DEPARTMENT OF HEALTH AND HUMAN SERVICES

\+ + + + +

FOOD AND DRUG ADMINISTRATION

\+ + + + +

RISK MANAGEMENT PUBLIC WORKSHOP

RISK MANAGEMENT PROGRAMS

\+ + + + +

THURSDAY,

APRIL 10, 2003

\+ + + + +

The Workshop met in the NTSB Board Room and Conference Center at 429
L\'Enfant Plaza, S.W., Washington, D.C. at 8:00 a.m., Paul Seligman,
Moderator, presiding.

[Present]{.underline}:

PAUL SELIGMAN, Moderator, CDER

STEVEN GALSON, Deputy Director, CDER

SUSAN ELLENBERG, CBER

DEBBIE HENDERSON, CDER

FLORENCE HOUN, CDER

JOHN JENKINS, CDER

TONI PIAZZA-HEPP, CDER

CLAUDIA KAROWSKI, CDER

ROBERT TEMPLE, CDER

ANNE TRONTELL, CDER

MARK WEINSTEIN, CBER

ROBERT WISE, CBER

I-N-D-E-X

Welcome and Introductions, Dr. Steven Galson,

Deputy Director, CDER 4

**Session 1 - Concepts of Risk Management,**

**When is an RMP appropriate and Risk**

**Risk Management Tools**

Overview of Guidance Development Process,

Good Risk Management, Dr. Anne

Trontell 8

FDA Presentation: Concepts of Good Risk

Management, Dr. Robert Wise 14

FDA Presentation: Risk Management Tools,

Dr. Toni Piazza-Hepp 19

Clarification Questions to FDA on

Concept Paper 23

Oral Presentations - Public Comment (preregistered)

Susan Perez-Gutthann, MD, PhD, MPH,

International Society for

PhRMAcoepidemiology Pharmaceutical

Association 50

Gary Stein, PhD, American Society of

Health-System Pharmacists 69

Kim Swiger, Rph, National Association of

Chain Drug Stores (Ikrops Super Markets,

Inc. 76

Janice Bush, MD,

Pharmaceutical Research and Manufacturers

Association 86

Anshe Vashishtha, MD, PhD, Watson

Pharmaceuticals 93

Discussion and Questions for Speakers 98

I-N-D-E-X (cont.)

**Session II - Evaluation of Risk Management**

**Programs and Elements of a Risk Management**

**Submission**

FDA Presentation: Evaluation of Risk

Management Programs, Dr. Anne

Trontell 156

FDA Presentation, Elements of a Risk

Management Submission, Dr. Claudia

Karowski 165

Oral Presentations - Public Comment (preregistered)

Gretchen Dieck, PhD,

Pharmaceutical Research and Manufacturers

Association 170

Sidney Kahn, MD. PhRMAcovigilance and

Risk Management, Inc. 178

Gerald Faich, MD. MPH, Pharmaceutical

Safety Assessment 192

Robert Nelson, PhD, Quantitative Data

Sources 202

Marilyn Dix Smith, RPh, PhD, International

Society for PhRMAcoeconomics and

Outcomes 215

Discussion and Questions for Speakers 222

Wrap up - Moderator, Workgroup Chair and

Co-Leaders 266

Adjourn 271

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

8:04 a.m.

DR. SELIGMAN: Good morning. If everyone will take their seats, we\'ll
begin in just about a minute.

(Pause.)

On the big screen is Dr. Steven Galson. Good morning and welcome to the
second day of the public workshops on risk management. My name is Paul
Seligman. I\'m the Director of the Office of Pharmacoepidemiology and
Statistical Science at the Center for Drug Evaluation and Research at
the FDA and I\'ll be serving as the Moderator for today\'s session.

On behalf of the Oversight Committee, I want to welcome all of you here
today. We had a very, I think, interesting and engaging discussion
yesterday and I\'m hoping for more of the same today. On my right or
your left down here in the front are two of the members of the Executive
Oversight Committee, Dr. Robert Temple and Deborah Henderson. In front
of me is the chair of the Oversight Committee, Dr. Steven Galson as well
as a CBER representative on the Oversight Committee, Mark Weinstein.
Thank you, Mark.

As most of you recognize, today is the second of three workshops and
today we\'ll be focusing on the Concept Paper prepared by the second
group entitled Rick Management Programs.

Following a brief welcome and introductions this morning, we will plow
right into the first session which will deal primarily with two sections
of the Concept Paper related to concepts and tools. And we will have
presentations from members of the working group, followed by oral
presentations from speakers who are seated before us, followed by a
break. Following the break, we\'ll have additional comments and then a
period for discussion and questions for the speakers.

After a lunch break, we will focus on the issues related to evaluation
and the elements of a risk management program and again have speakers
and discussion in the afternoon, followed by a wrap up.

There are basically two ways for the audience to participate today. If
you want to submit questions or comments, if you want, on 3 by 5 cards
which are distributed out at the front desk, you may do so and give them
to Chris Bechtel. Chris, if you want to just \-- or other members of the
support staff will be up and down the aisles.

In addition, as we did yesterday, there are microphones in both aisles
and just please line up and as Moderator, I will certainly recognize
you. I ask please, that anyone who wishes to speak identify yourself not
only by name, but the organization that you represent.

In addition, the docket for these workshops will be open and available
within 30 days after the workshop at the internet address indicated
above. The workshop website address is also indicated above which is a
way you can get copies of the Concept Papers.

We certainly encourage all of you to submit comments to the docket. We
think these would be extraordinarily valuable to us in the preparation
of the guidelines.

Finally, just a couple logistical reminders related to the use of this
Conference Center. Please, no food or drinks are allowed in the
Conference Room. There are places actually to view and to listen to the
proceedings and to watch the speakers, just out here in the audience in
a glassed enclosure. So if you feel like you need to eat and/or drink
during the proceedings, you\'re certainly welcome to sit up in that
area.

Restrooms are located in the registration lobby area and please note
that not only is there an emergency exit to the rear where you came in,
but also at the two sides in the front of the building.

With that, I\'d like to introduce Dr. Steven Galson who is the Deputy
Director of the Center for Drug Evaluation and Research who will provide
some introductory and welcoming comments.

Thank you.

DR. GALSON: Thank you, Paul, and on behalf of CBER and CDER, I want to
welcome all of you here. It\'s really good to see a large number of
participants like yesterday. We had a high level of participation
yesterday and we\'re really hoping for the same high level today. For us
to really perfect these Concept Papers and have them move on to the
guidance stage, we really need a high level of participation and a high
level of input from all of you, either by your comments today or in
written submissions to the docket. It\'s really going to be tough once
the process is all finished to take sort of basic intrinsic complaints
about it. So we really encourage you again to participate or send in
your comments.

The material that we\'re discussing today which is good risk management
really represents what I see as the key change from PDUFA 2 to PDUFA 3.
The newest PDUFA agreement for the first time lets us use, spend user
fees on risk management plans before approval and then after approval to
monitor them. This really is a quantum change and the methods that
we\'re going to implement to do this which is what we\'re discussing
today are really going to change in some ways how FDA regulates drugs
and biologics over their life span. So this very important.

Again, thanks for being here and I look forward to a very stimulating
day.

DR. SELIGMAN: Thank you, Steven, and with that let\'s proceed then with
the first session of the day on concepts of risk management and when is
a risk management program appropriate and a presentation on risk
management tools. With that, it gives me pleasure to introduce Dr. Anne
Trontell who is the Chair of the Working Group that was responsible for
the preparation of this Concept Paper who will provide us with an
overview of the guidance development process on good risk management.

Anne?

DR. TRONTELL: Thank you, Paul and let me add my welcome to all of you
who have traveled here today. We hope to get some very interesting and
meaningful constructive comments on this Concept Paper that we\'ll be
discussing on risk management programs.

This represents the work of the Centers for Drugs and the Centers for
Biologics. I\'d like to acknowledge, as a group, the efforts of the Risk
Management Working Group, the representatives of which you see listed
here. They\'ve been an extraordinary group in terms of their technical
contributions and dedication in preparing this Concept Paper and also
for preparing for today\'s session.

I\'d like to make a particular acknowledgment to Chris Bechtel who
served as the project management for this group and without which much
of this would not have been accomplished.

Let me set the overall context if I might, since all three PDUFA
guidances are grouped under the term risk management and this guidance
or Concept Paper shares that same name.

All three papers are obviously highly interrelated. Yesterday\'s Concept
Paper and tomorrow\'s both focus on the risk assessment components of
risk management. Yesterday\'s discussed pre-marketing risk assessment
and tomorrow, you\'ll hear about pharmacovigilance and
pharmacoepidemiology.

In distinction from those papers, today\'s Concept Paper will be
focusing on actions or interventions that are taken to reduce risks in
product use and these are of necessity based upon the assessments that
are described in the other two Concept Papers. So the interrelationship
is quite close.

To help in distinguishing this Concept Paper from the overall process,
we\'ve used the term risk management program and you\'ll hear more of
these definitions in the first presentation this morning.

We have also, for purposes of distinction, termed the overall process of
assessment and intervention, risk management planning. So watch your Ps
here. Sometimes it\'s planning and sometimes it\'s programs.

Just to briefly recapitulate the highlights that were described
yesterday, we\'ll be very eager for your comments today and also those
that you may submit in writing through the end of this month to the
docket. Based on those comments, we\'ll make revisions to this Concept
Paper and publish a draft guidance in the fall. You\'ll then again have
an opportunity to give us commentary and then we will work to publish
final guidances on or before September 30, 2004.

The format of today\'s meeting varies from yesterday\'s where an
external panel was used. The only prepared remarks that you will see
from FDA come from the work group and steering committee. We will have
two half day sessions, each of which will have two sections of the
Concept Paper. They will be presented in highlight form by members of
the work group and we\'ll have an opportunity for a few minutes of
clarifying questions after their presentations. Then we\'ll hear from
our registered speakers and open it up for discussion.

We\'ll do the same in the afternoon and just allow a few minutes to wrap
up.

The scope of the Concept Paper encompasses these four principal
sections, the first two which we\'ll consider this morning and the
latter two this afternoon.

The first is what considerations should be made in initiating and
designing a risk management program and we\'ll lay some important
groundwork in terms of definitions and when such programs might be
considered appropriate.

The next section discusses the processes for selecting risk management
tools and our proposed scheme for categorizing those tools into levels.

The next section discusses the importance of evaluation and methods by
which that might be done for risk management programs and the concluding
section echoes the previous ones by describing those elements that FDA
would consider important for any risk management program submission to
the Agency.

This morning\'s speakers include Dr. Robert Wise from the Center for
Biologics who will initiate the discussion of concepts, definitions and
when a risk management program might be appropriate. He\'ll be followed
by Dr. Toni Piazza-Hepp from the Center for Drugs, who will be
discussing tools and levels of risk management programs.

In the afternoon, evaluation processes and methods, in fact, will be
presented by myself since Dr. Diamond had an unexpected need to be out
of town. Submission elements will be presented by Dr. Claudia Karowski
from the Center for Drugs.

Certainly, everything that is contained in these Concept Papers are open
for your commentary, but in this morning\'s session, we have several
areas where we\'re particularly interested in hearing your feedback.
This Concept Paper, perhaps in contrast to yesterday\'s is certainly in
a more formative stage and we\'re very eager to receive your input on
these areas.

We would appreciate your commentary on how we\'ve defined a risk
management program and ask for any suggestions you might have to clarify
that or our definition of risk management program goals and objectives.

We would be very interested in your thinking on the determination of
when a risk management program is needed and what might be the best
roles for FDA and sponsors to take in making decisions about this need.

We also invite this morning your suggestions for ways that we might
capture the

ever-changing landscape of risk management program tools and how we can
incorporate that in a guidance. And similarly, we\'ll also want to hear
how meaningful you find our proposed categorization scheme for risk
management programs into levels.

In the afternoon when we discuss evaluation and elements of risk
management program submissions, we\'ll have further questions about
issues of pre-testing, evaluation and some of our potential
recommendations to require two evaluation methods for critical risk
management program goals as well as on risk management program
submissions.

That concludes my remarks. Thanks very much.

DR. SELIGMAN: Thank you, Anne. With that, let me introduce Dr. Robert
Wise who will be making the presentation on concepts of good risk
management.

Dr. Wise.

DR. WISE: Thanks, Paul. Good morning. I\'m very happy to be with you
this morning to describe risk management program concepts and as Anne,
who has just explained, we\'re going to try to distinguish between the
overall process and the specific risk management program which is the
subject of PDUFA 3 regulation. PDUFA 3 is not a regulation, but you all
know what I mean.

I\'ll be concentrating on definitions and concepts, particularly for the
risk management

program per se, what might be its component goals and objectives, and
when would a risk management program be appropriate.

Let me begin by saying that the products that we\'re talking about are
any drugs or biologicals regulated by CDER or CBER including vaccines
and plasma derivatives. The only exceptions are blood and blood products
other than plasma derivatives.

When we discuss FDA approval or licensure of a product, we mean that the
Agency has found the product to be safe and effective for the labeled
indications within the context of the labeled conditions of use.

We say that a product is safe to indicate that we believe the beneficial
actions outweigh harmful or undesirable side effects. We do not mean to
convey with the word safe, a total absence of risks.

Risk management refers, in our concept, at this stage, to methods
utilized throughout a product\'s life cycle to minimize risks and to
optimize the benefit risk balance.

The use of risk information from investigational and marketing phases is
essential for the implementation of risk management. Risk management
includes the identification and interpretation of risks and benefits in
actual use. Interventions, to minimize risks, are implemented as
necessary and intervention phases are likely to typically move from
design to implementation and then an evaluation of the implemented
control measures with successive revisions as needed, so that there can
be a cycling back, an iteration of modified control programs as needed
based on feedback.

Risk management planning, we feel or we suggest, applies to all sponsor
efforts to minimize a products risks and these include risk assessment,
standard pharmacovigilance and pharmacoepidemiology, special studies or
interventions and professional product labeling.

I want to clarify that when we refer to the package insert, we are
discussing professional package labeling at this stage. We\'re not
including within the package insert in this presentation, the medication
guides or other communications directed to consumers or other labeling
aspects, specifically, we\'re referring to the professional packaging
insert.

All products have risk management planning. Traditionally, the package
insert and

post-marketing surveillance dominate that aspect. Risk management
planning is generally covered by the various elements in the package
insert and the on-going post-marketing surveillance to watch for
surprises.

Risk management programs may be needed when a package insert and
conventional post-marketing surveillance are not felt to be sufficient
to minimize specific risks.

A risk management program then would be a strategic safety effort to
reduce risks referring to at least one specific risk reduction goal and
at least one utilizing \-- utilizing at least one intervention or tool
in addition to the package insert to control that risk or risks.

Examples of these kinds of interventions or tools would include
education, forms, processes and other methods to influence or control a
product prescribing, dispensing or actual use by patients. The fine
print here, of course, indicates that if you have blinked or breathed
during the preceding three slides, you consent to telemarketing during
dinner hours until the third generation.

(Laughter.)

This fine print simply reiterates that the package insert that we\'re
referring to as being already universal is the professional package
insert.

Risk management goals are tailored to particular risk concerns. They
describe the desired end result of a risk management program and they
would include a vision statement of the optimal drug use scenario. For
example, no patient with a particular condition such as pregnancy,
should receive this particular product, perhaps a teratogen.

The objectives of a risk management program are the intermediate steps
toward the risk management program\'s goals. The objectives will affect
processes, behaviors, or outcomes and multiple objectives may serve a
single goal. For example, both Pharmacy practice, manipulations or
controls and physician training might be harnessed in pursuit of a
particular goal.

How do we assess whether risks are undermining benefits and a risk
management program may be necessary? We propose that there is no simple
formula to compare risks with benefits. Risk and benefit numbers vary.
They vary in their types of measures and in their conceptual categories.
Therefore, we feel that a case-by-case judgment will be required by the
sponsor and/or the Agency on whether to develop, submit and implement a
risk management program.

FDA expects, however, that most products will be handled by the package
insert, the professional package labeling. We also would propose that
package insert revisions do not automatically imply a need for a risk
management program.

I would be happy to take brief, clarifying questions, but I think we\'re
holding most discussion for later.

DR. SELIGMAN: Thank you, Dr. Wise. I think what we\'ll do is have the
second presentation and then ask for any clarifications following both
of those.

Our second presenter is Dr. Toni Piazza-Hepp, who will be talking about
risk management tools.

DR. PIAZZA-HEPP: The next section of the Concept Paper does address risk
management tools.

(Pause.)

DR. SELIGMAN: While we\'re getting the slides up, let me just take a
moment to introduce some additional members of the Steering Committee
who have joined us since we began, Dr. John Jenkins, Dr. Victor
Raczkowski and Dr. Susan Ellenberg who are also at the front table, as
well as Dr. Florence Houn who is up here at the front. Welcome to you
all.

Toni, are we ready?

DR. PIAZZA-HEPP: Oh yes. A risk management intervention or tool is
defined as a process or system intended to enhance safe product use by
reducing risk. One or more tools may be used when designing and
implementing a risk management program and the choice of tools will be
influenced by the severity, reversibility and the rate of risk.

We have generally categorized the types of tools that are used in
current programs. The first category is education and outreach. The
professional labeling, also known as the package insert or PI, is an
educational tool used for all products, as Bob has mentioned, to
communicate risks and benefits. However, in our Concept Paper and our
guidance, we plan to focus on the tools that may be implemented beyond
the package insert.

Examples of education and outreach tools include health care
professional letters, other public notices and other educational
programs such as those offering continuing education credit.
Patient-oriented labeling, that would be dispensed with the product each
time a patient receives it such as medication guides or patient package
inserts are other types of educational tools.

Systems that guide prescribing, dispensing and use include patient
agreements or informed consents, enrollment of one or more stakeholders
in special programs, practitioner certification programs or special
conditions of dispensing, such as special packaging, limited supplies or
refills and types of check mechanisms to assure appropriate prescribing.

Restricted access systems are designed to enforce compliance with
program elements. These may include registration or enrollment of
physicians, Pharmacists and/or patients. They also may include
documentation of safe use conditions such as documentation of laboratory
tests before the product can be dispensed to patients.

The fourth category of risk management tools is suspension of product
marketing either with or without withdrawal of the product\'s
application.

In selecting and developing tools, the following points are at least
some of the factors that should be considered. The first is input by
stakeholders such as physicians, Pharmacists, patients and perhaps
others on the feasibility and acceptability of the tools. For example,
is there consistency with existing tools that are already accepted by
stakeholders? Is there documented evidence of success in achieving the
desired objectives based on other risk management plans?

Alternatively, if a novel tool is being considered, is there evidence of
success in other settings? The variability, validity and reproducibility
of these methods should also be considered.

In the Concept Paper, we have proposed a broad classification scheme for
risk management programs and we describe four levels. Risk management
planning considers all levels. The basis for program design will be
product risk. Risk management programs begin at level 2 which is where
program design would include measures beyond the package insert.

As the levels in this classification scheme increase, the divergence
from conventional prescribing and dispensing also increases.

A risk management program begins at level 2. At this level, measures
beyond the package insert would include education and outreach tools.
For example, the drug Ziagen is associated with

life-threatening allergic reactions that both prescribers and patients
need to be aware of. The drug has a box warning in the package insert.
In addition, it is dispensed to patients with both a medication guide
and a warning card that is

pocket-sized and lists the symptoms that patients should look for.

A level 3 program would include tools from level 2 plus systems guiding,
prescribing, dispensing and/or use. For example, Lindane now carries a
boxed warning addressing neurotoxicity. In addition, a medication guide
is dispensed with each prescription. Further, the package size is now
limited to one or two ounces and quantities prescribed should be limited
to only enough for a single application.

Lotronex is another example of a level 3 program. In addition to the
medication guide, physicians must attest to certain knowledge before
prescribing the drug. They then receive special stickers which should be
placed on each prescription before the Pharmacists dispenses it to a
patient and no refills are allowed without a new prescription.

At level 4, access to the product requires adherence to specific program
elements. For example, Clozaril is only available through a special
distribution system that requires a blood test before a Pharmacist can
dispense it to patients. Physicians, Pharmacists and patients must all
register to participate in the program.

Thank you.

DR. SELIGMAN: Thank you. We have about a half an hour for any questions,
comments, points of clarification for either Drs. Trontell, Wise or
Piazza-Hepp regarding these two elements of the Concept Papers.

(Pause.)

PARTICIPANT: My name is Karen Blesh. I work for Hoffman LaRoche and I\'m
interested particularly in your visions statement and this may either be
a comment or a clarification or both. When I read it, in the Concept
Paper, It was interesting that you said patients with condition A do not
receive drug B. And as I\'ve been listening to the discussions, I keep
hearing this notion of optimizing the benefit-risk ratio and it seems to
me that another kind of important way to conceptualize this visions
statement would be patients without indication A, do not receive drug B,
so that we focus more on the labeled indication for the product which I
would think would enhance the benefit-risk ratio for diseases that
perhaps aren\'t perceived as particularly life threatening or
particularly severe.

DR. TRONTELL: We thank you for that comment. I think that\'s another
useful way to think of how you might express the visions statement. We
gave one example, we're certain there are many others.

PARTICIPANT: It might be useful to industry to have several, have this
screened in several different ways, just to help broaden your thinking a
little bit about risk management. It\'s not just about minimizing risk.
I think it\'s also about maximizing your benefit impact.

DR. TRONTELL: Thank you. We appreciate that comment.

DR. SELIGMAN: Any other comments, questions?

MR. GOLDSMITH: My name is David Goldsmith. I\'m representing myself. And
I have a question for Toni and one for Bob.

Toni, you mentioned that the risk management program has the objective
to reduce the risk and I ask whether or not a risk management program
really has the objective of not only reducing risk, but maximizing the
benefit-risk balance and I noticed that in many of the risk management
steps that you\'re dealing with, there\'s nothing said about maximizing
a benefit.

Could you comment on that?

DR. PIAZZA-HEPP: I don\'t think we are addressing maximizing benefit in
this Concept Paper.

Anne, do you want to comment further?

DR. TRONTELL: We struggled, at least in this version of the Concept
Paper in trying to capture the dual roles of maximizing benefit and
reducing risk. And quite frankly, the Agency\'s experience is largest in
the area of reducing risk and that\'s reflected in this Concept Paper.

The mechanisms whereby benefit can be maximized, we would appreciate
your input. Certainly, individuals who are using a product
inappropriately, may not recognize its benefit and risk, the adverse
consequences that may be associated. That\'s one possibility, or trying
to direct the program to those individuals who are most likely to obtain
benefit. But beyond that, we\'d be very appreciative of any suggestions
that might come from members of this audience.

MR. GOLDSMITH: As a follow-up to that, the reason that I really raised
the question is that many of the things included in step 3 and step 4
programs are indeed directed towards reducing exposure to the drug and
therefore reducing the potential risk. But that also carries the impact
of potentially reducing the benefit to those patients who might need the
drug and have limited access. And one of the things that I found
conspicuously absent was the consideration of the loss of benefit
implemented with any risk management program and I think we need to
really focus in very carefully to maintain that benefit.

DR. SELIGMAN: Thank you. Next comment from the floor.

MS. SACHS: It\'s actually a question. Susan Sachs. I\'m also with
Hoffman LaRoche. I don\'t totally understand the distinction between
your risk management planning and your risk management program. I mean
could you expand on the planning a little bit? Thanks.

DR. SELIGMAN: Anne or Robert, who would like to take that one?

Robert?

DR. WISE: I\'ll take a first stab. We\'re trying to use the word
planning, risk management planning to describe the overall approach, the
universal, all encompassing pertinent to all products effort to maximize
benefits while minimizing risks or to optimize the risk-benefit ratio.
We\'re using the word risk management program to refer specifically to
the controlled program encompassed under the PDUFA 3 legislation which
will be a discrete submission documentation. It will be a component of
risk management planning, but risk management programs, we anticipate
would be implemented for only a relatively small minority of products.

DR. TRONTELL: I\'d like to try to add some clarification because
truthfully the boundaries here are somewhat blurred. When we spoke of
risk management planning as including Pharmacovigilance, we thought of
that process in the traditional passive way in which it has operated in
terms of the reports coming to your attention and to ours in addition to
the package insert.

In speaking to risk management programs, we were addressing instances of
active interventions where, in fact, something beyond the traditional
labeling and Pharmacovigilance were put into place. It happens in some
instances that aspects of data collection may in fact be tools that
constrain product use or may otherwise work to reduce risk or maximize
benefits. So the boundaries are somewhat blurry when you start to talk
about active surveillance systems and such, but we in this Concept Paper
wanted to focus in on those interventions that go outside of the large
majority of products approved by the FDA where the professional labeling
and the traditional Pharmacovigilance were operative.

DR. SELIGMAN: Yes.

MR. STANGOLD: Paul Stangold Associates. I just have a general question
and some of it comes from experience that some of us have had in the
disease management days where the focus, especially on the corporate
side is on one product and oversimplifying a group of people with
chronic disorders which rarely occur in isolation. So we\'re focused on
one product, one disease in a constellation of diseases in a group of
patients. And I just wondered if some of that thinking has gone into or
consideration for the complexity of the patient as a whole that we\'re
dealing with here in terms of integrating a risk management program into
a larger complicated patient who may have a risk management program
coming at them for another disease and another drug, for instance.

It can get very complex very easily. Chronic diseases themselves
certainly don\'t occur in isolation. I\'m just curious what your
thoughts were when you were writing?

