only for respiratory therapy drugs
112
1 but
also for injectables and oral solution, it is
2
even more important that the subject products be
3 easily
identified and readily distinguishable from
4
each other.
5
USP has provided the Compendial Operations
6
staff, the Dockets Branch, and the Office of Drug
7
Safety with more than 42 specific case studies
8
where mediation errors occurred because of the use
9 of
these products. We also have submitted
copies
10 of
the actual product containers involved in the
11
medication errors that were reported through the
12 two
USP reporting programs.
13 In addition to providing comment on the
14
concerns expressed to USP by health care
15
practitioners, the USP Safe Medication Use Expert
16
Committee unanimously voted to encourage FDA to
17
establish an alternate method of labeling for the
18
various drug products packaged in the plastic vials
19
being discussed today. This would
be in order for
20
these products to be clearly identifiable,
21
hopefully thereby reducing the numerous medication
22
errors that have occurred and likely will continue
113
1 to
occur.
2
The expert committee also suggested that
3 the
FDA cease approval of products in these
4
containers because their use continues to be the
5
subject of numerous medication error reports.
6
From April 20, 2002, through January 31,
7
2004, an additional 26 reports of actual and
8
potential medication errors have been received
9 through
USP's medication errors reporting programs
10
regarding the similarity in the labeling of
11
products in low-density polyethylene vials. The
12
problems with these containers continue, and the
13 USP
and the USP Safe Medication Use Expert
14
Committee recommends that FDA take any necessary
15
action to improve the labeling of low-density
16
polyethylene ampules and vials.
17
I thank you for your attention and your
18
consideration of USP's concerns.
If you have any
19
questions, I'll certainly try to answer them.
20
DR. GROSS: Thank you very much.
21
Are there any questions from the panel?
22
Jackie?
114
1
DR. GARDNER: I would just like to
ask,
2 Dr.
Sheinin, does USP have a recommendation of one
3 of
these methods over another?
4
DR. SHEININ: A recommendation?
5
DR. GARDNER: For solving this problem?
6
DR. SHEININ: Not at this point,
not that
7 I'm
aware of. The obvious solution to
me--and I
8
actually worked at FDA for 30 years before I went
9 to
USP--would be to have a label on the containers.
10 But
there are concerns with migration through the
11
low-density polyethylene. I'm
sorry I missed the
12 end
of the previous presentation where they were
13
describing perhaps some way to help identify these
14
products.
15
DR. GROSS: Robyn Shapiro?
16
MS. SHAPIRO: I just have a
question about
17
these report forms. Was patient
counseling
18
provided? And then, if yes,
before or after error
19 was
discovered? Does that mean about what
the drug
20 is,
how to take it, how to read it? What
does the
21
counseling refer to?
22
DR. SHEININ: I believe that the
115
1
counseling is provided by the professional who's
2 reporting
the problem to us. I don't believe USP
3
does the counseling.
4
MS. SHAPIRO: So we don't really
know what
5
that refers to.
6
DR. SHEININ: Unfortunately, the
Safe
7
Medication Use Expert Committee is not under my
8
area of responsibility. But as
far as I know, that
9
counseling would not be provided by USP, and we
10
probably do not know what the nature of that
11
counseling was. The form is
asking if there has
12
been any counseling.
13
DR. GROSS: Henri?
14
DR. MANASSE: Good morning, Eric.
15
DR. SHEININ: Hi, Henri.
16
DR. MANASSE: Two questions. We've talked
17
today about two major issues: one
is the leaching
18 of
chemical agents from various labeling techniques
19 and
embossments; the other having to do with the
20
readability issues and the packages themselves.
21
Has USP convened any technical experts on
22
either one of those issues to contemplate what's
116
1 the
existing science, what do we know, what do we
2 not
know, as well as what our reasonable solutions,
3
given what's known, in other industries or other
4
options for dealing with this problem?
5
DR. SHEININ: Not that I'm aware
of. It
6
certainly is a good suggestion, and I will take
7
that back to the committee and to Diane Cousins,
8
whom I think many of you probably know, and see if
9
there is a way that we could proceed in that
10
manner. I think it's a very good
suggestion and
11
something that should be done.
12
DR. GROSS: Okay. Thank you very much.
13
DR. SHEININ: Thank you.
x DR. GROSS: If there are no further 14
15
questions, since we remain ahead of schedule, Dr.
16
Paul Seligman will now introduce the issues and
17
questions that he has for the Advisory Committee.
18
DR. SELIGMAN: You should all,
members of
19 the
committee, have a one-page LDPE Discussion
20
Points. These, I believe, are in
the packages as
21
well for public distribution. Why
don't we simply
22
refer to these rather than booting up the slides.
117
1
You've heard this morning about the issue
2
related to the ingress of volatile compounds as a
3
problem with these particular containers and
4
various approaches to deal with this issue as well
5 as
not only--to deal with both the preservation of
6 the
purity of the drug, as well as ways in which to
7
improve the legibility of the label.
8
What we've asked in the first
question is:
9
Given the various approaches that you've heard
10
today, including embossing and debossing of
11
containers, the use of unit package overwraps, the
12
elongation of the bottom tab and using that as an
13
place to print critical information, the use of
14
paper labels, the use of ink directly on the vial,
15
various potential approaches including tactile
16
recognition, shrink wrap labels, and then we
17
actually even saw the use of glass ampules or
18
vials, what we're interested in the committee
19
addressing first off is to discuss the potential
20
advantages or disadvantages of these approaches and
21 to
identify in 1b any creative solutions or
22 alternate
packaging design that would improve
118
1
legibility and address the problem of ingress of
2
chemical contaminants and at the same time not
3
create additional problems.
4
We'd also like to have you put on your
5
thinking caps and consider if there are stakeholder
6
groups, such as manufacturers, practitioners,
7
consumers, and others, who might best advise FDA
8
about possible new packaging configurations that
9
might resolve some of these issues.
10
And then given what you've heard today and
11
based on our discussion, describe and advise us on
12 an
appropriate course of action to address not only
13 the
problem of ingress of contaminants but also
14
medication errors due to legibility and similar
15
packaging issues.
16
So those are the issues before us.
Peter?
17
DR. GROSS: We share in your
perplexity.
18
DR. SELIGMAN: Thank you.
x DR. GROSS: This is a difficult issue.
19
20
Thank you very much for the questions,
21
Paul, and we will initiate the discussion. The
22
agenda allows two hours for discussion, so why
119
1
don't we do roughly an hour, and then maybe we can
2
have lunch and then finish up, if that's okay.
3
MS. JAIN: Lunch is on its way.
4
DR. GROSS: Okay. Well, whenever lunch is
5
here, we will re-evaluate our timing.
But let's
6
begin the discussion now.
7
Anyone have any comments? Why
don't we do
8
this in an orderly fashion and take the issues as
9
Paul presented them, with 1a being the first.
10
They're all sort of interrelated, but why don't we
11 get
specific and talk about 1a first.
Leslie?
12
DR. HENDELES: I'd like to preface
my
13
comments by saying that nebulization of
14
bronchodilators is an obsolete way of treating
15
acute bronchospasm, and part of whatever we do
16
needs to focus on an educational program designed
17 at
using the meter-dose inhaler through a valve
18
holding chamber, which is far more efficient,
19
causes fewer side effects, less expensive way, and
20
it's the way the rest of the world treats acute
21
asthma. The United States has a
fixation on
22
nebulizer therapy that they won't let go of, for
120
1
some reason, especially pediatricians, but there's
2
clearly 10 to 15 double-blind, placebo-controlled
3
trials, a Cochran review, et cetera, that indicate
4
that there are much more efficient ways and it
5
would, of course, circumvent this problem for
6
asthma.
7
Now, having said that, I really like the
8
idea of having that foil pack, like the Nephron,
9
with a single unit, and I think that would solve
10 the
problem. It would allow for the bar
coding.
11 And
according to Karen, respiratory therapists
12
would be willing to carry that in their pocket. As
13 I
understand it, the reason why they carry single
14 units in their pocket is because when they
open the
15
foil pack, there's 12 of them there.
If there's
16
only one, they would probably carry it.
And, of
17
course, that could also be addressed through
18
professional education as well.
19
DR. GROSS: Leslie, for myself and
anyone
20
else who is not 100 percent clear on what you said,
21
would you contrast the two methods of medication
22
delivery again?
121
1
DR. HENDELES: Bronchodilators as
well as
2
inhaled steroids can be delivered by a pressurized,
3
meter-dose inhaler that's attached to a valve
4
holding chamber with an age-appropriate connection,
5
either a mouthpiece for older folks or a mask for
6
preschool kids that seals around their nose and
7
mouth, and you fire off a few puffs, such as four
8
puffs, into this chamber and it's equivalent in
9
efficacy to nebulizing a bronchodilator in the
10
emergency room. It causes fewer
side effects. It
11
takes a minute or two to give the treatment instead
12 of
15 to 20 minutes, and it's far more convenient
13 for
patients and cheaper. They don't have to
buy a
14
compressor for $150.
15
DR. GROSS: Could someone from the
FDA
16
comment on whether or not they want to tackle that
17
issue?
18
DR. SULLIVAN: That may not be an
issue
19 for
the FDA really to address. I don't think
there
20
would be any--the evidence being what it is, that
21
MDIs may effect just as great a degree of
22
bronchodilation as a nebulizer, it would be
122
1
something that physicians should interpret and use
2 in
their clinical judgment. I don't think
there
3
would be any rationale for the agency to pull
4
nebulizer solutions off the market.
I think that
5
would be very drastic. So from
our perspective, we
6
have to deal with them.
7
Now, if the medical community starts to
8
learn that maybe they are overusing nebulizers
9
through Dr. Hendeles' shaking the cage a little
10
bit, that's just great. But the
issue will still
11
remain for us.
12
DR. HENDELES: And, indeed, there
are
13
patients who might be unconscious, for example, or
14
would need the nebulizer, and there are drugs such
15 as
Tobramycin that can't be delivered by MDI.
16
DR. GROSS: Arthur?
17
MR. LEVIN: I realize it isn't
within the
18
scope of authority of the FDA to dictate clinical
19
practice, but part of the problem here is we're
20
dealing with a tension between an issue of
21
potential harm, which is the leaching of, you know,
22
substances that don't belong in the solution into
123
1 the
solution and the documented potential harm of
2
error. And we're looking at a
variety of
3
solutions, none of which is perfect and each of
4
which brings with it some question:
You know, does
5 it
solve the error problem entirely? Or by
solving
6 the
error problem entirely, does it still leave us
7
open to the problem of possible impurity?
8
In that context, I think the FDA does have
9
something to say, and then when we move to the
10
ambulatory setting particularly, where these issues
11 I
think get even more complicated--and we really
12
haven't talked about it--that if there are better
13
ways to deliver the product that relief us of the
14
burden of trying to figure out the perfect solution
15 on
these two different potential harms, that's
16 worthy
of comment. I mean, nobody expects you
to
17 be
able to pull the product from the market, but in
18
dealing with improving safety of products, I don't
19
think it's entirely out of character for the FDA to
20
make a comment that one of the solutions here is to
21 use
a different form of delivery that obviates the
22
need to talk about all of this.
You may not be
124
1
able to say, "You can't use the other," but you can
2
certainly say, "Moving in this direction seems to
3 be
a way to solve the problem," and I would say
4
particularly in the ambulatory populations.
5
DR. GROSS: Maybe we'll have one
or two
6
more comments on this particular issue.
Then we'll
7
have to get back to the questions raised by Dr.
8
Seligman in 1a.
9
Brian?
10
DR. STROM: yes, I'd like to in my
initial
11
start be more provocative. We're
hearing, as
12
Arthur is saying, between two safety problems,
13
without good data on either side to quantify each
14 of
them. We're using in one case
physiological
15
chemical tests and the theory that leaching might
16 be
a problem, and it's clearly understandable why
17 it
can't be quantified more than that. And
we're
18
hearing on the other side about medication errors
19
based on the spontaneous reporting system, which is
20
grossly incomplete. We don't know
how many there
21 are
out there other than the fact that we're seeing
22 a
number, and there are clearly many more out there
125
1
than we're seeing that could be studied more
2
concretely, potentially. But, in
either case, we
3
don't have good quantification, and so part of the
4
problem here is balancing two risks, neither of
5
which are quantified.
6
If we're hearing from Leslie--and you're
7 not
disagreeing--that there is a better approach
8
which is more effective and is safer, why isn't
9
that a regulatory reason for the FDA to remove the
10
nebulizers--this packaging?
11
DR. SULLIVAN: Well, I'm not
actually
12
agreeing. I'm aware of the
various articles that
13 are
out there. I have not reviewed those
studies
14
myself, seen the data myself.
Certainly the agency
15 has
not come to that conclusion that the MDIs have
16
these attributes, these costs, and effectiveness
17 and
so forth. And that's an open question, I
18
believe. Dr. Hendeles probably
knows that
19
literature even better than I.
20
But for the agency to come to a conclusion
21
like that is a very significant matter, and, again,
22
although we can make comments, it's not clear in
126
1
what context that comment will hold any water until
2 or
unless we were to, as suggested, remove them
3
from the market. And I think that
that's quite a
4
drastic step, and I think that as Dr. Hendeles
5
pointed out, there would be very good arguments
6
that there may be some populations who are only
7
served by the nebulizers, and, therefore, it would
8 be
unwise to remove them from the market.
9
So let me say that we haven't made that
10
determination, number one, and that even if we made
11 the
determination that for the average patient it
12 was
efficient in some way that you would like to
13
define efficiency, it would be hard for us to move
14 on
that.
15
So I understand your perspective and I
16
understand Dr. Hendeles' perspective that perhaps
17 the
American physicians are overutilizing them.
18 But
I don't think that's going to get around the
19
issues that we have to face.
20
DR. GROSS: Okay. I think that maybe the
21
sense of the committee is that this is advice
22
they'd like to give to the FDA to look into this
127
1
issue and decide how they want to proceed. But I
2
would like that the issue should be brought to the
3
attention of the national pulmonary organizations,
4 and
they in their guidelines should make this
5
recommendation because in that setting they might
6
have a significant clinical impact.
7
DR. HENDELES: It shouldn't be
limited to
8
physicians. I think health system
pharmacists and
9
respiratory therapists and those organizations play
10 a
role, too.
11
DR. GROSS: Absolutely. But that might be
12 the
way to begin to make the change, if that's what
13 the
scientific evidence indicates.
14
Okay. I know you've all been
trying to
15
avoid 1a, but we do have to address it.
16
[Laughter.]
17
DR. GROSS: And I saw Michael's
hand up
18
first.
19
DR. COHEN: Thank you very much,
sir.
20
First of all, let me just ask the
21
question: Are we talking only
about the
22
respiratory ampules, the LDPE, or are you talking
128
1 about all LDPE? Because there's a difference
2
between the two, and the way they may be labeled
3
might be different as well. So
that would be the
4
first question. Are there, in
fact--we need to
5
clarify that there are, in fact, LDPE ampules for
6
injectables and ophthalmics, et cetera?
Is that
7
what we heard earlier? That's
number one.
8
MS. HOLQUIST: Yes, and that was
one of
9 our
questions, too. Should we treat the
pulmonary
10
products separately than these other products that
11 are
packaged by other routes of administration?
12
DR. COHEN: I guess what I'm
saying is,
13
even if we do clarify what you just brought up, Dr.
14
Hendeles, we'd still need to address the issue of
15 the
labeling because there are other forms, if, in
16
fact, they're LDPE. So that was
the first thing I
17
wanted to mention.
18
Can I make a suggestion to the Chair that
19 we
go through each of these bullets, perhaps
20
separately? Or do you want us to
comment on all of
21
them at the same time?
22
DR. GROSS: I think that's a very
good
129
1
idea, Michael. Do you want to
begin with embossed?
2
DR. MANASSE: Peter, I wonder if I
could
3
just interrupt.
4
DR. GROSS: Yes, sure. Henri?
5
DR. MANASSE: I think before we
jump to
6
choosing between evils, I think we have to lift up,
7
perhaps, to the 30,000-foot level a minute and,
8
that is, if we're going to continue to use these
9
low-density polyethylene containers in the sizes
10
that we're going to use them, if that's a given,
11
we're going to have to more carefully understand
12 and
identify both the packaging and ingress issues.
13
I'm a little bit uncomfortable jumping to
14
picking what we think is the best when we don't
15
have all the information. I don't
think we're
16
totally educated on all the potential leaching
17
issues, all the potential chemical agents that
18
could cause degradation, et cetera, et cetera.
19
At the same time, I'd hate to see us jump
20 to
figuring out packaging solutions when at least
21 I,
for one, have not been presented with all of the
22
packaging options that might be a possibility.
130
1
We're limiting ourselves largely to pharmaceutical
2
packaging, and I'm amazed in this country how
3
creative packaging can become.
All you have to do
4 is
look at the cosmetics industry to see some of
5
that creativity. I'm not sure
that we've exhausted
6 the
dialogue around creative mechanisms by which
7
people can read this stuff, that they can handle it
8
without an intervening health professional, at
9
home, for example, and particularly relating to the
10
elderly. And I'm not convinced that
we know enough
11 yet
about what kind of package designs are utilized
12 in
other industries that might be applicable here
13
that could solve our problem in a much bigger way.
14
I don't want to be interruptive, Peter,
15 but it seems to me that we've got to look at
those
16
issues.
17
DR. GROSS: I think those are very
18
critical points, Henri. I know
from my point of
19
view, I'm not sure I got an answer as to why other
20
polymers have not been selected as opposed to
21
polyethylene, you know, like polypropylene or
22
polystyrene. Is there any
potential there? Can
131
1
that be looked at? Is
high-density any better than
2
low-density is another issue.
Should the thickness
3 of
the LDPE be made greater and that would probably
4
slow the migration? But would it
make a
5
significant difference over a period of time or
6
not? So there's just a tremendous
amount that's
7 not
known.
8
But in the absence of all the knowledge
9
that we need, which is the situation in most
10
instances that we have to deal with in life, just
11
read Robert Rubin's book, we still do have to
12
address the questions posed to us.
13
Does anybody have any other comments
14
before we address those specific questions? Yes,
15
Jackie?
16
DR. GARDNER: Since we aren't
experts on
17
this and what you're saying is correct, and since
18
Brian is leaving this committee and he always has
19 one
mantra, and that is, we need data, where are
20 the
data, and he won't be here anymore, so I'll
21
take that up for him, my suggestion would be that
22 we
ask, maybe starting with Michael, of these
132
1
options which is probably the most satisfactory on
2 the
face of it given everything we've heard today,
3 recommend
that maybe starting with that, some
4
studies be done to address the extent of the
5
ingress using that method, and has it solved that
6
problem? And so to that end, it
sounds like either
7 the
shrink wrapping of the ampule, as Michael
8
suggested, or the foil wrap, individual unit of use
9
sleeve, which I happen to like because it seems
10
like you could bar code it and also put
11
instructions and colors and other kinds of things
12 on
it, but pick one, the best that we can come up
13
with and ask them to study it and then tell us how
14 bad
it turns out to be.
15
DR. GROSS: Well, we don't even
know the
16
toxicity of the chemicals that are ingressing. We
17
don't even have that information.
Certainly a lot
18 of
products that are available commercially have
19 low
levels of toxin that are considered acceptable.
20 So,
I mean, that's another big area where we just
21
don't have the information.
22
Leslie?
133
1
DR. HENDELES: Did we learn
whether this
2
foil wrap actually prevents the problem or does it
3 add
anything else to the vial, the solution?
4 DR. SHAH: Well, it depends.
5
DR. HENDELES: Yes, okay.
6
DR. SHAH: Again, it goes back to
the
7
question of having adequate knowledge of the
8
chemical components which you have selected for
9 your
foil laminate and, critically, the adhesive
10
layer which is used. Most of the
time, the organic
11
solvents which are used in adhesives, they migrate
12
from the adhesive layer to the LDPE vial. As long
13 as
the adhesive layer is on the other side of the
14
aluminum foil, they may not have to worry about
15
that. You can use a sort of
adhesive layer, you
16 can
use pressure-sensitive materials which can just
17
fuse together. Then you can avoid
using adhesives.
18 Again, that's solving one problem
coming
19
from adhesive. However, the other
layers which are
20
used inside the aluminum foil, again, the product
21
composition, chemical composition does matter. If
22
there are small organic molecules which have a
134
1
volatile potential, there is a likelihood that it
2 may
migrate. However, the applicant can do a
3
one-time study and demonstrate that whatever
4
leaches into the drug product is not significant
5
enough to pose a safety issue. If
that is being
6
done, then that may be a possibility.
7
But we really don't know, I mean, in that
8
sense that it will solve the problem of not
9
leaching 100 percent.
T3A DR. GROSS: Okay.
We've been talking for
10
11 20
minutes, and we have still avoided the question.
12 So
anybody have any other comments before we
13
address the question before us?
14
[No response.]
15
DR. GROSS: Okay. At Michael's
16
suggestion, if that's okay with everybody, starting
17 at
the top, any comments on embossing?
Michael?