DR. TRONTELL: The Concept Paper to date, I think, has not yet reached
that level of addressing when multiple risk management programs may
impact on a patient. I think as we wrote it, described the levels, we
anticipated most products would be at Level 1 and Level 2. Then we might
realistically anticipate patients receiving multiple education
materials.

You make a very fair point that, in fact, the total burden needs to be
considered and among our challenges in addressing risk management was
trying to tease out where risk management began and these other
activities left off.

DR. TEMPLE: Toni, this may be premature and should follow the other
ones, the other presentations. Just tell me if you think that\'s true.
There\'s an implication, at least, that most of the things in labeling
that relate to risk will at some point at least be evaluated to see
whether people are actually doing what the labeling says.

Do you think that places any greater responsibility on both industry and
us to be sure that all the things we put in there are really sure
things? I\'ll give you my example. There\'s been a lot of question about
whether monitoring liver tests after statin use is sensible. There\'s a
lot of publications on this, so it\'s not just me wondering about it.

Do we have, will we have a greater responsibility to be sure that the
things we put in are actually beneficial or would actually be beneficial
than we have had up to now? There\'s a certain cover, your appropriate
part in putting all these warnings into labeling. We all are inclined to
do it. It seems the cautious thing to do. It\'s not crazy or anything.
But I wonder if we\'re actually going to evaluate all these things and
sort of feel very upset if they\'re not being done, whether the level of
assurance we have that they\'re good things to do has to increase in
response to all this. I wondered if you have been considering that?

DR. TRONTELL: The evaluation section will be discussed in greater depth
this afternoon, at least as we\'ve proposed it in this Concept Paper.
The evaluation that we would request of the company sponsors would be
for those interventions that extended beyond the traditional labeling.
Certainly, FDA has resources as well as industry to determine whether or
not a package insert\'s directions are being appropriately followed and
in fact, such examinations may be, in part, what leads to this very
difficult decision about whether or not more active interventions are
required.

PARTICIPANT: Greg Gogates with CRF Box. I have a question and I know
we\'re talking about all these programs and these plans and we\'re being
very, shall we say, USA concentric, but are we considering what other
countries are doing? We don\'t \-- there\'s a lot of good ideas out
there in the rest of the world. It seems that it would be kind of silly
to reinvent the wheel if someone else has already thought about this. Is
there any part of this group going to look and see what the rest of the
world is doing in these areas?

DR. TRONTELL: You are right that we have been very U.S. centric. I think
we have interactions with our colleagues in Europe and Japan through the
International Conference on Harmonization. Some of our initial focus is
based upon U.S. programs in part because systems of care delivery are so
different in various countries and applications or risk management may
pertain in other countries may not apply here.

We certainly do have mechanisms where we share such information, but on
the issue of how product use may be constrained or limited in licensure
are not areas where FDA has those abilities or we don\'t have
centralized prescription availability say, as it occurs in some foreign
countries. So we are eager for experience from other countries, but we
recognize our own somewhat widely dispersed health care system poses
special challenges in trying to address risk management of drug
products.

PARTICIPANT: That\'s fine. It just seems that maybe someone should say
here\'s the way the rest of the countries do it in a big tabular format
and say N/A, N/A or maybe, maybe, that type of a thing. At least this
way it wouldn\'t be forgotten as opposed to saying ad hoc, we\'re
different and we\'re not going to bother to look, that type of an
attitude.

One other thing too is I noticed you said earlier that you talked about
the difference between programs and plans. Well, my background is
quality and I think a program as being a general type of a thing where
you have a big program and a plan is specific, so it seems like you
folks had it swapped the other way around.

I don\'t know if you want to be in cohort with all of us quality guys,
but you may want to consider swapping those two.

DR. SELIGMAN: Great, thank you for that comment.

Dr. Galson?

DR. GALSON: Yes, just a quick response to your suggestion on the
international front. We have had some discussions on our developing
plans with our colleagues in Europe at the last U.S.- E.U. bilateral
meeting, dealing with drug regulation and I can tell you, we\'re really
ahead of the European regulatory authorities in thinking about risk
management from drugs and biologics in a comprehensive way. They do deal
with individual drug products, of course, as they\'re approved, but
there\'s not really the same level of work on a comprehensive framework
like what we\'re doing.

I suspect that we will learn some items about what they\'re doing with
individual drugs, but in terms of looking at this holistically, I think
we\'re really the leaders at this point in the world.

Thanks.

DR. SELIGMAN: Dr. Wise?

DR. WISE: It may be worth mentioning that lines of communication with
Europe and other parts of the world may be reopened in the near future
on this subject, at least. We\'re going to be presenting a symposium on
this exact series of risk management Concept Papers at the International
Society for Pharmacoepidemiology in August this year.

DR. VASHISTHA: As an internist working in \--

DR. SELIGMAN: Give your name and association.

DR. VASHISTHA: Dr. Anshu Vashishtha, Watson Pharmaceuticals.

As an internist working in drug safety, just some thoughts on if you
will on the underlying philosophy behind risk management program or risk
management planning. And it goes back to the question of where in this
picture do we have patient autonomy and where do we have professional
independence of physicians as prescribed as fitting in. In other words,
what is the role of the Agency and sponsor together, as we do this risk
management planning and risk management programs. Is there a role to
delineate risk information clearly for the prescriber and the patient to
make a joint decision about individual therapy or are we going to stick
to a more paternalistic model of we shall say this shall be used in this
situation and not otherwise. I\'m not necessarily saying that it can be
black or white, but patient autonomy is a growing kind of consideration
and I think we have to take that into account.

In individual patient situations or in minorities of patients, there is
the advantage of establishing with \-- staying with an established
therapy which happens to suit this individual or this subgroup of
patients where the overall risks for the population as a whole or even
the majority of patients may be more than the benefits. But in
individual subsets of patients, there may be positive, so I would say
that we take into \-- keep this into account as we go further, if we are
not too prescriptive and paternalistic, but maybe consider whether we
should delineate risk and benefit and then leave the decision to the
prescriber and the patient.

Any comments from the panel would be appreciated.

DR. TRONTELL: In this very preliminary Concept Paper, I would say that
we're actually trying to avoid, although I think we can\'t in this mine
field, avoid touching on or implying a certain philosophy and we don\'t
wish to imply in this anything that would challenge patient autonomy or
imply paternalism, either on the part of FDA or drug company sponsors.
We look to our role in risk management with the industry as one of
partnership and ideally, one of partnership that extends to
practitioners as well as patients and the manner in which we go forth
and elaborate. That will be our challenge.

DR. VASHISHTHA: Thank you very much. In that case, I would also
encourage the panel and the Agency to seek more active involvement of
prescribers. I think that is one piece of the group, professional
associations, which is not represented here. Individually, I am a member
of the American Medical Association, American College of Physicians,
American Academy of Pharmaceutical Physicians, so I think bodies like
this may want to be \-- you may want to seek their involvement and see
where they stand on this as well.

Thank you.

DR. SELIGMAN: Thank you. Dr. Houn.

DR. HOUN: I am thinking that for again most drugs, the individual
autonomy is preserved in that we\'re thinking the risk management plans
and programs pertain to drugs where labeling on the PI is insufficient
and we\'re really just again focusing on a handful of drugs where the
gentleman was saying the situation is that the benefits are overwhelmed
by risks and in that situation where you want to focus on a certain
subpopulation to get benefits, there might be a particular need to have
a lot more patient education so they can make an informed decision. But
in most situations, many \-- most drugs will not need to have that
intense intervention.

PARTICIPANT: Sam Yondrin, Millenium Pharmaceuticals. Just to follow up
on the comments about the U.S. focus here versus the rest of the world
and specifically with regard to the European Union, I do agree that the
efforts in the U.S. to date are much more comprehensive and systematic
in addressing this issue of the risk of injuries and deaths through the
use of medicines. However, we still need to remember that the majority,
you know, in terms of the burden of these injuries and deaths relates to
everyday use of drugs. And we all recognize that current professional
labeling which really is the mainstay of patient management doesn\'t
work. There are pointers in the past that the European labeling format
is a preferable format because the important risk information is
highlighted up front and the process of regulation rewrite with regard
to labeling in the U.S. has been on-going now for several years without
any outcome. And part of that process is actually supposed to align U.S.
professional labeling with European labeling.

And there\'s also the issue of patient package inserts which are
standard now in the EU. So I think we need to keep these aspects in mind
which probably ultimately are going to manage the burden of patient
injuries and deaths in the U.S. which we always hear statistics about.

DR. SELIGMAN: Dr. Galson, you have a comment?

DR. GALSON: Couldn\'t agree with you more about labeling. We are
finalizing final rule on the package insert and we hope that that will
be available to the public quite soon. As you know, we\'ve been working
on it for years. We\'ve taken comments. We\'ve made changes reflecting
comments and we look forward to those changes because they\'re going to
go a long way. First, towards making the labels more comprehensive, but
also in terms of \-- more understandable, but also in terms of achieving
more consistency around the world.

DR. WEINSTEIN: You mentioned that there was information about the
European labeling, perhaps providing more information or helping
patients more. I was wondering if you had a specific reference data to
\-- that we might be able to examine for that claim?

DR. SELIGMAN: Do you want to answer that question now?

PARTICIPANT: Is that a question for me?

DR. SELIGMAN: Yes.

PARTICIPANT: Can you repeat it?

DR. WEINSTEIN: You implied that perhaps the European labeling model is
one that we should adopt and I was just wondering whether you have
references for the notion that it might be better understood by patients
than what our labeling process is.

PARTICIPANT: You know that statement that I made is actually based upon
the fact that what\'s being proposed for the new U.S. labeling format is
better aligned with the European summary of product characteristics. And
I think that position has been arrived at by consensus thinking that
it\'s a better format.

Now, I\'m not sure if there\'s any evidence that actually substantiates
that. However, if we look at the CIOMS recommendation for the company
called data sheet format, we benchmark the European SPC format. And as
you know, CIOMS really is a think tank for drug safety and I know that
this tends to get forgotten a lot of the time and we tend to focus on
ICH. But if you look at the clinical safety data management concept
guidances, it always comes from CIOMS. And again, the CIOMS benchmark
the European SPC format and within the CIOMS we actually have FDA
representation there.

So I mean that\'s all I can say regarding the background for
recommending the European SPC format. But certainly from just a
practical perspective, it\'s a much more logical format because it gives
you the indications up front and goes into the contraindications,
warnings, precautions, drug interactions, ADLs and all this stuff about
clinical pharmacology and toxicologies at the end. Very important, but
not up front.

DR. SELIGMAN: Dr. Trontell.

DR. TRONTELL: We want to acknowledge the great expertise and thinking of
CIOMS in this arena and are certainly grateful for any documentation
they have for greater effectiveness of the format which they\'ve already
put into practice.

The Agency\'s own efforts to revise labeling you probably are aware, in
fact, based upon data largely focus group testing with practitioners,
that documented greater, comprehensive, legibility, cognitive processing
of that information. And it\'s that evidence basis that we seek and
we\'ll certainly pay closer attention to the other activities that were
done by CIOMS.

Thank you.

DR. SELIGMAN: I will take two more comments from the floor and then I
have some questions as well.

Yes, Dr. Campbell.

DR. CAMPBELL: Good morning, Bill Campbell, University of North Carolina
and Director of the Center for Education, Research and Therapeutics at
UNC and speaking on behalf of all seven centers at this time.

As you may know, we have conducted a series of five invitational
workshops on risk communication, risk management, risk assessment,
benefit assessment and so forth and we will have substantial written
comments submitted on these guidances, but just to summarize those, we
have found remarkable similarity between the findings and
recommendations from our series of workshops and the spirit and content
of the guidances and we believe these are excellent approaches that
capture the state of the art with regard to development guidances.

Specifically, with regard to the last several comments, we would
particularly commend the acknowledgement of different levels of risk
programs and risk planning. And in the current guidance, most of the
differentiation between level 1, level 2, level 3, level 4, have to do
with the distinctions around the tools. We would suggest that that is
appropriate, but it would also be appropriate to build distinctions
around levels of risk. For example, what is the difference between
moving from gradient 1 to gradient 2? We suggest that it would be useful
to identify what is the base level of risk that can be acceptable with a
PI, package insert, and passive surveillance. And perhaps moving to
level 2 would be a level of risk whether it\'s a clear safety signal,
that is well acknowledged and understood. Yesterday, we heard
discussions about those are really fairly few and well acknowledged,
transaminase, QT and so forth.

We believe that it would be useful in developing those gradients then to
identify not just the tools, but some greater description of the levels
of risk, both quantitative and qualitative and I wondered if you might
have thought a little bit about that.

Thank you.

DR. PIAZZA-HEPP: Yes, we have had some preliminary discussion in our
group regarding the development of just that triggering criteria for
when you would implement different levels. And we just said in general
that as the levels of risk management program increase, it relates to
the increased risk of the drug, but we certainly welcome any comments as
far as the types of factors taken into consideration, the types of
criteria that might be useful to determine what levels might be
appropriate for a drug. So we would welcome that comment.

DR. SELIGMAN: One more comment from the floor?

DR. HOUN: I think it was not only what are the levels of risk, but it\'s
actually that

risk-benefit ratio and that makes it very complicated because it\'s not
just the rate per thousand per hepatotoxicity, but that it\'s also what
is the benefit people get from that drug and so yes, we would definitely
welcome CERT as well as other input in those kinds of triggering
criteria related to not only risk, but benefit. Thanks.

DR. SELIGMAN: Ana?

DR. SZARFMAN: Hopefully my voice is better than yesterday. My name is
Ana Szarfman and I work at the FDA. I would like to make some comments
about the reporting rates. There are important limitations about using
reporting rates for picking up signals because we don\'t have the
nominators for every product that we need to monitor. For example, over-
the-counter drugs, it is not easy to have the nominator. Devices is
another product that we regulate that they don\'t have the nominator and
herbal supplements is the third and we can go on.

Drugs that are used in combination, we don\'t have the nominators or
they are actually used in combination and this is a fact of life, then
it\'s important also from the standpoint of the background of the
disease being treated and we need methods that can do multiple
comparisons and there are very big limitations with some of the methods
that are being used because we need to understand what\'s the big
picture.

Now that we are having this meeting at the National Transportation
Safety Board, having the big picture of maybe airplane accidents before
and after September 11th can help us interpret that the new \-- that
there is no increase in risk with increase in travel. And then I think
that we need to start thinking about using methods where can do multiple
comparisons, that we can compare every single drug that is being used to
treat the disease in question with all the possible controls that we
need because if not, we are only going to be able to study partial
problems.

DR. SELIGMAN: Thank you. Dr. Trontell?

DR. TRONTELL: Thank you for those comments. I wanted to take an
opportunity before we start to address some questions that have come in
writing from the floor to follow up on Dr. Houn\'s remarks to Dr.
Campbell on the CERTS on the issue and complexities of the increasing
levels of risk management programs because at least in our limited
experience with some of what might be considered Level 4 programs like
Clozapine or Thalidomide, that these are products that, in fact, have
substantial risks associated with them in which because of the special
nature of benefits associated with those drugs in a special population,
that benefit from them, they exist in availability, but in a highly
restricted form.

It\'s our anticipation and the somewhat vague wording that we
deliberately chose in this Concept Paper to describe this divergence to
recognize that in point of fact it\'s our expectation that it\'s
probably going to be a small number of drug products that reach this
very high level of stringency of controls. We might presume products
that have substantial risks, might not make it to market, but in
indications or situations where they have particular benefits is where
we tend to run into that situation. So there\'s an interplay, clearly,
as Dr. Houn said, between the benefits and the risks and assigning or
determining what program level is necessary. And clearly, we need your
suggestions in terms of how we might be able to make that clearer.

DR. SELIGMAN: I have a number of questions that were submitted on the
floor. Let me go ahead and read them and then we\'ll try to answer these
before we turn to our speakers.

The first question is by nature, risk management issues may not arise
until the end of phase 3 or NDA stage of development. When will FDA
initiate risk management discussions during the development process?
Will the guidance on formal FDA meetings be revised to include risk
management meetings? What can FDA do to introduce the risk management
requirements earlier in the development process?

Anne, you want to take that?

DR. TRONTELL: I think we\'ve only just since last October entered into
the brave new world of risk management submissions in the context of
NDAs and Dr. Wise\'s remarks this morning might have gone over somewhat
rapidly our attempts to describe when the consideration of a risk
management program might be appropriate.

We believe, in fact, that these are based upon data, on evidence of risk
and the degree of risk and that might be initiated either by the drug
company sponsor as they pursue development or FDA as its own independent
analyses might suggest of previously unrecognized risk or a risk at
greater level than had been anticipated.

So at this point, I don\'t think we can offer rules, but we certainly
are open to suggestions. To our way of thinking, there were sufficient
complexities. It was very hard to be prescriptive since that time point
when the risks start to undermine the benefits is one that we\'ve
struggled to try and define.

DR. HOUN: Certainly for a really new molecular entity, you\'re not even
sure if there\'s a signal or not with the \-- even when Phase III data
is submitted in the NDA, and we\'re struggling whether this is a signal
or not. And many times as Dr. Wise points out, it\'s because it\'s a
cyclical process, then the signal becomes clear post-marketing and then
the risk management program is discussed, usually in the context of a
labeling submission that we have to really revise the label and maybe do
some other implementation.

But in other cases where you\'re developing a drug that maybe a class
has been identified to have a concern, that it will be known up front we
better do the preclinical studies, discuss what they show and depending
on some of the data, during the end of phase 2 meeting discuss what
might be needed further in terms of managing risk and it could be a
formal part of that meeting because you have some familiarity with the
class of drug and issues with that.

DR. SELIGMAN: I do have one final question and then we\'ll do the
speakers.

How would FDA pursue enforcement of the risk management concepts? Anyone
want to tackle enforcement?

DR. TRONTELL: Again, the large question of a risk management concept
versus a formal program is one yet that we\'re still in the process of
defining. I think for certain risk management programs that have highly
specific and well-defined processes or measures that can be assessed,
there is the opportunity for FDA to work or work with the sponsor in
determining whether or not those processes of risk reduction are in
place. Toni gave the example of situations where a product should only
be dispensed with the accompaniment of a laboratory test. Certainly,
there have been efforts done in that instance by the sponsors to
document, in fact, that at an acceptable rate that, in fact, is being
done in practice. So there are mechanisms. We have not reached any level
of deciding exactly where industries and FDA\'s responsibilities may
fall.

DR. HOUN: Also, I think within the Agency, we have discussed drugs that
are approved under Subpart H for restrictions based on safe use or
distribution, there have been \-- there\'s a need to have the Agency
actually inspect and audit whether those systems are in place. And so in
terms of enforcement, we have visited programs where those designations
have been made for those particular drugs.

DR. SELIGMAN: Thank you. At this point, let me turn \-- to the four
speakers we have for this morning\'s session, the first is Dr. Susana
Perez-Gutthann from International Society for Pharmacoepidemiology.

Dr. Gutthann?

DR. PEREZ-GUTTHANN: Thank you. Good morning. It\'s a pleasure and an
honor to be able to provide these comments on behalf of the
International Society for Pharmacoepidemiology, ISP. The mission of ISP
is to foster the science of epidemiology and its application to study
the use, effectiveness, value and safety of therapeuticals, and it
provides an international forum for sharing this science and knowledge
for over 700 members in many countries that work in different settings,
ranging from academia, health authorities, research, profit and not for
profit organizations and Pharmaceutical industry.

The background of the membership is primarily in the areas of
epidemiology, biostatistics, Pharmacy, Pharmacology and medicine. The
comments that I provided next are based on a first round of input
provided by senior members of the society. We feel that this Concept
Paper is very useful in the overview of the Agency\'s views on
initiating and designing risk management programs, selection and
development of tools, the evaluation of the programs and we fine
particularly useful the idea of the web-based catalog of programs and
tools.

We have identified a number of suggestions and clarifications and I will
start with the one that is more conceptual and then move on with some
targeted comments to specific sections of the Concept Paper.

The first one is in regard to the risk management scope. We find that
the three Concept Papers suggest a fragmented view of risk management
and in a way there\'s a danger of consolidating what are now
institutional divisions between those working in safety, pre- and
post-approval, when what is really desirable and actually needed is that
the people working on both sides of the spectrum work together as early
as possible from early and through the

post-market.

Another area that we think needs clarification is the current definition
of Pharmacovigilance plan and risk management programs and I hope I
don\'t get my Ps mixed up. But depending on which Concept Paper one
reads, like if we go to Concept Paper 2, a risk management program as
the definition suggests are a more broader review of the risk profile of
the drug and the number of interventions, while the Concept Paper 2
restricts the definitions to the intervention that go beyond the package
insert.

There are a number of gaps in the current risk management program. If we
look at the whole concept of risk management planning in that the risk
management prior to launch is hardly addressed, specific activities,
time lines, the interactions with the Agency, relations to other
development planning documents and meetings would be very useful to plan
these activities.

Another area is the determination of background risks based on the
epidemiological analysis of the patient population which will help us to
anticipate the expected risk profile once they are exposed to the
therapeutic agent. This is where both areas that were a bit more fleshed
out in the PDUFA 3 documents, at least in draft.

Also, if we focus only on the risk management program, we are really
left with no formal document to provide an overall overview of the risks
and the decisions about moving beyond risk communications in the package
insert. And also the guidance currently, primarily focused on
medications.

So one proposal is that we would work on a dynamic and broader risk
management plan that would be initiated early in development. One
proposal would be at entry into humans, based on the data from the
clinical information that would be move along with a drug along the
development milestones with a specific Pharmacovigilance plan section
that would be fleshed out prior to approval and then that would move
with the drug into process approval period and safety review process.

And then the very specific risk management program would be initiated as
suggested in this Concept Paper. We\'re moving beyond the risk
communication through package insert for a specific issue, a number of
issues.

Let me move on to some more specific comments to the sections. Regarding
the assumption of use of tools, we think it is very important to point
that this is based on the assumption that there are risk factors for the
targeted adverse event that have been identified and that there is some
understanding on how these risk factors will be modified by your use of
the risk and prevention tools.

Also, regarding the effectiveness of the tools, we think it is important
to point out and that has come also from the international membership
that there\'s a wide range in the success of these tools and
particularly tools that were mentioned were the educational outreach and
academic detailing programs, the flag warning systems in Pharmacy
computers and the uses of the PI as a risk communication and
minimalization tool and we know there\'s initiatives on-going in this
area, but members provided extensive comments on the need to revise the
content of the PI if its goal is going to be a risk communication
minimization tool.

Regarding the choice of tools and risk management program levels that
are defined by the choice of these tools, we find a broad categorization
is very helpful in providing an overview of the level of concern and
action for specific agent and across therapeutic classes and we feel
that we need some additional clarification and guidance on the use and
guiding criteria to move from Level 1 to Level 2 and I think this has
been mentioned already in the discussion as some criteria could be the
frequency of the event, the public health effectiveness of the tool that
is chosen.

And again, the analysis of the existing programs and tools and how the
tools led to a specific categorization of what is already available that
could be available in the web catalog would be very useful.

Regarding the evaluation of risk management, it is a very particular
important area, not only for an evaluation of the effectiveness of a
particular program, but also for the success and the risk management
initiatives as a whole and we feel it\'s important to point out that
very often risk management programs will be targeting very severe, but
rare events that are per se difficult to measure. If a risk management
program is effective, the frequency will diminish even further and this
has important considerations for areas like powering a risk evaluation
program.

Also, and this has been discussed both today and yesterday, there is no
ready formula to determine risk when risk exceeds benefits and we all
talk about these risk-benefit ratios, but really not formally and not
point estimate that will allow us in the quantitative analysis of the
concept.

We\'re very pleased by the acknowledgement of the limitations of the
reports in the evaluation of risk frequency both going upwards or
downwards and given the above, we feel that a more prominent role of
formal pharmacoepidemiological studies in assessing the risk and
evaluating risk interventions is needed.

Some special considerations. We think it is important to evaluate the
impact of these programs on health delivery systems and over the last
year we have heard, particularly coming from a prescriber on Pharmacist
associations, that they are concerned about the potential proliferation
of what are not categorized at Level 2 to 4 risk management programs.

We think it is important to keep a therapeutic class balance in that we
should avoid that only new drugs within a therapeutic class with a
similar safety profile are the focus of risk management programs.

Finally, regarding international coordination, we know that there\'s a
lot of work in progress internationally and this provides an opportunity
to coordinate internationally early on the objectives of programs, the
process and the documents and thus avoiding the need to harmonize
everything later on and in particularly, in the European Union, the
heads of agency working group on European risk management strategy
issued in January of this year, the executive summary on European risk
management and in Chapter 5 they describe the elements of a risk
management plan. And they\'re already talking about slightly different
sections as it is outlined in this Concept Paper. There are
Pharmacovigilance specifications, Pharmacovigilance plan and then the
risk minimization tool.

So everybody is going in the same direction, but the documents might end
up structured and reported in a slightly different way.

And finally, we think it is very important that the guidelines should
emphasize the important role of the close collaboration between the
Agency, the sponsors and the experts in the decision to move beyond
Level 1 risk management programs, the choice of tools and the
evaluations.

ISP is firmly committed to providing an unbiased, scientific forum to
the use of those who are interested in the safety of Pharmaceuticals and
as such is committed to the advancement of risk management sciences. We
welcome the opportunity to work together with the patient in this and we
have engaged our full membership in a second review loop of both the
Concept Papers and the comments that have been provided already in
writing to the Agency, and we plan to submit further documents before
the April 30th deadline.

This commitment is also reflected in our annual conference and the
scientific program committee planning. We have focused our next
conference on risk management and there are, as Dr. Wise mentioned,
several workshops and sessions that are being planned, jointly with the
FDA staff.

So I take this opportunity to invite you to this first conference on
therapeutic risk management. It is already the 19th International
Conference on Pharmacoepidemiology. That will take place in August in
Philadelphia.

Thank you.

DR. SELIGMAN: Thank you very much. The next speaker is Thomas Menighan
from the American Pharmaceutical Association.

DR. MENIGHAN: Good morning. Thank you for the opportunity to present the
views of the American Pharmacists Association, founded in 1852 as the
American Pharmaceutical Association.

I\'m Tom Menighan, a long time community, home infusion and specialty
Pharmacy provider. For the last three years, I\'ve been involved in the
delivery of health information and tools to consumers via improved use
of technology in the internet. I\'m a former president of APHA and am
appearing today on behalf of the Association.

Our more than 50,000 members are Pharmacists providing care in all
practice settings including community, hospital, long term care, and
hospice settings, Pharmaceutical scientists, students and Pharmacy
technicians. In each of these settings Pharmacists help consumers manage
and improve their medication use and have a central role in helping to
maximize the benefit and minimize the risk of medications.

We frequently partner with federal agencies, consumer groups, the
Pharmaceutical industry and others to develop educational tools for
Pharmacists and consumers.

The Association did not receive funding to participate in today\'s
meeting and the views I\'m presenting are solely those of the
Association and its members.

Before I get to the substance of the Concept Paper, let me observe that
APHA supports the definition of risk management as detailed in the
paper. When one person says it, it\'s an idea. When two agree, it\'s a
movement. We\'d like to support the movement to adopt your definition.

To date, Pharmacists have had risk management programs thrust upon us
without input. We\'ve been carved out and left behind to explain
programs to patients when the programs are foreign to us as
practitioners. We could complain or we could be part of a solution and
we\'ve chosen the latter path.

We\'ve talked to the FDA, Pharmacy groups and the industry and we\'ve
put our best thinking together. We\'re prepared to work with the Agency
to develop a systems based, risk management program that is both
effective in mitigating risks and workable for Pharmacists, prescribers
and patients. We can no longer address risk management programs in a
separate manner. For that reality to be meaningful, we have to move
beyond dialogue to action.

We ask the FDA to include us in dialogue with drug sponsors early on
regarding the design of risk management programs.

Central to a successful risk management program is a clear understanding
of why and when products require these systems. While all drugs have
risks, there\'s currently no delineation process within the prescription
medication class to identify those products that may have a higher risk,
require more attention or special patient screening. A collaborative
effort by the Agency, manufacturers, health professionals and consumers
could outline a mechanism to facilitate this process. The Agencies could
publish the criteria in a draft guidance document to allow for public
comment.

Identifying what would trigger the need for a formal risk management
system should yield more consistency in the market place and help
professionals and consumers deal with those products appropriately.
Criteria for product involvement would also help ensure that the proper
products are placed into a formal risk management program.

Evaluating each product against the criteria will help identify those
medicines or devices that demand special attention to minimize drug in a
patient and separate out those who can be managed through more
traditional means.

I must take this opportunity to note that not only is it important to
place high risk products into a formal system, it\'s equally important
that products are not unnecessarily placed into such a program. If every
drug is placed in a system like this, and if those programs aren\'t
systems based, Pharmacists and other health care providers and patients
may become desensitized to potential risks.

The FDA currently uses a product by product approach to risk management
program development. When challenges are identified with one product, a
new program is developed to address the identified problems with little,
if any similarity to existing programs. This product by product approach
may yield success for a specific medication, but that success is short
lived in the real world as it requires such programs with increasing
frequency. Pharmacists become faced with a Thalidomide program, a
Clozapine program, an Isotretinoin program and so on.

Different mandated FDA programs for different medications make the
problem of medication use more complicated. While a program may work to
manage risk for one medication, combining that program with different
programs for different products generally generates a confusing
environment. Most physicians, depending upon their specialty only have
to think about one or two of the current products in risk management
programs. In contrast, because of the patient populations we serve and
the symptoms and diseases we treat, many Pharmacists must deal with
several and a growing number of programs, each program with different
structures and requirements. This tends to focus interest and attention
on red tape, rather than appropriate medication use.

APhA strongly supports a systems-based approach with standard tools such
as targeted education, participation agreements, patient screening and
training, enhanced interaction screening, compliance documentation and
program evaluation.

Each program would be built with the tools appropriate for the
product\'s risk level and each tool would have consistent structure when
used for any program. For example, if lab test verification is required
before dispensing for a product or for a different product within 30
days after dispensing, the system the Pharmacist enters to determine or
document that testing would operate in the same manner in both
circumstances. This limits the administrative burden generated by
multiple programs and allows Pharmacists and others to focus on patient
care.

Most importantly, appropriate tools should be identified and created for
each risk level. And a prototype system created now, much as the way
utilities, like water and electric are built before a housing
development is begun and contractors have standardized way to enter, to
access those utilities, then as the need arises and products that
require special attention are identified, they can be placed into this
consistent, workable system, waiting for a high risk product to be
identified and then creating a risk management program for that product
is not an acceptable solution because it only adds to the multitude of
vastly different programs currently in use. Implementation of a common
infrastructure will ensure consistent and dependable communications
among health care professionals in widely disparate health care systems
and will help Pharmacists, prescribers, manufacturers, the FDA and
patients to function more efficiently and minimize preventable risk.

By applying such a systems approach to risk management components,
practitioners can focus on effective clinical use of medications, rather
than being required to learn yet another scheme for a new risk
management program.

A consistent systems-based approach would also provide the framework for
health care providers to opt in to a risk management program and
eliminate the need for restricted distribution systems. We have no doubt
that an ample number of providers will step forward and qualify, if the
system is designed properly. Available technology would facilitate the
process allowing the enrollment of Pharmacists, prescribers, and
patients, and provide assistance for the required documentations. For
example, the current risk management program for Isotretinoin requires
the prescriber to affix a sticker to a written prescription to indicate
that the prescription may be dispensed. While some have applauded this
program, we must consider what happens when a prescription arrives in a
pharmacy without a sticker or what happens in a hospital when
prescribers do not use paper prescriptions? Clearly, our entire system
is moving away from paper prescriptions so such a system has been
designed for the past or perhaps the current situation, but certainly
not the future.

An ideal risk management program would allow providers to document
program requirements such as pregnancy tests in a network system. The
network could be managed primarily through internet-based mechanisms,
while all functions would also be available through telephone and mail.

Evaluation of risk management programs must include measures of actual
health outcomes, patient knowledge and compliance as well as analysis of
how the programs are working in pharmacy practice including all pharmacy
environments. As I mentioned earlier, existing risk management programs
can add an additional and often unnecessary administrative burden to the
pharmacy. It\'s important to evaluate how risk management programs are
working on a practical level for the Pharmacist, prescriber and patient.

Are health care providers receiving adequate information about each
program?

Are the pools working as designed without creating an insurmountable
barrier to care?

Have the tools created a notable change in health care professional or
patient behavior?

The FDA has taken the first step in evaluating risk management programs
currently in use, announcing a random survey of 5,000 Pharmacists to
measure their awareness of and participation in various programs.

We appreciate the Agency\'s step forward and encourage you to expand
those evaluation efforts.

I\'d like to reiterate the need for Pharmacists to be involved in the
develop of risk management system. It\'s important to remember that
every component of a risk management system plays into a much broader
situation, the much larger health care system in which pharmacists play
a crucial role. In order for our MPs to work within the system, we must
adopt an integrated systems-based approach. We strongly support such an
approach that allows pharmacists and other practitioners to help
mitigate risks and maximize benefits while eliminating or reducing
administrative barriers. Doing so may allow products to be managed
safely that might otherwise not even reach the market.

In the movie, \"Planes, Trains and Automobiles\" Steve Martin explains
to a boorish John Candy \"and another thing, when you tell a story, have
a point.\"

So what\'s our point? The point is that the professional pharmacy is
broadly involved in disease management programs that are often more
complex than risk management programs we propose. We have a history of
training pharmacists in positive collaboration with government, trade
and professional organizations. Nay-sayers who suggest Pharmacists
aren\'t ready or that only a few can handle this are simply wrong.

Most major chains, including the chain represented by my colleague from
NACDS and large numbers of independents test blood sugars, conduct
cholesterol screens, offer immunizations and use many types of on-line
documentation today.

Just go to [Pharmacists.com]{.underline} for the literature for real
life examples. How different are the risk management components we\'ve
discussed? Not much. In short, the point is we can do this.

APhA has sought and gathered preliminary comments from Pharmaceutical
companies, professional and trade organizations. While there\'s much to
be done before we can claim to have a fully vetted set of principles,
we\'re willing to do the work on behalf of the profession and for the
patients we serve.

In closing, I\'d like to offer these three comments. This is not an idle
exercise for APhA. We\'re investigating significant resources and
designing a system that\'s acceptable to the FDA, the professions of
medicine and pharmacy and the industry.

Two, we want to work with FDA and companies in a methodical way to
design, in advance, systems that will work for multiple products.
Technological advances should allow us to do this while accommodating
those who are still using paper.

Three, when you think risk management think Pharmacist as a significant
part of the solution to easy access and safe use for prescription drugs
in America. Thank you for your consideration.

DR. SELIGMAN: Thank you for your comments and also thank you for
reminding us about the recent name change of the organization to the
American Pharmacists Association.

Our next speaker is Dr. Gary Stein from the American Society of Health
Systems Pharmacists.

DR. STEIN: My name is Gary Stein and I am the Director of Federal
Regulatory Affairs for the American Society of Health-Systems
Pharmacists. ASHP is a 30,000-member national professional organization
that represents pharmacists who practice in hospitals, health
maintenance organizations, long term care facilities, home health
agencies and other components of organized health care. We\'re grateful
to the FDA for calling this meeting to receive input on the Agency\'s
approach to risk management of prescription drugs.

That bottom line there appears on our letterhead.

ASHP has a long-standing commitment to helping pharmacists help patients
manage the risks inherent in prescription and nonprescription medication
use and we recognize that the FDA has the same commitment, particularly
in regard to newer, high risk drugs. ASHP intends to provide more
extensive written comments on the FDA\'s approach to risk management by
the April 30th deadline, but today, I\'d like to discuss a couple of
important points.

Many of the risk management plans that have been implemented in recent
years fall short of what is needed to manage risk because they lack the
proper collaborative patient care efforts of all health care providers
who are involved in the medication use process. We are pleased that the
FDA\'s Concept Paper risk management programs addresses the need for
such collaboration.

First and foremost, there needs to be a fundamental reform in
prescription drug labeling. Current package inserts and dear health
professional letters are not adequate. Current labeling does not present
information on drug safety, efficacy or risk versus benefits that is
oriented toward a real practice environment.

ASHP suggests that the FDA in consultation with health care
practitioners develop an adjunct labeling for high risk drugs with a
poor protocol, basically a check list that progresses from diagnostic
workups to prescribing decisions based on the interpretations of those
work ups. Adherence to such a protocol would help influence
practitioners\' decisions to prescribe or not prescribe medications
based on patient selection criteria and interaction and liabilities of
one medication with other drugs or disease states. This type of protocol
would include proper patient counseling and provision of written patient
information.

ASHP believes that the development of this new paradigm is imperative
for an appropriate patient care process in all settings and for all
health care providers to ensure appropriate patient selection,
appropriate prescribing and appropriate patient monitoring.

Currently, physicians and Pharmacists often are not systematically
caring for patients because they\'re not coming from the same basis of
information. A standardized protocol, as we envision it, is a viable
tool for drug-risk management. It could be the basis for a collaborative
drug therapy management relationship between prescribers and Pharmacists
that is clearly in the best interest of patients.

We believe that the FDA has taken a step in the right direction when in
Section 2D of its Concept Paper, it suggests as a goal for a risk
management program judicious patient selection for therapy and
appropriate prescribing and dispensing to the appropriate patient group.

The second point that we would like to make relates to restricted drug
distribution systems, one of the tools that the FDA has been relying on
more and more frequently to manage the risk of new drugs. Increased
reliance on restricted, closed or eliminated drug distribution systems
for new high-risk drugs is a growing concern among ASHP\'s members.
These systems often exclude individual hospital, as well as community
Pharmacies and Pharmacists, from distributing medications directly to
patients. While a number of drugs have been related to restricted drug
distribution systems, neither the FDA nor drug manufacturers have come
forward with information on how well these systems work.

We hope that the survey of Pharmacists to find out how risk management
programs affect the practice of pharmacy that the FDA announced in the
[Federal Register]{.underline} in February will answer some of these
concerns.

Pharmacists are responsible for ensuring that medications are readily
available for patients who need them and that these medications are used
properly. Disruptions and nonstandardized distribution processes create
procedural confusion for pharmacy and other hospital staff and increase
the potential for mistakes. Any restricted distribution system with
special handling procedure that disrupts that central oversight role of
Pharmacists represents an interruption in standard medication use
policies and procedures in the health system setting.

In November of 2000 and again in January of last year, ASHP drew the
FDA\'s attention to this issue. We have suggested that when a
manufacturer implements a restricted distribution of a drug product, the
FDA should obligate the company to ensure that a patient\'s usual
Pharmacist relationship is not disrupted. ASHP also recommended that if
a restricted distribution system is being considered by the FDA, as a
condition for marketing approval, practicing Pharmacists and
professional Pharmacist societies should be consulted before any
restricted distribution requirements are imposed on the product. Open
hearings, at which Pharmacists can express their views concerning the
design of such a system and the impact those systems may have on the
safety and effectiveness of patient care, may be one mechanism to
accomplish this.

Pharmacists must lead, balance and manage all the considerations,
including safety considerations, about drug distribution. Any
distribution process that bypasses Pharmacists\' control or requires
exceptional procedures in such settings, would be contrary to the best
interest of patients.

But ASHP\'s members recognize that despite this general principle and
goal of standardization, some exceptions will inevitably have to be made
in a patient\'s best interest. An important point, however, is that
these should be truly extraordinary exceptions. The prospect of multiple
unique restrictive drug distribution systems is a frightening picture
for Pharmacists. Deviations that are unique and that generally differ
from standard practices create obstacles in delivering and administering
medications safely.

The patient-Pharmacist relationship should not be misinterpreted as
merely a product distribution function. The Pharmacist\'s minimum
responsibility is to assess the overall appropriateness of all
medications with regard to purpose, dosage and drug food interactions,
patient education and counseling and adherence or compliance.
Patient-Pharmacist relationships in which this level of care is
achieved, depend on mutual trust, the Pharmacist\'s thorough awareness
of the patient\'s overall medication use and the Pharmacist\'s actions
to ensure the timely supply of drug products.

Restricted systems that limit the Pharmacist\'s ability to develop these
relationships are disruptive. Restricted distribution systems that
involve physician to patient delivery prevent Pharmacists from providing
medication appropriateness, dosage and interaction checks, patient
education and counseling, monitoring and follow-up evaluation.

Thoughtful consideration needs to be given to the fact that some of
these medications may be initiated or continued for hospitalized
patients. Hospital pharmacies may not be able to acquire these
medications in a timely manner. This has an adverse effect on patient
care and cost. Restricted distribution systems make it difficult for
hospital pharmacies to acquire these drugs through the normal supplier
channels. This pulls resources from hospital systems that are already
stressed.

When I asked the Government Affairs representative of one company that
has a restricted distribution system for a drug what would we do in
hospitals that have computer order entry systems and no paper
prescriptions. The response was well, there must be some old
prescription pads somewhere in the hospital. Prescribers should root
around for them and put a sticker on them. That is not an adequate
answer.

ASHP believes that rather than unique drug product distribution schemes
the FDA in consultation with stakeholders, including Pharmacists, should
develop models for managing patients for whom any high risk drug product
might be indicated and prescribed that incorporate core protocols.

These models should focus on requirements for ensuring appropriate use
and monitoring such as patient work up and selection, provider and
patient education and patient monitoring. Such a system could answer a
number of our concerns about important issues such as uniformity of
procedures for patient selection, what kind of distribution systems are
most supportive of continuity of care and what kinds of approaches best
serve provider and patient education.

Thank you very much.

DR. SELIGMAN: Thank you. Our final speaker then before the break is Kim
Swiger from the National Association of Chain Drug Stores.

MS. SWIGER: Good morning. I\'m glad to be here to talk about this
important issue and also to take a break from my HIPAA responsibilities
within my organization.

My name is Kim Swiger. I\'m Category Manager for Pharmacy for Ukrops
Super Markets in Richmond, Virginia. I\'m appearing today as a
representative of the National Association of Chain Drug Stores of which
Ukrops is a member.

Ukrops operates 20 supermarket pharmacies in Virginia. NACDS, on the
other hand, includes more than 200 chain companies that operate 33,000
community retail pharmacies. Chain pharmacy is the single largest
segment of pharmacy practice, employing 100,000 Pharmacists. Those
Pharmacists fill 70 percent of the 3 billion prescriptions provided to
patients each year.

We appreciate the opportunity to appear today to contribute our
perspective on the development of an effective prescription drug-risk
management strategy and we commend the Agency for initiating this
dialogue.

Because pharmacists, physicians and patients will be the key
participants in the risk management program, it is imperative that our
input be considered during the development and process of risk
management programs. NACDS believes that the program development should
seek to avoid impractical situations where implemented. For example,
programs that requires stickers to be placed on risk managed
prescriptions seem to be a workable program. However, if there are
several risk managed drugs, each with its own color sticker and
different information on that sticker, it can create confusion for
physicians and Pharmacists.

While we recognize that each drug product is unique, a different risk
management approach has been developed for each current risk managed
drug. This fragmented risk management approach can create confusion for
professionals and patients potentially defeating the goal of creating
less potential for risk. We need a standardized, seamless,

computer-based system that can easily be accessed by practitioners to
deliver risk management services to patients.

We fear a future risk management system analogous to the situation that
has developed with the use of multiple drug formularies of various PBMs.
physicians, pharmacists and even patients themselves are often unaware
of which drugs are covered and those drugs requiring special
authorizations for coverage. This whole process is time consuming,
resulting in delays and confusing for patients, Pharmacists and
physicians. We should seek to avoid these formulary fragmented hassles
in current and future risk management programs.

Having said this, I would like to turn to some of the issues that the
Agency and the manufacturers consider for an effective standardized risk
management strategy for certain prescription drugs.

A fundamental question that has to be answered as Pharmacists consider
participation in these programs is the nature of risk and liability that
pharmacists will be asked to assume and how the pharmacists will be
compensated for taking on this additional liability.

While pharmacists are willing to participate in risk management
programs, many are concerned about this additional liability. In one
scenario, the pharmacy may be actually asked to bear some additional
liability while another scenario, the manufacturer may assume the
additional liability.

These factors must clearly be articulated to pharmacies as they consider
participation and payment to pharmacies must be commensurate with the
liability that the pharmacy will be asked to assume.

Regardless of the level of liability assumed, providing additional risk
management services to patients results in additional costs to
providers. The FDA traditionally has not become involved in the economic
issues relating to the financing of prescription drugs. However, if the
Agency is going to require that health professionals perform certain
additional activities relating to the management of a drug product, then
it is logical to assume that Pharmacists will be compensated for these
services. We would ask that any risk management program submission
include an explanation of the additional costs of training Pharmacists
providing these services and how Pharmacists will be compensated for
these costs.

NACDS believes that educating and training patients and health
professionals on the proper use of medications that have high risk
programs is an important component of the manufacturer\'s risk
management strategy. The FDA Concept Paper notes cases in which
physicians, patients and pharmacists are all held responsible in some
way for knowing the risk profile of certain medications. This
multi-lateral approach is probably wisest, given that it creates certain
checks and balances in the system that would be missing if only one
component were solely responsible.

Communications about risk management programs to pharmacies should
recognize that many chains also maintain their own important

inter-communication links and so \"Dear Pharmacist\" letters should be
sent to chain headquarters so that important information can be
appropriately included in communications to individual pharmacies and
Pharmacists. The Agency should also recognize that many patients speak
different languages, so that the risk management program should include
a component of how the manufacturer\'s materials would deal with

non-English speaking individuals.

We encourage manufacturers to develop these educational programs in
conjunction with Pharmacists and create an important feedback and
evaluation component to the FDA and the manufacturer from the retail
community pharmacy.

We also think that the program planning should include chain corporate
headquarters personnel. The fact is that implementation of risk
management programs at pharmacy level will have to be coordinated
through central office and be integrated into the pharmacies\' overall
clinical and quality assurance risk management programs.

For patient care, patient safety reasons, we are opposed to limiting
distribution of outpatient drugs to a restricted network of pharmacies
and total circumvention of the community pharmacy practice. Patients
should be able to obtain high risk drugs from the same health care
professionals that they currently obtain their other medications and
health care services. Patients rely on their community pharmacy to act
as a safety net in their medication therapy.

However, we recognize that not all pharmacies may choose to participate
in a particular risk management program. The FDA should provide any
community pharmacy the opportunity to participate, provided that they
meet the eligibility requirements of the program.

We also support the notion of allowing pharmacies to access these
products through traditional channels of the wholesale distribution.

We understand the interest in professional and patient registries, but
want to express our concern with the potential for multiple registries,
using multiple data bases.

There is value in developing a central registry or data base that can be
used by the manufacturer with a risk management program to identify
those patients, physicians and Pharmacists or pharmacies that are
eligible to participate in the program.

This system would also indicate the quantity of the medication that
could be dispensed, whether or not refills are allowed and any
monitoring or follow-up the pharmacy is required to do, as well as
whether the patient has met all of the qualifications.

We are concerned with the potential for the use of multi-colored
prescription stickers that indicate whether the patient has met these
requirements and believe that a real time system is more accurate and
reliable than relying on a paper trail.

NACDS is concerned about generic versions of the brand products that
have risk management programs. We believe that to minimize confusion for
the patient and the pharmacist that the program should be the same. We
also do not believe that risk management programs should be developed
with the goal of potentially making it more difficult for generics to
come to market, nor do we think that the FDA should approve generic
versions with different risk management programs from the brand.

Pharmacists can and should have an important role in risk management
program evaluation. It is clear that if a program cannot be
operationalized or done so in an efficient manner, then the goals and
the objectives of the program cannot be met. These manufacturers should
have both the clinical evaluation component as well as an operational
evaluation component to their programs. Because these programs have to
be incorporated into the general work flow of a physician\'s office or
pharmacy practice setting, the Agency should also recognize that not all
pharmacy practice settings are the same. Pharmacy chain corporate staff
should be included in helping to plan, assess and evaluate these
programs as should pharmacists providing direct care to patients.

Pharmacies can also provide feedback to manufacturers on how physicians
are implementing the risk management program or other trends with the
use of other medications or specific situations that might be related to
the use of risk managed drugs.

In summary, NACDS supports a risk management system that allows adequate
access to valuable prescription medications that might otherwise be
considered higher than normal risk and become unavailable to the normal
pharmacy distribution channel.

It would also provide the broadest possible participation of community
pharmacists. It would use standardized programs, processes and
technology. It would recognize the critical role of the pharmacist in
the health care team and lastly, provide adequate reimbursement for
expenses incurred through participation in the risk management program.

In addition to the input of a product manufacturer and the FDA, an
effective system would include the participation and input of
pharmacists, prescribers and patients. And I thank you for the
opportunity to comment on this important public health issue.

DR. SELIGMAN: Thank you very much. We\'ll take a 15-minute break now and
reconvene about 10:20. At that time we will have two more commenters and
then we\'ll have discussion about all the presentation subsequent to
that.

Let me remind people again that no food or drink in the auditorium and
if you have coffee and you want to drink it, you can do so in the
outside room.

Thank you.

(Off the record.)

DR. SELIGMAN: All right, let\'s begin. Let me introduce the next speaker
this morning. It\'s Dr. Janice Bush who will be representing PhRMA.

Dr. Bush.

DR. BUSH: Good morning. I\'m Janice Bush and I\'m speaking today on
behalf of PhRMA which is the Pharmaceutical Research and Manufacturers
of America. We want to thank you for this opportunity and we look
forward to providing input both here today as well as in the comments
later this month.

I\'m going to begin today with some general comments with regard to risk
management and then I\'ll move on to some specific comments with regard
to Session 1.

Some of the comments that you\'ll hear me say this morning are similar
to those that you heard yesterday and also this morning, but we think
they bear repeating and we think it\'s important to share our
perspective.

PhRMA supports FDA\'s efforts on risk management. In fact, PhRMA played
a key role in introducing the concept of risk management in the PDUFA 3
process and in bringing risk management earlier into the drug
development cycle.

We believe that risk management is a continuum. Risk management is an
on-going process through the product\'s life cycle to optimize the
benefit-risk balance. It includes activities or risk assessment, risk
communication, risk minimization and evaluation, but it is a continuum.
So again, this has the two pieces of being an on-going process, but also
including all those aspects in an iterative process.

Pharmacies need the assurance that the benefits of medications to
patients outweigh the risk in general use as the purpose of risk
management. We agree with the FDA that the ultimate goal of any plan in
its evaluation is to ensure that efforts and costs involved in an RMP
are expended on effective processes that achieve a positive benefit-risk
balance.

Any approaches that are considered should be based on the benefits as
well as the demonstrated risk profile of the drug product. PhRMA
believes that risk management programs and interventions should balance
access to drugs with the level of concern.