18
DR. COHEN: I have a few comments,
but,
19
again, we are talking about the respiratory use
20
specifically? That's fine if we
are.
21
DR. GROSS: Well, go ahead and
distinguish
22
what you want.
135
1
DR. COHEN: Well, I think for the
2
respiratory use, at least now there's not a great
3
variety of agents that are packaged in this type of
4
plastic, which may have an impact on my comments
5
with injectables, et cetera. I
don't know what the
6
future growth will be.
7
But with the embossment right now, I think
8
it's pretty clear that we really can't leave things
9 the
way that they are and that there are some
10
changes that we heard from--I believe it was from
11
Cardinal Health that possibly could help here. One
12 of
them was the large type, and I thought that was
13 a
world of difference between that and the old
14
type.
15
However, I should point out that we're
16
talking about clear containers now, colorless
17
containers. We're not talking
about color
18
containers, and there's a whole set of problems
19
with that that I don't even know if we're going to
20 get
into. But I would certainly discourage
the use
21 of
color differentiation.
22
But, at any rate--
136
1
DR. GROSS: Because?
2
DR. COHEN: Well, again, you know,
the
3
area of growth, confusion with other medications.
4 Are
you coloring them by class of drug or by
5
individual drug? If it's by
individual drug, are
6
there enough colors? Et cetera,
et cetera. But,
7 at
any rate, we can get into that a little bit
8
later.
9
But I also want to point out that when you
10
take these clear containers, what we saw was the
11
container against a dark background.
When you put
12
them against the table here or a lighter, white
13
background, the readability still leaves something
14 to
be desired. Plus, you know, the way that
the
15
photographer took the picture or something may have
16
impacted, you know, how we viewed that as well.
17 But
I still think it really does have some
18
possibility for us there with the large type.
19
The other concern with that, though, is
20
that in using that large type, it forced them to
21
place the strength of the medication on the
22
opposite side. In reality, I
still think there
137
1
will be some medication errors where people will
2
leave these on a counter or in a bin, for example,
3 see, you know, Ipatropium or whatever the
4
medication is, and not pick it up and turn it over.
5 So
you'll have some confusion between strengths
6
still.
7
So, with those caveats, I think that is
8 one
thing that should remain on the list, the
9
embossment with larger characters.
10
DR. GROSS: Anyone else want to
comment?
11
Yes, Stephanie?
12
DR. CRAWFORD: I'd actually like
to
13
address my question to the agency.
What would be
14 the
feasibility from a regulatory perspective of
15
increasing the type, knowing that other content
16
would have to be removed from the immediate
17
container?
18
MS. HOLQUIST: Well, right now
there is a
19
regulation for what's allowable for the smallest
20
size label, and it's pretty minimal.
Basically
21
it's the name of the product, either the
22
proprietary name, the established name, the
138
1
manufacturer, the lot number, and expiration date.
2 I
don't know how much less of that that you can
3
include because if there is a product problem with
4 a
specific lot number, you're going to need that
5
information with each nebule. If
it's on like one
6 of
these flanges and it's removed, that information
7 is
gone, so basically your stock is pretty much
8
wasted because you'd probably have to throw it out
9
because it's in doubt whether it's that affected
10
lot.
11
It would be great if nobody put a
12
proprietary name on there, but we know that's not
13
going to happen. So, you know, it
has to be the
14
name of the drug and it has to be the strength
15
because there are multiple products.
So I really
16
don't know how we could eliminate much more than
17
what's required on there.
18
DR. GROSS: Robyn?
19
MS. SHAPIRO: This is probably a
stupid
20
question. Can you different-color
the embossed
21
figures so that you have embossments, or whatever
22 the
noun is, in a different color so there is
139
1
contrast?
2
DR. SADEGHI: [Inaudible, off
microphone]
3
like a stamp, you have an ink layer [inaudible].
4
MS. SHAPIRO: Right.
5
DR. GROSS: Brian?
6
DR. STROM: I want to come back to
7
Michael's suggestion, which I think makes enormous
8
sense. I think from the list of
things you just
9
gave us that are now required, there is a very big
10
difference between the importance of the drug name
11 and
the strength versus the lot number, for
12
example. And to say that they're
equivalent, I
13
think from a clinical point of view, you don't need
14 the
lot number. And if there's a problem,
yeah,
15
you'd like to know the lot number, but chances are
16
it's going to have been thrown away by then. The
17
container will have been thrown away regardless.
18
It would be nice to have the lot number on
19 it,
but I would not by any means consider it
20
equivalent to the drug name. And
so the idea of
21
having the drug name in big print like we saw and
22 the
lot number on the flange on the bottom in small
140
1
print and the expiration date on the flange on the
2
bottom in small print--again, I don't think it
3
should be unavailable, but I think the two are
4
dramatically different in their clinical
5
importance. And to differentiate
between them in
6 the
label personally I would think would make a lot
7 of
sense.
8 DR. SULLIVAN: Let me see if I can
9
respond. I think we have to be a
little bit
10
careful because there is a specific regulation
11
about minimum requirements in labeling, and we can
12
presume that a lot of thought went into that. And
13 the
requirement is regarding drug products that are
14 so
small that you have to really minimize what you
15 put
on there. And through the process that
16
regulations were developed, it was determined that
17
this was the minimum set. And I
think we ought to
18 be
careful that in solving this problem we don't
19
perhaps brush aside what probably was considered
20
very carefully.
21
And I would think that in a setting of
22
particularly a drug recall that it would be
141
1
critical to be able to have the lot number there.
2 And
this is just an off-the-cuff remark, but I do
3
want to respect the process that apparently was
4
undertaken to make the regulation to think
5
carefully about what's the minimum amount of data
6
that should be there.
7
DR. STROM: If I can follow up,
let me
8
just clarify. I'm not saying--I'm
not disagreeing
9
with you. I'm not saying that the
data shouldn't
10 be
there. What I'm saying is the weighting
of the
11
data and the importance of the data and the utility
12 of
the data are very different, that the lot number
13 is
important when you have a recall, which is
14
hopefully uncommon. The drug name
and dose is
15
important every time you give it, and so the
16
data--I'm not saying the data should be eliminated.
17 I'm
saying there should be a differentiation
18 between the size and how they're
provided. So if
19 you
have a fixed amount of space, use most of it
20 for
what is most important and you need every day;
21 and
if you can't normally read the lot number
22
without a magnifying glass, who cares?
142
1
[Inaudible comment off microphone.]
2
DR. STROM: You can't anyway,
yes. Yes.
3
DR. SHAH: I think currently we
are doing
4 in
a sort of way that the lot number and expiration
5
date is going to on the bottom flanges, which is
6
always tiny, small. So I agree
with him that the
7
increase of the text size does make a dramatic
8
difference. So I think there is
an opportunity
9
over there to make an improvement as far as the
10
medication error is concerned.
11
DR. SULLIVAN: Yes, I thought the
basis of
12
that slide was that in order to increase this size,
13
we'd have to eliminate some of what's currently
14
required. And if we were to say
we agree with
15
that, we ought to think very carefully.
16
DR. GROSS: Leslie?
17
DR. HENDELES: A compromise might
be to
18 use
the first and second bullet where you increase
19 the
print size, leave on the essential information,
20 but
put one unit in a foil pack. That would
solve
21 all
of those problems.
22
DR. GROSS: Yes?
143
1
DR. STEMHAGEN: One of the things
that's
2 not
on the list is changing the size and shape and
3
differentiating by size and whether that's even a
4
possibility, you know, different doses at different
5
sizes and things. We saw a couple
different
6
shapes, but we didn't really talk about that kind
7 of
change in packaging.
8
DR. GROSS: Thank you, Annette.
9
Any other comments on embossing?
Arthur?
10
MR. LEVIN: In terms of shape and size--I
11
mean, it's a little off embossing, but are there
12 any
studies that look at the ability of people to
13
recognize that in the field? It
strikes me it's an
14
accident waiting to happen. But I
just don't know
15 if
there are studies out there that look at these
16
issues of differentiation by side and shape in the
17
clinical setting. If people are
indeed carrying
18
dozens of vials in their pocket, you're asking an
19 awful lot if you expect that to make a
difference
20 or
reducing the possibility they may pick the wrong
21
dose or the wrong drug.
22
DR. GROSS: I guess part of that
question
144
1
is: Does the FDA--can the FDA
sponsor research
2
studies to deal with some of these questions?
3
DR. SHAH: I'll just say one more
thing
4
regarding the shape--
5
DR. GROSS: No answer to that question?
6
DR. SHAH: No. I think we can take it to
7 the
agency, but I think it's a policy issue, and I
8
think they will have to consider that.
9
DR. GROSS: Okay.
10
PARTICIPANT: [Inaudible comment
off
11
microphone]--once you do that, [inaudible] same
12
product, and then you have to standardize it across
13 the
board. One manufacturer makes it this
shape,
14
another makes a different shape, [inaudible].
15
DR. SHAH: I was just making the
same
16
point, that, you know, if you are just going to
17
rely on the shape, oh, this particular shape is
18
associated with this drug product and somebody
19
decides to make for some other drug product a
20
similar shape, then we are still going to have a
21
similar problem.
22
DR. GROSS: Brian?
145
1
DR. STROM: Just involved with the
shape
2
thing, I think it's probably--I'd be interested in
3
Michael's answer, but my reaction is it's similar
4
probably to the color issues, which I think is what
5
Michael is suggesting. To the
degree you give
6
people an alternative cue, they'll use that cue
7
instead of the name, and you're more likely to have
8
errors, therefore, because people are using that
9 cue
instead of the name. I would rather
people
10
have to use the name but it be legible.
They're
11
less likely to make errors, I think.
But, again,
12 you
know, I'd like to see data.
13
DR. STEMHAGEN: I was thinking
that we're
14
trying to squeeze a lot of information on a small
15
thing. If it were bigger, you'd
have a little bit
16
more space to make the print larger.
That's where
17 the
size issue was--
18
DR. GROSS: Let me see if I can
summarize
19 the
sense of the group on the embossed issue:
If
20
embossing is to be continued, it should be done
21
where the drug name and dose is much larger print,
22 and
yet we still have to consider what to do about
146
1
expiration date and lot number, although that could
2 be
smaller. Is that sort of the sense of
the
3
group?
4
PARTICIPANT: Yes.
5
DR. GROSS: Okay. Let's go to number two,
6
unit package overwrap. Anyone
want to comment on
7
that? Yes, Jackie?
8
DR. GARDNER: As mentioned
earlier, I
9
favor this one in conjunction with the former so
10
that the embossed product that's inside would also
11
have the larger, more legible features that were
12
mentioned in bullet number one, and this would give
13 us
the opportunity for a good deal more in the way
14 of
information, identification, and bar coding.
15
DR. GROSS: Henri?
16
DR. MANASSE: I would urge us or
urge the
17
agency and the manufacturing industry to explore a
18
mechanism whereby that outer overwrap cannot be
19
separated until actual use of the drug from the
20
original vial. So when you rip
off the outer wrap,
21
that then opens the package for use.
22
DR. GROSS: So your comment
addresses the
147
1
issue brought up by many of the respiratory
2
therapists that they'll take it out of the wrap and
3 put
all of them in a jumble in their pocket, and
4
then the wrap is sort of useless for
5
identification.
6
DR. MANASSE: Exactly.
7
DR. GROSS: I don't know if
that's--I
8
guess anything's mechanically possible to attach
9 the
two.
10
Any other comments on the wrap?
Michael?
11
DR. COHEN: Just I absolutely
agree with
12
what Henri was saying about, you know, having a
13
foil wrap but being able to tear it at the same
14
time as you open the container.
15 And just to point out that I have
16
absolutely no doubt that people will remove--unless
17 we
do that, people will remove them from the
18
overwrap. We've seen that with,
you know, nurses
19
administering drugs that are packaged in cartons,
20 for
example, and sent as unit doses or some other
21
type of outer wrap.
22
DR. GROSS: Okay. So the sense of the
148
1
group is that the unit package overwrap is a
2
reasonable idea, but we still have to deal with the
3
issue of it being discarded well before the drug is
4
administered. Is that fair
enough? Well, the new
5
data curmudgeon's comments, Jackie, about having
6 more
data, we all agree with.
7
[Laughter.]
8
DR. GROSS: Okay. The next is the
9
printed, elongated bottom tabs. I
know the one I
10 saw
that I liked with the refresh label. The
black
11
writing, although small, was pretty clear, even for
12
these eyes. Any other
comments? Can you see it,
13
Arthur?
14
[Laughter.]
15
DR. GROSS: Okay. Any other comments?
16
DR. STROM: Is there a concern
about
17
leaching in that setting?
18
DR. GROSS: Dr. Shah, could you
answer
19
that? If you put a printed label
on the tab
20
attached to the main vial, I guess it's
21
theoretically possible that some of that print
22
could eventually leach in, but it's less likely.
149
1
DR. SHAH: Again, if that is in an
2
overwrap pouch and then it is a closed environment
3 and
if there are volatile solvents into the glue
4
which has been used, then, yes, that is a
5
possibility. That will be exactly
the same thing.
6
Instead of the close contact, it is a little bit
7
away, but it still will have that possibility.
8
DR. GROSS: Okay. Any other comments on
9 the
elongated tabs? Do people like them?
10
DR. STROM: Let me suggest, maybe
this is
11 a
summary, I think, of the sense that they look
12
attractive, but if they raise the same concern
13
about leaching, they're no advantage.
So what's
14
needed before a decision is made is a similar study
15 to
the kind that you did with the marketed products
16 to
find out if, in fact, there's leaching, given
17
what we're hearing is it's just theoretical.
18
DR. GROSS: Right. More data.
19
DR. CRAWFORD: Dr. Gross?
20
DR. GROSS: Yes, Stephanie?
21
DR. CRAWFORD: Could I just add
that I
22
think and the sentiment of the committee right now
150
1 is
that we're not making a recommendation for this
2
because we don't have evidence that it won't cause
3
more problems than it solves for this particular
4 one.
5
DR. GROSS: So we need some data
before a
6
sense can be formed, and that, you know, probably
7
applies to almost everything that we're going to
8
comment on.
9
Okay. Paper labels, not glued to
the tab
10 but
glued to the actual vial where the medication
11
is. Any comments on that?
12
DR. HENDELES: Isn't there a
problem with
13
that?
14
DR. GROSS: Oh, well, this is what
we're
15
supposed to say, yes. Right. So Leslie's vote
16
is--
17
[Laughter.]
18
DR. GROSS: Leslie's vote is,
hello,
19
there's a problem.
20
[Laughter.]
21
DR. GROSS: Okay, Michael?
22
DR. COHEN: Obviously there's a
concern
151
1
about the safety at this point. I
should point
2
out, though, that whether we put labels on it or
3
not, I think in some cases with unit-dose drug
4 distribution,
the pharmacy is going to put labels
5 on
them of their own. So that's going to
probably
6
seep in if we don't do something to change it
7
otherwise.
8
DR. GROSS: Okay. So the--yes, Henri?
9
DR. MANASSE: Michael raises a
really
10
important point which hasn't been part of the
11
dialogue today. As manufacturers
decrease the
12
production of unit-dose packaged drugs, it forces
13
hospitals into being in the packaging business.
14 And
most hospitals are not experts in packaging,
15
and, consequently, this issue of the leaching and
16 the
paper label attachment is probably a warning
17
that has to go out to hospitals who do engage in
18 the
packaging business, because we've now
19
introduced a packaging phenomenon that's not well
20
understood.
21
DR. GROSS: Leslie?
22
DR. HENDELES: By extension, then,
152
1 pharmacists in the community who compound
nebulizer
2
solutions need to have that same warning. It
3
shouldn't be just in the hospital because that's a
4
whole other problem that's outside the control of
5 the
FDA. But, still, if there's a potential
6
problem with commercial products, it's equally a
7
problem with compounded nebulizer solutions.
8
DR. GROSS: Yes, Arthur?
9
MR. LEVIN: I want to follow up
because I
10
always thought we were hardly using unit-of-use
11
packaging from manufacturers as a source compared
12 to
everywhere--it's one of these things, America
13
versus everywhere else in the world where
14
unit-of-use packaging is the standard.
And you're
15
saying it's getting--actually, there's less
16
unit-of-use packaging being delivered by--which is
17
really troubling. You know, if
that's the trend,
18
then looking at solutions that are dependent on
19
manufacturers to do the right thing is crazy,
20
because then we need to really be looking at where
21
they get--at the repackaging problem.
So, I mean,
22 I
think that's another piece of data that we need
153
1 to have, that if we're looking to have
2
manufacturers use unit-of-use packaging as part of
3 the
solution or most of the solution to the
4
problems we're discussing, and indeed they're doing
5
less and less of that and there's repackaging at
6 the
community pharmacy level, the mail-order
7
pharmacy level, or at the hospital or other
8
dispensing level, then all of this is besides the
9
point. So we need to know more
about that.
10
DR. GROSS: Michael, another
comment?
11
DR. COHEN: The term unit of use
is
12
different than unit dose. We were
speaking about
13
unit dose, meaning the individual dose for that
14
patient. Unit of use would be
package that
15
contains perhaps a supply of medications just for
16
that patient.
17
DR. GROSS: Okay. So the sense of the
18
group with paper labels seems to be it's less than
19
ideal and it's probably something that should be
20
avoided. But, once again, there
is no data to show
21 the
human toxicity from the observed leaching of
22
compounds, and that would just make, you know, life
154
1
easier if it was at all possible to get that, which
2 it
may not be.
3
Ink without label is probably even worse
4
than paper labels, but, Curt, did you want to say
5
something?
6
DR. FURBERG: I just want to say
that for
7 the
paper labels, is it possible to have a warning
8 box
like we have for drugs, warn against using
9
paper labels directed at the pharmacists.
10
DR. GROSS: Gene?
11
DR. SULLIVAN: You're saying that
if
12
manufacturers proceeded--or continued to use
13
embossed or debossed and the pharmacist chose--they
14
thought it was best to take their own label and
15
stick it on?
16
DR. FURBERG: Yes, that's
correct. I
17
mean, have you ever addressed that, warnings
18
directed at the middleman, the pharmacist, rather
19
than at the health care provider and the patient,
20
warn them against doing things to the vial?
21
DR. SULLIVAN: Right. I think--
22
DR. FURBERG: Any label, doing
whatever,
155
1
removing the overwrap, et cetera.
2
DR. SULLIVAN: You're right. It seems
3
unwise for people who are not expert to be using
4 materials
that are not well characterized and
5
applying them directly to a permeable container
6
closure system, and certainly that is something
7
that--a practice that shouldn't be undertaken. I
8
think that we're today trying to talk about what to
9 ask
the manufacturers to do in regards to what they
10 can
do to improve the legibility so that perhaps
11
pharmacists won't feel compelled to do what maybe
12
they are doing.
13
DR. SHAH: Can I add to that? Especially
14 on
the labeling, there is clearly a warning that
15
says open just prior to use, so they are not
16
supposed to remove it from the container.
17
DR. FURBERG: You can add to that.
18
DR. SHAH: Yes, we can add it, but
this is
19
just the practice and that's what happens, I guess.
20 And
I guess at that point I don't think the agency
21 has
a control over that, and I think that's another
22 way
to educate the people and then get the message
156
1
around, I would think.
2
DR. SULLIVAN: It's been our
informal
3
assumption that if they were individually wrapped,
4 it
would greatly decrease the likelihood of
5
respiratory therapists, you know, going in the
6
morning and unwrapping 20 and then putting them in
7
their pocket to care for patients through the day.
8 I
think that's probably less likely, and we could
9 get
some input from the speaker from the
10
Respiratory Care Association.
Intuitively, it
11
seems less likely that would occur.
I think you
12
can't, just as you can't--you know, patients at
13
home may take out five pills from their bottle and
14
they're divorced from the labeling, that could
15
happen. It's been our assumption
that it would be
16
much less likely if there was just one vial per
17
pouch.
18
DR. FURBERG: But you could still
use the
19
overwrap to have a warning.
20
DR. GROSS: Karen?
21
MS. STEWART: [Inaudible, off
microphone.]
22 I
think if it--the problem comes when they package
157
1
multiple [inaudible].
2
DR. GROSS: This is another
favorable push
3 for
a unit package overwrap.
4
Is there anyone who would like to speak in
5
favor of ink without label directly on the LDPE
6
vial? Michael?
7 DR. COHEN: I don't want to speak in favor
8 of
it, but one of the examples that was shown was
9 an
injectable with the ink embossed--or printed
10
right on the label. That was the
Naropin
11
injection. And I'm wondering, you
know, if there's
12 a
concern with patients with respiratory disorders,
13 is
there a concern with systemic use of a drug like
14
that? Do we know anything about
that, as a matter
15 of
fact?
16
DR. SULLIVAN: So the question is: Is
17
there a difference in our concern regarding the
18
level of contaminants? I think
from a
19
pulmonologist's perspective there is, that
20
particularly because of the nature of the patients
21 we
treat, who can be very sensitive--you know, I
22
touched on it my talk. We haven't
spoken too much
158
1
more about it, but patients that actually develop
2
specific immunity. So they're
allergic to things,
3 and
atopic patients, asthmatics, are more likely to
4
develop specific immunity, and probably
5
physiologically, humans are more likely to develop
6
specific immunity when drugs are administered by
7 the
inhalation route than by other routes, like
8
oral or even IV. So I understand
your point about
9
separating these drugs. The issue
of there being
10
multiple routes of administration is important
11
because you mix up between the routes.