We agree that specific risk reduction goals should be tailored to the
specific risks of concern for a drug. Decisions which are made
concerning individual drug benefit and risk in RMPs must be based on
scientific evidence.

I think you heard this voice very sincerely and impassioned this morning
from several people. Any risk management program should rely on a
systems-based set of interventions and the specific tools should be used
consistently across RMPs.

You also heard this yesterday, no drug is risk-free and no drug can be
made risk-free. Efforts to identify all risks prior to approval may not
be feasible without significant delays in drug development.

And our final general point, collaboration is essential. We agree that
regulatory industry interaction and collaboration on the development and
approval of risk management and pharmacovigilance plans is critical. And
also, we think that significant improvement in the benefit-risk balance
of risk interventions will require collaboration among the many
stakeholders, including FDA, academic institutions, health care
providers, pharmacists, professional societies and patient groups.

Now it\'s my Session 1 comments. Package insert and post-marketing
surveillance. The FDA states in the Concept Paper that for most
products, the risk management program will be handled by the information
contained in the package insert. PhRMA agrees that an appropriate
package insert, along with good post-marketing surveillance should be
the risk management plan for the majority of drugs.

The package insert is the cornerstone of risk management plans. PhRMA
agrees with the FDA that the package insert is one of the cornerstones.
We understand that the package insert and labeling is being addressed
via other initiatives, but we want to reiterate how important it is to
improve the package insert so that it may be more useful to physicians
and health care providers.

Since the package insert is the basic level of risk management, the
package insert must be improved to make it more standard and meaningful
to health care providers.

If there are not standard criteria and an even playing field, there\'s a
concern that risk communication may not be as effective as it could be.

Risk management should be on case by case. The draft Concept Paper
states that the need for a risk management plan will be applied on a
case-by-case basis using standardized criteria. We believe that specific
criteria will be needed to develop that delineate when it\'s appropriate
to institute a risk management plan beyond the package insert and post
marketing surveillance. Without specific criteria about when one is
needed, we are concerned that the decision may appear to be arbitrary
and inconsistently applied.

Details should be provided about how the FDA plans to ensure that
products of the same class with similar safety profiles meet RMP
expectations in a uniform manner. Since some sponsors and some divisions
may have different ideas as to the intensity of an RMP for a product
needed, this will be very important.

We have several concerns about the level scheme. There are no objective
criteria presented for selection of levels, nor is it clear what the
value of using levels will add to patient protection. The levels seem to
be based completely on risk and not the benefit-risk balance. And the
levels may be subject to misinterpretation.

In essence, we feel that the level scheme is not needed and may be
counter productive. If it is clear when a risk management program beyond
the package insert and post-marketing surveillance is needed, then the
rest of the program should be determined on a case-by-case basis using
specific risks as the driver for what tools are needed.

Also, a level may serve as either a symbol or code or some kind of icon
that may say to physicians or patients that one drug is safer or more
harmful than the other and that may be the basis for the
misinterpretation.

Tools needed for individual products will depend on their specific
benefits and risks. This will drive the goals and objectives of an RMP.
I mentioned this just now and this can be the alternative to the level
scheme.

You heard this earlier, actually from one of the FDA folks and I think
that it would be important. PhRMA suggests that FDA include a complete
review of all current and past risk management plans so as to determine
or to demonstrate the value of these overall programs as well as the
value of the individual tools used to achieve the objectives. This may
help a developing criteria for deciding when to implement an RMP.

The review should also indicate how these programs have been evaluated
to show that they achieve their objectives. We think this is a critical
feature lacking in this document as it would provide an evidence-based
rationale for this new initiative.

We have a concern about the health care system that you\'ve heard
earlier. Care must be taken not to overburden the health care system by
using too many resource-intensive tools in RMPs. In addition, the system
may become overburdened by inconsistent or ad hoc approaches or tools
used to address certain issues.

I mentioned this earlier as one of our general principles, but it bears
repeating. Benefit and risk are important in communication. Risk
communication is certainly going to be an important component of RMPs.
However, a discussion of risk outside of the context of benefit is
likely to have limited usefulness in improving safety if patients then
avoid needed, useful medications. In other words, if patients are
frightened about using medications that they need due to a message on
risk and that it either keeps them from using the drug or from using a
different drug which may, in fact, have even a more risky profile, then
safety will not have been served.

Now these are the end of the prepared comments, but we do have a couple
more questions for the FDA.

What is a bona fide tool? The Concept Paper discusses that a number of
tools are available and gives some examples. But when does something
become a tool? In other words, what are the criteria for becoming an
appropriate, acceptable tool?

And the last question, how will acceptable benefit-risk balance be
decided? There are no risk-free drugs and drugs can\'t be made risk-free
and yet still be useful for patients. How will acceptable benefit-risk
balances for given products be determined?

Now this is just a rhetorical question. It will really need to be
addressed each time a product is under discussion or review. So industry
needs to know how this will be determined.

Again, thank you for your time. We look forward to other opportunities
to provide input.

DR. SELIGMAN: Thank you for your comments. The final speaker this
morning is Dr. Anshu Vashishtha from Watson Pharmaceuticals.

Dr. Vashishtha.

DR. VASHISHTHA: Good morning. I\'d like to thank the Panel and Working
Group for putting together a Concept Paper so we can all think about
risk management approaches.

I\'d like to begin by being inspired by Dr. Salzman, since we are in the
NTSB hall to take another transportation analogy as I talk about how we
approached the risk management issue. I think if we look at accident
rates and car trips, a longer car trip is like a high risk event, it has
a higher chance of having an accident than a shorter car trip, but since
there are more shorter car trips, more accidents actually occur in trips
that are shorter and around the home than in longer trips, if you take
the total number of accidents.

So I think we need to pay attention to where we\'ll get more return for
risk management. And since the Concept Paper itself mentions that the PI
means the risk management tool in the majority of products, I think if
we leave it whole and not addressing that, do I understand the Agency is
separately addressing it, but if we don\'t address the package in the
context of risk management, we are not taking that big chance impacting
a lot of outcomes.

So with that as background, I\'m just going to have some comments on the
role of PI and some related comments.

So I think we\'ve already discussed that we have to consider the cost
impact of risk management programs and I think it\'s being already
pointed out by an earlier speaker and we would recommend also that for
generic products, particularly this is important because they provide
the benefit of low cost and for generic products, the risk management
should rely on the risk management by an innovator that has been done
over a long exposure and it seems appropriate the draft comments of
using the package insert as the commonest risk management program are
appropriate.

I also would again emphasize and agree with the suggestion that any
burden on a product for any risk management program beyond the package
insert be justified by the demonstrated effectiveness and need and
perhaps a review of any interventions that have been done is a good way
of doing it and should be done before the guidelines \-- the draft
guidelines.

Coming back then to the package insert, since again, this is like the
short car trip where most of risk management in day-to-day practice as a
prescriber, as a patient, is based on the package insert. So I think we
\-- I don\'t\' know if we need a separate evaluation of the role of the
package insert or it can be incorporated into one of the papers that we
have now, but it\'s clear you just have to look at the [Physicians Desk
Reference]{.underline} or a collection of product labels to see that in
helping the physician and patient make the decision of benefit-risk
balance, the current package inserts are not helpful, are not very
helpful in the majority of the cases.

What you need to do to make this decision is to have a clear
understanding of the benefit, and a clear understanding of the risk.
Hopefully, in a way that says what is the likelihood of risk, not just a
listing of all that has been reported with that product or the past
without any categorization and a clear delineation of benefit. And that,
I think, is lacking.

What is needed for that is the likelihood of the risk and how \-- what
is the likelihood of relationship of the risk to the drug use as opposed
to just having been observed during drug use.

So I think again, enhancing the package insert, both in terms of content
and perhaps access, we are talking about systems approaches, are package
inserts keeping up with where we are with information technology. Do we
need to rethink how we provide package inserts and updates to
prescribers and patients. I think that if we may have a role in that in
terms of doing it for the whole industry as opposed

to each manufacturer on its own.

In terms of not clearly indicating the population that has been exposed
to the product, perhaps they can begin ranges. I think some of the CIOMS
committees have talked about indicating the range of exposure. Is it a
product that has had a limited exposure, less than a thousand patients,
less than a few thousand; a moderate exposure up to tens of thousands or
a vast exposure. That again tells the prescriber what is the context in
which the package insert information has been derived, what is the data
upon which it is derived on?

Another limitation is that it doesn\'t indicate the causal relationship
with the drug. Perhaps a categorization on again is the event a
reaction, it\'s really considered drug-related or just observe the drug
in post-marketing or clinical trials without a clear relationship based
on pathophysiology or other factors for causal relationship.

And again, there\'s not always consistent frequency of adverse outcome
and again, maybe Dr. Salzman can give some comment perhaps some measure
of the CIOMS frequency, really common, common, rare, very rare or more
medical concept, the number needed to treat concept for adverse events
and how many patients are treated to report one event, which again, may
be very difficult to get for post-marketing data, but at least we can
think about how to convey a quantitative estimate of risk in prior
information.

So those are I think the points that would enhance the package insert as
a tool to manage risk in the hands of the prescriber and the patient.
And again, I would urge you to consider ways that we can improve the
content and the access so that again, I think a comment was made earlier
about the Dear Doctor letters not working. I myself have \-- I\'m guilty
of not opening them very often, very promptly, so clearly there needs to
be some better way of package insert and updates being communicated.

Another factor which I think probably belongs in the risk management is
about obtaining outcomes of pregnancy and including it in the package
insert, by follow-up of pregnancies.

With that, then I would like to end my comments by commenting that we
pay a little more attention in either the risk management context or
separately on the package inserts and enhancing their content.

Thank you.

DR. SELIGMAN: Thank you very much. The floor is now open for comments
and questions related to all the presentations, both by FDA as well as
the speakers this morning. And while people are coming to the
microphone, I have some questions that were also submitted on cards. So
let me just start with one of those as a way of initiating the
discussion and then we\'ll go to the floor.

The first question that I received has to do with controlled substances
and the mismanagement concerns regarding their use and abuse and whether
these considerations regarding the management of controlled substances
are being included in the guidelines.

Anne, you want to take that?

DR. TRONTELL: The working group does include representation from
controlled substance staff. I think our intent or hope in this first
step was to try and speak generically, but clearly there are lessons we
may learn and things we may also be able to inform on controlled
substances. There is a form of risk management and scheduling of drug
products with controlled substances that again provides perhaps some
potential precedent for setting things into levels. But we also face, I
think, particular challenges in the controlled substance area because
this is an instance where instances of adverse events relate to
deliberate or intentional misuse of products and I would consider those
challenges that quite frankly we hadn\'t addressed in this first Concept
Paper.

DR. SELIGMAN: Let me go ahead to the floor then.

Please identify yourself.

DR. SACHS: Susan Sachs from Roche. Earlier, I had asked you for the
distinction between the risk management plan and the risk management
product and in line \--

DR. SELIGMAN: Program, right?

DR. SACHS: Program, I\'m sorry.

DR. SELIGMAN: Don\'t get the Ps mixed up.

DR. SACHS: I\'m totally confused.

DR. SELIGMAN: Thank you, go ahead.

DR. SACHS: I\'m sorry, risk management program and risk management plan
and in line 122 it says \"FDA anticipates that for most products that
risk management planning will be handled by the information contained in
the PI.\"

Now most of what we\'ve heard was that the PI will be the risk
management program and not the risk management planning because planning
includes assessment which is much earlier than the package insert.

I would also \-- I\'ve also heard people stand up here and say RMP, risk
management plan and I would just plead that when you write the final
document that the clarification between risk management plan which I see
as a epidemiologist is much broader than a risk management program be
clear because it\'s very confusing.

Thank you.

DR. TRONTELL: We clearly have some work to do in terms of making our
terms clear and even using them clearly ourselves and as we heard from
one of our colleagues in the quality arena, we\'ve actually employed the
term and the reverse sense is they may be there.

At one point I proposed we just called them \"Betty\" and then get over
it.

(Laughter.)

I think we do have a challenge and I think there\'s clearly some
ambiguity in the Concept Paper which we\'ll strive to address. Risk
Management Programs to try to add clarity would be those that go beyond
the package inserts. So those, in fact, are ones where there is an
active intervention and perhaps this reflects our thinking that
conventional pharmacovigilance, though clearly involving a lot of
effort, has a large passive component to it and that risk management
planning encompasses pharmacovigilance as well as the package insert at
baseline and then as we defined programs, you\'ve really moved into a
different realm where we, in fact, expect most drug products will live.

DR. SELIGMAN: Thank you. Yes, Gretchen.

DR. DIECK: Gretchen Dieck for Pfizer. Actually, one of my comments is to
suggest renaming what we\'re talking about today risk minimization
programs because that\'s actually what they are and what I\'m assuming
you\'re trying to do. And that may itself provide some clarification and
distinguish it from the broader area of risk management.

I also have a question regarding risk management or risk minimization
plans and programs and that is what is the responsibility if you have a
drug that has a long-term risk management intervention strategy with it
that is relatively extensive and the drug reaches the end of its patent
life and generic companies come in. Will the generic companies also have
the same obligation for carrying out the risk minimization or
intervention strategy and if there\'s need to escalate the strategy
after the drug has gone off patent will the generic companies also play
a role in determining new methods and testing these methods as well.

DR. TRONTELL: I can try and respond to that based on the Agency\'s
limited, but we anticipate growing experience of generic products coming
for those products that already have a risk management program. That\'s
certainly the case for Clozapine and particular arrangements were made
there. Some responsibility is taken on by the innovator and others
shared by the generic companies.

And in the case of the Isotretinoin and risk management program and
it\'s changing to a SMART program, there was explicit consideration on
how FDA could through regulatory mechanisms make sure that generics used
as close to an identical risk management program as the innovator. I
think our expectation though certainly didn\'t address it in this
document is that a generic product should have no lower standard and no
different standard of risk management and certainly not to confuse risk
management options for the same product, just depending on who happens
to be manufacturing them.

But you make a good point. We have not addressed it here. In part, our
being very particular on what we called the package insert was a
reflection of what, in fact, may occur to try and guarantee the generics
follow the same standards and programs that exist for the innovator. In
the case of isotretinoin, much of that risk management program exists
formally as part of labeling and that gives us the authority to require
generics to have essentially an identical program.

DR. DIECK: Thanks, Anne.

PARTICIPANT: I\'m Eleanor Proveto, and I\'m with the Weinberg Group and
I\'m also here in my role and capacity as a member of the DIA Board,
Drug Information Association and the incoming president for this \-- for
2004.

I wanted to comment on something that I perceive as a potential conflict
in demands on the sponsor based on some things that we heard yesterday
and the reliance on the PI as the first level that we\'re hearing about
today.

Yesterday, especially when we heard Judy Jones\' comments and some of
the other comments from the speakers from FDA, we heard about a reliance
on information about how the drug is going to be used in the real world
and how that really should be used as a guide for thinking about risk
management planning and in my experience in the real world, the PI
starts to play \-- it plays a very small role in things like the
development of drug utilization review criteria, disease management
programs, all of those clinical practice guidelines. The PI plays a very
small role in all of that.

And I think if we encourage sponsors to go out and do this investigation
in the real world to try to investigate and predict how the drug is
going to be used in real world scenarios, they\'re going to come back
with the finding that in a real world scenario the PI plays a very small
role and I guess my question is does that automatically start into Level
2 because how they found out this information and they have this demand
to go the next step and figure out something more than just the PI
because that\'s the practical scenario.

And I would like to ask some of the individuals who spoke on behalf of
the Pharmacist associations this morning who gave us such a practical,
real world view of operationalizing all of this, if they could comment
on the PI in their world and whether or not this could set sponsors up
for potential conflict.

DR. MENIGHAN: I can\'t say we\'ve explored that issue as much as we have
many of the other issues, so I\'ll speak for a moment, just from my own
personal impressions, if I can.

I have high hopes that the paperless labeling initiatives that PhRMA has
underway and in testing, I haven\'t looked at those for three or four
months, but when I looked at them, I was very hopeful that that
initiative would make the labeling much more meaningful, the package
insert much more meaningful in a real world, every day scenario for
pharmacists, at least, who have computers fired up all day long and I
believe that there\'s an easy access to reliably the most current
information on a product, including any warning letters that may have
come out, readily available in such a system, that it would likely
become meaningful than the current package insert that\'s stuffed down
in a bottle that nobody can read past the age of 25 and that it may be
up to date or may not, depending on when that package landed on the
shelf in the pharmacy.

And then as far as the warning letters that go out, as we commented last
year before a different group within FDA, the warning letters have no
particular way to be assimilated in a pharmacy. They come in. One
pharmacist may be on duty and see it or not. The next pharmacist that
comes in may or may not see it. I guarantee there\'s not a very good
system for filing those where they\'re readily retrievable. And so they
become almost meaningless, unless you happen to be the pharmacist who
read it.

And then you may or may not remember it in the context six months later
of filing 300 prescriptions in a day and you\'ve got to retrieve that
little piece of information somewhere and it\'s not in your system.

So unless it\'s systems-based, it won\'t work and I applaud the efforts
of PhRMA to move toward a paperless labeling system and we think that
can help us a lot.

MR. MAYBERRY: Yes, I am Peter Mayberry and my question this morning is
on behalf of the Pharmaceutical Printed Literature Association.

There\'s been much talk this morning about the PI and the
post-surveillance monitoring as sort of the workhorse for the risk
management approach.

My question to the working group is since the PI is geared towards the
doctor and the pharmacist, and the post-market is basically to find
adverse events that are going on, was there any thought to adding a
third leg to the stool of PPI requirements so that the patients know
what the potential risks are directly from FDA approved literature.

DR. TRONTELL: We appreciate that suggestion. Currently now, I don\'t
think we have an exact number. There are probably several hundred PPIs
in existence.

And in setting, if you will, the workhorse as being the PI and
pharmacovigilance, we wanted to be able to encompass the greatest
breadth of products. Clearly, we agree that PPIs have value, but since
they\'re done on a subset of all approved drug products, we didn\'t
consider making them a requirement. There are other forms, certainly
many from industry, certainly from pharmacy as well, many other forms of
information that target the consumer and there are also a number of
initiatives in that area to try to give patients information.

I agree to its value, but as we have categorized it, it currently sits
at Level 2.

MR. MAYBERRY: Just a quick follow up to that point, it\'s my
understanding and correct me if I\'m wrong, that manufacturers are
routinely submitting PPI language now as part of their new drug approval
process. Is that a correct assessment of the situation? Clearly,
there\'s things that have been on the market for a number of years may
not have PPIs, but products that are being approved now, again, it\'s my
understanding that they\'re routinely coming with PPI language.

DR. TRONTELL: Products coming in now do not routinely have PPI\'s, but I
would note that, in fact, many products do have them. Those PPIs are not
necessarily related to any specialized communication that may be
necessary to the patient about benefit or risk, but often reflect
industries wanting to use these as the summary, as the basis of
information for them to be able to do direct to consumer advertising. So
quite frankly now, having a PPI status for a drug product may send two
potential signals to an outsider who isn\'t otherwise informed, one
being that there were concerns that were felt to be a need for
additional information and it may also just be a product for which this
was used as a mechanism to get at the brief summary.

MR. MAYBERRY: Thank you.

DR. SELIGMAN: Is there anyone else from the FDA who wants to comment on
how frequently PPIs are used or how they\'re used? No. Okay

Yes.

MR. GOLDSMITH: My name is David Goldsmith. I\'m representing myself
still.

(Laughter.)

Many of the factors at Level 3 and 4 in the RMPs really are touching on
perhaps not so lightly the practice of medicine in pharmacy. And that
actually raises several questions, the first of which is how well do we
understand how a physician translates the population based statistics on
either the benefits or the risks into an individual assessment on a
specific patient? The probability is not enough and it\'s not the whole
story. And I would suggest to the FDA that prior to going ahead on this
that they consult with the papers that were written by Jerry Avorn about
10 years ago and perhaps those of Bruno Striker and Miriam Sircambaum
that have carefully looked at what influences physician prescribing and
also pharmacy based.

The second point that it raises is what is the potential role of the
state medical and pharmacy boards, vis-a-vis the FDA and the industry in
determining or influencing the medical practice and I would like to ask
the FDA to provide their assessment of where they think this is going.

Thank you.

DR. TRONTELL: We would very much appreciate the complete references that
you cite because we do agree that there\'s an important need to figure
how FDA may be able to meaningfully influence without necessarily
intervening or trying to control the physician-patient relationship
since that is not our province. So we would be eager to hear that.

I think, in fact, our categorization of products into levels and perhaps
are not clearly stated. Intention to limit the number at Levels 3 and 4
to a relatively small population reflects the fact that it\'s only in
circumstances where perhaps prior efforts or lower levels were
inadequate or unsuccessful in terms that we obviously need to define.

In terms of the role of state medical boards and pharmacy boards, again,
these are areas where FDA can have good collaboration and partnership.
We obviously don\'t have control over those segments, but we have, in
fact, had discussions with a number of them who have come to us out of
their concern for trying to manage this fragmentary health care system
and how they may be able to support some of FDA\'s initiatives.
Certainly, the State Boards of Pharmacy have approached us in that
regard.

DR. GALSON: Let me make one comment on that as well regarding the State
Pharmacy Boards. I think you realize that we don\'t have authority,
regulatory authority over the state pharmacy boards. It\'s very, very
difficult for us to implement changes that involve them. It would
probably require going to 50 state pharmacy boards and negotiating
agreements. There are organizations that represent them and we\'re not
ruling out this as a possible route, but just pointing out that it\'s a
very challenging way to go for the Agency.

MR. GOLDSMITH: As a follow up, yes, I do clearly understand that the
remit of the Agency does not cover the State Boards of Pharmacy and
medicine. But in effect, what the FDA is now doing is they are almost to
some extent bypassing that by imposing upon Pharmaceutical companies to
actually implement it for the FDA.

DR. GALSON: If you have suggestions other than very general ones you
provided, please let us know because I think we would really appreciate
specific ideas.

DR. SELIGMAN: I am just going to turn to a question that we received via
a card regarding the FDA and whether we are aware of data regarding
effectiveness of restricted prescribing programs and what we\'ve
learned.

Anne, do you want to comment on that?

DR. TRONTELL: We\'ll be talking about evaluation in this afternoon
session, but we have limited numbers of such programs and only in those
instances where those programs have made tracking components, we have
information on effectiveness. I think in the case of Thalidomide and in
the case of Clozapine, I think we have some compelling evidence that
those programs have been very effective in reducing pregnancy exposures
and agranular cytosis, respectively.

But we\'re in a paradoxical situation at the other end of the spectrum
we have through our own studies and certainly studies from other
individuals, evidence that the PI and the PI as it may often be
accompanied by dear health care practitioner labeling has not shown in
population studies terribly large changes in physician prescribing
behavior when those have been modified. So the effectiveness information
we have is incomplete for these broader educational efforts and not
terribly compelling. We have much more complete for these very
restrictive and to some people\'s vision, somewhat onerous programs.

In the intermediate area on sticker effectiveness, we anticipate having
such information on the isotretinoin program within the year.

DR. FRANZEN: Tim Franzen from Lilly. A comment and a question regarding
the concept and perhaps an issue of focus for how practitioners may
understand the concept of risk management.

I think we all appreciate hearing in general what is intended by the
discussion of risk management. I think it\'s interesting in talking to
professional colleagues, both physicians and pharmacists with whom I
train, the term risk management evokes quite a different thought such as
do you mean needle stick injuries or are you talking about insurance and
liability issues and so forth. And I\'m not bemoaning the fact that the
term risk management has been chosen. It was clearly appropriate and
discussed in the context of PDUFA 3.

The question would be, does this create an educational opportunity in
almost an imperative to practice type communities. What is meant by
Pharmaceutical Risk Management and does this create the opportunity then
to provide a venue for explaining some of the likely changes that will
come to pass for practitioners in terms of labels, in terms of risk
management plans and if you will, in shaping expectations about risk
management can and should be. I would be very interested in the expert
committee\'s comments on this.

DR. HOUN: I think actually, internally, there\'s still a lot of
discussion on this term risk management and I think earlier you heard
this issue of well, where\'s the benefits. Is it truly a term we want to
have minimize risk, maximize benefit management? And I think it is an
opportunity to try to clarify when it comes to drugs and biologics and
adverse events and who can benefit the most, what do we want to do to
get the best outcome. So it is an educational opportunity.

I think we need concrete suggestions on not only terminology, planning
programs to help clarify things, but you know even just conceptually, if
we want to bring in the benefits part, the drugs are often, their
benefits are indicated by their approved indication and yet if we \--
there was one suggestion, I think, by the representative from Roche
about optimizing patient\'s use who have the \-- optimizing the
risk-benefit by indicating for patients who have the indication and
those that don\'t have the indication don\'t get drug B. That whole
concept is a little bit different than how we were approaching it.
Again, I think it is an open opportunity for us to hear your feedback
and your wisdom on how to make this successful. I don\'t think we\'ve
captured it clearly and we are looking to help clarify things. So
you\'re right, this is a very good educational opportunity and there is
a lot of confusion on the terminology and our intent as well.

DR. FRANZEN: I appreciate that and I think the opportunity to balance
the benefit and risk statements and also to really communicate to
practitioners is a tremendous opportunity to impact public health and to
improve utilization of medications. It just seems like a moment in time
for all of us and your comments are most encouraging on that. Thank you.