12
The specific concern about the chemical
13
impurities to me is particularly important for
14
inhalation drugs.
15
DR. COHEN: I guess it leads me to
ask the
16
question then: Will you allow--I
mean, we have
17
already several injectable products in this type of
18
plastic. There will be saline and
heparin and, you
19
know, various products like that.
And I'm
20
wondering, I guess, if you would allow then the use
21 of
ink on these containers, because that would
22
solve our problem if there's no concern at FDA for
159
1 the
ink and the volatiles from the ink. With
2
systemic use.
3
DR. GROSS: Yes, Brian?
4
DR. STROM: Speaking not as a
5
pulmonologist but a general internist, I worry
6
about IV injection of contaminants more than
7
pulmonary. I mean, yes, it may be
less sensitizing
8
perhaps than the lungs, but, still, IV injection of
9
contaminants I would think would be at least as
10
worse.
11
DR. SULLIVAN: Well, I mean, of
course,
12 all
the products are carefully controlled, and I
13
don't have the expertise--maybe Dr. Shah
14
does--about the particular controls that are put on
15
oral products or IV products. But
we very closely
16
control inhalation products because of the issues
17 of
irritants and because of the issues of
18
sensitization. And which is a
greater risk I guess
19 I
won't firmly state, so--
20
DR. GROSS: The sense of the group
seems
21 to
be, in the absence of human data of actual risk,
22 our
recommendation would be to avoid the ink
160
1
without label directly on the vial containing the
2
medication. Is that fair? Anybody disagree with
3
that?
4
DR. COHEN: I have a--
5
DR. GROSS: Michael disagrees.
6
DR. COHEN: These types of
packages are
7
used widely in other countries for parenteral
8
medications, and I don't know that there's been
9
anything ever reported, you know, as an adverse
10
effect specifically tied to the inks.
I don't
11
know. But, you know, I express
the same concern
12
that Dr. Strom has. If there's
any evidence at all
13
that there's leaching of the ink through the
14
plastic, through the semipermeable membrane, that
15
would be a concern systemically.
I just didn't
16
know.
17
DR. GROSS: Leslie?
18
DR. HENDELES: There's actually
precedent
19
with sulfites and tartrazine, other substances in
20
medications that cause reactions in selected
21
patients. So I think if there's
any way of
22
avoiding putting something in that you don't know
161
1 to
be safe, you should avoid it because there are
2
examples of other contaminants causing the reaction
3
than the drug.
4
DR. GROSS: The question is for
the
5
specific ones, do we know them to be unsafe? Yes,
6
Brian?
7
DR. STROM: I guess my sense in a
8
data-free world that we're operating in here is to
9
share the concern that you expressed, Peter, of a
10
consensus of let's not use it here because of the
11
risk of contaminants. But I would
take that
12
further in two ways. One is I
would extend that
13 for
intravenous use; and, second, I would call for
14
data. It would be nice to know if
any of these
15
things mattered, not just in terms of measuring
16
contaminants but even in animal studies, if we
17
can't identify it.
18
I would think in the respiratory situation
19
would be one of the hardest places to get data on
20 the
clinical importance of them. But perhaps
in an
21
intravenous setting, it might be more possible to
22 get
some data in terms of different products of the
162
1
same drug, for example, that have ink on the label
2
versus don't have ink on the label and is there a
3
difference in subsequent allergic reactions to
4
them.
5
DR. GROSS: Okay. The next one is tactile
6
recognition, use of textures on the LDPE vials.
7
Anyone want to comment on that?
And maybe could
8
someone from the FDA elaborate on what you mean by
9
textures. Do you mean smooth
versus rough? Or do
10 you
mean feeling the letters? What's meant
by
11
that?
12
MS. HOLQUIST: A combination of
any of
13
those things, by using the type of letters that you
14 can
feel, by the different shapes, or should we
15
make the vial feel from for different products? We
16
just threw it out there as another suggestion.
17
DR. GROSS: Jackie?
18
DR. GARDNER: It seems that the
point that
19 was
brought up about standardization with various
20
manufacturers applies here as well and should be
21
considered.
22
DR. GROSS: Good point.
163
1
Michael?
2
DR. COHEN: Again, I'll join the data
3
camp. I don't think we know much
about the tactile
4
cues. I mean, from a human factor
standpoint it
5
certainly makes sense, but using them on actual
6
drug products, I don't know of any history with
7
other products where that's been successful.
8
Perhaps the shape of the container as a
9
tactile cue, the octagonal shape, the hexagonal
10
shape, et cetera, square. We used
to do that with
11
insulin vials, for example. That
might have been
12
effective. But if that's the
case, I don't think
13 you
have enough different shapes that could be
14
used, and it also puts burdens on the manufacturers
15 and
elevates the cost when you have these different
16
shapes.
17
DR. GROSS: Again, a suggestion to
the FDA
18
from a research point of view.
When we had that
19
conference--I guess it's almost a year ago now--on
20
look-alike, sound-alike drugs and someone spoke on
21
human factor engineering, it might be interesting
22 to
get some input from that kind of person and have
164
1
them test some of these issues.
2
Brian?
3 DR. STROM: I would also echo my comment
4
before, like with color. Anything
that takes
5
people--there aren't enough options in textures in
6
order to replace the use of names.
And anything
7
that removes people's attention from the drug name
8 I
think might be more likely to cause problems than
9
less, though, again, that's supposition without
10
data to prove that.
11
DR. GROSS: That brings up an
issue that
12 the
Joint Commission has dealt with on using two
13
patient identifiers. Should
there--you're
14
suggesting you'll confuse people, and, you know,
15
does that rule apply at all to drug use that there
16 be
two kinds of identifiers, or at least not
17
another identifier that might confuse them?
18
DR. STROM: I guess my--I think
the
19
difference versus the Joint Commission situation,
20 the
Joint Commission is asking for two unique
21
identifiers for the patient. What
we're talking
22 about
here would be one unique identifier, which is
165
1 the
name, and another unique identifier, the
2
texture or the color--which isn't unique. There
3
aren't enough unique options in order to make it
4
unique. If it really was possible
to have--you
5
know, how many products are we talking about here,
6 30,
40? There aren't that many
textures. And if
7 it
were really possible to have enough unique
8
colors or unique textures, you might think about
9
that, though I would still think then training
10
people to remember which texture corresponds to
11
which name would be hard as well.
12
So it's different than the Joint
13
Commission situation where you're talking about a
14
patient's name, which is unique to that patient,
15 and
both identifiers have that same name.
The
16
equivalent here would be having the drug name both
17
embossed and also on the overwrap.
And we are
18
suggesting that that makes sense here.
19
DR. GROSS: So the sense of the
group
20
seems to be that tactile recognition is not
21
recommended and may confuse. Does
anybody disagree
22
with that?
166
1
[No response.]
2
DR. GROSS: Okay. The next item is shrink
3
wrap labels as an example that was circulated
4
around, and not attached to the LDPE vial itself
5 but
to a tab or an appendage attached to the vial.
6 Is
that what the FDA means by that? Anybody
have
7 any
comments? Michael?
8
DR. COHEN: This would be my
number one
9
preference, as I mentioned before, because it gives
10 you
so much flexibility. You can easily see
the
11
black type on a white background.
You can put bar
12
codes on it, et cetera. But, you
know, I have a
13
concern if FDA has a concern about the volatility
14 of
those inks, except, you know, I'd love to see
15 the
studies that you were talking about because it
16
just seems to me that this is not an ink that is in
17
direct contact with the LDPE plastic.
It's on the
18
overwrap itself. I understand that
it still might
19 be
volatile within that micro environment, et
20
cetera, but it might be at a level that's not even
21
close to, you know, causing a problem.
I just
22
don't know. But I'd love to see
the studies.
167
1
MR. LEVIN: Just a point of
information.
2 I
would guess that there are inks and there are
3
inks. Are there vegetable dye
inks? Are there
4
different kinds of inks that may increase or lessen
5 the
potential toxicity?
6
DR. SHAH: Yes, as I mentioned in
my
7
presentation, there are water-based inks and there
8 are
organic solvent-based inks. So if you
have
9
carefully selected ink formulations in which you do
10 not
have volatile components, then there is pretty
11
much not any likelihood of any volatile to be
12
present in the ink formulation that may migrate to
13 the
vial. So that is a possibility. People can
14 think
about that.
15
MR. LEVIN: Is that something that
the
16
agency could stipulate, that inks used--I mean, for
17
example, if this was the model and then further
18
stipulate that inks used would have to not--you
19
know, would not contain volatile substances to
20
minimize risk? It's a question.
21
DR. SHAH: I don't know. I will have to
22 ask
our, you know, upper office and then find out
168
1
about that. I'm not sure about
that.
2
DR. GROSS: Any other
comments? Yes,
3
Brian?
4
DR. STROM: I just want to echo
the
5
comment that in many ways this is attractive. It
6
just would be nice to see before that the kind of
7
studies of contaminants that we saw before
8
deciding. So I guess my
recommendation would be a
9
conditional, this is preferable after those studies
10 are
done. Without those studies being done,
we
11
don't know that this is any better than the current
12
approach in terms of leakage.
13
DR. GROSS: And that's part of one
of the
14
requests, that whatever we recommend doesn't create
15
additional problems. So we do
need that data.
16
Okay. So what Brian said I think
sums up
17
what the group thinks. Fair
enough? Okay.
18
The last is glass ampules, and perhaps
19
someone could comment from the FDA or Michael or
20
anyone, why did we move away from glass ampules in
21 the
first place to plastic? Was it accident
prone
22 or
what?
169
1
DR. COHEN: I'm sorry. I raised my hand
2
too--I don't know why we moved away from it, but
3 I'd
hate to be a respiratory therapist if I had to
4
crack open all those glass ampules.
5
DR. GROSS: Right. So it's an accident
6
issue.
7
MS. HOLQUIST: Also, I think it
lends to
8
errors, as you saw by Marci's slide with the
9
acetylcysteine where it comes in an IV route and a
10
respiratory route, and so it was confused because
11 it
looked like an IV product.
12
DR. GROSS: Okay. Any other comments on
13
glass? Brian?
14
DR. STROM: In follow-up to that
comment,
15
should we think about a recommendation that the
16
plastic--especially if the plastic is being widely
17
used now in respiratory and it's not being widely
18
used elsewhere but beginning to, that, in fact,
19
that distinction--we're talking about tactile and
20
whatever--be kept clean, i.e., that the plastic be
21
used for respiratory and for parenteral use it be
22
glass?
170
1
MS. HOLQUIST: I think it's a good
2
recommendation, but, again, it's something we have
3 to
bring back to the agency and provide to all the
4
other review divisions that are involved. It's not
5
just the pulmonary division.
6
DR. GROSS: Okay. I guess you're all
7
getting hungry. I'm not sure if
lunch is here, but
8
we'll probably break pretty soon.
9
Annette, did you have a comment, or
10
anybody?
11
[No response.]
12
DR. GROSS: Okay. So the sense then is
13 the
last comment that Brian made, if glass is used
14 at
all, there probably should be a distinction that
15 plastic
be used as pulmonary inhalation medication
16 and
glass be used for other uses, such as
17
intravenous use. Is that fair?
18
[No response.]
19
DR. GROSS: Okay. Why don't we take a
20
break and we'll address 1b, 2, and 3 afterwards.
21 We
have an hour for lunch.
22
[Luncheon recess.]
171
1 AFTERNOON SESSION
2 [12:50 p.m.]
3
DR. GROSS: Okay. We will begin where we
4
left off, and that is Item 1b.
The question was:
5
Please identify creative solutions or alternative
6
packaging designs that improve legibility and
7 address
the problem of ingress of chemical
8
contaminants, and at the same time, do not create
9 new
problems.
10
Would anyone like to comment?
Leslie?
11
DR. HENDELES: How about tying a
ribbon
12
around the end of the plastic vial, and on that
13
ribbon you can imprint "Albuterol, 0.083 percent."
14
DR. GROSS: I don't know whether
to say
15
thank you or less levity.
16
[Laughter.]
17
DR. HENDELES: Yellow ribbon.
18
DR. GROSS: Okay. So you're tying a
19
yellow ribbon around the medication.
20
DR. HENDELES: Yellow for
Ipatropium, red
21 for
Albuterol.
22
DR. GROSS: All right. That's a creative-
172
1
DR. HENDELES: Red and yellow for
the
2
Duovent.
3
DR. GROSS: Okay. Are there any other
4
creative suggestions? Jackie?
5
DR. GARDNER: You know, there are
6
thousands, and I have information that the
7
manufacturers are actually working on some of them.
8 And
so I think rather than trying to come up with
9
good ideas, however good that was, Les, maybe what
10 we
should do is encourage the people who have the
11
most to gain from this to bring forward creative
12
solutions that put all these objectives into play
13 and
give us some things to choose from--maybe not
14
today but when they're ready--because they will
15
have tested them as well.
16
DR. GROSS: Like we saw this
morning,
17
okay.
18
Henri?
19
DR. MANASSE: I think as we
consider new
20
options and new directions in this area, I would
21 hope
that the industry and the FDA would very
22
carefully consider symbologies that are
173
1
electronically readable for patient verification.
2 I
think the system is moving in that direction.
3
There are available technologies for that
4
verification, and particularly patient-level
5
verification. Adding these
technologies is going
6 to
be important. I know what the issues are
in
7
terms of the bar code and the size of the bar code,
8 but
there are other symbologies that can be
9
applied, like dot matrix technologies, et cetera,
10
that wouldn't take the kind of space.
But as we
11 get
creative in this packaging, I think we should
12 be
real sensitive and help motivate and move the
13
verification mechanisms along.
14
DR. GROSS: Any other
comments? Yes, Art?
15
MR. LEVIN: Just to reiterate the
16
importance of also looking at the community
17
pharmacy, ambulatory population, including the
18
elderly, that use these products where the
19
solutions may have to be different, frankly, than
20
they are in the inpatient clinical setting. And
21
remember that that's probably an increasing
22
population of use, and that we need probably to
174
1
look at the research that's going on now in health
2
literacy and cultural competency, et cetera, et
3 cetera--in
other words, a very broad view of what
4 we
need to know and sort of think out of the box on
5 how
to make this happen.
6
DR. GROSS: I think that's a very
good
7
point. Just like they say
children are not little
8 adults, the elderly are not young adults,
and we
9
have different considerations for all those groups.
10
I'm amazed--oh, thank you, Brian, for
11
coming up with something.
12
[Laughter.]
13
DR. STROM: I just wanted to
return to
14
Leslie's comments about the relative benefit and
15
safety of these products as a class versus the MDIs
16 and
whether there should, in fact, be at least
17
labeling comments or instructions that might
18 provide some of the alternative data or in
some way
19
begin to push the field toward using the safer
20
alternatives instead.
21
DR. GROSS: Okay. There being no more
22
comments for Item 1b, we'll move to number 2.
175
1
Please consider which stakeholder groups--we've
2
discussed some of this already, but we should
3
emphasize it now--be they manufacturers,
4
practitioners, consumers, or others, can best
5
advise the FDA about possible new packaging
6
configurations that may resolve the issues we've
7
discussed.
8
Jackie already suggested we should
9
encourage the manufacturers themselves to do this.
10 And
consumers.
11
Yes, Henri?
12
DR. MANASSE: Peter, I again want
to
13
reiterate I think we ought to bring in the cosmetic
14
industry packaging people. They
have done some
15
incredibly innovative things in packaging.
16
I think another sector that has a lot of
17
experience in packaging has been the Department of
18
Defense as we look at pouching food, for example,
19 and
sustaining it and everything else. So I
think
20 our
colleagues in the military may be helpful here
21 as
well.
22
DR. GROSS: I heard someone say
space,
176
1
involve NASA.
2
DR. MANASSE: NASA.
3
DR. GROSS: Okay. Leslie?
4
DR. HENDELES: In regards to the
5
consumers, there are two lay organizations of
6
people interested in asthma. One
is Mothers of
7
Asthmatics, and the other one slips my mind. But
8
there are two organizations, and getting their
9
input might be worthwhile. I can
e-mail you the
10
name of that second organization.
11
DR. GROSS: Fine. Michael?
12
DR. COHEN: I just want to say
whatever
13
anyone comes up with, I really think it will be a
14
great idea to involve organized respiratory
15
therapy, organized pharmacy, and probably--I don't
16
know if FDA can do this, similar to what they do
17
with the drug names, as we heard at the last DSaRM
18
Committee meeting, the idea of failure mode and
19
effects analysis for any of these packaging changes
20
that are made to make sure that--or minimize the
21
chance that there might be a
22
medication-error-related problem with them.
177
1
DR. GROSS: Yes, a rigorous FMEA
approach
2
could be very helpful.
3
Yes, Curt?
4
DR. FURBERG: I just wonder
whether this
5 is
a unique problem in the U.S. If it's
not, let's
6
check and see what other countries are doing, other
7
regulatory agencies, other countries.
8
DR. GROSS: Okay. Good point.
9
Brian?
10
DR. STROM: One of the things we
talked a
11 lot
about this morning is the need for additional
12
data here. Some of it clearly
needs to be
13
generated by the manufacturer, but I wonder if
14
there might be funding agencies--ARC, for
15
example--more applied perhaps to CERTs.
Perhaps
16
there's people in the CERTs who might be interested
17 in
studying some of these issues.
18
DR. GROSS: Good idea.
19
Michael?
20
DR. COHEN: Just think a little
bit more
21
about that. It isn't even just
these products.
22
It's other medication-error-related problems with
178
1
labeling, packaging, you know, where is color
2 appropriate,
all that kind of stuff. It would just
3 be
so helpful beyond this if we could get the right
4
research done. It just doesn't
seem like things
5
have been moving in that direction for whatever
6
reason.
7
DR. GROSS: Curt?
8
DR. FURBERG: One way of getting
research
9 is
to set up a meeting and invite people to come
10 and
present, and maybe it's time now to have a
11
two-day workshop on these packaging issues and
12
invite industry representatives, scientists, and
13
others. It's one way of advancing
knowledge.
14
DR. GROSS: Like was done for
look-alike,
15
sound-alike names a year ago.
16
Brian?
17
DR. STROM: Following up on Mike's
idea of
18
broadening the question, if the question were broad
19
enough, you might be able to get the right group at
20 NIH
to be interested, focusing not so much on the
21
specifics of the drug and the drug label because
22 they're
not going to care about that in the drug
179
1
labeling, but issues of patient perception
2
and--well, safety is really an ARC issue. NIH
3
isn't interested in patient safety.
But it's--but
4 NIH
would be more interested in sort of
5
understanding patient perceptions and, you know,
6
what is it that--you know, issues of color and
7
tactile and sort of, you know, more broader,
8
definitive, and maybe the National Institute of
9
Mental Health, maybe issues--maybe the NHLBI given
10 the
importance of this for respiratory, but NHLBI
11
probably would care less about that kind of thing.
12 But
NIMH or the National Institute of Nursing
13
Research might be another that might be interested.
14
Another might be NIA, actually, the National
15
Institute of Aging, which has a pharmacology
16
program and the issues here in terms of the elderly
17
being able to read labels correctly and perceive
18
drugs correctly would be a big one.
So in terms of
19
looking at sort of who could potentially fund this,
20
fund the necessary collection of data in a way that
21 FDA
can't, the NIA might be a logical one.
22 DR. GROSS: Any other comments?
180
1
[No response.]
2
DR. GROSS: Well, that was very
creative.
3
Thank you. That was very helpful.
4
The last question, number 3,
is: Given
5
what you have heard today, please describe an
6
appropriate course of action to address the
7
problems of ingress and medication errors due to
8
legibility and similar packaging issues.
9 Henri?
10
DR. MANASSE: Peter, I'd like to
focus on
11 the
ingress issue. I guess I'm impressed by
how
12
little we know about ingress in these kinds of
13
plastics, the kind of chemicals that are creating
14 the
problem, the impacts that the ingress has on
15
active ingredients. And it seems
to me that FDA
16
ought to be stimulating knowing more about this and
17
then from that making a determination as to whether
18 or
not the appropriate statutory and regulatory
19
things are in place to be able to pursue requests
20
about these issues, particularly the toxicities,
21
through the application processes and the master
22
file, et cetera.
181
1
DR. GROSS: Leslie?
2
DR. HENDELES: I recommend that
the agency
3
just revise that draft guidance to take into
4
account some of the issues that we discussed under
5
1a. I mean, I think that would be
the appropriate
6
direction.
7
DR. GROSS: Okay. Art?