DR. GALSON: Just a quick comment, agreeing completely with Flo. I
mentioned this a few times in public, but I\'ll take the opportunity to
do it again which is nothing in the PDUFA language or in our efforts on
these guidances are meant to fundamentally change the way that the
Agency does the balancing of risk and benefit. That\'s not the intent of
this part of PDUFA and it\'s not our intent in writing these guidances.
This is going to be a fundamentally case-by-case decision and I don\'t
see how with all the range of risks that we have with drugs, the way
that we do balancing of risk and benefit plugged into a formula, one of
the early questioners said it well, how will we make the

risk-benefit decision? I don\'t know how to answer that except to say
it\'s got to be a case-by-case basis informed by data.

With regard to the name of the document, there\'s no perfect name. I
think no matter what we pick there are going to be problems with it. I
think what we need to do and as we\'ve heard already we want input from
you all is make sure that it\'s very clear in the text of the document
what we mean to do with regard to risk and benefit with this document
and how we\'re really trying to refine the way that we manage risk
rather than change the way we balance risk and benefit. And we need to
communicate that clearly and we\'re certainly striving to do that.

DR. SELIGMAN: Yes, next comment, please?

PARTICIPANT: I\'m Mary Lou Scovern from Bristol-Myers Squibb and my
question drives to process. We have the therapeutic area advisory
committees and there\'s a risk management advisory committee as well. I
would like if you would comment on the scope of input for the
therapeutic area advisory committee and for the risk management advisory
committees. For instance, is it expected that for instance CRAC or ODAC
would provide input on the necessity for risk management programs and
the content and evaluation be examined in the risk management advisory
committee or will you expect the therapeutic area advisory committee to
evaluate the whole program?

DR. GALSON: I think the model that has been evolving is that when we
have a difficult risk management question with the drug, we combine an
advisory committee that is a joint one. We have members from the risk
management committee and then the subject matter experts. I expect we
would follow that same sort of model.

DR. KAHN: Sidney Kahn, Pharmacovigilance and Risk Management,
Incorporated.

I\'d like to offer two unrelated concepts for potential discussion. The
first one relates to the methods that are currently being used to
communicate changes in the benefit-risk to users of similar products.
And I think we\'ve had ample evidence over the past few years that those
methods are probably suboptimal and can be improved.

May I offer a suggestion that perhaps it is now time to change the
method of communication and the type of audience to some degree.
Clearly, physicians, prescribers must continue to receive updated
information on benefit-risk changes. But there are other players in this
arena who have at least as much of a vested interest in ensuring the
optimization of benefit-risk for products as physicians and I am
thinking here about pharmacy benefit managers and their supporting
organizations and health maintenance organizations of various types. Is
there a place for direct communication of changed benefit-risk
information to those parts of the health care system over and above the
continued communication to physicians and for pharmacists and other
health care professionals because those organizations often have their
own internal processes that actually may be more effective at
disseminating information to the people working in the environments than
the barrage of letters. That\'s point one.

Point two, which is entirely unrelated, relates to the issue of labels
that become obsolete and basically useless as a result of changes in
medical practice and I refer here particularly to some of the labeling
for the anti-retrovirals where in many cases certainly some of the
labels for the older products on the market were crafted based on
experience as monotherapy in different patient populations and whose
applicability in the days of HAART is basically irrelevant and not
useful. And I would ask the Agency whether there are any opportunities
to revisit approved labeling in the light of changed medical practice
standards and so that the labeling can be made more reflective of
appropriate use of the products in the current environment.

DR. GALSON: Just to ask a clarification. Are you talking about labels
that are not reflecting the current FDA approved label. Are you asking
about how do we make our labels even the most recent approved one more
reflective of medical practice?

DR. KAHN: It is more the latter because if you take, for example, the
labeling currently for AZT or for Didanosine or Stavudine (11:11:36),
they mostly reflect monotherapy experience which is entirely irrelevant.

DR. GALSON: John, do you want to address that question or just the
general way that we keep our labels up to date?

DR. JENKINS: I think he\'s raising a very good question. Is this on?

DR. GALSON: Dr. John Jenkins who is the Director of our Office of New
Drugs.

DR. JENKINS: I think you are raising a very good question and it\'s one
that we have struggled with over the years of how to keep our labels
timely because the example that you\'re giving, AZT, when it was
approved, it was studied primarily as a monotherapy and most of our
labeling in the clinical trial section of the adverse event section is
usually based on the controlled clinical trials that led to approval and
then there\'s often added periodically afterwards, information about the
post-marketing experience, but we don\'t tend to systematically go back
at any given time and maybe take out the information that was in there
as the basis for the approval and substitute information that may be
more appropriate to the current use of the drug, primarily because we
don\'t have controlled clinical trial data in that setting in many cases
so you\'re right, the labels are often discordant with how the drug is
used and I think we\'d be open to suggestions about how we can go about
doing that better.

One place that I think we can probably try to do a better job for
updating our labelings is to do that in concert with when we get
supplements submitted for changes to the labeling and a new efficacy
supplement or other types of supplements. We probably could do better
systematically taking that opportunity to update the label, in general.
But we have not done that as well as we probably would have liked to.
And maybe Dr. Temple would have comments as well.

DR. TEMPLE: Yes, I totally agree. Another area where many labels are out
of date is oncology where in the old days there were very broad
recommendations which isn\'t at all the style we use now.

We\'ve thought periodically about \-- I mean John is right. A supplement
is a very good time. Another time to be triggered would be the time of
the annual safety report or something like that. But it\'s a lot of work
and they\'re not organized very well for doing that.

The result is new information of all kinds doesn\'t get into labeling.
Even new controlled trials, unless they\'re accompanied \-- unless
they\'re generating a new supplement don\'t get in. So we\'ll approve an
antidepressant based on five trials. There could be 30 in the label, in
the world, with all kinds of additional information. We don\'t see them.
We don\'t review them necessarily and they\'re never reflected in
labeling.

So I agree with John. All suggestions are welcome, but it\'s a very
major problem.

DR. HOUN: Maybe we can get some comments, too, from the Pharmaceutical
industry on their labels and how they view the outdatedness and what
kinds of hurdles they might have to overcome in terms of updating it so
we can understand it better.

DR. JENKINS: Along that line, Dr. Temple and I have had numerous
conversations that I can recall about fundamentally the sponsors\'
responsibility to keep their labeling up to date. Of course, we share
that responsibility, but I think we probably need to be exploring better
mechanisms by which we can keep those labels up to date and reevaluate
periodically whether the information that was used for the approval, 5,
10, 20 years ago is still relevant for how the drug is utilized and
current practice. I think again, the AZT example is a very good one. I
can\'t imagine that anyone ever receives AZT as a single agent, but I
personally don\'t know what the labeling says about adverse events or
dosing instructions when used in combination with the cocktails that are
used these days to treat HIV.

DR. TEMPLE: Just another example, again, it\'s not obvious what to do
about it. The most prominent display of what the most common adverse
reactions are is the table of more common adverse reactions that appears
in every label, but that is fixed and never changes after the first
submission even though 15 years have elapsed. It\'s not that that\'s the
best representation of what the drug actually does and yet to change it
would involve reviewing all the trials and somebody putting it all
together and doing a meta-analysis or something and those things don\'t
usually happen unless there happens to be a new study that generates a
new claim. Then you do get improvements.

We\'ve actually, for what it\'s worth, but it\'s a lot of work, gone and
looked back at in the context of new claims we\'ve gone and looked back
at what we fondly call the telephone book. That\'s the list of all kinds
of crazy things that follows the table and asked a few companies to
eliminate them which is what our current adverse reaction guidance urges
and after some reluctance initially, we\'ve gotten people to do that,
but each of those is a major project.

DR. SELIGMAN: Dr. Franzen, do you have a comment pertinent to this?

DR. FRANZEN: Yes, Tim Franzen from Lily and I think reflect some of the
perspective of some of my colleagues as well in terms of saying this
opens up a very interesting area of discussion because certainly when
one talks about benefit-risk relationships an important part of that is
what is the burden of evidence necessary in order to help inform
practitioners about new developments. Clearly, on safety, the standard
would be if there is an acceptable and valid case report, that would be
sufficient for a sponsor, for example, under 31470(c) to add something
to our labels voluntarily relative to a safety update.

Conversely, for an efficacy finding, for a multi-drug therapy and
oncology patients, it\'s been cited and so forth, the burden of proof
and the necessity providing adequate and well-controlled trials to the
satisfaction of agency reviewers in order to enable label inclusion is
clearly a difference and in many ways an appropriate difference, but
perhaps this is the time to revisit how does one better inform the
benefit-risk relationship in labeling so that it does begin to capture
evolving medical practice without requiring excessive documentation or
perhaps at an appropriate standard of utilization. I think Dr. Gormley
may have a comment relative to that as well. But I\'m very glad to hear
you open up that as an opportunity for us to dialogue further.

DR. GORMLEY: Glenn Gormley from AstraZeneca. I participated yesterday on
the panel. I want to support what my colleague, Tim Franzen said. I
think as an industry we would be very interested in opening this
dialogue. We\'d be very interested in understanding what it would take
to have those new trials introduced into our labels and if there\'s a
way that we could trimline that process and allow that data to be
reviewed appropriately and reflect emerging data, safety and efficacy, I
think it will be great for patients and for the Agency and for us. So
maybe that\'s a broader question than we can deal with today. But one we
ought to open up.

DR. SELIGMAN: Any other comments actually pertinent to this particular
point? Yes, go ahead. Sorry to skip a line. I thought it would be good
just to keep \-- this is a particularly interesting and important topic
I want to explore further.

MR. GOLDMAN: Steve Goldman, Steve A. Goldman Consulting Services, LLC. A
couple points on labeling. Bob Temple, how many years ago did you give a
list of products that have clinical efficacy that\'s been used in the
literature for many years and offer the opportunity for people to submit
on products that were off patent and others for getting second or third
indications?

How many people took you up on that, if I remember? Am I correct?

Imipramine comes to mind. As a neuropsychiatrist, it\'s in every
treatment guideline for the treatment of PAG disorder that Imipramine is
a gold standard treatment. It\'s not in the label. It was never approved
for that. And that was not taken up.

So one point I would make to my industry colleagues is that opportunity
was offered. Again, Bob, I think it was about four or five years ago, I
think the list?

DR. TEMPLE: It\'s probably 15 years ago.

(Laughter.)

MR. GOLDMAN: No, it\'s something more recent. There was a list of things
that came out.

DR. TEMPLE: We actually offered the opportunity to allow the societies
to identify things that weren\'t in the label yet.

MR. GOLDMAN: Right.

DR. TEMPLE: Actually, John can probably talk about this. We\'re doing
much better at getting supplemental indications for drugs that have
patent life.

If they don\'t, it\'s really, really hard.

MR. GOLDMAN: That\'s one thing. Secondly, there was a study done several
years ago and I know Dan Spiker talks about it a lot about the overdose
information that is in labeling and how in some cases at least 10 years
out of date. We have to look at the reality of what people use for
information. The focus groups that Nancy Ostrove and others did for the
labeling initiative that the PDR remains one of the most sources that
people take first. Three o\'clock in the morning on the wards people are
still reaching for PDRs. MedWatch\'s own studies that we did showed they
were up to five safety-related labeling changes per year and the printed
PDR is out of date in that essence, as soon as it\'s printed in terms of
not having things on line. So we are asking a label to be the basis for
promotion. We are asking it to look at all the information we have when
a product is approved. We are asking it to be revised as soon as new
information comes in. We\'re asking it be communicated in 6. font in
terms of things that people are using. That\'s a lot to ask from a label
and yet that is what we do. So I am also delighted to hear that it
appears to be on the table that we look how we\'re using the label as a
risk communication tool about the information that goes in, how often it
is updated, how often the information is communicated and as Sidney was
pointing out, how that information is communicated.

DR. GALSON: I just want to make sure folks are aware, some of you have
heard about our project called DailyMed. This is an attempt by the
Agency working with the National Institutes \-- NIH, National Library of
Medicine and the VA to create an electronic warehouse of our labels
which currently, believe it or not, does not exist.

And what this will allow is people to get real time copies of our
approved labels. It will also allow groups and vendors that are
interested in packaging the information for specific audiences such as
patients and drug stores or people with disabilities or any kind of
group that have a need for special segments of the information to
package it in a potentially different way for those purposes while being
consistent with our approved label. We think this will bring us into
this century in terms of updating the labels and also allow us to
address better the issue of how we communicate changes to all these
various groups who are very important other than physicians. If we\'ve
got an electronic data warehouse then the PBMs can find out about label
changes at the same time as everybody else.

MR. GOLDMAN: That\'s admirable and I certainly applaud that. I would
point out that for several years MedWatch has been summarizing all the
safety related labeling changes for at least five years. They\'re up on
the web. They\'re published monthly. One of the main jobs I\'ll be
talking about tomorrow is how we get better reporting in and who we\'re
communicating to.

One last point, I do not see a physician group on the agenda. Am I
correct, for these three days of the meeting?

DR. SELIGMAN: That is correct.

MR. GOLDMAN: I think that is a point that needs to be observed.

DR. SELIGMAN: Bob, go ahead.

DR. TEMPLE: It\'s been a while since I read it, but I think this is
true. The proposed rule on safety reporting, I believe places particular
emphasis on periodically updating the section on overdose because we
recognize along with the previous comment and others that it\'s a
section that is virtually useless and has no reflection of current data.
And I think it does that.

So whether that will lead to the kinds of sections on overdose we really
want remains to be seen and also the rule has a way to go, but that is
something.

Also, the labeling proposal that we\'re looking at comments on does
identify recent changes. So it will be somewhat more possible to see
them if you call up the labeling from DailyMed, it will be right there.

DR. SELIGMAN: You\'ve been waiting patiently.

PARTICIPANT: Thank you. Another area to comment on, one of the things I
was struck with is the broad definition of risk management and yet
we\'re managing risk through a series of interventions and I thought it
was important to pay attention to the broader environment in which drugs
are marketed and FDA does have some control of the marketing, but
there\'s an opportunity here in I think at least two ways to do two
things. One is to use the fair balance section of advertisements as a
means of communicating whatever risk management messages are perceived
of importance to the audience, so actually capitalize on existing
regulations and try to make that section of the advertising labeling to
be more consistent with the goals and objectives of the risk management
plan.

Also, one of the things that occurs to me is that DDMAC reviews
advertisements by looking at the package insert, but what we\'re saying
now is it\'s going to be a risk management plan that includes the goals
and objectives section and that DDMAC may need to review that as well to
make sure that marketing interventions are not only consistent with the
PI, but consistent with the broader risk management plan. So I think
there\'s a need to bring in other parts of FDA, especially the marketing
regulation aspects to make sure it\'s consistent with the risk
management planning.

DR. SELIGMAN: Thank you. Another comment?

PARTICIPANT: Yes, I\'m Bob Fenishall, a consultant, but once at FDA.
I\'d like to return the discussion to the question of updating labeling
and I just wanted to first of all bring to the attention of some people
you may not be familiar with just how much work is involved. I was
involved in two major relabelings while at FDA, one of sodium
nitroprusside and one of the quinidine products as a group and the first
thing is it is difficult to relabel drugs because often without bringing
new hazards to the front or bringing new warnings or raising the level
in the current terms of risk management, it nevertheless is perceived by
the effective sponsors as being an admission that the process had got
away from them that things were being neglected. And of course, it\'s
not easy to say that that is wrong. In fact, this happens when the
process had got away from them and things were being neglected. But
it\'s very difficult from the Agency\'s point of view to proceed with
these and then it\'s difficult in the other sense which is that in the
two cases I\'ve mentioned each of those is something like 5 or 6 months
out of my life. Those are major projects. They at the time they were
undertaken by us, could have been done by few people in the division. It
just requires a bunch of talent which may or may not be available and it
happened to come to me.

One of the things that makes it difficult, another point which may be of
broader interest is that when one looks at older labels, it is very
often not known to anyone at the Agency, at the sponsors or anywhere
where things came from. Why is this in the label? And they said well, I
don\'t know. The guy who did that died 10 years ago.

(Laughter.)

And one can go back to the so-called annotated label submitted with the
application without success and certainly the more recently added
shopping list of adverse reactions very often consist of cases which
seem fairly convincing at the time, but now there are new data of
various kinds to render them somewhat less compelling, but they\'re very
difficult to base those decisions on any available reassembly of the
data and that\'s why the alternative has been the wholesale elimination
of sections because some of it may be good, but most of it is dross.

And the final thing which came up actually with both of those products
and has come up with another product I\'ve been involved in more
recently which is not yet been \-- a revision of which has not yet been
approved, most of the business in sodium nitroprusside, something like
95 percent at the time I did this labeling was generic. There were two
innovators, the later one, who was still maintaining a hand in, who were
not making any money out of this product. You had nothing but a kind of
honor interest in maintaining their hand. Their incentive for putting
effort into this was extremely small and now, of course, there are
products where there is no innovator any more, where the product is
listed entirely as a generic. There is no mechanism for getting that
labeling maintained. There is no incentive on anyone\'s part to get that
maintained and no money at the Agency for keeping that maintained.

And this is obviously going to increase as more and more products become
generic. Some are superseded, of course, by superior products, and so we
can perhaps forget about them. But they remain on the market. This is a
genuine problem which as one of the speakers mentioned this morning,
this is where the money is in the sense of this is where the real risk
is. The greatest majority, the great majority of events are going to
come from Level 1 products which because they\'re the most numerous and
perhaps the risk is highest in the higher categories, but there are very
few of them.

This is an unintended problem today. It was when I was at the Agency and
it remains so.

DR. SELIGMAN: Thank you. We\'re going to switch microphones.

DR. GOLDHAMMER: Alan Goldhammer, PhRMA. I just want to quickly address
the point that Dr. Goldman made about labeling, current labeling, not
necessarily being accessible to Pharmacists and other health care
practitioners.

We\'ve had a project underway at PhRMA for about three years and I know
a number of people at the FDA have seen it that would, we hope, promise
real time delivery of the most current drug labeling, at least at the
pharmacy level. We did a pilot this past summer in 10 D.C. area based
pharmacies with two different vendors, having slightly different
approaches. It was well accepted by the pharmacists. We\'re pursuing
this and hope to do a larger trial this coming year in a couple of
hundred pharmacies. We did actually do during this alpha test two label
updates where we had both a new efficacy claim and a brand new drug
going on the market. These were into the system and available to
Pharmacists within 24 hours. So I think that the days of relying on
printed material which, as you pull it out of the box, may be six or
more months out of date and then have to rummage through files looking
through dear Pharmacists letters for safety updates, our hope is that
that will be a thing of the past.

DR. JENKINS: I wanted to return to a question I think Alan\'s comments
just raised again. We didn\'t get a chance to talk, ask questions to
some of the presenters before the break and some of the pharmacy groups.
There were a couple of things that they raised that I\'d like to maybe
follow up on.

One I think relates directly to what Dr. Goldhammer just mentioned and
that\'s there was a lot of comments about there needs to be a systems
based approach to how this information is communicated and shared and
I\'d be interested in hearing your thoughts about how that system should
be developed and who should pay for that system. I know the pharmacies
already have a pretty advanced, elaborate system for insurance
information, for example. When I go to CVS, it\'s rather remarkable that
they don\'t even need my card any more to know what my health insurance
is and whether they\'ll pay for my prescription drug or not. So what are
the thoughts about how that system would be created and who\'s going to
pay for it?

DR. MENIGHAN: Tom Menighan, APhA. We spent a lot of time thinking about
that and writing about it and collecting comments and thoughts from
other organizations and as I said, our plan isn\'t fully vetted yet, but
the notion would be that there could be a common infrastructure built.
The technology certainly exists for that today. We have patient
registries. What we don\'t have are common data sets that everyone
agrees are the right sets of data to collect about a patient and while
that may be very extensive for one risk managed drug, it may only
include name and address for another. But the component itself would be
standard.

As to who pays for that, well, if I\'m a company that has a risk managed
drug and I want to see that product marketed effectively and safely, I
pay for a lot of things to see that that happens. It seems to me sort of
a natural progression that the manufacturer pay something for that risk
management component as well. It\'s not our belief that Pharmacists
should do it for free.

With regard to how the system is built in the first place, I think there
are a lot of different ways that that might happen. It could be that
somebody would invest in a prototype. It could be that some sort of
relationship with the FDA is developed where \-- and I\'m just throwing
out brainstorming ideas here where through prospective user fees of some
kind are used to fund a common system that any PhRMA company could use
at any time and it becomes the utility that\'s used. It has deemed
status within the FDA for \-- if you use that system, you\'re meeting
the risk management requirements and you don\'t have to, as a PhRMA
company, invent your own new way of doing it.

I think we can talk about all of those things. The point is let\'s talk
about it. Let\'s get after it because it\'s do-able. The technology is
there. It\'s not that tough. You heard common themes among pharmacy
organizations. I would suggest that many physician organizations feel
the same way, even though they\'re not represented here today.

DR. JENKINS: Can you comment further about the data systems that
currently are present in pharmacies? There may be one or more systems.
I\'m just not really sure, but it\'s rather remarkable that every
pharmacy seems to be linked into some sort of a data base and it seemed
to be focused primarily on claims, insurance issues, but how did that
system come about? Who paid for that? Is that a model that could be
utilized for a systems-approach to risk management for dispensing drugs?

DR. MENIGHAN: That\'s a long question to answer. I\'ll try to be brief
and then would be more than happy to sit down with you and spend more
time unpacking it.

It\'s sort of two-fold. The systems, the existing technology today for
risk management wasn\'t necessarily developed by the same folks who
developed pharmacy management systems that are used in processing
claims, assimilating orders, getting labels printed, maintaining records
in a pharmacy. But they\'re certainly accessible by those systems.
pharmacy management systems today increasingly submit claims via the
internet which means many stores, an increasing number of stores now
have access to the internet. They didn\'t use to. Pharmacy evolved in
developing a common data set for claims submission. That goes back 30
years to an organization called NCPDP, the National Council for
Prescription Drug Programs that began to sit down as a group of folks
interested in the claims process and developed a common data set which
became the universal third party claim form which was about this size.
And I remember as a practitioner pharmacist filling it out by hand.
We\'ve evolved a bit. That data set has expanded, but it\'s expanded
through a collaboration among players in the industry.

I believe we could take it a step further and expand the kinds of data
that one might need to capture about a patient that would then integrate
them into a risk management system. For example, diagnosis, intended
use. Things that pharmacists have lusted after for years, but haven\'t
captured yet unless it\'s in some sort of organized health system that
does that. But that helps in the treatment system.

If a pharmacist knows those things and if diagnosis is important in
managing risk, then that piece becomes available to the pharmacist to
manage that risk. So again it\'s existing technology. It\'s just a
matter of time and effort.

DR. JENKINS: One other question I had in follow-up to some of the
comments from the pharmacists earlier this morning was about the issue
of reimbursement to pharmacists for their involvement in some of these
risk management activities. Some of these plans now involve making sure
that the stickers on the prescription or making sure the blood test has
been done before you give out Clozapine and I\'m interested in hearing
more of your thoughts about what do you mean by reimbursement and what
are your thoughts about where that reimbursement is coming from?

DR. MENIGHAN: Kim may have comments as well from NACDS and I would
invite her to do so, but again, if a manufacturer has an interest in
seeing a product used effectively and safely, they do lots of things
today to see that that happens. They detail doctors. They spend a lot of
time and energy detailing doctors to make sure doctors know how to use
it. If a drug is a risk managed drug, they go an extra step. They may
have a formal education system for physicians to ensure that they know
how to prescribe it effectively. There may be a continuing ed. program
available for pharmacies or there may be a restricted distribution
system because the manufacturer wants to ensure that the pharmacists who
managed that product know how to do it and they\'re afraid that the only
way they can do that is by working with one pharmacy organization that
can assure that level of education.

And they may have a system in place to do that that\'s common to all of
their pharmacies and so on.

So I think to the question of who pays for it, I think the manufacturer
pays for it. I think there\'s value in that, however, in that
manufacturers also have an interest in increasing access to their
products. And if you can push the activity of risk management down the
food chain, past the physician to the pharmacist who works with the
physician and basically the physician who prescribes the drug is the air
traffic controller and the pharmacy just works based on what the doctor
has prescribed, basically, that once that prescribing decision has been
made, the pharmacy can be put into use in terms of managing the risk of
the use of that drug. You push it further down the food chain and all of
a sudden the barrier to prescribing that the doctor has in being the one
who has to put the sticker on, goes away. So now you push down a little
bit further who does \-- who sees that the pregnancy test gets done, for
example, to the pharmacy. Pharmacies can do that, but you have to pay
them for it. They\'re not going to do it for free. Somebody has got to
pay them. Who pays them? The people who sell the drug.

DR. SELIGMAN: Kim, did you have a comment?

MS. SWIGER: I think I would agree with many of the comments that Tom
just made. Pharmacists, typically for years have given away our services
and unfortunately that\'s put us in a predicament to now convince many
individuals, patients, manufacturers, government, insurance agencies
that we should be paid for cognitive services. Physicians are able to
bill for a more complicated office visit. We\'re not able to bill for
the additional time that goes into counseling a patient, the
interventions that go on, all the problems with insurance that you seem
to think are seamless, but on the back end are actually very time
consuming when it doesn\'t flow as easy as it may look.

And with a pharmacist shortage and the number of prescriptions that are
being filled, we need to begin to be compensated for those services that
are beyond getting the right pill in the right bottle to the right
patients. So in this case I think there\'s a lot of people that can pay
for those services, but in this particular instance with risk
management, I agree with Tom that it should come from the drug
manufacturers.

DR. SELIGMAN: We will hear from the manufacturers and then we\'ll go to
the floor.

Yes, Janice.

DR. BUSH: Is this on?

DR. SELIGMAN: As long as the button is up, it should be on.

DR. BUSH: Yes, this is the age old question. It\'s a great idea, but
who\'s going to pay for it. And I think one thing that we all agree on
is that pharmacists are key players in managing risk for
pharmaceuticals. Absolutely. And I think we all agree they should be
paid for.

Now one intriguing option that I heard, actually one of your colleagues
brought up at a risk management meeting that I attended a few months ago
was that perhaps third party payers should be ponying up for some of
this extra money for pharmacists. And she used the example that if a
drug is used for anesthesia and say insurance would pay for the
anesthesia drug, they would also pay for the anesthesiologist who hangs
around administering the drug, making sure the drug is used safely. So
therefore, they might have a vested interest in making sure the
Pharmaceutical that they might be paying for would be used safely. I\'m
not saying that\'s the total answer, but I happen to like that answer
\--

(Laughter.)

\-- that she gave, so you know, another perspective.

DR. SELIGMAN: Do we have anyone from the insurance industry here?

(Laughter.)

If not, we\'ll turn to the floor then.

MR. GOGATES: Greg Gogates with CFR Box. I just wanted to bring
everybody\'s attention, I know a physician who lives in my neighborhood
who turned me on to this. There\'s a little book called Hippocrates that
sits on your PDA and every time I synchronize my PDA with my laptop, up
pops the latest information. It just uploads the latest and greatest
information. I have no idea how the system is paid for. It\'s a free
system, but what I would say is here we are worried about getting these
type of things out there and they exist. It seems to me that we ought to
be building on those existing systems. I\'m sure there\'s other
competitors out there that do the same thing, but go to
[hippocrates.com]{.underline}, log into your PDA and next thing you know
you have all the latest and greatest drug information, along with
pricing. So I mean what more do you want? Here we are trying to create
the wheel and they\'re already out there.

DR. GALSON: How do you know it\'s the latest and greatest?

MR. GOGATES: You\'re right, I don\'t.

(Laughter.)

I don\'t, but I know a lot of physicians who are using it, so I hope it
is.

DR. TRONTELL: Just by way of a quick comment, the MedWatch program of
the Food and Drug Administration, in fact, takes its safety alerts and
monthly drug updates and makes them available through Hippocrates, so to
individuals who subscribe actually do have that avenue.

DR. SELIGMAN: Please.

DR. ELLENBERG: Susan Ellenberg, CBER. I actually, I wanted to ask a
question to Dr. Bush from an earlier presentation. You made a comment
with which I\'m extremely sympathetic and that is you\'re concerned
about with developing risk management programs having a whole variety of
kind of ad hoc things that may overburden the system.

And while I am sympathetic with that, it\'s hard to know how to avoid a
situation like that when we\'re kind of really at the beginning of
thinking about how systematically to do these things, the best way to
really find out is to sort of allow people to try different approaches
that seem optimal in given situations and then learn something about
what works best. I don\'t quite know how you skip the \-- how you skip
the step of sort of trying things out, although I mean I really take
your point that I can see that it can be burdensome to do things in
different ways, so I wondered if you have any thoughts about that?

DR. BUSH: I think one of the other points that I made and Bob, you
actually weren\'t in here when I was making the point, but I think it
went to what you \-- something you had said earlier about going back and
\-- we\'ve been doing a lot of risk management kind of here and there
with a lot of different products for many years. There\'s nothing new in
this paper that somebody hasn\'t done before. We\'ve just sort of done
in a lot of different ways.

So I think the question is can we go back and look at some \-- some of
these things seem like they would be good theoretically and of course
that\'s why we did it, but did they really work? Were they really
effective and if you have to balance all the resources that were used
and all the "pro forma's" that had to give their time for free and all
the other things that happened, was it really worthwhile?

I don\'t know that we have those answers yet. And I guess I\'m just
saying that part of this whole initiative might be going back and
critically looking at some of the previous activities and trying to kind
of validate was this really a good thing to do and if it is, the best
practices, those should be the ones that we move forward and try to do
them in a consistent manner.

DR. ELLENBERG: Right. I would certainly agree that we would be foolish
not to do that, but I also think we\'re probably, it probably is going
to have to be a place for trying out some new things, based on what
we\'ve learned.

DR. BUSH: Of course, I mean medicine evolves. We\'ve got to be
innovative. I mean absolutely.

DR. MENIGHAN: If I could just follow up on who pays for it issue.
Pharmacists aren\'t asking to go to the Cayman\'s every time they manage
the risk of one particular drug.

(Laughter.)

This need not be a windfall for Pharmacists. It can be done in an
affordable way if you employ systems that may get simple and easy for
Pharmacists to use and by simple and easy, read inexpensive. And simple
and easy for manufacturers to pay for it. It need not be a windfall. It
need not be a burdensome issue for manufacturers. It could be a blessing
in disguise for them.

So I would suggest that rather than resisting who pays for it, that we
engage in dialogue about how it gets done.

DR. SELIGMAN: Bob, do you have a comment? Bob Temple, and then two
comments from the floor and then we\'ll break for lunch.

DR. TEMPLE: Only the observation that the Clozapine distribution system
has been periodically evaluated and has some fairly obvious successes.
Its two goals are to make sure that no one with a white count that\'s
very low continues to get the drug and to also make sure that no one
who\'s had a reaction, who\'s had a hypoleukemia gets the drug again
because they\'re at particular risk. And we know from this that the
mortality rate of agranular cytosis is way below historical norm. It
used to be considered 10 percent. I don\'t know if that\'s really still
true in 2003. But it\'s much lower than that. It\'s like 1 percent or
less. So that is presumably because you discover it earlier and whether
you die or not with agran. is sort of a random thing.

There\'s also data on whether people who have been avoided been given it
again. So that one, at least, has been \-- it\'s fairly obtrusive and
costly, obviously, but that one, at least has been evaluated for that
purpose.

And more evaluations, obviously, are needed. The CERTS are taking a look
at the Dofetilide program and at least have some preliminary impressions
that it\'s increased use of quinidine, but \--

DR. BUSH: And just to build on that. I think you need to look at the
overall effectiveness of a program, but then also look at the pieces
too, because a lot of times, and by design, there are redundant pieces
because you want to make sure that whatever your goal is is achieved,
but do those pieces really contribute what they need to be as well and
so I think it\'s more \-- it is complicated which is why it\'s hard to
do, but that\'s something that needs to be looked at.

DR. SELIGMAN: Yes, comments from the floor?

MR. MAYBERRY: Again, I\'m Peter Mayberry with the Pharmaceutical Printed
Literature Association and rather than a question, I felt it important
that somebody stand up for the printed PI in this discussion. The
printed PI has played a major role in ensuring that drugs are dispensed
properly and that risk managed as best possibly from the physician and
the Pharmacist standpoint. And there was reference to the PhRMA effort
and it\'s called the paperless insert, the paperless labeling initiative
rather, I apologize. We believe that that\'s a misnomer. We believe that
the technology which is available to ensure that the information on the
PI is updated immediately is a tremendous benefit, but we urge the
Agency and everybody in the audience when you think of this effort to
think of it as an adjunct to the printed PI, rather than a replacement
for the printed PI because one cost savings that PhRMA has been very up
front about is once this electronic system is in place, they hope to
come to the Agency and seek regulatory relief to do away with the
printed PIs because why print these things when they\'re already
available on the internet. And that, of course, will be a discussion
several years from now probably, but in the interim, we are pleased to
know that the PI is a part of the risk management structure and we hope
that you guys keep it.

DR. SELIGMAN: Thank you. One last comment.

DR. GOLDHAMMER: Yes, Alan Goldhammer, PhRMA. I\'d briefly like to
address Tom Menighan\'s point. I think it was a result of Dr. Jenkins\'
question. I think there probably are opportunities to explore some of
these ways of electronic transfer of data structures and so forth.
We\'ve been engaged with FDA for some time on the things that we do with
FDA. We\'ve also been working on setting up a trusted third party, what
we call an information broker which will be a secure site where
information can go back and forth from many different avenues, probably
could even involve the pharmacy community. We haven\'t explored that yet
and then finally, I know that FDA and some of our members and I\'m
getting involved in it, there\'s a lot of standards work going on with
the Standards Group Health Level 7 which is [hl7.com]{.underline} or
[.org]{.underline} or something like that on the internet. Just type in
hl7, you\'ll pull it up. There\'s a whole bunch of stuff in that area
which may be amenable possibly to some of the issues along the lines of
structured data bases that you\'re looking at.

DR. SELIGMAN: John, you had an additional comment?

DR. JENKINS: I don\'t want to stand in the way of this group getting to
lunch, so I\'ll be very brief and I don\'t think I\'ll ask for a
response from Dr. Bush, but it occurred to me that you asked two
questions at the end of your presentation to FDA and really, I think
those questions should be answered by PhRMA as well because it\'s the
drug manufacturers\' responsibility to make sure that their products are
safe and effective, just as it is FDA\'s responsibility to try to ensure
that as well.

So I think both of your questions really are questions that PhRMA should
address in its comments back about these Concept Papers. As I understood
the question, one question dealt with how do we validate a tool for risk
management and I think in my experience at FDA as often as not, it\'s
actually the sponsor who has come up with the proposed risk management
program including the tools that have been proposed to be used, so I
think it\'s legitimate to ask PhRMA and the industry to help us answer
the question of what are the validated tools and how do you go about
validating a new tool. And I think the same is true of your second
question which I encapsulated as how do you calculate the benefit-risk
ratio. Again, that\'s fundamentally something that the companies do
presumably every day. You must make those decision as you\'re going
through drug development at each stage, do the benefits of this product
outweigh the risk. So I think it\'s something that the industry shares
in responsibility for and can help us better articulate how those
decisions are made, so I\'d encourage PhRMA to answer those questions
that you pose in your written comments back to the Agency.

DR. SELIGMAN: Thank you very much, Dr. Jenkins. Yes, we certainly will
eagerly look forward to those comments and the answers to those
questions.

We will take a break now for lunch and return at 1:15. We\'ll take an
hour and 15 minutes and we\'ll start the afternoon session then.

Thank you.

(Whereupon, at 11:56 a.m., the meeting was recessed, to reconvene at
1:15 p.m.)

A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N

(1:16 p.m.)

DR. SELIGMAN: If everyone will take your seat we\'ll begin this
afternoon\'s session.

At this session we\'re going to focus on two areas of the Concept Paper
related to the evaluation of and the elements to be included in a risk
management submission.

The first presentation is by Dr. Anne Trontell who will be talking about
the evaluation of risk management programs.

Anne?

DR. TRONTELL: Thank you, Paul, and welcome back from lunch, everyone.
Thank you for your excellent comments this morning. We look forward to
more after this session.

I\'ll be discussing the third major component of the Concept Paper which
is that portion that deals with the issue of evaluation of risk
management programs. These processes and methods that we\'ll be
discussing in conceptual form can be applied to risk management program
tools, to objectives or risk management program goals themselves.

And as we stated in the Concept Paper, the Agency is considering making
a recommendation, in fact, two recommendations; one being that if a risk
management program is instituted that it be accompanied by a risk
management evaluation plan; and the second being that risk management
tools deserve some level of pretesting prior to their implementation.

Let me first address what may be obvious to this audience which is why
we think evaluation is important. If a risk management program is
designed to reduce risk, minimize risk or maximize benefit-risk balance,
it\'s important to know whether, in fact, that is working. This
assessment of effectiveness can be done at two time periods: potentially
prior to implementation of a particular risk management program tool to
help predict, in fact, whether that tool will achieve its desired effect
prior to putting it into full implementation in the field.

And certainly, and perhaps most importantly, after implementation of
risk management program, it\'s important to determine whether or not a
risk program\'s desired objectives are being served by its tools and
various elements.

Evaluation itself has a goal, in our minds, and that is to ensure that
efforts undertaken in the name of risk management are expended on
effective interventions. Or stated in the converse, I think none of us
want to spend our valuable time or resources on those interventions that
are not effective or adding value.

The other importance of evaluation is to guide both the Agency and
industry and looking at risk management programs to optimize the
programs themselves in terms of effectiveness and to consider
modifications or redesign as may be necessary. These may, in fact, lead
to either an increase or a decrease in the level of the risk management
program interventions.

A little more about pretesting of risk management program tools.
Although we don\'t so state in the Concept Paper we might presume this
would be for those tools which are novel or otherwise unexplored.
Pretesting allows an opportunity for the various stakeholders that
we\'ve discussed this morning to have input into that tool. It also
allows an opportunity for those components that address education or
comprehension of risk communication materials to be formally tested to
see if, in fact, those materials are understandable by their intended
audiences. But pretesting may also give us a viable opportunity to pilot
test some important factors such as feasibility, acceptance or other
factors that might influence a particular tool or collection of tools
for a health practitioner\'s adopting it into practice or for a patient
to incorporate it in his or her lifestyle, or even for those individuals
who handle reimbursement through various mechanisms.

FDA has outlined several overall considerations in approaching risk
management program evaluation. One consideration is the selection of the
outcome measure that\'s used for the purpose of evaluation. Ideally, the
outcome measures that would be used would be well-defined,
well-validated and closely related to the risk management program goals
and objectives.

A second consideration, and probably somewhat obvious to state to this
audience is that as much as possible, that we seek representative and
quantitative data to evaluate effectiveness and in some instances, we
may need to be satisfied with quantitative data that are not
representative.

Now in some instances such data are not available or simply impractical
to obtain and in those instances we certainly do consider and welcome
qualitative data as they may be appropriate, and in particular, again in
the areas of education and comprehension of risk communication, such
data may, in fact, be quite helpful and certainly more than we have now
conventionally.

One other consideration that we have broached in the Concept Paper is
the consideration that two complementary evaluation methods may, in
fact, be valuable for those key goals or objectives of a risk management
program. Our reason for making that consideration is, in fact, as we
know and I\'ll describe shortly, evaluation methods have limitations in
their application and the window that they give us to risk management
program effectiveness, using two mail outs, some complementary in
offsetting limitations of each.

In looking at evaluation methods we here articulate what are common
considerations, limitations and trade offs that are made with any
outcome measure, whether we\'re talking about risk management programs
or other systems. And these include the validity of the measurement, its
accuracy and the timeliness with which the data are available to
informed decision making. As I mentioned previously, representativeness
is obviously an ideal and we seek to minimize biases to the greatest
extent possible. But in addition to these largely technical and
methodologic concerns, we also acknowledge the considerations in doing
evaluation are the social burdens, including privacy of having such
evaluation methods as well as the costs of implementing them.

How can risk management program effectiveness be measured? Talking about
the outcome measures that can be used for tools, objectives or goals, we
hope with these to target some desired change or absolute level of one
or more patient health outcomes. This would be the ideal situation
where, in fact, the evaluation measurement were metric, is actually
capturing the outcome of interest rather than a surrogate of that
outcome.

However, we\'re not so fortunate always to be able to measure outcomes
directly or at all, and in many instances in efficacy, as well as in
safety we must be content with surrogate measures. If it is that case
that we have to rely on surrogates, it\'s important for those surrogates
to be well characterized as to the scientific or other basis that link
those surrogates to the primary health outcome of use. The stronger the
link, obviously, the better the metric.

But again, in the real world in which risk management programs exist and
in light of some of the power and other methodological limitations
alluded to this morning, we may have to content ourselves with process
measures that may indirectly measure whether or not the desired
behaviors that would support a risk management program are in place.

Similarly, if those behaviors themselves may be difficult to track, we
may have to look at indirect measures of behaviors, important behavioral
underpinnings of behavior such as comprehension, knowledge or attitudes
about the risk behaviors that we\'re trying to promote.

A few words about the evaluation systems that have been traditionally
employed. In looking at safety as well as some extent looking at the
evaluation of risk management interventions. We\'d like to note at this
point that the FDA does not consider, in general, that the spontaneous
adverse event reporting system is a reliable outcome measure for the
success or failure, if I might use those words, for a program. However,
emphasize we do not in any way wish to diminish the great importance of
those spontaneous adverse event reporting system for purposes of signal
detection and generation. However, because adverse event reporting is
influenced by a number of factors to varying degrees, we know that
changes in the numbers and rates of events reported to us may arise for
other reasons than, in fact, that the occurrence of the event itself is
changed.

So that we look at changes, a persistent signal may, in fact, represent
a concern or again, it may not, and similarly, we take little comfort
with the decline in the rate of a spontaneous adverse event after a risk
management program may be implemented.

Turning to administrative data systems which we touched upon in some of
the presentations earlier this morning, these offer a measure of
convenience and certainly a population basis for assessing
effectiveness, but it\'s important to recognize that the populations
that are captured in various administrative systems may not necessarily
represent the general population. These are largely individuals who may
have some form of health insurance and in fact, in looking at any data
resource, it\'s very important to consider those individuals who are not
present or who may be systematically excluded, since those, in fact, may
be reasons that place those individuals at higher risk for some of the
very events we\'re trying to avoid.

Lastly, I\'d like to mention the potential of survey instruments or
other active surveillance systems that may ask patients or health care
providers whether or not risk reduction efforts are, in fact, being
undertaken or whether they believe they\'re being effectively
implemented.

Such systems may offer a very useful source of information, but we must
acknowledge that there may be reporting biases from individuals when
asked if they\'re being compliant with desired behaviors and also
sampling errors where some individuals more sophisticated than I can
talk about the relative merits of different methods of recruiting
individuals and how that might influence the types of participants who
are giving you feedback.

There is additional discussion that I think you will enjoy tomorrow when
the good clinical pharmacovigilance and pharmacoepidemiologic practices
group discusses administrative data because many of the same limitations
that apply to those data systems for purposes of assessing adverse
events also relate to their ability to be used for tracking the
evaluation of performance of risk management programs.

Thank you.

DR. SELIGMAN: Thank you, Anne. Our next speaker, Dr. Claudia Karowski
will be talking about the elements of a risk management program
submission.

DR. KAROWSKI: Good afternoon. This final presentation of the Risk
Management Program Concept Paper largely incorporates information
already presented today. The focus of this presentation is on the
elements of a risk management program, what the FDA would like to see in
a submission and how this submission might be organized.

When a risk management program is being considered, the submission would
contain four major sections: the background section, which would
characterize the risk and the rationale for the approach. The submission
would contain a section which describes the targeted goals, the
objectives to meet those goals and the risk management program level.
The tool section would describe one or more proposed tools or
interventions and an evaluation section which would describe a plan for
evaluating component tools and the overall risk management program.
Finally, the submission would describe how the risk management program
will be reported to the FDA. These sections will be discussed in further
detail.

The background section would fully characterize all the risks to be
managed or minimized and the corresponding risk management program goals
for each identified risk. It would also address the rationale for why a
risk management program is being considered and created.

The background section would contain sufficient detail to address the
following sample questions pertaining to risk. What is the safety risk?
Who is at highest risk? Are there specific populations at risk such as
children or pregnant women? Are the risks predictable? Are the risks
preventable? And why is a program needed.

One section of the submission would be devoted to the goal, objectives
and levels section of the risk management program level. This section
would describe the risk management goals which as previously defined are
risk reduction endpoints or the desired endpoint of the risk management
program. And these goals should be targeted to the specific risk
concerns.

The section would also describe the objectives which are the
intermediate steps to achieve the risk management program goal.
Additionally, this section would address how the objectives and goals
are related or how the objectives will ultimately translate into
achievement of a risk reduction goal.

The FDA recommends that this section also describe and categorize the
overall risk management program into a level that reflects the severity,
frequency and the duration of the product\'s risk. This would include
the rationale for choosing that particular level over other levels and
conditions or outcomes that would prompt a change in level. For example,
if a sponsor proposes risk education and communication which is a Level
2 under the proposed classification scheme, the sponsor would address
the metric and the corresponding value of that metric that would prompt
progression to a Level 3 or higher.

Where applicable, the goals, objectives and level section would discuss
potential unintended consequences of the risk management program,
especially if there are therapeutic alternatives with similar risk
profiles. In such a situation, an extensive risk management program for
one product in a therapeutic class may unintentionally encourage the use
of equally risky products that do not have an effective risk management
program. Anticipating such situations will assist FDA in considering
whether similar products should have a risk management program.

Another unintended consequence is the possible illicit access of the
product via the internet or other outlets that circumvent the risk
management program, because the risk management program may be perceived
to be burdensome by practitioners or patients.

The tools section would identify the interventions or tools that would
be used as part of the risk management program. This section would
provide the rationale for choosing proposed tools to achieve the desired
objectives. It should also address the feasibility to implement the
tools based on any assessments done of stakeholder support, abilities,
or infrastructure.

The tools section would also indicate how the tool would be applied in
the risk management program. It would identify all stakeholders and who
would play a part in the application of the tools. And this section
would provide a description of how the tools fit into the overall risk
management program and its relation to other tools.

Finally, the tools section would include an implementation scheme that
would describe how and when each tool of the risk management program is
implemented and coordinated. Overall, timelines and milestones for risk
management program rollout would be specified.

The evaluation plan section addresses the success of tools in achieving
the overall objectives and goals. As such, the evaluation plan section
would describe the nature and timing of data collection and analyses to
be used to assess the performance of the tools. The data collection and
analytical plan will pre-specify the methods of evaluation as well as
validity and precision for measuring risk management program
effectiveness. Thus, the evaluation plan would discuss measurements for
sensitivity and specificity for the outcome, power and confidence
intervals, as well as potential measurement errors or biases.

The evaluation plan would also include a schedule for conducting
analyses and submitting reports to FDA. They would address the overall
success of the tools in achieving the risk management program goals and
objectives.

Progress reports based on the evaluation of the risk management program
should be submitted to the FDA. These reports are distinct from the risk
management program submission and could possibly be included in PSURs or
traditional periodic reports. These reports would address the tools\'
performance, address whether risk management program goals and
objectives were achieved and when possible would contain primary data
analyses and statistical estimation.

And finally, provide overall conclusions on the success of the risk
management program.

Thank you.

DR. SELIGMAN: Thank you very much. The moderator is going to use a
prerogative to move on to the next five registered speakers since they
have signed up to directly address and provide comment on the Concept
Paper related to the evaluation and elements. So I\'m going to go to the
first speaker, Dr. Gretchen Dieck from PhRMA.

DR. DIECK: It\'s a pleasure to be here today to provide PhRMA\'s
comments on Concept Paper II and my comments will be directed to the
afternoon section looking specifically at the evaluation of risk
management programs and recommended elements of the risk management
submission.

PhRMA agrees with the FDA that in certain circumstances a risk
management program or risk intervention strategies can be an effective
way of minimizing risks without \-- but we would urge it not take place
by reducing access or restricting access to the drugs whenever possible.

At this point, PhRMA would like to make the distinction between
theoretical risk and established risk. And this is not something that
we\'ve talked about earlier today. And this is where you have
theoretical risk, for instance, a drug that may have mild to moderate
increases in QT prolongation for which there have not been clinical
evidence of outcomes, negative outcomes. PhRMA believes that the next
risk management activity should be more risk assessment and that would
not move it into a risk management program or risk intervention
strategy.

However, for drugs where there\'s established risks, these could be
drugs that are being evaluated prior to approval or for issues that
emerge in the post-approval time period, that it would be appropriate
and some assistance to use risk management program or intervention
strategies to evaluate the drug. Acutane and birth defects is a good
example where here\'s a known risk in a very extensive risk management
program and risk intervention strategy is appropriate.

A concept that has been discussed over and over today is the concept of
overburdening the health care system and I would even expand that to
patients as well. PhRMA believes that risk intervention should be as
simple as possible and this is a concept that is the theme for some of
the comments earlier this morning. If you keep it simple, as simple as
possible, you have a greater likelihood for the intervention of the
program to succeed.

We do believe that health care providers, Pharmacists and patients can
be part of an effective risk management program, but the more elements
that you add to a risk intervention program, for instance, including
patient responsibility for recognizing science, symptoms or conditions,
asking the Pharmacists to get documentation from the physician that the
patient does not have a condition or has not taken or is being on
another drug and so forth, that increases or the likelihood that there
will be failures somewhere along that spectrum.

We do urge that in response to the issues that Tom raised this morning,
we do agree that Pharmacists play an important role in providing
important service regarding risk management or risk intervention and
with the question of, who pays ultimately the patient pays for that
service.

We agree with the concept of pretesting methods and evaluating metrics
and so forth. As an epidemiologist, I think that this is very important
and the more time you put up front in terms of evaluating your methods
and your measures, the greater the likelihood that what you\'re seeing
is what you really intended to measure.

But PhRMA believes that there\'s a great deal of time that it takes to
do this effectively and in the post-approval period where you have an
emergent safety issue that needs to be addressed quickly, you may not
have time to use a new method or to evaluate a new method and pretest it
sufficiently. I think that should be taken into consideration and this
type of extensive pretesting may be more effective for drugs prior to
approval that have an established risk that\'s been identified or for
drugs in the pre-approvals period. If it would be applied in the
post-approval period, it has to be understood if new methods are needed
that we need to have the time to pretest that method.