8
MR. LEVIN: As we encourage
manufacturers
9 to
be innovative in finding solutions, I'm worried
10
about the issue of standardization because I think
11
when everybody's looking at error prevention,
12
standardization is certainly one of the big fix
13
items. So I'm just raising the
question of how do
14 we
balance the tension between innovative solutions
15 and
creating industry standards so that we don't
16
have ten different ways that people are doing
17
things, causing even more confusion than we have
18
now. And I think it speaks to
Henri's point about
19 how
the agency perceives its authority to require
20
standards. Once finding the gold
standard, then
21
what does the agency do with that, and does it need
22
additional authority, for example, to require that
182
1 that be the gold standard for all of these
products
2
which have basically been out there on the market?
3
They're not going to be new drug applications. But
4
could they go back and say, In the future over a
5
period of time we expect you to convert to this
6
gold standard of packaging?
7
DR. GROSS: Any other comments?
8
[No response.]
9
DR. GROSS: Okay. Well, I want to thank
10 the
presenters as well as the Advisory Committee
11
members for this thoughtful exchange of
12
information. And at this
particular point, we are
13
going to adjourn for a bit because the Lotronex
14
part of the agenda was scheduled to begin about 3
15
o'clock. I think we'll be able to
begin at 2:30.
16 Is
that it? 2:20. Okay.
17
If there's any change in that, we'll get
18 the
word around because everybody's staying pretty
19
close. Okay. Thank you.
20
[Recess.]
x DR. GROSS: Good afternoon. I think we'll
21
22
call the meeting to order. I'd
like to begin by
183
1
reintroducing the people who are sitting around the
2
table because we have a new group as part of the
3
open public hearing. So if we can
begin--oh, there
4 he
is. Next to Brian is?
5
DR. KRIST: My name is Alex
Krist. I'm
6
with Virginia Commonwealth University.
I'm a
7 member
of the Gastrointestinal Drugs Advisory
8
Committee, and I'm a family physician.
9
DR. GROSS: Brian?
10
DR. STROM: Brian Strom,
University of
11
Pennsylvania.
12
DR. MANASSE: I'm Henri
Manasse. I'm the
13
executive vice president and chief executive
14
officer of the American Society of Health-System
15
Pharmacists.
16
MS. SHAPIRO: Robyn Shapiro,
Director,
17
Center for the Study of Bioethics, Medical College
18 of
Wisconsin.
19
DR. STEMHAGEN: I'm Annette
Stemhagen from
20
Covance, a contract research organization, and I'm
21 the
industry representative to this committee.
22
DR. GARDNER: Jacqueline Gardner,
184
1
University of Washington, Department of Pharmacy.
2
MR. LEVIN: Art Levin, Center for
Medical
3
Consumers, and I am the consumer member of this
4
committee.
5
DR. FURBERG: Curt Furberg,
professor of
6
public health sciences at Wake Forest University.
7
DR. GROSS: Peter Gross. I'm Chair of
8
Medicine at Hackensack University Medical Center
9 and
New Jersey Medical School, and I'm Chair of
10
this Advisory Committee.
11
MS. JAIN: Shalini Jain, Executive
12
Secretary, Drug Safety and Risk Management Advisory
13
Committee.
14
DR. CRAWFORD: Stephanie Crawford,
15
University of Illinois at Chicago, College of
16
Pharmacy.
17
DR. SELIGMAN: Paul Seligman,
Director,
18
Office of Pharmacoepidemiology and Statistical
19
Science, Center for Drugs at the FDA.
20
DR. BEITZ: Julie Beitz, the
Deputy
21
Director in the Office of Drug Evaluation III in
22
CDER.
185
1
DR. JUSTICE: Robert Justice,
Director of
2
Division of Gastrointestinal and Coagulation Drug
3
Products at FDA.
4
DR. TRENTACOSTI: Ann Marie
Trentacosti,
5
Medical Officer, Division of Gastrointestinal and
6
Coagulation Drug Products at the FDA.
7
DR. AVIGAN: Mark Avigan, Director
of the
8
Division of Drug Risk Evaluation in the Office of
9
Drug Safety.
10
DR. GROSS: Okay. Shalini Jain will read
11 the
conflict of interest statement.
x MS. JAIN: The following announcement
12
13
addresses the issue of conflict of interest with
14
regard to this meeting and is made a part of the
15
record to preclude even the appearance of such at
16
this meeting. Based on the
submitted agenda for
17 the
meeting and all financial interests reported by
18 the
committee participants, it has been determined
19
that all interests in firms regulated by the Center
20 for
Drug Evaluation and Research present no
21
potential for an appearance of conflict at this
22
meeting with the following exceptions:
186
1
In accordance with 18 U.S.C. 208(b)(3),
2 Dr.
Brian Strom has been granted a waiver for
3
consulting with two competitors on unrelated
4
matters. He receives less than
$10,001 per year
5
from one firm and between $10,001 and $50,000 per
6
year from the other.
7
Dr. Maria Sjogren has been granted a
8
waiver under 208(b)(1) for consulting with the
9 sponsor
on unrelated matters. She receives less
10
than $10,001 per year.
11
A copy of the waiver statements may be
12
obtained by submitting a written request to the
13
agency's Freedom of Information Office, Room 12A-30
14 of the
Parklawn Building.
15
We would also like to note that Dr.
16
Annette Stemhagen has been invited to participate
17 as
an industry representative, acting on behalf of
18
regulated industry. Dr. Stemhagen
is employed by
19 Covance
Periapproval Services, Incorporated.
20
In the event that the discussions involve
21 any
other products or firms not already on the
22
agenda for which an FDA participant has a financial
187
1
interest, the participants are aware of the need to
2
exclude themselves from such involvement, and their
3
exclusion will be noted for the record.
4
With respect to all other participants, we
5 ask
in the interest of fairness that they address
6 any
current or previous financial involvement with
7 any
firm whose products they may wish to comment
8
upon.
9
Thank you.
10
DR. GROSS: Dr. Paul Seligman will
give an
11
introduction to the Lotronex issue.
x DR. SELIGMAN: Good afternoon. It is my
12
13
pleasure to introduce the second topic for today's
14
meeting. This afternoon we'll be
hearing an update
15 on
the Lotronex Risk Management Program. On
April
16 23,
2002, the Gastrointestinal Drugs Advisory
17
Committee and this committee met and recommended
18
reintroduction of Lotronex tablets to the market
19
with certain restrictions, such as having patient
20 and
physician registries and physician
21
certification training for prescribing.
22
On June 7, 2002, FDA approved the
188
1
restricted marketing of Lotronex with a risk
2
management program that was mutually agreed upon by
3 the
Lotronex manufacturer, GlaxoSmithKline, and the
4
FDA. The details of this plan
will be described in
5 the
subsequent presentations.
6
Today, GSK will be presenting an update
7
report on how the drug is being prescribed within
8 the
parameters of the risk management program and
9
what the impact of this program has been. The
10
purpose of this discussion is primarily
11
informational in nature to provide the committee an
12
update. As a consequence, we have
allocated a
13
limited amount of time for presentations and
14
discussion.
15
The risk management program that was
16 implemented contained many but not all of the
17
elements recommended by the Joint Advisory
18
Committees in April of 2002. As
we gain experience
19
with risk management programs, we think that it is
20
important that there be a public airing of how well
21
these programs function and whether they meet the
22
goals that were set out for them.
189
1
With that, I thank you for your attention
2 and
I thank the committee for being here today.
We
3
will have both the speakers at the open public
4
hearing as well as the speakers who are on the
5
agenda to have them use this podium in front of the
6
committee.
7
So, with that, Mr. Chairman, I turn the
8
proceedings over to you.
9
DR. GROSS: Thank you, Dr.
Seligman.
x We will proceed with the
open public
10
11
hearing now. First I need to read
this statement.
12
Both the Food and Drug Administration and
13 the
public believe in a transparent process for
14
information gathering and decisionmaking. To
15
ensure such transparency at the open public hearing
16
session of the Advisory Committee meeting, the FDA
17
believes that it is important to understand the
18
context of an individual's presentation.
For this
19
reason, FDA encourages you, the open public hearing
20
speaker, at the beginning of your written or oral
21
statement to advise the committee of any financial
22
relationship that you may have with the sponsor,
190
1 its
product, and if known, its direct competitors.
2 For example, this financial information
3 may
include the sponsor's payment of your travel,
4
lodging, or other expenses in connection with your
5
attendance at the meeting.
Likewise, FDA
6
encourages you at the beginning of your statement
7 to
advise the committee if you do not have any such
8
financial relationships. If you
choose not to
9
address this issue of financial relationships at
10 the
beginning of your statement, it will not
11
preclude you from speaking.
12
The first speaker is Dr. Sidney Wolfe.
13
DR. WOLFE: Right on time. In August
14
2000, almost four years ago, we petitioned the FDA
15 to
ban alosetron because, in our view, its serious,
16
life-threatening adverse effects outweighed the
17
marginally better-than-placebo effectiveness. At
18 the
time of our petition, FDA was aware of 26 cases
19 of
ischemic colitis in people using the drug.
In
20 the
major randomized, placebo-controlled trials
21
prior to approval, there had been three cases of
22
ischemic colitis in 832 patients, or 1 per
191
1
277--again, with good ascertainment, in contrast to
2 what
we are having here--but none in 700 placebo
3
patients. According to an FDA
memo, in one large
4
trial with adequate ascertainment--this is a
5
different trial--adequate ascertainment of ischemic
6
colitis, 10 out of 1,819 women being treated with
7
alosetron for diarrhea-predominant irritable bowel
8
syndrome developed ischemic colitis over the
9
24-week duration of the trial.
There were no cases
10 in
the 899 patients in the trial treated with
11
traditional therapy. By the time
marketing was
12
stopped in November 2000, there were 85 cases of
13
ischemic colitis reported to the FDA among the
14
estimated 275,000 patients who has used the drug.
15
Even though this is called the Drug Safety
16
Committee, you know as well or better than I that
17
this all has to be viewed in the context of drug
18
benefit and, therefore, review of the evidence for
19
benefit for at least one of the major trials for
20
this drug is appropriate.
21
In an analysis we published in the Lancet
22 of
data from one of the clinical trials, which had
192
1
been misleadingly portrayed in a previous article
2 in
the Lancet by percent change as opposed to
3
absolute scores, the figure of our look at the
4
actual data can be seen on the second page of the
5
testimony. And what you can see
is there is barely
6 a
perceptible--it's statistically significant, but
7 no
one can possibly believe that this is clinically
8
meaningful, the difference at 1, 2, 3, months
9
between those given 2 milligrams of alosetron,
10
twice the dose being used now, for starters, and
11 those
being given the placebo.
12
This excellent, hard-to-exceed placebo
13
response rate--and that's certainly the challenge
14 of
treating this illness, is that the placebo
15
response rate is extraordinarily high.
This is
16 consistent with findings from a published
review of
17 27
randomized, placebo-controlled studies testing
18
various treatments for irritable bowel syndrome in
19
which the median placebo response rate was 47
20
percent, percentage improved, with rates as high as
21 84
percent, and 11 studies had placebo response
22
rates of 60 percent or higher.
Unlike alosetron,
193
1
placebos do not cause ischemic colitis.
2
Because IBS is a poorly defined disease,
3
which, although capable of causing significant
4
distress in some individuals, is neither progressive nor
5
life-threatening, the occurrence of
6
serious adverse reactions such as ischemic colitis
7 and
bowel obstruction without ischemic colitis,
8
sometimes requiring surgery, tips the benefit-risk
9
equation against the use of this drug.
10
The experience during the first one-plus
11
years of this risk management program has hardly,
12 as
Glaxo claims in its statement, "been
13
successful." Among the
problems, somewhat
14
predictable because of the lack of the kinds of
15
controls that could realistically be taken only
16
under an IND, were the following:
17
Twenty percent of the patients getting the
18
drug not have all of the three criteria specified
19 for
getting the drug, which include frequent/severe
20
abdominal pain, and frequent bowel urgency or fecal
21
continence; and disability/restriction of daily
22
activities. They may have one or
two, but these
194
1
were the criteria, and 20 percent did meet these
2
criteria.
3
Secondly, only 42 percent of patients with
4 a
Lotronex prescription has pre-enrolled in the
5
survey program and only 36 percent completed the
6
baseline questionnaire.
7
From the prescribing doctor's perspective,
8
again, because this is not required, it happens, 20
9
percent of prescribing doctors were not enrolled in
10 the
prescribing program for Lotronex. That
may or
11 may
not have something to do with the fact that so
12
many of these average reactions were not reported
13 by
physicians.
14
These are all elements that certainly were
15
thought of if it not specifically suggested by FDA
16
staff and ourselves at the meeting a couple of
17
years ago, and you can't do these things unless the
18
drug is there under an IND.
Marketing isn't
19
compatible with those kinds of restrictions.
20
The most alarming finding during this
21
period was the reporting of eight cases of ischemic
22
colitis and, according to the manufacturer, eight
195
1
additional cases of "complications of
2
constipation." I say
according to the manufacturer
3
because they list eight, and the FDA talks about
4
five. The latter included a case
of partial
5
intestinal obstruction, one in which there was
6
exploratory surgery for small intestinal
7
obstruction, and a patient with diarrhea and
8
intestinal obstruction.
9
Assuming the accuracy of the estimate of
10
9,365 patients getting alosetron during the risk
11
management program, the rate of ischemic
12
colitis--again, this is a low estimate--spontaneous
13
reports was 8 per 10,000 or 8 per 9,365, or about
14 0.8
per thousand, and it's actually higher than
15
the, again, spontaneous rate of reports during the
16
earlier mktg phase, which was 85 per 27,000.
17
There are, of course, differences in the
18
conditions for reporting that might explain some of
19
this discrepancy, but I don't believe begin to
20
explain all of it. Enrolled
physicians agreed to
21
report all serious adverse events as a condition of
22
participation, but obviously 20 percent didn't
196
1
participate, and even those who did, so it appears,
2
four of the eight cases of ischemic colitis were
3
reported by patients, not physicians.
Similarly,
4
none of the eight cases of serious complications of
5
constipation were reported by the prescribing
6
physician. One was reported by a
nurse. Either
7 the
patients did not tell the physicians who
8
prescribed the drug that they had gotten ischemic
9
colitis or physicians violated their agreement to
10
report such cases.
11
The fact that 11 of 16 cases of ischemic
12
colitis or complications of constipation were
13
reported by patients as part of the Lotronex
14
patient follow-up survey program may compensate for
15
some, but we don't believe all or even most of the
16
serious reporting deficiencies by participating
17
physicians. There is little
question that just as
18 the
85 cases of ischemic colitis reported during
19
2000 were but a fraction of the actual cases, so,
20
too, are these recent RMP, risk management program,
21
ischemic colitis cases.
22
For effective, life-saving drugs, such as
197
1
some cancer therapies or the anti-psychotic drug
2
clozapine, risk management is a critical part of
3
their use, and we strongly support, as the FDA
4 knows,
risk management in those kinds of
5
circumstances. But alosetron
joins an increasing
6
number of other drugs, none with unique, clinically
7
significant benefits, that have been the subject of
8
ultimately failed FDA-approved risk management
9
programs--the diabetes drug Rezulin, the painkiller
10
Duract, the GI drug cisapride, the blood pressure
11
drug Posicor--and were taken off the market.
12
When I testified before this committee in
13
2002, I stated, "The reintroduction of Lotronex
14
into the market, even with the restrictions
15
proposed by Glaxo, would be a serious public health
16
mistake, likely, if not certain, to result in the
17
need to ban the drug again."
It is time to end
18
this failed effort to resuscitate markets and to
19
take alosetron off the market. As
we suggested in
20
2002, there is no reason why, under a carefully
21
controlled IND, the drug could not be made
22
available to, I would estimate, the several
198
1
thousand, at most, people who might still choose to
2 use
it. This has previously been done for
the
3
diabetes drug phenformin and the GI drug cisapride
4
after they were taken off the market.
5
I'd just like to emphasize that of the
6
reported 9,000-10,000 people using the drug, in the
7
FDA's Executive Summary it says only 10 to 20
8
percent of these people were refilling it. So we
9
may, in fact, be talking about a group of people
10
that is one, two, three thousand people, not the
11
100,000 that the company claimed would be using the
12
drug and which they used to help fend off an IND
13
approach back a couple years ago.
14
Given the marginal evidence of
15
effectiveness and the continuing serious risks of
16 the
drug, Glaxo's suggestion to relax the
17
restrictions on availability of alosetron to
18
increase its use is nothing but ghoulish. A quote
19
from the end of their statement:
"The primary
20
concern at present relates to the low rate of
21
product prescribing given our understanding of the
22
target population...This may reflect unintended
199
1
barriers to prescription..." and they elucidate
2
some of the unintended barriers, which is the time
3 the
physician has to spend explaining to the
4
patient the benefits and risks of the drug and so
5
forth. I find that this attitude,
certainly it's
6
consistent with trying to sell more drug, but it's
7
inconsistent with the public health.
And just in
8
closing, I would just repeat it's time for this to
9 be
taken off the market. It gives risk
management
10 a
bad name to keep doing things like this.
11
I'd be glad to try and answer any
12
questions. That's just about ten
minutes.
13
DR. GROSS: If there are no
questions,
14
thank you very much, Dr. Wolfe.
15
The next speaker, Dr. Lawrence Wilderlite.
16
DR. WILDERLITE: Good
afternoon. My name
17 is
Lawrence Wilderlite. I am a practicing
gastro-
18
enterologist in Chevy Chase, Maryland.
We're part
19 of
a private practice group of 13 gastroenterologists with
20
three offices in the
21
metropolitan area, downtown Washington, in Chevy
22
Chase, and on Executive Boulevard here in
200
1
Rockville.
2
In the past, I was a speaker for
3
GlaxoSmithKline upon the introduction of Lotronex
4 in
2000 and presently am a consultant for
5
GlaxoSmithKline.
6 I have been asked to talk today about
the
7
prescribing habits of this drug and the inability
8 of
patients to actually have access to the drug
9
because of the restrictions that have been placed
10 on
this.
11
I have had extensive experience with the
12 use
of alosetron when it was first introduced, and
13 our
group has used it, given the patient clientele
14 we
have, many times. And we have had a
favorable
15
response with the drug and felt the drug to be
16
quite helpful in our patient population.
17
Inasmuch as there has been no new
18
medication or no recent introduction of any drug of
19
this type over the last 20 years for the treatment
20 of
irritable bowel syndrome, we felt that this was
21
going to be a very important agent and something
22
that we would be able to use to help patients that
201
1
suffer from irritable bowel, in which we have no
2
effective treatment today.
Initially upon the
3
introduction of this drug, it was embraced by the
4 GI
community and was embraced by gastroenterologists that I
5 can
talk to in the Washington
6
area.
7
When Lotronex was recalled in 2000, it
8
left a void, and that void is still vacant today.
9 I
feel our patients have no alternative to treat an
10
illness that at times can be very devastating.
11
Although not life-threatening, it is basically
12
destructive to patients' lives and destructive to
13
their ability to function in an environment in
14
which they live.
15
The present registration system for this
16
drug is extremely tedious. It
takes a lot of time
17 to
register a patient for this. The patient
needs
18 to
fill out papers. The GI doctor has to
fill out
19 the
papers. The patient has to be advised
about
20 the
side effects of the drug. The doctor has
to
21
register to be an appropriate agent to distribute
22 the
drug.
202
1
At the end of all this, we in our office
2 do
refer patients to a website where they can get
3
more information about Lotronex, where they can
4
understand what the complications and the possible
5
side effects of the drug are before they enter into
6 the
program or begin taking the medication.
We
7
find--and I am not a member of that prescribing
8
group. There are only two people
in our group of
9 13
that elected to be registered for distribution
10 of
the drug, and of those two people, it came
11
because they were quite friendly with one of the
12
Glaxo representatives who asked them if they would
13
register for this.
14
We find that patients become stigmatized
15
after they read the side effects of the drug. As
16
appropriate to Dr. Wolfe's comment, that many
17
patients will not fill the prescription when
18
they're given it. Many patients
will not take the
19
medication appropriately. Many
patients will stop
20
taking the medication. Patients
will forget to
21
take it or take it on an alternate-day basis rather
22 than
appropriately because they're afraid of having
203
1
some side effect and feel less is better than more.
2 And
eventually some of them will not come back or
3
will not fill the prescription or, like many
4
irritable bowel patients, these patients fail to
5
come back again or don't show up in an office and
6 go
home and continue to suffer the symptoms they
7
have.
8
Physicians, because they won't register
9 for
this program, go back to treat these patients
10
with conventional methods, of which we have no
11
conventional methods. Increasing
fiber,
12
anti-diarrheal type of agents that have been on the
13
market and have been shown to be of little help to
14
patients who suffer from this disease.
15
The physicians fear--and when talking to
16
other doctors--that because of all the publicity
17
given to the side effects of the drug, should a
18 patient encounter a side effect or an adverse
19
reaction to this medication, the physician is now
20
liable for some litigation or malpractice suit,
21
and, therefore, they're not pushing to use the
22
drugs. They're not rushing in to
join this type of
204
1
prescribing program.
2
The amount of time that this prescribing
3
program takes is enormous. It
takes a lot of time.
4
There are many physician phone calls.
There's a
5 lot
of interaction with the patient.
Unfortunately, in
6
today's environment where there is
7
little compensation for the amount of time paid
8
because of the insurance environment that we have,
9 this type of interaction is difficult, and
10
physicians shy away from spending the amount of
11
time that is necessary to educate the patients for
12
this.
13
The process is extremely cumbersome, and I
14
find that in a group of physicians that we're
15
friendly with in the Washington area, very few will
16
enter into this registration process.
What I do is
17
refer patients to other people in our group. It
18
changes the physician-doctor relationship, or I
19
refer them to other doctors that I can find who are
20
outside of our group to take care of these
21
patients, or we continue to use the remedies that
22 we
have in place.
205
1
I feel that whether it be alosetron or
2
not, the GI community desperately needs a
3
medication to treat diarrhea-dependent irritable
4
bowel syndrome; that the mechanism that is in place
5
today needs to be streamlined to allow access to a
6
medication that I feel can help irritable bowel
7
sufferers.
8
The use of this drug is extremely limited
9 and
extremely confined to approximately--given Dr.
10
Drossman's (ph) classification, less than 5 percent
11 of
people are available to receive this drug.
I
12
feel personally that this is too confining and that
13 the
drug or the use of this drug should be opened
14
up. As different from the
previous speaker, I
15 think
the drug is helpful and the drug needs to be
16
freed up a little bit more in a more streamlined
17
process to allow access to patients.
18
I thank you and I am open to any comments
19
that you have.
T4A DR. GROSS:
There being none, thank you
20
21
very much, Dr Wilderlite.
22
We will proceed now with the sponsor
206
1
presentation. Dr. Craig Metz, the
Vice President
2 for
U.S. Regulatory Affairs at GlaxoSmithKline,
3
will present their risk management program for
4
Lotronex.
5
MS. JAIN: Dr. Metz, before you do
your
6
presentation, we just wanted to introduce another
7
committee member that joined us in the interim.
8 Dr.
Maria Sjogren joined our group. She is a
9
representative for the GI community and also is a
10
member of the GI Advisory Committee.
Thanks for
11
participating.
x
DR. METZ: Good afternoon. My name is
12
13
Craig Metz, and I am going to be providing the
14
sponsor's update on our experience with the
15
implementation of the risk management program for
16
Lotronex today.
17
Joining us today are a number of external
18
consultants who are involved with various aspects
19 of
the risk management plan for Lotronex and would
20 be
happy to answer any questions that you might
21
have regarding their specific areas of responsibility for
22 the
RMP or any general questions that
207
1 you
might have for them. I'm going to take
just a
2
quick moment to introduce our consultants.
3
We have Dr. Robert Sandler with us from
4 the
University of North Carolina. Dr.
Sandler is
5
involved with our Risk Management Plan Advisory
6
Board.
7
We have Dr. Lin Chang from the University
8 of
California at Los Angeles, who has been involved
9
with our educational program as well as a general
10
consultant to us for some time on Lotronex.
11
We have Dr. Andrews from Research Triangle
12
Institute. She's involved with
our epidemiology
13
program, specifically the patient follow-up survey
14 for
Lotronex, and she serves as the data
15
coordinating center for the follow-up claims-based
16
research.
17
We have Dr. Jerry Gurwitz with us from
18
Meyers Primary Care Institute, University of
19
Massachusetts. Dr. Gurwitz is
also involved with
20 the
epidemiology program.
21
And, finally, we have Dr. James Lewis here
22
from Georgetown University who chairs our Safety
208
1 and
Review Committee.
2
Three underlying themes will form the
3
basis of my presentation today.
Those themes are
4 the
successful implementation of the risk
5
management plan for Lotronex from the standpoint of
6 the
appropriateness of the prescribers, the
7
patients, and the behaviors that have been produced
8
through this program; the impact of the RMP itself
9 on
the safety profile and on the prescriber and
10
patient, as well as on individual components of the
11
risk management program itself; and the cycle of
12
continual RMP evaluation and revision that is a
13
normal part of the stewardship involved with
14
conducting a risk management program.
15
During the course of my presentation, I'm
16
going to share information with the committee that
17 we
didn't have when we last met to consider a risk
18
management program for Lotronex, and that
19
specifically is data on the impact of the
20
interventions that we've attempted to put into
21
place here. It's our hope that
this data will
22
guide our discussions with the agency and the
209
1
proposed modifications that we might make to this
2 RMP
as we move forward. But as importantly,
the
3 RMP
for Lotronex has been a very rich learning
4
laboratory for us with regard to general issues
5
regarding conducting a risk management program and
6 the
impact of these different interventions in
7
real-term use. So we hope that
this information
8
will tend to serve to inform discussions regarding
9 the
applications of these interventions elsewhere.
10
In my presentation, I'm going to provide a
11
very brief background summary.
I'm going to
12
identify the goals of the RMP and describe the key
13
elements of the RMP with results to date where
14
appropriate. I will finish with
some conclusions
15
regarding the implementation of the RMP and a
16
discussion of what we've identified as emerging
17
issues.
18
Many of you will be familiar with the
19
chronology of key regulatory events.
Dr. Seligman
20 has
already covered some of these. Again,
the
21
product was voluntarily withdrawn in November of
22
2000. The agency and
GlaxoSmithKline were
210
1
inundated with calls from patients demanding that
2 the
drug be made available to them again.
3
Subsequently, we submitted an sNDA in
4
December of 2001 and met with some members of this
5
committee and the GI Drugs Committee in April of
6
2002 to discuss the information included in that
7
sNDA as well as the general framework that was
8
being proposed for the RMP for Lotronex.
In June
9
2002, that supplemental NDA was approved and the
10 product
was actually reintroduced in November of
11
2002 with a revised indication statement and a risk
12
management program in place.
13
What we were striving to achieve when we
14
developed the risk management program for Lotronex
15 was
a framework that would mitigate the risks
16
associated with complications of constipation and
17
ischemic colitis, but would do so in a way that
18
would not create extraordinary barriers to patient
19
access. And I think as we
consider the information
20
being presented today, success should be measured
21
against this intent.
22
We intended to achieve this through a
211
1
focus on the following four goals:
making Lotronex
2
available to those patients for whom the
3
benefit-risk is most favorable; prescribing
4
Lotronex to appropriate patients by qualified
5
physicians; educating physicians, pharmacists, and
6
patients about the risks and benefits of Lotronex
7 and
how to manage those risks; and providing a
8
framework for ongoing RMP evaluation.
9
A key element of making Lotronex available
10 to
a patient population for whom the benefit would
11
clearly outweigh the risk was revising the
12
indications statement to establish women with
13
severe diarrhea-predominant IBS as the target
14
population for treatment. On that
basis, Lotronex
15 is
currently available for women with severe
16
diarrhea-predominant IBS who have chronicity of
17
symptomatology, generally lasting six months or
18
longer; have had anatomic of biochemical
19
abnormalities of the GI tract excluded; and have
20
failed to respond to conventional therapy.
21
Additionally, diarrhea-predominant IBS is
22
defined as severe if it includes diarrhea and just
212
1 one
or more of the following: frequent and
severe
2
abdominal pain or discomfort, frequent bowel
3
urgency or fecal incontinence, disability or
4
restriction of daily activities due to IBS. And,
5
again, I would stress that only one of these
6
criteria are required for the patient to qualify
7 for
treatment--not two, and certainly not all
8
three. Only one. Later in my talk, I'm going to
9
come back to this description of a 5-percent
10
estimate for the severe diarrhea-predominant IBS
11
population.
12
And, finally, the indications statement
13
states that in men, the safety and effectiveness of
14
Lotronex has not been established.
15
So the four key components of the RMP that
16
we've developed for Lotronex are:
enrollment of
17
qualified physicians in a physician prescribing
18
program; a program to educate physicians,
19
pharmacists, and patients about IBS and about the
20
benefits and risks of Lotronex; a reporting and
21 collection system for serious adverse events
22
associated with the use of Lotronex; and, finally,
213
1 a
plan to evaluate the effectiveness of the RMP for
2
Lotronex. In the rest of my
presentation, I'm
3
going to go through each of these components in
4
order.
5
To begin with, we have the prescribing
6
program for Lotronex, and this was developed to
7
address the goal of prescribing Lotronex to
8
appropriate patients by qualified physicians. This
9 is
a picture of the key steps card that helps the
10
prescribers navigate their way through the
11
prescribing program for Lotronex.
It's going to be
12
difficult for me to use the pointer here in a very
13
effective way, but you have the slide in front of
14
you, and I'm going to walk you briefly through some
15 of
the steps.
16
So the physician, in the upper-left-hand
17
portion of this chart, decides to enroll in the
18
prescribing program for Lotronex.
They receive a
19
prescribing kit that I'm going to describe to you
20 in
a minute. The physician identifies an
21
appropriate patient for treatment, goes through a
22 counseling
activity with that patient, gets the
214
1
patient to sign the patient-physician agreement
2
with the physician. That
agreement is then placed
3
into the patient's chart, and a copy of that is
4
given to the patient. The
physician at that point
5
affixes a Lotronex sticker to an original
6
prescription, and at that point the physician also
7
encourages the patient to enroll in the patient
8 follow-up
survey for Lotronex.
9
At that point the patient has a
10
prescription with a blue sticker on it that they
11
take to the pharmacist so that the pharmacist can
12
fill that prescription. And,
again, even the
13
pharmacist has the opportunity to encourage the
14
patient to enroll in that patient follow-up survey.
15
As you can see, this is a fairly complex,
16
multi-step process. The act of
physician
17
enrollment actually involves the physician signing
18 an
attestation form that attests to his ability to
19
diagnose and treat IBS, to diagnose and manage
20
ischemic colitis, to diagnose and manage
21
constipation and complications of constipation, as
22
well as acceptance of responsibilities that include
215
1
education, completing the patient-physician
2
agreement that I've just described, reporting
3
serious adverse events, and affixing stickers to
4
prescriptions. In a while I'll
share feedback that
5
we've received from physicians relative to the
6
impact of this process on their practice.
7
The prescribing kit for Lotronex that the
8
enrolled prescriber gets contains the key steps
9
card that we've just discussed, prescribing
10
information, medication guides, patient-physician
11
agreement forms, the prescribing program stickers,
12 and
the patient follow-up survey pre-enrollment
13 cards.
14
These are some of the steps that I've
15
already described on the key steps card, but,
16
again, there are a couple of things I'd like you to
17
note. First of all, this is
what's in the retail
18
pack that the patient receives.
It's a box that
19
contains 30 tablets, a package insert, a medication
20
guide, and the patient survey card.
I have to
21
remind you that no refills are allowed currently
22 for
Lotronex. All prescriptions have to be
216
1
original, and all prescriptions have to have an
2
affixed sticker. There is no
faxing, no electronic
3
transmission of prescriptions for Lotronex. Those
4 are
not allowed.
5
In the event that a physician uses up the
6
supplies in their initial kit, they can call the
7
coordinating center for the PPL, and that
8
coordinating center will check their name against
9 the
list of enrolled prescribers, and if they're on
10
that list, they'll be sent a refill kit.
11
In the next portion of my presentation,
12 I'm
going to address the educational program that
13 was
developed to support the introduction of
14
Lotronex.
15
The educational program for physicians is
16
anchored by these two modules:
Lotronex Tablets:
17
Understanding the Risks and Benefits, and Current
18
Thinking about IBS: An
Educational Review on
19
Irritable Bowel Syndrome.
20
In addition to that, 345,000 "Dear Doctor"
21
letters were mailed at the time of product
22
reintroduction, and we've put a reminder program in
217
1 place
that I'll discuss with you in a moment that
2
provides additional access to key educational
3
messages for physicians.
4
For the patient, education consists of the
5
medication guide, which, again, they can get from
6 two
sources. They can get that from the
physician,
7 and
it's also included in product packaging.
8
Physician counseling and the requirement
9 to
sign the patient-physician agreement further
10
reinforces the key product messages contained in
11 the
medication guide.
12
On the pharmacist level, at the time of
13
product reintroduction 113,000 "Dear Pharmacist"
14
letters were mailed. Through an
initiative that's
15
well outside the scope of normal product launch
16
activities, we also had 25,000 outbound telephone
17
calls to pharmacists. Those calls
resulted in over
18
12,000 requests for additional information on
19
Lotronex. We were impressed with
this, and we
20
think that this clearly indicates the potential
21
power of these types of outreach activities focused
22 at
the pharmacist level.
218
1
In addition, we sent an informational
2 piece on Lotronex to the National Board of
State
3
Pharmacists to be cascaded into the newsletters of
4 its
individual member states. And, finally,
as
5
with the physician, reminder letters to pharmacists
6
also provide important information regarding
7
Lotronex.
8
There are a large number of additional
9
educational activities that GSK has implemented to
10
provide further support for the appropriate use of
11
Lotronex. These include a
telephone conference
12
series with physicians, speaker programs,
13
informational booths at professional society
14
symposia. There's a website, and
we have call
15
centers that can answer questions and provide
16
information on the PPL itself. It
can provide
17
medical information, and they provide the sources
18 of
information to the practitioner and health care
19
community.
20
And, finally, we're also providing
21
independent grants for IBS education that's
22
delivered at professional society symposia and
219
1
through other communication media.
Again, while
2
components of this educational program are
3
obviously targeted towards a prescriber audience,
4 the
materials are available to the general health
5
care practitioner community as well.
6
The next element of the RMP that I'd like
7 to
discuss is the reporting and collection of
8
serious adverse events and adverse events of
9
special interest associated with the use of
10
Lotronex. This essentially
comprises a safety
11
overview.
12
Again, it's important to remember that
13
there are some differences in the conditions under
14
which AEs are reported currently versus the
15
conditions that existed when the product was
16
initially marketed. We currently
have a different
17
target population for Lotronex:
females with
18
severe diarrhea-predominant IBS, with the
19
qualifiers that I've already discussed.
Through
20 our
educational program, we believe that we have
21
better-informed patients and physicians.
We have
22 an
agreement from physicians to report serious
220
1
adverse events, and we have the patient survey,
2
which is proving to be a non-traditional source of
3 AE
information, and the way we're handling that
4
information will be discussed in just a moment.
5
So what are our sources for adverse
6
events? They consist of the
typical spontaneous
7
reports and reports arising from a clinical trials
8
program, but they also include the patient
9
follow-up survey program.
10
The focus of our adverse event reporting
11 is
on these diagnoses and outcomes of special
12
interest that were highlight as an area of concern
13
during the initial marketing period, and those
14
include ischemic colitis, mesenteric ischemia,
15
occlusion or infarction, serious constipation,
16
complications of constipation, as well as outcomes
17 of
special interest like intestinal or anorectal
18
surgery and death.
19
Adverse events are reported in a typical
20
fashion stipulated by the regulations.
We have
21
expedited reporting for serious, unexpected,
22
spontaneous reports, and we also have expedited
221
1
reports for serious, unexpected, and attributable
2
survey and clinical trial reports.
But, in
3
addition, we have a special agreement to expedite
4
reports for all adverse events of special interest,
5
regardless of their seriousness or expectedness.
6
The patient survey that we've been
7
discussing a little bit is intended to measure
8
patient knowledge, behavior, and certain RMP
9
process elements. But through the
process of
10 either
completing these forms in writing or over
11 the
phone, patients occasionally report adverse
12
events. As part of the continual
process of RMP
13
evaluation and revision, we have developed a system
14 for
processing this adverse event information
15
arising from the survey. To
maintain patient
16
confidentiality within the survey, Research
17
Triangle Institute de-identifies the information on
18 the
adverse event report and forwards it to GSK.
19 The
GSK pharmacovigilance staff assess these
20
reports for seriousness as well as special interest
21
diagnoses.
22
For those cases assessed as serious or
222
1
possibly including diagnoses of special interest,
2 RTI
requests patient consent for GSK follow-up with
3 the
prescriber. When that consent is
granted,
4
GSK's Pharmacovigilance Department follows up with
5 the
patient's prescriber in a fashion similar to
6
that that would be used during a spontaneous
7
reporting context. And, again,
adverse events
8
arising from the survey are reported to the FDA as
9 the
data warrant.
10
So what is our experience to date?
From
11
November 20, 2002, until February 6, 2004, we have
12
approximately 10,000 patients treated with
13
Lotronex, or about 34,000 prescriptions.
This has
14
generated 127 post-marketing AEs, which include all
15
spontaneous reports plus all patient survey reports
16
that are deemed to be serious or reports of special
17
interest as I just described on the previous slide.
18
Of the 127 post-marketing reports that
19
we've received, 37 have been considered serious.
20
Seventy-five percent of these 37 reports were GI in
21
origin. What we're going to focus
on are the 19
22
patients or cases that had diagnoses and outcomes
223
1 of
special interest.
2
Of the eight reported ischemic colitis
3
cases, six were medically confirmed.
Those same
4 six
patients had colonoscopic or biopsy findings
5
consistent with ischemic colitis.
Three of the
6
eight cases resulted in hospitalization.
All of
7 the
cases of ischemic colitis resolved without
8
sequelae. We have no reports of
mesenteric
9
ischemia. We have no reports of
serious
10
constipation. We do, however,
have eight reports
11 of complications
of constipation. Three of those
12
eight reports have been medically confirmed. Three
13
involved fecal impaction. Three
were associated
14
with intestinal obstruction; there was one ileus,
15 one
ulcerated colon. Three of these eight
patients
16
were hospitalized, and three patients were managed
17 in
the ER only.
18
Four outcomes of special interest have
19
been reported. There is one
report of surgery
20
which could not be confirmed by the patient's
21
physician. This same patient also
had a diagnosis
22 of
special interest involving a complication of
224
1
constipation. No deaths
attributable to Lotronex
2 have been reported. Of the three deaths that have
3
occurred in patients taking Lotronex, two of those
4
deaths came through the survey process and were
5
reported by family members. One
of those was in a
6
patient with cancer, multiple myeloma.
The other
7 was
in an AIDS patient. The other report
that we
8
have is a physician report of a suspected pulmonary
9
embolism in an obese patient with a very complex
10
medical history.
11
So, in summary, with regard to the safety
12 of
Lotronex, we have not seen any new safety
13
issues. Recognizing that we have
a very low rate
14 of
prescribing, we feel that the ischemic colitis
15 and
complications of constipation cases that we've
16 seen
are similar to those seen during the original
17
marketing period, and we believe that the outcomes
18
associated with those cases are generally less
19
severe. We're also pleased by our
review of the
20
individual cases that suggest that prompt and
21
appropriate action is being taken by the patient
22 and
the physician. What we're hoping to
achieve
225
1
here is to change patient and physician behavior.
2 We
believe, in fact, that is what's going on.
3
But the final component of the risk
4
management plan involves the implementation of a
5
plan to evaluate the effectiveness of the Lotronex
6
risk management program. This plan
consists of
7
three components: a retrospective
study to compare
8 the
roster of physicians identified in a general
9
prescription database as prescribers of Lotronex
10
with a roster of physicians enrolled in the PPL,
11 the
prescribing program for Lotronex; the patient
12
follow-up survey program that we've mentioned; as
13
well as a longitudinal, claims-based observational
14
study program.
15
First, the physician roster comparison.
16
This is a study to compare physicians prescribing
17
Lotronex within and outside of the prescribing
18
program for Lotronex. The way
that's accomplished
19 is
when the M.D. sends the enrollment form to the
20
database vendor, the vendor sends that enrollment
21
data to GSK. In parallel with
that, GSK purchases
22 a
prescription data set from MDC Health.
Those two
226
1
data sets are compared against each other, and
2 through that process we determine who is
3
prescribing within and outside of the program, and
4
that information is reported to the FDA on a
5
quarterly basis.
6
So what have we learned? These
are the
7
data that we have generated to date.
As you can
8
see, the number of prescribing program for Lotronex
9
enrolled prescribers has generally remained at or
10
above 80 percent since the program was initiated.
11
We're actually quite pleased with this aspect of
12 the
RMP. This is the pattern of prescribing
by
13
physician specialty for the quarter beginning
14
October 2003, which is representative of our
15
overall experience. Prescribing,
as you can see,
16 is
being driven primarily by the
17
gastroenterologists. I think what
is even more
18
important is, of the prescriptions that have
19
actually been written, 87 percent of those
20
prescriptions had been written within the
21
prescribing program for Lotronex, and we believe
22
that that's a very good result.
227
1
In the initial marketing period, 50,000
2
physicians were prescribing Lotronex.
Currently,
3
only 5,053 have even enrolled to prescribe Lotronex
4
through the prescribing program for Lotronex. What
5 is
particularly disconcerting is the fact that
6
approximately half of the few prescribers who have
7
enrolled have not written a single prescription.
8
This may be a reflection of some of the RMP
9
barriers that I'm going to discuss in a few
10
moments.
11
And, again, part of the evaluation and
12
revision of an RMP program, we've developed a
13
follow-up system for non-prescribing-program
14
prescribers. When these
prescribers are first
15
identified, an enrollment kit is forwarded to the
16
prescriber. In addition, we
forward a reminder
17
letter to the prescriber's local pharmacy. If
18
there is a second occurrence of prescribing by a
19
particular non-enrolled prescriber, we forward them
20 a
reminder letter. If they transgress a
third
21
time, we forward a firmer reminder letter to them.