PhRMA also agrees with the limitations of spontaneous reporting and we
also agree that it\'s an important signal generation tool. But we do
agree with the comments that Anne made earlier that changes in reporting
rates may not be easily interpreted. And if you have a decrease in
reporting rate after a labeling change has occurred, it may be \-- it
may not be indicative that the risk has changed, the risk has
diminished, it may be simply there\'s a certain amount of awareness and
understanding and people simply are not motivated to report those
adverse events as a result. But I would add a different interpretation
although, the persistent signal on reporting rate or an increase in
reporting rate after a label change occurred, it may be due to media
attention or greater awareness on the physicians\' part and now they are
motivated to report those in for whatever reason.

And actually, in reality, I do want to add this. The current, in the
current environment, what the Agency is actually doing right now is they
will ask PhRMA companies after a labeling change has been made, they
will come back several months later and ask has your reporting rate
changed and some companies have been asked for risk management plans
based on the fact that the reporting rate has not changed. So I throw
that out as a suggestion that maybe if this is the FDA\'s opinion that
it be shared with others within the Agency.

We have questions regarding acceptable levels of impact. There\'s been a
lot of talk about risk minimization, but how and who decides what level
of risk minimization is acceptable? What is your minimization goal? Anne
spoke of certain behaviors that you can test or opinions and so forth,
but at what point what is our ultimate goal in terms of reducing the
absolute risk and how do we measure that and what are those
determinations? How do we set the threshold for these changes?

Related to this are the iterative aspects of risk management programs.
When a risk management program is needed, PhRMA agrees that periodic
evaluation is very important in terms of evaluating whether or not the
program is reaching goals that have been agreed to. And it may result in
some instances of escalation of a risk management program because what
was originally planned did not work, but conversely it may be decided
that what was put out there originally was too burdensome and you do
need to scale it back somehow. We need to discuss how we can discover
these measures and to enter into a dialogue with the Agency and have an
effective way of de-escalating a program, if you will.

We also feel that with respect to the elements of a risk management
program submission, we don\'t really have any comments to make on the
elements of the submission other than to ask for flexibility. It seems
to be very directive or prescriptive at this point in time and if you
really want \-- we have it in these discrete levels, but it\'s actually
a continuum of risk and a continuum of types of activities that would go
into a risk management program, depending on the drug and the safety
effect that\'s being looked at. And what we would ask is that there be
some sort of mix and match, if you will, with respect to the elements of
the risk management program and some of the very directive aspects could
be discussed with the Agency, again, dialogue here is key.

We also have some additional questions for the Agency as we did this
morning. And again, how will the evaluation of the risk program be
carried out? When we had the discussions early on with the Steering
Committee with respect to the PDUFA 3 and adding risk management in
earlier to the drug approval process and having it a continuum through
the drug\'s life cycle, what was key in those thoughts was dialogue at
very different aspects along the drug approval process and although it
has been mentioned verbally in the concept papers themselves, it seems
to be a one way communication and we would ask the Agency how they would
look toward adding the dialogue actually into the Concept Papers
themselves.

Finally, how will the FDA ensure that risk management programs are
consistently applied? And here I get back to Dr. Temple\'s example at
the end of the morning session with the drug Tikosyn or Dofetilide where
a risk management program that had a very restricted distribution aspect
to it was given to this drug that had relatively a similar safety and
efficacy program or profile as quinidines and Sotalol. And what happened
as a result of the restricted distribution program because certain
knowledge around dosing or initiating therapy was that the drug, the
restricted distribution program had barriers to physicians wanting to
prescribe the drug and as a result, patients were using other drugs that
had similar safety profiles or perhaps were safety profiles. So a
question that we have for you is how do we go and assure that drugs are
not unfairly singled out for risk management programs and that it\'s
applied appropriately.

Thank you.

DR. SELIGMAN: Thank you, Dr. Dieck. Our next presenter is Dr. Sidney
Kahn from Pharmacovigilance and Risk Management, Incorporated. And let
me encourage the speakers, we seem to be having a slight problem with
the volume with the microphones, so please stand close to the mike or
try to raise the volume of your voice. Thank you.

DR. KAHN: Good afternoon and as I said yesterday thank you very much for
the opportunity to present here and my other general comment before
commencing is that as I said yesterday, I think the FDA is to be highly
commended for taking a proactive and forward thinking approach to these
new ideas and to involving a broad range of stakeholders in getting
input to make them as effective as they can possibly be.

Obviously, the ultimate goal of any program has to be, as we said
yesterday, to reach the ultimate goal of ensuring that the efforts in
the costs expended are expended in effective processes that serve to
maximize the benefit-risk balance. And I believe that needs to be the
over-arching principle that we follow throughout.

In that spirit, I\'m going to run through some comment of some of the
paper\'s points and of course, many of these have already been covered
by several of the previous speakers earlier today and in fact, just in
the last few minutes.

DR. SELIGMAN: Excuse me, Dr. Kahn. Do we have the right presentation on
the screen in front of us? We do? Okay.

DR. KAHN: Those are purely introductory and unscripted comments.

(Laughter.)

My first slide \-- I believe there\'s one part of risk management
planning and programs that this current concept document does not really
address adequately and yet that is very well described in the 1999
reports of the Task Force on Risk Management which is the role of
therapeutic use using the ICH terminology or Phase IV study program to
help characterize risk of the consumable products. We all understand
that once a major product is launched that most manufacturers will, in
fact, conduct pretty extensive studies of that product in its clinical
use to ensure a number of things including crass commercial purposes,
the fact that it helps prescribers to get a familiarity with that
product and hopefully they\'ll use it appropriately for their patients.

However, there are, in fact, things that could be done to improve the
usefulness of therapeutic use studies. Currently, these are very
fragmented. They\'re often done by external organizations like CROs. The
data bases are inconsistent and the data are very rarely, if ever,
brought together, integrated or looked at as a whole which is a great
pity because for the most part these studies are conducted in the
efficacy population. Now the population for which the FDA believes the
drug is safe and effective, and therefore the optimal evaluation of that
information would be of benefit. And in fact, you can think along these
lines of therapeutic use studies being comparable in some ways to the
proposed large simple safety studies widely in the pre-marketing risk
assessment Concept Paper yesterday.

Because manufacturers are already doing this, the assessment and
reporting of those trials should not pose much of an additional burden
and with implementation of relatively simple and nonburdensome measures
it should be possible to be integrated and evaluated. And as a result,
the information so gathered could allow the \-- which really have to be
considered in many cases even in this larger population treated in real
life, with real concomitant medications and co-morbidities, but you may
still be able to detect the signals that you haven\'t seen before and
use them as the basis for other approaches including targeted
pharmacoepidemiology studies and where appropriate active surveillance
program.

I want to make a couple more comments on

\-- am I in the right place here? I seem to be missing a slide in my
notes.

Sorry. This is tomorrow\'s presentation.

(Laughter.)

DR. SELIGMAN: We will get to the right presentation here in a second.

DR. KAHN: My apologies, I do apologize for that. I was getting carried
away here. We\'ll come back to Phase IV programs tomorrow.

Okay, risk management, as has been said repeatedly, involves the entire
health care delivery system and patients cannot be excluded. So they
have to be involved and they have to be informed. The key caveat that I
see here is that because risk is intrinsic to many aspects of the whole
health care delivery system, there is a contention that if you only have
a hammer you see everything as a nail and FDA should not fall into that
pitfall, that trap of trying to fix deficiencies in other parts of the
system by imposing really unwarranted burdens over that part of the
system over which it itself has control. I just put that up there as a
kind of general caveat.

I have a proposal that comes back to labeling which we\'ve talked about
a number of times and this is something that I would like to throw out
for discussion and would be interested in hearing people\'s views on
this. In my humble opinion for the majority of products, the most
critical information that a prescriber needs before deciding to give
this to a patient is which patients should not get that medication. By
the time a prescriber looks at the prescribing information for a
product, the PDR, Hippocrates, Mobile PDR or whatever, he or she already
has an idea in their mind of what they want to use that product for. So
I don\'t think it\'s normal for physicians on average to look at a
products\' indication in detail using the prescribing information. What
they\'re looking for is dosing and they\'re looking for, sometimes
they\'re looking for cost, but I think they ought to see as pretty much
the first thing under the label heading of the name of the product is
any contraindications that have been established for that product. You
should not give this product to people with impaired renal function. You
should not give this product in conjunction with inhibitors of cytokine
P4503A4 and so on. That to me would be the most important risk
management tool that the labeling can provide because it can also show
up in all the \-- every time the prescriber opened up the label and also
would be updated and would be seen as not having to search through the
label. So although FDA currently has labeling regulations proposed out
there and that this is not part of it, I would still strongly urge the
Agency to consider this as an option going forward.

Another innovation and this is not quite so much of an innovation as the
former would be for companies from cytokine manufacturers to change some
of their emphasis of promotion. Obviously, it does no one any good,
certainly not the patients and certainly not the Pharmaceutical
companies if patients get inappropriate treatment. That\'s not what any
of us is here for. And it\'s clear that the sales force that companies
have are extremely knowledgeable in the products. They\'re well-trained
or they should be and they are well uniquely placed to inform educated
physicians on how to use their company\'s products optimally.

So I believe that the pharmaceutical companies have an obligation for
public health protection to have their sales forces emphasize to
physicians the contraindications of warnings, as I said earlier, what
patients should not take the products or what particular precautions
need to be taken in certain patient sub-populations. And that there\'s a
culture change that has to take place in some ways here because company
salespersons are currently remunerated based on how many prescriptions
get written. Well, they should actually be given awards for how many
inappropriate prescriptions are not written. I don\'t know how you do
that, but then I don\'t know how we do a lot of other things in business
management program either. I also would consider the companies to apply
their considerable marketing ingenuity to the construction of such a
scenario. And as a matter of interest, some of us are aware that in
Japan about 18 months ago a newly mandated program was instituted that
required sales representatives of companies marketing new products to
pay monthly visits to physicians for six months to educate them
primarily on the safety aspects of those new products. It\'s not yet
clear how well that system is working or will work and we\'ll find out
in due course as results of that intervention become available.

I want to make a note on clarifying status of Section 2(c), what is risk
management planning. Currently, the wording of the section says FDA\'s
proposing the sponsor of every product submitted for approval should
consider how to minimize risks from the product\'s use. In fact,
there\'s a misimplication here. The implication is that this is not
being done currently, when in fact, that is really what the entire drug
development process that we have in place today is aimed at doing, at
least at the first cut of the initial approval, so I think it\'s
misleading to suggest that this is something that\'s not being done.
Rather what we have to do is decide how we can take the current process
and improve it so that we can optimize that benefit-risk balance for
patients.

Turning to risk management program outcome measures the FDA proposes
that pragmatic specific and measurable program objectives of resulting
processes or behaviors leading to risk management plan goals being
achieved, clearly this is essential. You have to be able to assess the
outcome of what you\'re doing or you have no idea whether it has any
effect. But the difficulty I foresee and I\'d really like to hear some
feedback from the Agency, in particular, on this is, where does this
information come from? If you go to, for example, the CERTS, they\'re a
very defined subset of the population and probably not at all
representative of the broad slough of clinical practice, so the results
that you get from such a plan in the CERT may not necessarily be
applicable across the board.

Are there sources of data like HMO databases. We have problems with
HIPAA which are going to becoming increasingly difficult as time goes on
and the fact that they are not necessarily always completely current
which is particularly problematic if you have a newly implemented risk
management plan for a product that doesn\'t have a large number of
exposures because it\'s going to take you a very, very long time to
collect enough data to determine whether the plan you propose is
actually being effective or not.

For an example, one of the examples given is the goal that no patient
with Condition A will receive Product B. Well, that\'s a laudable goal,
but is it realistic? I believe that for such a goal, not only do you
have to define the goal, but you have to define the metric, but you also
have to define a level of acceptable response because it is
inconceivable for any human activity to have a 100 percent compliance
with every plan at all times. We can\'t \-- I don\'t think there\'s any
human activity that would lend itself to this. Therefore, we have to be
in a position where we can establish acceptable and achievable
compliance levels for each program which will again be conditioned
obviously by the nature of the risk and whether there are backup
measures available in the case of system failure and the example I\'ve
given is the possibility of pregnancy termination after inadvertent
exposure to a teratogen such as Accutane.

The concept of risk management compliance for most products, I strongly
support the position that the package insert is the only risk management
program needed for most products, but would like to also add that
specifically for novel molecular entities that this be coupled with an
educational focus by the companies\' sales forces which I think should
for brand new entities should probably be considered Level 1, not Level
2. I would like to see that considered as an option because I think that
would have a lot of benefit.

And it\'s worth noting that because as I stated yesterday, the
benefit-risk balance based on labeling alone is currently acceptable for
at least 97 percent of products based on the number of drug withdrawals
over the last 15-20 years and I would go back here and say that my prior
proposal on the change in the label format to put the contraindications
of warnings right below the name of the product may actually be able to
increase that a little bit more and that remains to be determined as
does the validity of many of the other labeling proposals which have
been made.

I would like to address a few caveats here though, most of which have
been addressed previously. The likely impact on the overall health care
system does have to be considered and that includes the fact that care
provision may become fragmented if patients have to go to specific
physicians and specific pharmacies to get particular products. It is
also \-- it\'s not cost neutral and the risk, as was mentioned earlier,
raising barriers to receiving the appropriate care if additional hurdles
are placed in the way of getting effective medications.

Systematically, if you have large numbers of products with specific
customized risk management plans, this will add complexity, cost and
burden to personnel and systems in the health care delivery system and
with consequent increased potential for error and failure to produce the
desired outcome as a law of unintended consequences which I think we
have to really be very careful to avoid. Thus, for maximal
effectiveness, risk management plans, as has been said repeatedly, must
be highly selective, must be focused, targeted, limited in number.

I think what\'s very important and hasn\'t been mentioned so far is that
all users have to see them as being essential, that the benefit of the
risk management plan is appreciated by all and it\'s not seen purely as
a burden or another hurdle to be overcome and finally, of course, it
would have to be demonstrably effective at a cost acceptable to whoever
is going to pay for it.

I am treading on dangerous ground here because I am not a pharmacist and
I don\'t speak for any pharmacists, but I believe that Pharmacists are
very well placed to monitor and ensure the correct use of the majority
of medicinal products, certainly those that are dispensed in the
out-patient setting.

Pharmacists are almost certainly professionally under used in many cases
because of many issues. There\'s a shortage of Pharmacists at the
moment, which means that many are working long hours and are filling
prescriptions and that\'s all they do. They don\'t have time to do
additional activities in many situations, especially from what I\'ve
seen in the commercial pharmacies. They need an incentive. We\'ve heard
about that, that Pharmacists don\'t get paid anything to do this. In
fact, if a Pharmacist does not fill a prescription because of some
misinformation, the Pharmacist is likely to get nothing because they
only get paid for filling prescriptions in most cases. So there needs to
be an incentive.

There needs to be some change in the geometry. The pharmacies I go to
have no place where a Pharmacist can sit down and talk to a patient in
private and we clearly can\'t have people discussing sensitive medical
information in open, public spaces. That would be totally inappropriate.

And finally, I\'m not going to go into the issue of burdens like such a
sticker program which have been addressed elsewhere much better than I
can do it.

I have two more slides. The question that was posed in the Concept Paper
on evaluation of trade- offs of risk management programs, obviously one
evaluation method will not suffice for every program and multiple
evaluation methods will be needed to assess effectiveness.

Additional requirements though for evaluation, I think we need to set up
before we go forward too far, some uniform criteria for determining
which products actually do require a formal management program over and
above Level 1. If so, what is the appropriate level of the risk
management plan which will be driven by the balance of assessed benefits
and risk of the product? The criteria for determining metrics of
effectiveness measurement and as I mentioned earlier, we need some
criterion for deciding what level of compliance with that plan is
required and acceptable. And there are certainly guidelines and
mechanisms such as risk management advisory committee that could ensure
consistency of approach to these types of activity across all the FDA
divisions so we do not end up with disparate approaches by different
parts of the Agency.

My final slide addresses the point that Dr. Dieck made very eloquently
which talks about what I see as the potential downside of an injudicious
use of risk management plans which is that of unintended therapeutic
substitution. If your risk management plan drives prescribers and
patients away from the use a drug, particularly if it\'s a newer drug
with a better safety profile than an old established product which
doesn\'t have a risk management plan, think of theophylline, think of
warfarin, new products may have risks that are substantially lower than
that, but under the current climate of approval would require a risk
management plan when, in fact, they are substantially safer than the
older products they may eventually replace, but there would be perverse
incentives to use the older products rather than the newer ones, based
not only misperception of risk, but also on cost because these are not
costly interventions. So that has to be taken into account as well.

And if possible, if comparative safety data are available for a newer
versus older product which is always very difficult, then there should
be some mechanism for informing prescribers that the newer product may
be preferable to an older one, but despite or maybe even because the
newer product has a risk management plan attached to it.

That concludes my comments. Thank you very much.

DR. SELIGMAN: Thank you, Dr. Kahn. The next speaker is Dr. Gerald Faich
who is from the Pharmaceutical Safety Assessments.

Dr. Faich.

DR. FAICH: I am Gerry Faich. I\'d like to thank FDA for the opportunity
to address this audience. Is the slide up?

I speak to you coming from a background of FDA, as well as having held a
senior position in a large contract research company, as well as someone
who has consulted with a large number of Pharmaceutical companies and
others around safety issues.

And on the other hand, the views I present are entirely my own. The
first thing I\'d like to say and I\'d like to say clearly is I believe
the Risk Management Concept Paper probably can be seen and is seen by me
as the single most important safety initiative that FDA has undertaken
for many years. I applaud the Agency for the effort. I think it has
tremendous potential. I found the Concept Paper to be concise and well
written, maybe a few too many Ps, however.

(Laughter.)

I particularly found that the pre-test and evaluation sections were
excellent and I\'d also like to say that I support the International
Society of pharmacoepidemiology comments that were made this morning.

My concerns, in fact, are carrying these concepts or translating them
into actual practice. I think the process of doing so has a number of
implications and raises a number of concerns. Those concerns, I believe,
relate to three areas. The first area is what will be the FDA processes
including communications to sponsors and what are the timing implication
issues involved with that?

The second area is what about labeling and educational research and the
third area is what are the consequences of restricted marketing?

So let me go through each of those three. The first one, what about FDA
processes? I urge FDA to make every effort to coordinate between offices
and across divisions because I have seen that differing application of
general concepts across reviewing divisions has caused enormous
confusion and a lot of wasted effort along the way. And I fully
recognize that this is not an easy proposition, that reviewing divisions
differ, one to the other in terms of both their philosophies and the
nature of the data they review, that offices differ in terms of their
expertise in epidemiology, statistics and clinical sciences, but
nonetheless, again, I urge that every effort be made to attempt to make
this as uniform as possible, at least at the principal level.

The second issue is that if each application is going to be looked at
for the question of is a risk management program indicated, then the
earlier the better that such a concern be signaled to sponsors. I don\'t
believe for a minute, based on my background, that sponsors are likely
to be as

proactive around some of these issues as one might want them to be and
that they more often than not, in fact, will look to FDA to signal to
them that there\'s a need for something more to happen and this is
merely a plea for doing that as early as possible in the NDA review
process, allowing time for the called for pretesting and allowing time
for dialogue between sponsors and FDA.

I certainly think already I have found that there\'s confusion in the
regulated industry around what\'s new about risk management. Is it, in
fact, our different form of write up of the integrated safety summary
and of course, I believe this concept paper goes a long way for pointing
out that it\'s much more than that, but I\'ve had the experience already
of encountering considerable confusion, if not resistance around that
issue.

The Concept Paper suggests that there are, as you all know, four levels
of risk programs. Improve the labeling, I would call labeling impact,
Level 1; Level 2, go beyond the labeling with education, MedGuide and
the like. Level 3, restrict prescribing, dispensing and distribution
through guidance and Level 4 is to document such guidance at Level 3
level and add further restrictions if you will.

With that in mind, let me talk about Level 1. We\'ve heard a lot about
concern about labels. It seems to me that the Level 1 requirement aims
to improve the impact of information already in the label and I\'m well
aware that FDA has worked on a labeling proposal. I\'m simply here to
say that I think that the goal here ought to be improve the design
overall of labels and the content and we have to ask ourselves what do
we really know about how to write an effective label? What do we know
about cognition research, comprehension research? What do we do today
about evaluating each label before it\'s put in place? Do we, in fact,
survey knowledge, attitude and practices after a label is in place and
of course, the answer, in general, is no. It seems to me that this Level
1 concept opens up the door to very necessary research. This is just one
example of that for us to be reminded that there is a body of science
out there that speaks to cognition research for labeling. It\'s largely
been used for OTC labels. I took this from Ruth Day\'s presentation at
the FDA Arthritis Advisory Committee last month and I would urge people
to look through those and other literature available about cognition
studies for labeling.

It\'s perfectly clear, this is \-- Bob will like this. It says \"prove
all things.\" It\'s perfectly clear that we need to think about
validating the utility of risk interventions that are in the label. Bob
mentioned cholesterol lowering and measuring cholesterol levels. One
could point to the issues of liver enzyme monitoring. Does it make us
feel better or does it make the patient feel better? Does liver enzyme
monitoring really prevent liver failure as opposed to reversible more
mild forms of liver disease. And what level of labeling compliance are
we going to hold the sponsor to or should we expect, is it 100 percent
compliance? Is it 50 percent compliance? Is it just compliance with
baseline and then as needed monitoring, despite what the label says? I
think those are areas we need to think about.

Once again, there is literature, by the way, and I salute Drs. Campbell
and Cahill in a workshop that they put on for the CERTS, looking at
label communication. It actually appears in this month\'s
[Pharmacoepidemiology and Drug Safety]{.underline} and I would urge
those interested to take a look at that.

Another example is an article published by Dan Fife and Alex Walker and
others that looked at a dear doctor letter issue involving Cisapride.
They examined, they used data in an automated data base and they
basically found that after a single highly targeted letter, there was a
decline in the prescribed use of concomitant medications with Cisapride
and their conclusion was that explicit, well publicized drug warnings
can change prescribing behavior.

Now I only point this out to say that I think that we should all be in
the mode of evaluating this enterprise because there\'s much to be
learned.

When we talk about levels 2, 3 and 4, again, I\'ve had the experience
even at this early stage of talking to people and I think the message
hasn\'t gotten out there. A Level 2, 3 or 4 is an intervention that goes
beyond the package insert. It is an activity that is targeted and will
include something that is more than mere education, shall we say.

One has to identify the targeted risk and the targeted program. If
that\'s true, the same issues are involved here as I was talking about
raising with labeling issues and that is how do we communicate at Level
2, effectively and efficiently? What will be done to test the
intervention, both pre-approval and in pilot testing and how will it be
modified afterwards? Again, I\'m not saying \-- I\'m not raising these
as barriers. I applaud this whole enterprise, but I think there\'s much
to be learned and we should go at it with the sense that this is going
to be a learning proposition.

An example of that is an article by McDonald in [JAMA]{.underline}
recently, last year, where he looked at all the randomized trials that
were done to examine the impact of a variety of interventions on
improving patient compliance and the final result of that meta analysis
of these trials was this following quote: \"curt methods of improving
medication adherence for chronic health problems are complex, labor
intensive and not particularly effective.\" That\'s a devastating
statement, it seems to me, and again, we need to be mindful of it and
not delude ourselves into thinking that the process is the outcome.

There is similar literature, by the way, that has looked at the impact
on physicians of clinical guidelines and that literature points out that
the thing that blocks the acceptance and use of clinical guidelines is
the lack of awareness, a lack of familiarity, disagreement with the
recommendation that\'s being made, disbelief that the outcome will
really occur and inertia and experience in previous practice and then
finally, external factors, the ones we\'ve been talking about,
inconvenience, time consumption and cost.

Larry Green, many years ago, at Yale, talked about a preventive behavior
model which basically says you pursue or undertake preventive behaviors,
perceive them to be in your interest and when the cost is not unduly
high and I think again, that literature should be \-- we should be
mindful of that literature.

At the Level 3 and 4 and I\'m repeating here and I apologize. I believe
these should be applied quite judiciously. There\'s no doubt that any
Level 3 or Level 4 intervention will, in fact, limit use. And may limit
use well beyond the group that we\'re trying to limit the use for. They
are likely to be effective, but if the barriers are such that accepting
them will shift prescribing to other products, that creates another
problem as you\'ve heard.

One of the programs that\'s in the field that hasn\'t been mentioned
today, I don\'t believe, is the Lotronex experience. You\'ll recall that
Lotronex is a Glaxo drug for irritable bowel syndrome and was withdrawn
in November of 2002 because of a rash, if you will, of bowel necrosis
and severe constipation resulting in hospitalizations. It was
re-marketed in January of this year with a risk management plan. That
plan is targeted to assuring the use in women with diarrheal dominant
disease and to detecting early warning signals so that the drug can be
stopped. It has a number of components. The only reason I show it here
is because here we are in April and I think by May or June it would be
nice to know how this program is doing because we all have something to
learn from it.

You\'ve heard Dofetilide mentioned before, a drug for atrial
fibrillation, that prolongs QT interval. It has to be dosed carefully.
Dosing is titrated to QT prolongation and adjusted for renal status. It
has to be initiated in the hospital and the risk management program for
it called for registering the hospital, the patient, the doctor and the
Pharmacist. The consequence of that fairly stringent registration
program is the drug has had very little use at all. Gretchen Dieck
mentioned this before and one has to ask whether that\'s good or bad.

So let me conclude with a couple of statements. One, once again I
applaud the concepts. I look forward to seeing these further developed
and applied. I believe that early communication between FDA and sponsors
is going to be critical if this is going to work. I urge that FDA think
about how to achieve better coordination within the Agency and I urge
that testing in a research mentality be held as interventions are
developed, so that we might know what works and what doesn\'t work.