22
Now, the response to this process to date
228
1 is
hard to determine, but overall what we're seeing
2 is
75 percent of these non-enrolled prescribers
3
comply in some way; 25 percent of them actually
4
enroll and 50 percent of them stop prescribing
5
Lotronex. And, again, this is a
very dynamic
6
situation. It can wax and wane
over quarters, but,
7 in
general, this has been the response to this
8
follow-up process.
9
Let's talk about the patient follow-up
10
survey program, which is the next element of the
11 RMP
that we'd like to discuss.
12
The objectives of this program are to
13
assess patient knowledge of the risks and benefit
14 of
Lotronex to assess patient behavior in relation
15 to
the recommendations in the risk management
16
program and assess the extent to which the patient
17
satisfies the product labeling requirements for
18
treatment with Lotronex.
19
This is a flow diagram of how this survey
20
process works. We receive the
pre-enrollment card,
21 and
upon receipt of that, an enrollment package is
22
forwarded to the patient, and that starts the
229
1
survey cascade, as you'll see on the left-hand
2
side. If we don't receive survey
forms back from
3 the
patient in prescribed time frames, there's
4
actually a contact from RTI to the patient to
5
encourage them to complete and return those forms
6 to
us.
7
So, to date, we have a 42-percent
8
pre-enrollment rate for all patients who have
9
received a prescription for Lotronex; 55 percent of
10
those were issued by the prescribing physician.
11
And, again, we didn't expect that.
That's a little
12 bit
atypical. It's much higher than we
expected.
13
Most of the patients that we see in the
14
survey are middle-aged patients that are typical of
15 the
population that you would expect to be
16
receiving drug and having diarrhea-predominant IBS.
17
Eighteen percent of the patients are over the age
18 of
65 years, and 7 percent of the patients are
19
indeed male. Thirty-six percent
of the patients
20
that receive a prescription have actually completed
21 the
baseline survey form and entered the survey
22
proper.
230
1
So, again, I think you can see from this
2
table that what we've enrolled in this patient
3
follow-up survey program is a very motivated cohort
4 of
patients. Recognizing the grace period
for
5
receipt of follow-up questionnaires from patients
6 for
whom that follow-up period has expired and
7
questionnaire responses were due, I think you can
8 see
that almost all of those responses have been
9
received across time. So, again,
it seems like a
10
very motivated cohort of patients, and they're
11
doing their homework and sending it in.
12
What have we learned about these patients?
13
Well, this table indicates that there's a very high
14
rate of compliance with the key elements of the RMP
15
process and also demonstrates that the discussions
16 and
activities that we wanted to have occur are
17
indeed occurring. I think you can
see 97 percent
18 of
the patients discuss with the doctor how
19
Lotronex can help them; 95 percent discuss the
20
reasons with the doctor why you would discontinue
21
Lotronex; 91 percent have received the medication
22
guide; 87 percent recall that a blue sticker was,
231
1 in
fact, put on their prescription. So,
again,
2
from a compliance perspective, we're pleased at
3
what we see coming through the patient follow-up
4
survey.
5
Importantly, as far as patient
6
appropriateness for treatment is concerned, this
7
table shows that this survey cohort comprises an
8
appropriate patient population for treatment with
9
Lotronex. Ninety percent of these
patients met the
10
treatment and severity criteria.
And, again, if
11 you
look at the individual criteria for treatment,
12 95
percent have diarrhea; 98 percent had IBS for
13
more than six months, the chronicity that we were
14
looking for; 96 percent had previous treatments for
15
IBS; and 97 percent have said they had inadequate
16
relief of symptoms. And, again,
we believe that
17
these are clear indicators of patient
18
appropriateness.
19
If you look at the severity conditions
20
that are required--and, again, I'll remind you that
21
only one of these is required to qualify the
22
patient for treatment, not all three.
You have
232
1
cramps or bloating present in 87 percent, ranging
2 up to a somewhat or very hard life in almost
all of
3
these survey patients. And if you
look at the
4
presence of all three severity conditions within an
5
individual patient, you see that 80 percent of
6
these patients have what you would describe as
7
very, very severe DIBS. They have
all of the
8
severity conditions. And, again,
I'll remind you
9
that only one was required to qualify a patient for
10
treatment. So I think this is a
potential RMP
11
impact issue that we're going to come back to at
12 the
end of the discussion.
13
The final component of the RMP evaluation
14 is
a program of longitudinal claims-based
15
observational studies. The
objectives of this
16
program are to describe or characterize patients
17
receiving Lotronex, to describe or characterize
18
compliance with the prescribing program for
19
Lotronex, and to evaluate the incidence of events
20 in
patients treated with Lotronex versus an
21
appropriate comparison group.
22
These are three database sources that
233
1
comprise the longitudinal studies.
In the
2
aggregate we have approximately 8.5 million covered
3
lives in this program. Again,
recognizing that
4
there's a lag period of about six months from the
5
prescription to potential data extraction, 121
6
users of Lotronex have been identified through
7
September of last year, the majority of which have
8
come from the Engenics(ph) database.
These 121
9
users received 277 dispensings of Lotronex and
10
seemed to fit a pattern consistent with data that's
11
been collected from other portions of the RMP; 89
12
percent of the patients are female; 69 of the first
13
dispensings are coming from gastroenterologists.
14
Importantly, this is an RMP process check: 70
15
percent of the patients' records did contain a
16
signed patient-physician agreement.
And,
17
obviously, it probably goes without saying that
18
program viability is being impacted by low product
19
uptake.
20
At this point, I'd like to take a moment
21 to
give you our overall evaluation of the
22
implementation of the risk management program for
234
1
Lotronex.
2
We certainly believe that we have
3
successfully implemented all of the elements of
4 this complex, integrated risk management
program.
5 We
are pleased by the number of physicians
6
prescribing within the PPL context, but we're even
7
more reassured by the fact that the overall number
8 of
prescriptions coming out of the PPL is so high
9 at
87 percent. Data from the patient
follow-up
10
survey program indicates that the key product use
11
that we wanted to have delivered to the patient by
12 the
physician is, in fact, being delivered and that
13 the
patients being selected for treatment are
14
appropriate.
15
We believe that patient and physician
16
behavior is consistent with the goals of the RMP.
17
Recognizing once again that we have a very low
18
prescribing rate, we still feel that qualitatively
19 the
adverse events and special interests that we
20
have observed are few and the outcomes being
21
observed are generally less severe.
22
We have entered into this process of
235
1
continual RMP evaluation and revision, and through
2
that process we've devised a program for follow-up
3 for
non-prescribers. We've revised the
patient
4
survey questionnaires to include new questions.
5 And
we've developed a reporting paradigm for
6
adverse event information arising from the patient
7
follow-up survey.
8
While we certainly believe that the RMP
9 has
been successfully implemented, we also feel
10
that there is still much work to be done to
11
optimize product availability to appropriate
12
patients. For the remainder of
the presentation,
13 I'm
going to focus on the key issues that have
14
arisen regarding the impact of the risk management
15
program on product use relative to Lotronex. These
16
issues are certainly instructive in a general sense
17
when one considers the use of these risk management
18
interventions for other products.
19 So the issues that I'm going to focus on
20
really are impact of the RMP on the practitioner
21 and
patient, which can be collectively viewed as
22
potential product access issues, and the impact of
236
1 the
RMP on some of its individual components.
2
These are sources of feedback and data
3
that we've been collecting on the RMP.
We've done
4
some fairly unique physician- and patient-focused
5
field research. We have
information coming out of
6 our
clinical trials programs. We have
interactions
7
between our sales force members and practitioners.
8 We
have information coming into our customer
9
response center. And we have
interactions with our
10 key
opinion leaders.
11
What are we learning? At the
prescriber
12
level, we've received considerable feedback on this
13
attestation process. Physicians
are unaccustomed
14 to
signing a document like this and feel that
15
somehow there's been a unique transfer of liability
16
from GSK to the prescriber. One
might wonder if
17
that isn't being somehow reflected in the fact that
18
treatment seems to be being reserved right now for
19
patients that only have the most severe
20
presentation of severe diarrhea-predominant IBS.
21 In
addition, physicians feel that having to sign an
22
attestation form is an affront to their
237
1
professional training and somehow constitutes an
2
unnecessary duplication of the licensure process.
3 So
one of the questions that we're dealing with
4
right now is: Is there a less
intrusive way to
5 ensure prescribing by appropriate physicians
with a
6
focus more on education rather than attestation?
7
As you've already heard this afternoon,
8
we've learned that fulfilling the RMP requirements
9 is
time-consuming and falls well outside of the
10
normal clinical practice patterns.
There's also
11
some uncertainty regarding the origin and purpose
12 of
the RMP. Some people believe it's an IND
study.
13
People genuinely misunderstand the current
14 marketing
context for Lotronex. To us, this
15
represents a communication or education challenge
16
that needs to be addressed for Lotronex.
But,
17
again, it needs to be proactively considered in the
18
implementation of other RMPs. We
need to address
19
that confusion before it occurs.
20
As previously mentioned, physicians have
21
also expressed some confusion about the importance
22 or
utility of certain labeling statements like the
238
1
statement that the severe diarrhea-predominant IBS
2
population comprises about 5 percent of the total
3 IBS
population. They really don't know how
to use
4
that information when considering whether or not
5 the
patient that they're looking at should be
6
treated with Lotronex. So it's
information that
7
confuses rather than enlightens.
8
From the patient perspective, we've
9
learned that the language in the product labeling
10
tends to frighten the patients rather than inform
11
them. We are getting this message
clearly from our
12
field research, but even more importantly, this is
13 a
clear message coming out of our clinical trials
14 program,
and that's a context where we believe that
15
patients typically feel safer receiving medication
16
because of the oversight that they get.
17
In our current clinical trial program, 28
18
percent of the patients who were screened for study
19
inclusion who the physicians believe would
20
otherwise be appropriate for Lotronex therapy
21
refused to participate because, after reading study
22
information that's similar to product labeling,
239
1
they stated that they were afraid to take Lotronex.
2
And, again, this is a phenomenon that we don't have
3 any
precedent for within our GSK clinical research
4
programs.
5
And, finally, there is this
requirement to
6
sign a special document, this patient-physician
7
agreement, that is somewhat disconcerting to some
8
potential patients. Again, it's
something unusual,
9
they don't typically have to do it, and it gives
10
them pause.
11
As far as the claims-based observational
12
studies are concerned, again, it's obvious that the
13 low
physician-patient uptake has had a serious
14
effect on this program. Currently
we have 10,000
15
patients and have extracted data from 121. At the
16
current rate of prescribing, where we need 2,000
17
patients to support meaningful analyses, we would
18
need 155,000 patients treated with the drug, and
19
that could take 15 years at the current rate. So,
20
again, this is a problem that we're going to have
21 to
address as we move forward.
22
Again, you know, we certainly believe that
240
1
we've successfully implemented the RMP for Lotronex
2 and
are effectively managing risk. However,
we
3
have identified a number of RMP-related issues that
4 may
be posing a barrier to access by appropriate
5
patients. And our ultimate goal
is to modify the
6 RMP
to improve product access for appropriate
7
physicians and patients while continuing to
8
effectively manage the risk.
9
Ten thousand patients have received
10
Lotronex since the product was reintroduced.
11
Current estimates from the literature suggest that
12 the
severe DIBS population ranges in size from
13
111,000 to perhaps as high as 2.9 million. It is
14 not
10,000. We will continue to work with
the FDA
15 to
close this apparent gap between patients who
16
need Lotronex and those who are receiving it.
17
And with that, in the interest of time and
18 out
of respect for the mental health of the
19
Advisory Committee, I will stop talking and yield
20 to
the podium to Dr. Justice.
21
DR. GROSS: Thank you very much,
Dr. Metz.
22
The next speaker is Dr. Robert Justice,
241
1
Director, Division of Gastrointestinal and
2
Coagulation Drug Products, who will give the FDA
3
update on Lotronex.
x DR. JUSTICE: Good afternoon. I would
4
5
like to take a few minutes to discuss our view of
6 the
Lotronex update that you've been provided.
7
I will cover six topics:
background on
8 the
adverse event and marketing situation around
9 the
time of withdrawal and on discussions about how
10 to
provide access; risk management goals and how
11
they are being met; patient access issues;
12
physician enrollment process issues; labeling and
13 the
tension between informing and frightening; and,
14
finally, our conclusions.
15
This slide is taken from a presentation at
16 the
April 2002 Joint Advisory Committee meeting and
17
presents data on the number of cases of ischemic
18
colitis, small bowel ischemia, and serious
19
complications associated with--complications of
20 constipation associated with Lotronex during
the
21
period of initial marketing in 2000.
22
For ischemic colitis, there were 18 cases
242
1 in
the clinical trials, 84 cases in post-marketing,
2 for
a total of 102 cases, with 11 surgeries and two
3
deaths. For serious complications
of constipation,
4
there were 11 cases in the clinical trials, 113
5
post-marketing, for a total of 124 cases, with 35
6
surgeries and two deaths.
7
In 2000, there were approximately 534,000
8
prescriptions and 275,000 patients.
Off-label uses
9
included diarrhea, inflammatory bowel disease,
10
custodial care, managing nursing home patients, and
11
constipation-phenomenon irritable bowel syndrome.
12
The prescribers at that time were
13
predominantly primary care physicians:
32 percent
14
were general practitioners or family practitioners,
15 24
percent were internists, and 31 percent were
16
gastroenterologists.
17
Given the adverse events of ischemic
18
colitis, small bowel ischemia, and serious
19
complications of constipation, four options were
20
considered: restricted distribution
to
21
gastroenterologists only; IND access; suspension of
22
marketing until a hearing before an advisory
243
1
committee; and withdrawal.
2
As you've heard GlaxoSmithKline chose to
3
withdraw the drug from the market in November of
4
2000. In 2001, access became an
issue, and
5
approximately 5,000 e-mails from patients were
6
received by the FDA.
7
In 2002, GlaxoSmithKline and the FDA
8
agreed upon a restricted distribution and risk
9
management program, and Lotronex was reintroduced
10
into the market.
11
The Lotronex risk management program
12
includes four goals. The first is
enrollment of
13
qualified physicians in a physician prescribing
14
program. A decision was made to
allow enrollment
15 of
physicians possessing certain qualifications for
16
diagnosing and managing IBS and drug adverse events
17 as
opposed to certifying physicians by developing a
18
whole new program of education and certification.
19
Physician attestation of qualifications is allowed,
20 and
this is not a precedent for FDA or for
21
physician maintenance of privileges or licensure.
22
Participating physicians must attest that they are
244
1
knowledgeable of the benefits and risks of Lotronex
2 and
about the management of IBS and drug adverse
3 events. The attestation and the patient-physician
4
agreement include features of informed consent so
5
that patients and physicians are fully able to
6
decide about the appropriateness of Lotronex
7
treatment.
8
The second goal is the implementation of a
9
program to educate physicians, pharmacists, and
10
patients about the risks and benefits of Lotronex.
11
The third goal is the implementation of a
12
reporting and collection system for serious adverse
13
events.
14
The fourth goal is the implementation of a
15
plan to evaluate the effectiveness of the Lotronex
16
risk management program. We
believe that these
17
goals are being achieved.
18
Regarding the issue of patient access,
19
GlaxoSmithKline estimates that there are 185,000
20
women with severe IBS in the U.S.; however, as
21
you've heard, only about 10,000 have tried the
22
drug. Whether additional women
will seek treatment
245
1 is
unclear. Some will decide not to start
Lotronex
2
after discussion of the risks and benefits. Others
3 who
start the drug may not continue. In the
4
clinical trials that excluded severe diarrhea
5
patients, those on Lotronex had a 13- to 16-percent
6
increase over placebo in the median percentage of
7
days with urgency control. In the
subset of
8
patients with urgency at baseline on five or more
9
days per week, there were 13 to 21 percent more
10
patients on Lotronex compared to placebo, with
11
urgency no more than one day in the last week of
12 the
trial.
13
The goal of GlaxoSmithKline and FDA is to
14 ensure
access to patients whose
15
diarrhea-predominant IBS is so severe that they
16
will reap the benefits of the drug over its risks
17 and
be under the care of qualified physicians.
We
18 are
working together to try to identify unintended
19
barriers to patient access.
20
Regarding the physician enrollment
21
process, physician responsibilities in the
22
prescribing program must be clear, and the program
246
1
still needs to ensure that only qualified
2
physicians are enrolled. These
doctors must attest
3 to
their abilities and knowledge and take on
4
responsibilities such as patient counseling,
5
reporting of adverse events, and applying Lotronex
6
blue stickers on prescriptions so pharmacists will
7
know that they're enrolled in GSK's prescribing
8
plan.
9
Not all physicians may wish to accept
10
these responsibilities or are able to manage the
11
disease and drug adverse events.
However,
12
GlaxoSmithKline and FDA are looking at ways to
13
improve the physician enrollment process and are
14
evaluating other possible means of attestation to
15
ensure qualifications. For
example, phone-in
16
attestations may be an option as well as the
17
current fax-in forms.
18
As was mentioned, there is a perception of
19
liability transfer to the physician.
Perhaps the
20
fact that liability is not being transferred can be
21
made clearer.
22
Regarding the issue of labeling, there's a
247
1
tension between describing risks that may be
2
frightening and providing adequate information to
3
allow patients and physicians to make informed
4
decisions. FDA will consider
labeling changes that
5
enhance clarity and education.
However, any
6
changes in the labeling such as the indications
7
must be supported by clinical trials data on
8
effectiveness and safety. In
addition, the
9
labeling must include accurate information on the
10
magnitude and severity of adverse events.
11
In conclusion, we recognize that there is
12 a
tension between managing risk, providing access
13 to
the drug, ensuring appropriate use, and business
14
considerations. How drugs are
used is influenced
15 by
many parties in the health care system.
We
16
think there may be room for improvements in the
17
risk communication and processes and are working
18
with GlaxoSmithKline on them.
Overall, at the
19
present time the risk management program appears to
20 be
managing risk and assuring appropriate use.
21 At this point I would like to open it
up
22 to
committee questions of GlaxoSmithKline, FDA, and
248
1 for
further discussion. Thank you.
x DR. GROSS: Thank you, Dr. Justice. 2
3
Are there any questions from the committee
4
members for any of the speakers?
Jackie?
5
DR. GARDNER: Two points of
clarification,
6 if
Dr. Metz could help me. The first is
whether
7
there is any restriction on the quantity of drug
8
that can be prescribed. I
appreciate that your
9
packages come in 30s, but a prescription for 90 is
10
allowable, for example. Is the
quantity
11
restricted?
12
DR. METZ: Right now, what we're
requiring
13 is
a prescription--what we're providing to the
14
patient is a package of 30. It is
possible that a
15
physician could prescribe multiples of that. But I
16
don't think we have any direct data on whether that
17 is,
in fact, happening and on what scale it's
18
happening.
19
DR. GARDNER: But it's not
prescribed by
20 the
program.
21
DR. METZ: No.
22
DR. GARDNER: And the second
question I
249
1
have relates also to access but to the
2
post-marketing surveillance.
Regarding your
3
population-based surveillance, do you know whether
4
this drug is on the formularies of those HMOs?
5
DR. METZ: You're going to have to
speak
6 to
a microphone, Bob.
7
DR. SANDLER: Right now our
estimate is
8
that 87 percent of prescriptions are reimbursed in
9
some fashion when covered through managed care. So
10 it
may not necessarily be on a formulary, but it
11
will be covered.
12
DR. GROSS: Stephanie?
13
DR. GARDNER: Dr. Metz, I'm
sorry. That
14
doesn't answer our question, because if it's not on
15
those formularies, you're not going to find scrips,
16 and
there's no point in doing the post-marketing
17
surveillance
18
DR. METZ: Dr. Gurwitz?
19
DR. GURWITZ: My name is Jerry
Gurwitz. I
20
represent the HMO research network CERT, the Center
21 for
Education and Research on Therapeutics, that is
22
conducting one of the studies, and nine health
250
1
plans are involved in our study, our component of
2 the
epidemiology program. In all of the
health
3
plans involved in our study, the drug is available.
4 The
access to prescribing the drug varies according
5 to
the plan. Many of the plans require
prior
6
approval for a prescription. But
none of the plans
7
forbid prescribing, and all of the plans, if
8
approval is given, will allow it to be prescribed.
9
DR. GROSS: Okay. Stephanie?
10
DR. CRAWFORD: Thank you.
11
Dr. Metz, in slide 46 on patient
12
appropriateness--this is the one where you have the
13
categories for men and women and overall met
14
treatment and severity criteria for women, 90
15
percent, men, 84. I have actually
two questions.
16
My first one is: Why is the men
not zero
17
based on the label indications?
18
DR. METZ: Well, there's a
difference
19
here. It's not indicated for use
in men, but men
20
that are using it can still meet the criteria for
21
treatment. So there's a
difference here. You
22
know, the question is: If we had
a box in there
251
1
that said women for whom it was--or patients for
2
whom it was indicated, then you'd have a number for
3
females, but for men you would have zero because
4
it's not indicated for use in men.
But now the
5
real question is: Of the men that
receive
6
Lotronex, did they have the disease that would have
7
qualified them for treatment for Lotronex? And the
8
answer to that is 84 percent of them did have the
9
disease. Is that--
10
DR. CRAWFORD: I understood how it
was
11 meant. I guess I'm asking are you--the second
12
question, which is not so quick, is:
You were
13
rather general in some of the things you were
14
alluding to, saying perhaps things from the
15
sponsor's perspective could be handled through
16
education, et cetera. Can you be
more specific?
17 And
as part of that, are you also saying that
18
perhaps the indications should include men or not?
19
DR. METZ: No, again, right now
we're not
20
considering any change in the indications statement
21
because, as Dr. Justice has suggested, those types
22 of
changes are going to require data from
252
1
additional clinical research.
2
I think what we're looking at
and, again,
3
what we're working with the FDA on is looking at
4 the
product information, the product labeling, and
5
trying to provide a little more balance, trying to
6
present the information in such a way that it's not
7
naturally intimidating or frightening to the
8
patients. So, you know, we're
looking at making
9
modifications that provide balance and clarity, and
10 I
think that's the approach that we're trying to
11
take as far as the risk management program is
12
concerned.
13
And as far as the attestation process, as
14 Dr.
Justice mentioned, we're taking a look at that
15 and
seeing where the points of tension are between
16 the
physician attestation process and see if
17
there's another way to address it to take some of
18 the
venom out of that, if you will, and make it
19
more acceptable to the practitioner.
20
Again, that's an area that we just have to
21 focus
on because the feedback that we've gotten
22
from the field indicates that that's an issue for
253
1
some of the practitioners.
2
DR. GROSS: You mentioned that 80
percent
3 of
the prescribers were in PPL.
4
DR. METZ: Right.
5
DR. GROSS: How did the other 20
percent
6
write for the drug? And why was
it honored?
7
DR. METZ: Okay. Well, they can write a
8
prescription for the drug. There
is no mechanism
9
that we have to keep them from doing that. But it
10
would be akin to a physician writing an off-label
11
prescription for a product, which they have the
12
right to do.
13
Now, at the pharmacy level,
obviously,
14
there is a little bit of tension created because
15 for
the pharmacists that are aware of the program,
16
they're faced with filling a prescription that
17
doesn't have a sticker on it and what they're going
18 to
do about that.
19
So, again, we've addressed that with some
20 of
our follow-up information. We have that
21
follow-up letter that goes to the pharmacist when
22
we've identified non-enrolled prescribers, just
254
1
reminding them that this is the program that's in
2
place for Lotronex and, you know, encouraging them
3 to
hopefully contact the prescriber and say, you
4 know: Are you enrolled? I got a letter from GSK
5 or
from the prescribing program for Lotronex that
6
says there ought to be a sticker on these
7
prescriptions.
8
But, again, we can't force that
9
conversation to occur, and what we're finding is 13
10
percent of the prescriptions that are written are
11
coming outside of the program.
12
But, again, you know, we have no benchmark
13
against which to judge that, but 87 percent is
14
pretty encouraging to us, frankly.
We're very
15
relieved because we had no idea what would happen.
16
DR. GROSS: And from the patient's
point
17 of
view, I guess it's not possible in the current
18
program, but would it be possible once the patient
19 and
the physician work out their agreement to have
20 the
patient obtain prescription renewals, let's
21
say, for the next two monthly ones, attain them
22
without a visit and maybe just see the physician
255
1
four times a year instead of monthly for
2
prescription renewal?
3
DR. METZ: That's an excellent
point, and
4
oddly enough, we're in some discussion around how
5 to
address that issue. Because, again, I
think
6
with these risk management programs, you start out
7 in
one place, and after you've had some experience
8
with the product being marketed under those types
9 of
programs, you use the data to decide where to go
10
next. And I think we feel that
maybe the time is
11
right to take a look at this refill procedure and,
12 as
you've suggested, make sure that the important
13
conversations occur first early on.
But then after
14 that,
once the patient is in a "stable situation,"
15
perhaps you could provide for refills and, again,
16
reduce the need for those recurrent visits. I
17
think that's a very good point.
18
DR. GROSS: Henri?
19
DR. MANASSE: Dr. Metz, I have two
20
questions. One relates to the
intense time that it
21
takes both physicians and pharmacists to
22
participate in this program and do the required
256
1
safety net activities. What kind
of dialogue has
2
gone on within GSK to deal with the time, cost,
3
financing component of the management of the
4
program? Question number one.
5
Question number two: Have you explored
6 all
of the different places and mechanisms by which
7
prescriptions get filled by patients and the fact
8
that all of these different ways probably require
9
different ways of managing the program?
I refer
10
specifically to where the patient has a choice in
11
terms of going to pharmacies, both in hospitals and
12 in
communities, versus forced mail-order, for
13
example, in some health plans--my point being,
14
again, and my question relating then to how have
15 you
thought about these issues, and are there ways
16
that these can be tinkered with, if you will, to
17
enhance the participation of providers?
18
DR. METZ: Let me try to answer
the first
19
question first, as best I can remember it, and that
20 was
with regard, if I understand it, to the
21
internal burden with GSK of running this very
22
complex program--
257
1
DR. MANASSE: It's placed on the
providers
2 and
the time and energy that it takes and the
3
problems of remuneration we heard from one of the
4
speakers today.
5
DR. METZ: Well, you know, again,
if I
6
understand the question, we are looking into that
7
issue, and we're trying to decide which of these
8
points should be addressed--you know, what points
9
could be addressed to relieve as much of that
10
burden or tension as possible, while maintaining
11 the
integrity of the RMP framework itself.
And,
12 you
know, it's a balancing act, and we're into
13
those discussions with the agency, and we're going
14 to
look for ways to make this less onerous without
15
undermining the integrity of the system that we
16
believe has worked fairly well up to this point.
17
DR. GROSS: Brian--
18
DR. METZ: Now, there was a second
19
question, and that second question was really have
20 we
looked into the other mechanisms or avenues for
21
patients filling prescriptions and whether, in
22
fact, there are any barriers there that we didn't
258
1
envision that we should perhaps address moving
2
forward. And, honestly, we have
not looked into
3
that right now. We'd be
interested in hearing some
4
views on that because I think that's a very
5
important point. And, again,
we've been, you know,
6
dealing with this, but I think as we move forward
7 and
if we consider some other ways to address the
8
refill phenomenon, that's got to come into play.
9
So, again, we'd be interested in hearing
10
some advice about that.
11
DR. STROM: I have two
questions. One is:
12
When we met about this two years ago, one of the
13
ideas of the attestation and the debate about
14
attestation and certification and
15
gastroenterologists, primary care doc, was the goal
16 to
have this drug prescribed by a subset of
17
physicians who really knew how to use the drug.
18 And
given the numbers you just described about
19
10,000 patients and 5,000 docs, or even 2,500 docs
20
prescribing it, that's an average of four patients
21 per
physician, which isn't very impressive.
22
What proportion of patients are getting
259
1
their prescriptions from physicians who are
2
prescribing it to more than one patient?
3
DR. METZ: I think we have a slide
on
4
that. Yes, we've got a bar graph
with the numbers
5 of
prescriptions. Just a second. We'll see if we
6 can
find that.
7
But you're right, again, if
8
you--recognizing that no refills are allowed, some
9 of
those numbers that you see are original
10
prescriptions for the same patients, so you're
11
absolutely right, the number of patients per
12
physicians who do choose to treat is pretty low.
13
DR. STROM: But, if anything, that
argues
14
there should be fewer certified physicians rather
15
than more.
16
DR. METZ: Okay. Here we go.
Here's the
17
prescribing activity, and what we see here, this is
18
total numbers of prescriptions.
And, again, it
19
gets hard to put a denominator with that because we
20
don't have any refills that are allowed.
But,
21
anyway, I think what you can see is in the one to
22
five range, very negligible.
There are a few, a
260
1 few
more actually, roughly twice as many dedicated
2
prescribers, if you will, that are driving
3
prescriptions beyond six to ten, out to greater
4
than 15 prescriptions. But it's a
very small
5
cohort.
6
DR. STROM: The second
question: As you
7
were talking about, one of the key issues here is
8
mitigate risk, and when dealt with this two years
9
ago, one of the concerning questions, obviously
10
through no fault of anybody, is that there was no
11 way
to predict--let me back up. It appeared
that a
12
relatively small subset of patients actually
13
benefited from it. We saw two
sets of data
14
indicating only about 10 percent of patients
15
continued the drug long term for a symptomatic
16
drug, and it looks like that's what happening again
17 now
that the drug is on the market. So
there's
18
only a small subset of people who get the drug who
19
will benefit. And there were no
risk factors that
20
were identified in the data then that could predict
21 who
was likely to benefit and who was not.
22
In the same way, the risk of suffering a
261
1
serious event is obviously much less than 10
2
percent, but even in your new experience here with
3
incomplete reporting, it's still one in 300
4
patients suffering serious events.
And part of the
5
problem is, at least as of two years ago, we
6
couldn't predict who would benefit.
We also
7
couldn't predict who would be hurt.
So that the
8
only way to mitigate the risk was to restrict its
9
access and to, in fact, limit it to as few people
10 as
possible, because 100 percent of the people who
11 got
the drug would be at risk of getting the
12
adverse events, where only roughly 10 percent of
13 the
people who got the drug would benefit from the
14
drug.
15
In the interim, where you've got other
16
clinical trials underway and additional experience,
17 are
there any more data you could share with us
18
that would give information about predictors of
19
either who is likely to be that 10 percent who
20
benefit or who is likely to be in that one in 300
21 who
will suffer serious adverse events?
22
DR. METZ: No, we don't have any
new
262
1
information. Our clinical trials
program is
2
ongoing, and, again, we just simply don't have that
3
information available as we sit here today. And,
4
again, you're absolutely right, the ischemic
5
colitis we believe is idiosyncratic; therefore, we
6
can't predict.
7
However, what we do think that we're
8
seeing here is some improvements in the outcomes,
9
and, again, our goal for this risk management
10
program was not based on a target number but was
11
based on changing behavior, prompt recognition and
12
action on behalf of the patient and physician. So
13
that's where we are right now.
14
DR. STROM: But just as a
follow-up
15
comment, the logic of two years ago, which you're
16
describing to me still holds, is if you can't
17
predict who's going to benefit and you can't
18
predict who's going to be hurt from it, the only
19
answer is--we didn't want it unavailable because we
20
thought there were people who clearly needed it,
21 but
the only alternative was to greatly limit its
22
access as much as possible.
263
1
DR. METZ: Well, again, you know,
we feel
2
that with this specified target population, we've
3 got
a target population for whom we believe the
4
benefits will outweigh the risk.
And we believe
5
it's an appropriate target population for
6
treatment, and we believe within this framework
7
that we have developed here, risk can be
8
effectively managed and people can have the
9
opportunity to benefit from Lotronex.
And I think
10
that's what we're trying to provide here is that
11
opportunity. So, you know, we'll
finish our
12
clinical trials program and hopefully be generating
13
some data that we can share in the future. But we
14 are
where we are.
15
DR. GROSS: Robyn has the next question.
16
MS. SHAPIRO: I think this may
pick up
17
some of that. As I understand it,
then, part of
18 the
qualification requirements for the doctor is so
19
that he or she could properly manage in the event
20 of
something bad happening. But it's not
clear to
21 me
from your presentation about what you want to do
22
about what you've already put in place to try to
264
1
make that happen. In other words,
the perception
2 of
the liability transfer I think is ridiculous,
3 and
they will always be afraid about that and upset
4
about that. You're not going to
answer that.
5
Anytime when you want to require qualified
6 people, that's an affront, I guess, to
licensure
7 and
training. But if you believe that that's
8
important to be able to pick up--I don't think that
9 any
of these issues are significant enough or even
10
credible to go back on the required training thing.
11
DR. METZ: Let me just address
that
12
question in two ways. First of
all, we're not
13
talking about completely walking away from
14
something. What we're talking
about is trying to
15
modify what seemed to be perhaps the most offensive
16
elements of it. They don't like
the signature
17
process. So, you know, as Dr.
Justice has
18
suggested, is there another process to ensure that
19
they're qualified yet somehow or another doesn't
20
serve as an affront to them and recognizes some of
21
those sensitivities. But,
actually, I'd like to
22 let
Dr. Sandler address just some comments from his
265
1 perspective
on this process and some of these
2
intangibles, if you will.
3
DR. SANDLER: I think that as a
physician
4 the
program has incredible barriers and I think
5
it's hard to convey. And to sit
down with a
6
patient and ask them to sign this form I think is
7
insulting for physicians and somewhat demeaning.
8
I think to be able to give the patient an
9
information sheet and to sit down with them and say
10 if
you get constipation, stop the drug and call me,
11 if
you get bad abdominal pain, stop the drug and
12
call me, that permits me to educate that patient,
13
just the way I do with every other patient. This
14
program becomes special, and by doing that we set
15 up
barriers. And we're denying access to a
drug
16
that helps a lot of people. Dr.
Stronk (ph), whom
17 I
admire a lot, said that everybody has a risk but
18
nobody has a benefit. Well, going
into it, the
19
probability is everybody has a chance to benefit
20 and
everybody has a chance to risk. We can't
21
predict.
22
MS. SHAPIRO: But you're talking
about
266
1
what was going to be my second point.
My first
2
point is: Do we do away with the
required
3
qualifications attestation? And
that's different
4
than the agreement and the time that it takes to do
5
that. But let me just talk about
that, too, and
6
then you can come in on both.
7
One of the points in here is that it must
8
scare patients away because after they go through
9
this process, whether it's the signing of the form
10 or
hopefully, more importantly, the discussion,
11
some of them don't want to take the drug. Well,
12
that's informed consent.
13
DR. SANDLER: That's fine.
14
MS. SHAPIRO: I mean, that is what
the
15
plan is. When they hear things--
16
DR. SANDLER: What about the
patients that
17 are
denied the chance to even get the drug because
18 Dr.
Wilderlite, he's a competent gastroenterologist, and
19
he's afraid to use the drug. He's
afraid
20 of
litigation, he's afraid of--and the process is
21 so
time-consuming that we've set up barriers so he
22
doesn't want to use the drug.
267
1
MS. SHAPIRO: The time-consuming
thing
2
just gnaws at me because while I'm very cognizant
3 of
the fact that, particularly today, doctors don't
4
want to talk to patients because they don't get
5
paid for it, they have to talk to patients, and
6
particularly when they're dealing with a risky
7
drug, they have to talk to patients.
And our
8
reimbursement system should figure out a way to
9
make it worthwhile. But even
before it does, they
10
have to talk to patients.
11
DR. SANDLER: I couldn't agree
more. So
12 let
me answer your question about the attestation
13 and
then answer your question about talking to the
14
patients. There's probably a way
to do this short
15 of
a doctor saying, "I attest that I know how to
16
take care of IBS patients. I know
how to take care
17 of
ischemic colitis," signing a form.
I think
18
there are ways that the agency and the sponsor
19
could work to figure that out.
20
MS. SHAPIRO: Without assuring
that they
21
do? Without kind of assuring that
they really do
22
know how to pick up on the signs and symptoms that
268
1
would suggest that a patient's in trouble?
2
DR. SANDLER: Well, the system now
doesn't
3
assure it either. They just sign
the form and say
4
they can do it.
5
MS. SHAPIRO: Okay. Well--
6
DR. SANDLER: There's no way to
guarantee
7
it. They're licensed--
8
DR. GROSS: I think we're going to
have to
9 go
on to the next question. Alex, do you
have a
10
question?
11
DR. KRIST: The question that I
was
12
wondering leads a little bit on what Brian was
13
saying. Back in 2002, there were
discussions about
14
whether the lower dose, which is now the starting
15
dose, would have less risks of adverse events and
16
whether the risk of adverse event would go down
17
over time or whether most of the risk was when a
18
patient initially started the medication. And I
19
heard you say earlier that we don't necessarily
20
have information about who's going to be at risk.
21 But
part of my question that I'm wondering is I'm
22
just interested in the systems in place for
269
1
watching this to see if the lower dose will result
2 in
less adverse events and if the risk of adverse
3
events will change over time that a patient is on
4 the
medicine.
5
DR. METZ: Well, you know, again,
we have
6 a
survey that gives us information about the
7
starting dose that patients are taking, and we're
8
reassured by looking at that patient survey data
9
that they are indeed starting with that initial
10
dose that we wanted them to use.
But I think in a
11
longitudinal way, I'm sure that we have the ability
12 to
monitor across time in the fashion that you've
13
suggested.
14
Elizabeth?
15
And, again, that's some
information
16
hopefully that we'll get out of that ongoing
17
clinical program that was part of our series of
18
Phase IV commitments. You know,
that's the richest
19
context for that type of information, but I'll let
20
Elizabeth--
21
DR. ANDREWS: We do at every
follow-up in
22 the
survey, we ask what their current dose is, and
270
1 I
don't have the exact percentage. I can
get it.
2 But
a substantial number of people are still on the
3
lower dose. I think your question
was something
4
else, which was what is the efficacy at the lower
5
dose.
6
DR. KRIST: The risk across time.
7
DR. METZ: Risk of adverse event
on the
8
lower dose and the risk of adverse event over time.
9
And, again, within the survey context, we don't
10
have the ability to do that, but we have a very
11
large clinical trials program underway, and those
12
doses are included there, and that is going to be
13 the
richest source of that information. But
those
14
studies are not completed yet.
They are enrolling.
15
DR. GROSS: Curt?
16
DR. FURBERG: We heard quite a bit
about
17 the
good news, and I want to commend GSK and the
18
agency. We didn't hear much about
the troubling
19
news, at least two aspects of it.
One is the very
20 low
participation rate and the patient follow-up
21
survey program, 36 percent responded.
I find that
22
very, very troubling. And the
other one is the low
271
1
physician reporting rate those serious adverse
2
events. Most of the serious
events came from
3
patients.
4
So my question then is to you and your
5
company: What are you doing about
it? One thing
6 is
to take care of the issues and increase the use,
7 but
you also have to get better information, better
8
data for us that we can assess the impact of the
9
program.
10
DR. METZ: Well, as far as, you
know, the
11
general perspective on survey participation in this
12
type of context, I think I'll let, again, Dr.
13
Andrews address that. But I would
tend to disagree
14
with you. You know, given the
experience with
15
these types of instruments, we're not disheartened
16 by
36 percent.
17
Now, you know, are there other things that
18 we
should look at or could look at to change
19
participation rates in future surveys and what are
20 the
dynamics around the patient's willingness to
21
participate in these surveys? I
think these are
22
interesting research questions that I think we need
272
1 to
look into as this field evolves. But
I'll let
2 Dr.
Andrews talk--
3
DR. FURBERG: I think you're
saying you're
4
going to overcome barriers for the other areas.
5
This is an area that also has barriers, as you
6
said, and you need to overcome them.
And 36
7
percent is unacceptable, in my view.
8
DR. METZ: I'll let Dr. Andrews address
9
that.
10
DR. ANDREWS: Well, 36 percent
is--the
11
issue is whether the patients are representative.
12 Are
there biases because of the low participation
13
rate? A 36-percent participation
rate doesn't
14
necessarily mean that it's biased, just as a
15
90-percent participation rate might not mean that
16 it
is completely unbiased.
17
What we have looked at in terms of
18
representativeness is we've looked at the age and
19
gender of the patients, geographic region of the
20
prescriptions, and specialty of the physicians, and
21
compared with sales, and we see the patterns are
22
almost identical. So that is--
273
1
DR. FURBERG: It doesn't carry the
day at
2
all. I mean, those are fairly
insignificant,
3
nonspecific factors. The reason
why someone
4
doesn't respond could be that they had a bad
5
experience and just said, "I'm just out of it."
6 And
we never find out about it. I think we
have an
7
obligation to get as complete information as we can
8
from that part of the program.
9
DR. METZ: Again, that's a point
well
10
taken. Would we be happier if it
was 50 percent or
11 60
percent? We would both be happier.
12
DR. FURBERG: I'm just suggesting
devote
13
some effort to that as well.
14
DR. METZ: Yes, I agree. And the second
15
point that you made, I'm sorry, Dr. Furberg, was?
16
DR. FURBERG: The physicians, the
lower
17
reporting of adverse events. Most
of the events
18 are
coming from patients, which is unusual.
And
19
here are they objecting to it, or is it just--
20
DR. METZ: Again, I'm not a
physician. I
21
don't even play one on TV. But
I'm going to
22
pretend for just a moment.
274
1
You know, when we talk about seriousness,
2
seriousness means different things to different
3
people. To a practitioner, they
have a practical
4
definition of seriousness based on the practice of
5
medicine. We have a regulatory
definition of
6
seriousness based on the regulations, and perhaps
7
what we haven't done a good job of doing is
8
communicating to the practitioner community what it
9 is
we want them to report here. We've said
you
10
should report, but I'm not sure that we educated
11
them as far as what to report.
12
DR. GROSS: Our next question is
from
13
Maria.
14
DR. ANDREWS: I was going to make
the
15
comment, I just wanted to make sure that you are
16
aware that the participation in the survey is
17
voluntary.
18
DR. FURBERG: I understand that.
19
DR. ANDREWS: And so for a
voluntary
20
program, the participation rate is actually quite
21
high.
22
DR. FURBERG: I'd disagree with
that,
275
1
DR. SJOGREN: Actually, I'll take
up that
2
point because where I work, we have several
3
programs in which we do follow-up, and it is across
4 the board 30-percent response. When I looked in
5 the
literature, it is 30 percent no matter what.
6 And
so we put a follow-up program in place thinking
7
that we were going to do better, and it came out
8
right at 30 percent. So their 36
percent I think
9
falls within the literature, at least from what I
10
recall in my research. It's
unfortunate, but
11
that's us, that's human beings.
We don't like to
12
answer questionnaires; we don't like to be followed
13
up. And I think that's part of
the problem that
14
you're facing, and I don't think you're going to be
15
able to solve it. Just look in
the literature and
16
you'll see everybody's 30 percent.
Actually, you
17 are
6 percent above.
18
But the question I wanted to--or the
19
analysis that I did looking at the data and looking
20 at
what the FDA gave me to review is that indeed,
21
although there were patients that has ischemic
22
colitis, all of them resolved.
And I think, you
276
1
know, talking as a clinician--I mean, I wear
2
several hats, but one of them is as a clinician.
3 If
things resolve, you don't think that they are
4
serious. So that's possibly the
cause why my
5
colleagues are not reporting to you.
6
Now, if we are in the midst of a clinical
7
trial and you have an ischemic colitis or you have
8 a
hospitalization, then you absolutely report as a
9
serious adverse event, but not in the practice of
10
medicine. And these observations
are part of the
11
program that you and the FDA put together.
12
The fact that, when I did some rough
13
calculations, you had less than 4 percent adverse
14
events in this program and then, as was pointed out
15
before, the serious adverse events--by seriousness
16
considering ischemic colitis or some other
17
diagnosis--was 0.3 percent. So
the program is a
18
success in regards to if you apply this medication
19 to
the appropriate patient. Then you have a
small
20
rate of adverse events in general and not
21
dismissible but a small rate of serious adverse
22
events especially when those serious adverse events
277
1
resolve, because you remove the drug and the
2
patients just can go back to their normal life.
3
So I think, you know, the program that you
4 put
together is very good because it proved the
5
point that the appropriate patient that takes the
6
drug, then the risks are minimized.
7
So talking now on the subject of being a
8
clinician and having ten gastroenterologists that
9
work with me and many friends in the community,
10
I've asked in the past if they use Lotronex, and
11
they've all told me no because when they enroll or
12
attempted to enroll, they got boxes and boxes and
13 boxes
of paperwork to fill out, that it is
14
horrendous. They're very upset,
the community of
15
gastroenterologists in general, because there are
16
patients in which, although the disease may not be
17
life-threatening in the sense that they die, it is
18
life-threatening in the sense that the guys cannot
19 get
out of the house or have to have an office
20
right next to a bathroom. There
are things in
21
gastroenterology that should not escape us, and I
22
think the appropriate patient with this drug should
278
1
have access to it.
2
And I think that the reason for meeting
3
today is to find a way to make it more accessible.
4 Obviously, there were very serious side
effects
5
before. There was
misunderstanding. There were
6
physicians that perhaps were not following the
7
letter of the intent of the FDA.
But those things
8 I
think we can work with and make the program more
9
feasible for our patients and for our physicians.
10
DR. METZ: Okay. That's our intent. It's
11 a
continual cycle of evaluation and revision.
The
12
advantage that we have right now is at least for a
13
change we have some data that we can deal with as
14 far
as the potential impact of these things.
And,
15
yes, there are things both good and bad that we
16
need to address as we move forward.
But we think
17
it's important to continue to make this available
18 to
these patients because this disease really
19
insulates them from their activities of daily
20
living.
21
DR. GROSS: Mark, did you have a
comment
22 you
wanted to make?
279
1
DR. AVIGAN: Right. I just wanted to
2
speak to the observation of the adverse events, the
3
eight cases of ischemic colitis that were basically
4
predicted and pretty much on track with the usage
5
that currently exists. And then
the question came
6 up
of the distribution of severity of outcomes out
7 of
those eight cases.
8
Just to point out that the severe
9
outcomes, the bad clinical actors that were
10
observed in the previous experience, and just to
11
sort of go back to the April 2002 tabulation, so in
12 the
post-marketing sort of ratios, out of 84 cases
13 of
ischemic colitis, 10 developed surgical outcomes
14 and
two were associated with death. So it's
a
15
subset of the denominator of ischemic colitis. So
16
there may--there are two possibilities.
One is the
17
early observation of ischemic colitis by the
18
clinician, the patient really mitigates the risk
19 for
a bad outcome. But the other is that
because
20
there were less patients exposed, you don't have
21 the
full distribution of severity of outcomes
22
because of purely the number that actually got the
280
1
adverse event.
2
I just wanted to point that out, and I was
3
going to ask you if you--and we already spoke about
4
this a bit, whether you could distinguish between
5
these two because that's an important point about
6
your evaluation of the success of the risk
7
management.
8
The second question--and I just raise it
9 as
a question raised before--you mentioned that of
10 the
patients who are currently treated, 80 percent
11
have all three severity criteria.
So my
12
question--and you may not have the answer, but one
13
that should be raised--is: Of
those patients who
14
have frequent and severe pain, which is the first
15
criteria, what percentage of those have frequency
16
urgency or incontinence and/or the third criteria,
17
which is the restriction in lifestyle?
In other
18
words, what is actually the--if you already have
19
one, what is the percentage of all three in order
20 to
understand whether you're being overly stringent
21
because 80 percent have all three?
22
DR. METZ: Let's take the second
question
281
1
first. And, Dr. Chang, maybe from
your clinical
2
perspective, it's the issue that we've discussed
3
around what's the likelihood that a patient would
4
have one or two of these things versus having all
5
three. Again, so the issue is,
you know, is it
6
fair to hypothesize that this all-three phenomenon
7
does really represent a severe end of the spectrum?
8 Or
is there something else going on here?
9
DR. CHANG: There have actually
been
10
studies that have shown that if you have pain,
11
that's a predictor of impact of quality of life.
12 So
I would imagine that the patients with severe
13
irritable bowel syndrome who have severe pain or
14
frequent pain are really going to have number
15
three, which is disability or disturbance of
16
quality of life.
17
There hasn't been data on the urgency or
18
fecal incontinence, but you can imagine that you if
19 you
have fecal incontinence, you're going to have
20 an
impact on your quality of life every time you
21
step out the door. But if you're
going to assess
22
urgency and that with pain, I don't think they're
282
1
really tied together. I think
it's tied with
2
discomfort. But with quality of
life, you have to
3
only look at a subgroup of IBS patients, which are
4 the
diarrhea predominant group. And my guess
would
5 be,
my impression is that urgency is probably a
6
strong predictor of impact on quality of life in
7
that group of patients.
8
DR. METZ: So it sounds like one
and three
9 and
two and three go together, but one, two, and
10
three seem to define, you know, a severe end of the
11
spectrum. And I guess as far
as--you know, we've
12
been talking about these diagnoses of special
13
interests and these outcomes, and if I could just
14
have Dr. Lewis make a comment from his perspective,
15
having reviewed this and chairing that Safety
16
Review Committee.
17
DR. LEWIS: Thank you. I chair a Safety
18
Review Committee which we look at all the events of
19
special interest regarding what is reported to be
20
ischemic colitis or constipation complications.
21 And
in doing that, it's revealing that certainly
22 not
all the cases that are filed as that diagnosis
283
1
turn out to be that diagnosis. We
spent weeks
2
developing criteria, methodology to put together a
3
true way to diagnose these conditions, which can be
4
done for any adverse event. I
mean, we do it for
5
liver disease and other things.
6
And with the cases that we've seen in this
7
program, while many of them were ischemic colitis,
8
several of them were not by the criteria that we
9
use. The first and foremost is
somebody has got to
10
look in the colon and see if it even looks like
11
ischemic colitis. People can have
rectal bleeding
12
from lots of different reasons, and pain. It could
13 be
diverticulitis, for example. So we have
14
criteria that we use.
15
We also then--what's not shown here is we
16
made a causal relationship jump to whether Lotronex
17
might have been responsible for the constipation or
18 the
ischemic colitis, and there we have similar
19
criteria and methodology we put together, and only
20 a
minority of those cases could we actually say
21
Lotronex seems to be responsible in a probable or a
22
definite manner.
284
1
We still don't know why ischemic colitis
2 occurs.
The latest epidemiologic studies suggest
3
that it might even be the very far spectrum of what
4 we
call irritable bowel syndrome. Remember,
we
5
still are learning about this syndrome.
We now
6
know it's not just with Lotronex.
Tegasorade
7
(ph)--I just got my letter yesterday, the "Dear
8
Doctor" letter telling me Tegasorade, which works
9 on
a different serotonin receptor, is also
10
associated with the condition. I
haven't reviewed
11
those cases so I don't know how accurate it is.
12 But
it is a learning process. I think we're
13
learning more about ischemic colitis in the last
14
couple of years and into the future than we ever
15
expected to, and it's important that we do that.
16
But just in terms of what we continue to
17 do
is try to identify in the future what patients
18
might be at risk, and that will be very important
19 to
know so that we might not give certain patients
20
Lotronex or the other drugs as well, because right
21 now
we don't know. And some form of
monitoring is
22
certainly important. An
educational program that
285
1
we're doing and telling patients what to expect and
2
stopping the drug if they get those symptoms is
3
crucial.
4
DR. GROSS: We have three more
questioners
5
before we close for the afternoon:
Art, Annette,
6 and
Jackie.
7
MR. LEVIN: I've been struggling
with how
8 to
put this as a question rather than a rant, but
9
first of all, just a few comments and then my
10
question.
11
I assume you're aware that in the context
12 of
risk management programs, this is risk
13
management lite compared to some others.
There are
14
other programs out there that manage the
15
prescribing and dispensing of medications about
16
which we serious questions as to the trade-offs
17
between risks and benefits and a lot of unknowns
18
that manage it much more rigidly than this does.
19 And
the notion that we're scaring patients away, I
20
mean, I would call your attention to the Med Guide,
21
which I think is mild and doesn't even follow the
22
guidelines in having the black box warning at the
286
1 top
of the Med Guide. It gets into the
risks, I
2
think, in a very general way.
3
That said, it strikes me in listening to
4
your presentation that you're looking to the wrong
5
entity to fix the problem, if there is indeed a
6
problem with access, because I think having
7
barriers is what risk management is about. I mean,
8 it sort
of defines it.
9
I think we have to recognize that this was
10 an
extraordinary case, the first time in history
11
where a drug which had been withdrawn came back on
12 the
market and about which there was little known
13 about how to predict risk, and that
everybody,
14
including all of the patients that testified that
15
day, seemed willing to ensure this special program
16 in
order to have access to the drug.
17
I think the problem is in the prescribing
18
community. I mean, I would ask
you to think about
19
where is the problem. And I am
somewhat--I'll use
20 the
word--angry that the prescribing community
21
describes a conversation with a patient about
22
benefit and risk and signing their name to a
287
1
page-and-a-quarter attestation as so burdensome
2
that they opt out of this program.
And it strikes
3 me
that if a physician believes that this is a drug
4 for
the patient sitting in front of them, it
5
borders on either misconduct or malpractice not to
6
prescribe that drug because they have to sign an
7
attestation or they have to go into a program which
8 is
designed to protect them and to protect the
9
patient from harm.
10
I would argue that your education--it's
11 not
a matter of relaxing the risk management
12
program. It's a question of
educating the
13
prescribing community that the things they're
14
afraid of they should not be afraid of, that this
15
program is in place to benefit everybody, and
16
they've got to give it a chance.
And maybe if we
17 do
learn how to identify patients that are at risk
18 and
can be more scientific in selecting who gets
19
this drug and not, we can change the program.
20
To date, there's no more data than we've
21
ever had, and I would argue to look to altering the
22
risk management program at this stage is simply
288
1
unacceptable in terms of protecting the public
2
health. And I think really what
we should be
3
thinking about is how do we educate the prescriber
4 community to get over their fear and to
prescribe
5
this drug when they believe it's appropriate for a
6
patient. You guys are very good
at educating
7
doctors about your products. You
detail very well.
8 And
I don't know why you can't be doing educational
9
detailing to that effect.
10
DR. METZ: On that?
11
MR. LEVIN: Yes.
12
DR. METZ: I didn't hear the
question so--
13
[Laughter.]
14
VOICE: It qualifies as a rant.
15
DR. METZ: You said you weren't
going to
16 do
that, but I feel--so do you feel comfortable
17
with my answer then? Thank
you. I mean--
18
DR. GROSS: You can advise
physicians
19
there are billing codes for time they spend with a
20
patient, which goes along with Art's comment.
21
Annette?
22
DR. STEMHAGEN: I just wanted to
confirm,
289
1 in
terms of the evaluation criteria, we're
2
talking--I think you have Slides 45 and 46--about
3
compliance and appropriateness.
And very high
4
percentages, everybody looks great.
But my
5
understanding is this is only based on that 36
6 percent. So we could be getting the best compliers
7
because they're the people feeling motivated, I'm
8
doing what I should and I'm going to tell you about
9
it. So understanding all the
limitations of survey
10
research, I do it all the time, trying to urge that
11
there be some other mechanisms put in place to
12
evaluate it, to get a higher percent so we can
13
really feel comforted by the percentages.
14
DR. METZ: You know, we put that
program
15 in
place. That's the claims-based
epidemiological
16
research which was to look at that at the back end,
17 if
you will. But, unfortunately, that
aspect of
18 the
program is dependent on patient uptake, and
19
right now it's not providing any value.
20
DR. STEMHAGEN: Well, I'm not sure
21
exactly--in terms of the claims database, there are
22
patients' self-reported criteria for whether you
290
1 are
the right candidate, and that's not going to be
2
captured in the claims database.
You'll have to go
3
back to the records, and that may still not be
4
captured unless the physician specifically asks
5
those questions.
6
So while I agree it's another evaluation
7
tool and I think it's an important one, I'm not
8
sure it's going to get to all of these questions,
9
either.
10
DR. METZ: You know, again, you're
right.
11 We
have to make some qualitative assumptions about
12 the
generalizability of that cohort, you know, to
13 all
patients that are receiving Lotronex.
And you
14
heard Dr. Andrews speak to the kinds of things that
15
we're looking at. But, you know,
you can't say
16
definitely, you know, these people are
17
representative. We hope that they
are, obviously.
18
DR. GROSS: Jackie?
19
DR. GARDNER: In 2002, when we
met, one of
20 the
discussions was around whether to restrict
21
prescribing to gastroenterologists, and I recall
22
that the Chairman of the Gastroenterology Advisory
291
1
Committee, I think--I may be ascribing it
2
incorrectly to him--said that won't work because
3
some of us have taken our practice in some other
4
directions--and I wanted to say liver disease or
5
something that he said. And so
that's why it
6
wasn't restricted to gastroenterologists;
7 therefore,
an attestation program was set up with
8
their concurrence because not every gastroenterologist knows
9
guts and so on--
10
DR. METZ: Is going to look at
IBS, right.
11
DR. GARDNER: Right, exactly. And some
12
family practitioners really do.
13
I'm struck by the difference in this
14
meeting and one we had a couple of months ago
15
around Accutane, in which those prescribers also
16 are
severely restricted. They have the same kind
17 of
sit-down and sign things. They've got to
do
18
pregnancy tests. And we heard a
lot about a lot of
19
things at that time, but I didn't hear this kind of
20
resistance to getting involved in these programs.
21
So my point is that FDA, with a risk
22
management program that is at least as onerous as
292
1
this one, nonetheless, has somehow managed to find
2 a
way to make it more acceptable to the
3
constituency such that, as you know, not only is
4
Accutane tremendously prescribed, more even than we
5
probably would want it to be, perhaps, but it also
6 has
four generics and yada, yada. I mean,
it's not
7
running into this prescribing limitation issue.
8 And
so I would suggest that you all look to models
9
within FDA for ways to handle this attestation to
10
make it--to eliminate this accessibility burden.
11
DR. METZ: And, again, we take the
point
12 on
perhaps an additional educational focus.
We do
13
have a large educational program ongoing, and,
14
again, that's another area where one could make
15
modifications and see if you can get some
16
incremental gain out of that. But
that's a
17
multifactorial problem. Let's
face it. There are
18 lot
of things intersecting here that need to be
19
addressed in a careful, prudent way.
And I think
20
that's what we're about here.
21
DR. GROSS: A special request from
22
Stephanie for the last word.
293
1
DR. CRAWFORD: Thank you, Mr.
Chairman.
2
Actually, I was just asking for a word, not
3
necessarily the last.
4
I would like to actually give you a kudo
5
because I've read some of the press that appear
6
today--that made it appear that the risk management
7
program is negative before we had this meeting. I
8
want to congratulate you on your risk management
9
program for alosetron because many aspects of the
10
program seem to be working.
11
From the information presented, one of the
12
major concerns that this committee expressed two
13
years ago was what appeared to be a very large,
14
inappropriate prescribing.
Without a question,
15
that has gone down. I am not
convinced that the
16 low
numbers of prescriptions of patients is due
17
mainly to unreasonable barriers.
It could be that
18
it's being prescribed more appropriately and
19
patients are making good, informed decisions. We
20
don't know. I know all the
discussion we've had
21
from that.
22
That said, however, I am in favor of any
294
1
improvements to the existing programs.
Specifically for me,
2 I
would be in favor of revising any
3
language that would ensure that the patient
4
agreement forms are clear and informative, and I
5
will just leave it at that, and also possibly
6
extending the supply, dispense. I
don't want to
7
discuss in terms of what you say, the refill
8
phenomenon as much as I prefer that any changes be
9 in
terms of the day supply, because it's a huge
10
difference if the physician prescribes a 30-day
11
supply and you can refill it three times versus if
12 he
or she prescribes a 90-day supply that you're
13
refilling three times. So think
in terms of day
14
supply, not refill, if there is any change to that.
15
Thank you, Mr. Chairman.
16
DR. GROSS: A pleasure, Ms. Vice
Chairman.
17
[Laughter.]
18
DR. GROSS: We began the meeting
and we'll
19 end
the meeting with a thank you to Brian Strom for
20 his
invaluable service to the committee. We
really
21
appreciate having you as a colleague over the last
22 few
years. Would you like to make any
comments?
295
1
DR. STROM: Sure. Thank you.
I guess I
2
began with a comment, and it's only fitting I end
3
with a comment.
4
I just wanted to follow up on a few loose
5
ends and some comments that were made.
One is I
6
think compared to Accutane, and in response to
7
Art's comment also, there's a big difference here
8 in
efficacy. And I think to blame it on the
9
physicians and to say the physicians don't want to
10
prescribe it--well, there may be a reason they
11
don't want to prescribe it.
That's something to
12
keep in mind.
13
Second, I think the use of the claims
14
databases make sense. I think it
is striking that
15 the
proportion of users in the claims databases,
16
given the population numbers we saw, is much lower
17
than the proportion of the general population we're
18
seeing. So what it's saying is
our managed care
19
organizations are saying don't use this, even more
20
than the rest of the general public is.
21
Third, Curt talked about 36 percent and
22 the
concerns of 36 percent, and there was a lot of
296
1
argument about 36 percent.
Personally, as an
2
epidemiologist, I would consider that a shockingly
3 low
number. On the other hand, I think it's
4
important to realize certainly no NIH grant would
5 get
funded with anything less than 80 or 90
6
percent. From a marketing study,
it's high, but
7
it's--I think we heard in the Accutane situation
8
about numbers that were comparable.
So I don't
9
fault the survey, necessarily. I
think in part
10
it's the situation. But I think
it's important
11
that what that means is we're missing two-thirds of
12 the
people and we're missing, as Annette was
13
saying, the two-thirds that are probably most
14
likely to be the problem people.
So we can't rely
15 on
those data because they're giving us biased
16
information.
17
The same thing in underreporting.
18
Clearly, there's vast underreporting, as you
19
indicated. I don't blame the
system because docs
20
don't report, you know, exactly as you're saying.
21 But
what it does mean is the rates we're looking at
22
here are much lower than the real rates that are
297
1 out
there.
2
I want to emphasize again that part of the
3
goal here is to create a barrier, and the barrier
4 is
working. And so the goal isn't to
eliminate the
5
barrier.
6
And I'll conclude with just a comment.
I
7 was
one of those who was skeptical of the program
8 two
years ago. I think it's working. I mean, I am
9
very encouraged in many ways by what we're seeing.
10 I
wouldn't want it changed in major ways.
Until we
11
have data on predictors of efficacy or predictors
12 of
adverse events, then I think it should be
13
refocused accordingly.
14
DR. GROSS: I'd like to thank
Glaxo and
15 the
FDA people for their presentations and input,
16 and
once again thank the Advisory Committee members
17 and
advisers for their comments. Thank you
all.
18
Have a good trip home.
19
[Whereupon, at 4:29 p.m., the meeting was
20
adjourned.]
21 - - -