Thank you.

DR. SELIGMAN: Our next speaker is Dr. Robert Nelson from RCN Associates.

DR. NELSON: I want to thank the FDA for allowing me to make comments on
this series of Concept Papers. I\'d like to also echo a number of
previous speakers. I think they\'re really good and I think they\'re
really in the right direction and I\'m really excited about the fact
that drug safety is once again a high priority.

For the record, a little bit about my background. I\'m a retired public
health service officer. I spent 23 years in the Commission Corps, 20 of
which was at the Food and Drug Administration. I\'m not a consultant in
drug safety since I retired in 1998.

But while I\'m excited about this drug safety era, I, like only Dr.
Temple amongst the current people here, go back quite a bit with the
Agency and we\'ve seen drug safety become high priority three, four,
five, six times in the last 20 years and then each time it\'s dropped
off and taken a back seat again.

I hope that that will not be the case this time. And it caused me to do
some thinking as to why it\'s occurred in the past. So I\'d like to
begin my talk today, I guess, two things to possibly raise some issues
that may prevent the fall of the drug safety initiative again and maybe
to open some controversy.

When I looked at the major barriers to the characterization of drug
safety profiles for drugs, this is what I came up with. FDA\'s
priorities, since the 1962 amendments, while it was originally and I
don\'t know how many people realize that the first organization of the
FDA drug environment after those amendments were really to a bureau of
new drugs and a bureau of old drugs with the old drugs supposed to be
focused on everything we\'re talking about today.

But I don\'t actually go back that far. But the priority has been on the
new drug and rightfully so, given the limited resources the Agency has
had over the years and hopefully, we\'re seeing a shift with equal
priorities between pre-marketing and post-marketing. So I see that as an
encouraging sign. In the past, that wasn\'t the case at all.

The second one is tort liability. And by this I\'ve seen over the years
about companies afraid to find out the safety issues related to the
drugs because of liability issues. But I also think that has shifted. I
think as a result of the Fen-Phen decisions, the concept of duty to one
has been redefined, so that the idea that the company is responsible for
assessing their data and submitting it to the Agency if the information
level is now the precedent. And I think that will change the way and it
is changing the way many of the companies respond to drug safety issues.
So I think those are two very positive changes that have occurred.

Now let me get to the next three that still need, I think, to be looked
at. The third one is marketing freedom. Companies, especially since the
direct to consumer advertising which has changed the whole dynamics of
the marketplace out there, companies don\'t want to be held back by
safety data. They want to be able to market their drug freely, so they
only see and as anybody from industry knows, the marketing department is
the department with the resources and the power in the companies. So
they don\'t want to be held back by this stuff called safety data. So I
think that is a blanket on moving forward with risk management.

Now interestingly, the next one is FDA\'s own restrictions on marketing.
I\'ll get a little bit into this as I go on because there are actual
interpretations of regulations that the Agency applies as to what kind
of safety claims could be made on labeling and comparative safety claims
and I\'ll go into that further because I think that could be modified.

And then lastly and it will be one of the main focuses of the talk will
be the lack of dedicated data sources for health outcomes and adverse
reaction data. That\'s an issue of supply and demand I think. Nobody has
gone out and supplied it, whether that be the pharmacy group or whether
that be the IMS or some other big company because the demand hasn\'t
been there. So maybe there could be something that switches the demand
to put these market forces into play.

As you all know, this risk management strategy requires that things be
measured at baseline quantitatively, interventions be put into place and
then the impact of those interventions be measured quantitatively. The
problem is \-- and so metrics are the key to a success here. The problem
is this quantitative data are required on health outcomes, but they
really don\'t exist and neither spontaneous data which are qualitative
or record linkage which are semi-quantitative at best, can accurately
measure change.

So I think the quality and type of current post-marketing safety data is
the Achilles heel in the whole post-marketing plan and strategy that the
Agency\'s putting out and it\'s something that certainly needs to be
addressed.

This little diagram is a conceptual diagram, of course, that\'s very
obvious to anybody in this field. I don\'t have a pointer, so I\'ll just
walk it through. On the top, of course, we have the general population
with disease X. On the left is what you normally find in the clinical
trials environment. You take a sample of that population, you try to get
it as homogeneous as possible for internal validity considerations, you
do your studies, you collect your safety data and you have a very good
comparator group and you\'re able to put your ISS together with rates.

However, in the clinical practice environment, we never get there. And
what we really need to do is to be able to sample that clinical practice
environment, so that we can get the same types of indexes of safety in
the post-marketing phase. And again, I think the emphasis needs to be
less on identifying risk than profiling the safety of the drug. That
includes getting rates on known reactions that are also important.
Because if we\'re going to get to labeling and have labeling actually
mean something to the prescriber, it needs to have rates of not only the
really unusual stuff, but also the known reaction, but those rates need
to not come from the clinical trials that could be two, three, four,
five years old, but what occurs in various clinical practice
environments.

This is hard to get, but I think this is where we need to begin to think
about it. So I think this is just a reiteration of the kinds of things
that I was just saying about what\'s required in labeling. What we have
available now is really just qualitative data and the data from the
clinical trials. We need to get better quantitative data on serious
common and the less serious, as well as the very common reactions, as
well as risk factors, drug-drug interactions, etceteras. That\'s in
addition to the qualitative data on the very serious and rare kinds of
things that would come out of this spontaneous reporting system.

Now interestingly, there are two standards of evidence in the Food, Drug
and Cosmetic Act. There\'s the one that anybody that does a clinical
trial is aware of which is the substantial evidence criteria of two
adequate, well-controlled studies, etceteras. But there\'s also a second
standard in there called the substantial clinical experience standard.
That was the standard that was intended to be applied to the
post-marketing environment. For things like comparative safety in labels
and also for collection of safety data and labels, but I don\'t see why
it couldn\'t also be used for some of the discussion items on new
efficacy terms that were discussed this morning when drugs are no longer
used, whether they were approved like the anti-retrovirals for
monotherapy and now are used as cocktails, whether this kind of
substantial clinical experience standard couldn\'t be used to assess the
current medical practice an annotate those labels.

So I think that\'s something that needs to be explored by the Agency and
I\'m glad to see there are a number of policy people here today and I
challenge them to go back and to look at this and see how it could be
applied to do some of the things that really need to be done to make
these labels as informative as possible, not only in the benefits of the
drug as they\'re currently being used in clinical practice, but to
characterize the safety profile, not just finding the risk and sticking
them on there in a qualitative fashion. That doesn\'t convey much
information to a practitioner and we all know that.

So some of the facts, as I see them, they\'re my facts, is of course
risk management strategies and I prefer strategies, of course, over
plans, requires quantitative data on health outcomes. Labeling claims
also for relative safety, one drug versus the other, if we\'re going to
put it in the label require quantitative data. Informative safety data
in labeling from clinical practice also requires quantitative data, so
there\'s a lot of reasons to be going and looking for this kind of data.

And I believe only through this kind of data on the labels and
subsequent documents can rational drug therapy be promoted. The problem
is quantitative data are expensive and \-- well, this is redundant of
what I\'ve said \-- so what I propose is that we merge some of the
goals. If we\'re trying to promote public health by assessing the safety
profiles of the drug and managing new risk, we should also be moving
towards accurate marketing and accurate labeling and I think that all
can be done if we can characterize the safety profile of Pharmaceuticals
from the clinical practice environments. And I think that if we can do
that and we can have the Agency apply the clinical, substantial clinical
evidence criteria to those quantitative data, we could possibly meet all
three goals.

So this is a little different than we thought in the past, but I
encourage the Agency to give it a little bit of thought and maybe a lot
of thought if we\'re lucky.

Now specific to some of the questions that you had on this section, so
I\'ll spend the next few minutes on the next four slides addressing
those questions to give you my opinions which I think are quite
different than some of the other speakers we\'ve heard this morning.
What should prompt a risk management program for a new drug?

I actually think that the program should be consistent with the
administrative law in FDAMA as well as the PDUFA 3 goals that I saw, and
routinely applied to the following product categories: Routinely apply,
unless the companies can show that it\'s not necessary, all potential
block busters, given that their potential for huge exposure in the
population is so great.

Any product that will be planning to use direct to consumer advertising
in the first three years, again, for the same reason. If within six
months or a year after a market launch millions of people are exposed to
the drug, even a toxicity as rare as 1 in 10,000 can affect quite a
number of people in a very short period of time.

Any cosmetic or lifestyle product. All drugs with a residual concern
from the clinical trials.

And, any drugs that have safety problems that were previously identified
from marketed drugs in a pharmacologic class. And again, this is for
risk management programs above Level 1 as routine.

Regarding selection and development of risk management tools, first, of
course, you have to define the goals. And if it is just to find new and
unusual rare adverse reactions that\'s one set of plans. If it\'s to
quantitate the known reactions that you\'ve see in clinical trials, as
well as the above, you\'ve got a different strategy. And I think that\'s
really where you need to go. I think the amount of information that will
be conveyed to clinicians when they\'re prescribing, if they know what
the rates of known reactions are in clinical practice environments, I
think it\'s a lot more than they have in the current kinds of labeling
and of course, I really applaud the new format regulations for labeling
and I\'m glad to hear they\'re moving forward. But what I want to
address in this talk is the content because I think that\'s the weakest
part. And only when you have quantitative data can you really have
information and maximize rational drug therapy.

As far as evaluation, again, it sounds like a broken record, unless you
have some quantitative data on these outcomes, you don\'t have true
metrics. You need to dedicate a drug safety data base. There are some in
the U.K., for example, you know such as GPRD and the South Hampton
Research Group, but there\'s never been any dedicated drug safety data
bases put in place in the United States. Ironically, a company like IMS
can tell you exactly who prescribes what, when, how and so on, but
nobody has gone out to create a sampling scheme to assess the outcomes
as a result of those prescribing patterns.

We certainly cannot use for evaluation medical records or administrative
data for many reasons. One is they use proxy variables of ICD-9 codes
which are not adverse reactions, so it makes it very difficult to handle
that, since they\'re not specific and there\'s all kinds of
misclassification that goes on there, so small risks cannot be found
even if they\'re important. And if you\'re looking to reduce the risk by
half, you\'re not going to ever see anything in these kinds of data
bases, and certainly not qualitative data bases like spontaneous
reports.

Lastly, recommended elements of risk management program. I was
encouraged to see by some of the stated goals in PDUFA that there would
be a submission on a new product plan at the early NDA meetings. I think
that is very important because I think these plans do need to be
developed as early as possible, constantly modified as new information
develops and then performed rigorously, consistent again with the FDAMA
and PDUFA 3 guidelines.

I also believe, strongly, that new drug development is a continuum that
does not end at the time a drug hits the market and the rigor that takes
place post-marketing should be the same as the rigor that existed
pre-marketing. And I think the PSUR needs to be considered conceptually,
at least, if not identical in format to a continual integrated safety
summary that follows that continuum all the way past marketing.

The electronic common technical document calls for an annotated label. I
hope we can also keep that annotated label concept going forward in
time, linked to the PSUR.

All submissions for epidemiological research need to be as well
documented as any clinical trial and the ISPE guidelines go a long way
to addressing that, but I think they also need to be updated. And this a
second policy question for FDA. If people do submit record linkage or
administrative epidemiological studies using those types of data sources
what\'s the status of that with the Part 11 compliance issues, if
they\'re going to be submitted for regulatory considerations, my
understanding is that they also need to be Part 11 compliant. I\'m not
sure very many of them are.

With that, I\'ll close and thank you again very much.

DR. SELIGMAN: Thank you. The final speaker is Marilyn Dix Smith from the
International Society for Pharmacoeconomic and Outcomes Research.
Following her presentation, we\'ll be taking a break.

DR. SMITH: The International Society for Pharmacoeconomics and Outcomes
Research is a nonprofit organization founded in 1995. We have over 2,000
outcomes researchers and users of outcomes research information from
over 60 countries in the world.

I am presenting this presentation today on behalf of the ISPOR Risk
Management Special Interest Group. Actually, we are kind of an eclectic
group of researchers and users of outcomes research information
encompassing quality of life researchers, as well as
pharmacoepidemiologists as well as health economists, physicians and
pharmacists who are on PNT committees, trying to make health care
decisions and with that we have a multitude of special interest groups
including managed care, quality of life, medication compliance, risk
management, clinical practice and health technology assessment.

A little more about our organization. We\'re about divided equally in
its membership from where people work from the industry so we have both
sponsors of drugs as well as those who are doing the research coming
from research organizations, as well as academia, as well as government,
and clinical practice. So we\'re trying to bring together all of the
stakeholders in looking at outcomes research and looking at the research
that actually is being applied.

The mission of the organization is to translate outcomes research into
practice to ensure that society allocates scarce health care resources
safely, fairly and efficiently.

The vision is to combine these methodological issues as well as the
applied issues on how you translate this assessment of health care
services into practice and make sure that the practice side has
something to say about what methods should be used and that\'s part of
what our organization is about.

The core of our organization has been key academicians who are helping
us develop modeling guidelines, good research practice on prospective
studies, as well as retrospective database studies, as well as quality
of life, now patient report outcome studies. And overall reaching on
this is assuring that these methodological issues and methodological
guidelines are really approaching the real health care issues that are
addressing us today as well as developing a code of ethics.

And now with this, I will continue with ISPOR\'s FDA Concept Paper
issues to consider. FDA represents a coherent and well thought through
Concept Paper. It emphasizes having a clear rationale for developing
risk management plans, pre-testing communications and evaluating
interventions with a mind toward continuous quality improvement.

There are several issues that FDA should consider in its evaluation and
of its plans. As we have worked with the FDA on such issues as health
related quality of life and patient reported outcomes, as well as
economic evaluation, ISPOR members stand ready to help provide research
support for FDA\'s continuing evaluation of its plans and concepts.
Because we are an organization of practicing health system Pharmacists
as well as physicians as well as researchers, we feel we have most of
the stakeholders gathered together in our organization.

FDA\'s definition of risk management provides a life cycle view of
minimizing risk. However, by FDA\'s definition, maximization of benefit
may also help improve safety. FDA should now explore how health
improvements may increase safety.

I think this has been mentioned previously. Better outcomes measures may
aid and improve FDA\'s ability to understand benefit-risk ratio by
making benefits and risks more directly comparable. Better benefit
measures may also help FDA and the drug industry develop clear direction
for marketing efforts focused on improving safety, not merely selling
more drugs. For example, understanding benefits better could help decide
what information should be used as part of the drugs\' fair, balanced
message to improve the safe use of drugs.

A use of pharmacoeconomic modeling may be applied to risk-benefit
decision making, may help FDA and the industry better define when drugs
are safe as well as determine when risk management plans are necessary.
For example, you\'re not just looking at the drug itself, you\'re
looking at the educational intervention, as well as what\'s happening in
the practice and using that to say a modeling technique or a decision
analysis of these and doing a modeling prior to implementing a program,
may help in determining what are the true benefits of any of these
tools.

Outcomes assessment may also help companies in both the development of
and the evaluation of risk management plans. FDA\'s concept paper
emphasizes behavioral outcomes as the ultimate goal of many risk
management plans. Outcome researchers are well-trained to use existing
data bases and design original studies to examine behavioral outcomes.
ISPOR members are ready to participate in the risk management planning
process.

The outcomes assessment or using TQI, total quality improvement, is a
way of assessing both the program itself as well as the measurement and
having a constant feedback will help in assuring that the programs that
are being implemented are truly measuring that which is to be measured.

Pretesting of various tools is important. However, the methods used for
such testing should be sufficiently rigorous to scientifically
acceptable. The use of qualitative research is acceptable for generating
hypothesis, however, qualitative is not acceptable for confirming the
value of educational tools or other risk management tools. And I think
this was brought up before.

Developing a strong rationale for each tool or combination of tools will
require developing a much stronger research base. Measures such as
rationale and such rationale do not necessarily currently exist. We need
to review the literature on the use of these tools in achieving
informational, motivational and behavioral goals. We need to develop our
own research agenda to understand how such tools work in general. FDA
and other branches of the government need to support such research. In
addition, each drug is developed and used with a specific context that
can change the meaning and impact of the interventions.

Pretesting and pilot work are essential to assure that tools make sense.
FDA\'s four level risk management system is likely to be problematic for
fully describing the level of risk management necessary. It may provide
false signals to prescribers and patients that one drug is more
dangerous than another. For example, a drug may have only educational
informational intervention, simply because there\'s no system available
to guide prescribing.

Another drug may ask for a patient agreement to obtain patient\'s
commitment for compliance. The second drug should be considered more
risky because it is Level 3 management plan. Some more thought should be
given to the use of the level to the specific risk management. If levels
are used, how will they be specified?

Measures of success of risk management plans should be specific enough
to provide feedback on how the plans should be changed if objectives of
final goals are not met.

At ISPOR, we have, as I said the risk management special interest group.
For more information about that risk management group and their
activities, it can be found at [www.ispor.org]{.underline}.

We have several meetings coming up this year. Our next one will be in
May in Arlington, Virginia which our risk management special interest
group will be sponsoring two sessions on risk management. This was
Tuesday afternoon. Commissioner Mark McClellan will be speaking in the
morning and in the afternoon we\'ll be talking about risk management
programs and risk management and its theoretical basis as some of the
applied issues.

Also, we are in other parts of the world, too, so we are indeed a very
diverse group of researchers. Thank you.

DR. SELIGMAN: Thank you, Dr. Smith and thank you to all the speakers
who\'ve been with us this afternoon.

I\'d like the speakers to return to the table after we take a 15 minute
break so that they\'re available for questions and comments. Thank you.

(Off the record.)

DR. SELIGMAN: I have a handful of questions and comments that I\'ve
received from the floor. Let me, first of all, encourage you, many of
you who have submitted lengthy comments on 3 by 5 cards, that I would
encourage you to submit those actually to the docket, if you don\'t
mind. I think there\'s some very interesting and worthy comments and
observations that have been sent to me here at the front of the dais and
the best way to ensure that they are part of our consideration as we
prepare the guidance is to make sure that they are formally submitted.

I\'m going to start by taking a couple of questions that were handed to
me and then we\'ll open up the floor. The first one actually had to do
with the ICH common technical guidelines for submissions and the
observation and I will read that the FDA\'s integrated safety summary
exceeds the CDD requirements already and the question was asking where
does the sponsor provide the risk management plan, the

risk-benefit discussion doesn\'t cover this. Is it Module 1?

Does someone \-- Toni, do you want to answer that?

DR. PIAZZA-HEPP: Yes, to date, we\'ve been asked that question. We have
been recommending to firms to place their risk management plan or
program in Module 1. So that\'s the advice we have been giving to date.

DR. SELIGMAN: All right. The next question I have on a card has to do
with, does FDA have any plans to take a retrospective look at drugs that
are already on the market or to require sponsors to take a look at them
to see if a risk management plan would be useful or is this a
prospective-only initiative? And a similar question asked about if we
approve of a drug now with a risk management plan, would we then go back
and ask sponsors who are currently marketing a drug in that particular
class or have a similar risk profile to also implement a risk management
plan?

John, you want to take that?

DR. JENKINS: Yes, I think we can answer that in a couple of parts. The
risk management program that\'s part of PDUFA 3 is intended to be
focused on new products approved during PDUFA 3. So starting with
products approved October 1, 2002, those products are the ones that are
covered specifically by the risk management program that\'s in PDUFA 3.
But obviously, we\'re constantly looking at already marketed products to
make decisions about whether additional risk management efforts are
needed. I don\'t think we have a systematic plan that we\'re going to go
back and expect every sponsor to look at every marketed product and
decide whether a risk management plan is necessary. I think we\'ll
continue to do that in the format that we have done in the past which we
look at new safety signals. We look at new information as it comes to us
to make decisions about where it\'s appropriate. I think an example the
agency just a couple of weeks ago announced new labeling and what you\'d
call new risk management plan, I guess at Level 2 or maybe Level 3. I
forget how Anne described it for Lindane. An old product. It has a long
history of some safety concerns and based on re-looking at some of the
information we decided to make some new changes. So hopefully that will
address the question. No systematic plan to ask everyone to do a look
for a risk management plan of already marketed drugs, but clearly if new
signals or new information becomes available, as we\'ve always done,
we\'ll have to look at those products and make decisions about whether
additional actions are needed.

DR. SELIGMAN: Thank you. I will open up now for questions or comments
from the floor.

MR. STANG: Paul Stang, Gulf Associates. My first point is just towards
this morning\'s session. My understand from several other meetings, when
people talk about the automated Pharmacy systems and retail Pharmacy, my
understanding was the number of warning flags and messages that come up
for any given drug are so overwhelming that they\'re actually ignored by
the Pharmacists themselves. So I just want to highlight that to the
Committee to go back and either pick up that information and understand
really how effective that system is in its current state and how again
that might be changed in terms of communicating information to the
Pharmacist, if in fact, we\'re looking for the Pharmacist to be the
ultimate point of control for some of these issues.

I\'ve heard it many, many, many times and it didn\'t appear to come up
this morning and I just wanted to highlight that one point.

DR. TRONTELL: If you would like a response now?

MR. STANG: Sure.

DR. TRONTELL: I think this issue was addressed partially at the Part 15
hearing last May where some individuals suggested in the specific
instance that you raise that the signal to noise ratio in these pharmacy
fail safe systems, in fact, was very low, and in fact, the warning
screens came up for what might be considered less important
contraindications or interactions and came up as equally as frequently
for the ones that were quite severe and were absolutely
contraindications and at that forum there was a recommendation that
those, in fact, go into some form of classification in terms of priority
so that individuals could discern what was something that was truly
actionable as opposed to just, you know, one more thing that you could
override.

MR. STANG: My second point gets back to Gretchen\'s point about risk
minimization which I thought was a very good term to think about because
when we think about the evidence for risk and what we\'re asking to
produce for the evidence around risk and follow-up for these
interventions in risk management, there\'s also evidence of benefit and
I know that other portions of the Agency have been down the road about
looking at what constitutes credible evidence of benefit and I\'m
wondering if there isn\'t an interplay here and potentially an
opportunity to put benefit or perhaps benefit and risk in context in a
way that not only enters the labeling, but allows a little bit more
flexibility in how that information is communicated to give that fair
balance. It\'s just getting at how benefit comes into this whole
equation as well. Certainly that information will be captured in a lot
of these programs and these program assessments which, in effect, become
part of the delivery of the drug itself.

DR. HOUN: Right now where the benefits appear is the indication. That\'s
what the drug is good for. The clinical trials can give you more
information on how good, what\'s the magnitude of effect.

When we look to maximize benefits, one way to look at the indication is
the good effect it has to outweigh the risks and some drug manufacturers
have chosen benefits that people would say are I don\'t know, they\'re
different terms like maybe they\'re lifestyle benefits or maybe they\'re
symptomatic benefits or maybe they\'re symptomatic benefits in a mildly
affected group and is there a way to make benefits in a group that\'s
harder to treat or has failed other treatments or a larger benefit is
experienced by more people, so yes, I mean I would think that we need a
lot of advice of not only this minimization of risk where I think the
majority of today we\'ve been talking about, but on benefits, how to
present them, how to maximize them so that those would be very good
comments to get.

MR. STANG: Thank you.

DR. TRONTELL: And I might just add one or two words to Flo\'s suggestion
because we had some preliminary discussions within the workgroup and
exactly as stated, we really look to the indication section to describe
benefits, but I think on a case by case basis as the Agency weighs
approval, where there may or may not be a prominent safety signal, the
magnitude or the nature of the disease that\'s being treated, if this is
a symptomatic condition or cosmetic condition, we\'ve since learned that
many symptomatic conditions may, in fact, be quite disabling for certain
components and that then presents the decision, as well as the
availability of other therapeutic alternatives. It might appear to some
that our tolerance for safety problems may be somewhat different for
those products where there\'s few therapeutic alternatives available to
the population that\'s afflicted, so those are just some of the very
preliminary thinking we\'ve had and given the nature that it was so
preliminary, it\'s not well developed in the Concept Paper that you have
seen today.

MR. STANG: Very good, thanks.

DR. TEMPLE: I missed the question, so tell me right away if I\'m
answering the wrong thing. But attempting to limit the population, is a

long-standing part of risk management. Just examples that come to mind,
the second line therapy \-- Clozapine is only supposed to be used if
people fail to be respond to other antipsychotic drugs. Bepridil is only
supposed to be used in people who can\'t benefit from any other
anti-angina drug and Lotronex is only for people who are sort of
immobilized by their irritable bowel disease. Now we don\'t enforce
that. I don\'t know of any risk management program where you have to
prove how sick you are. Even Dofedilide by the way is only for people\'s
whose lives are made miserably by their attacks of atrial fibrillation.
So that\'s really inherent in all of these, but you\'re right, we
generally do that by putting it in the indications section and I don\'t
know any case where we\'ve tried to enforce it in any way or make people
prove it.

PARTICIPANT: Bob Fenishall, Washington. I want to turn to the question
of evaluating the risk management measures that are being taken. And I
was a little surprised at the document. My experience with the Agency,
obviously, is that the Agency doesn\'t really do a lot of designing of
things. It is a valuative Agency and so I came to these documents
thinking well, the design might not be that terrific, but the evaluation
part is going to be the strongest. That\'s not what we found. That\'s
not what I found. And the reason I say that\'s not what I found is that
it seems to me that what we\'re talking about in deciding what sort of
risk management measures to begin or to continue, this is like a dose
management problem. This is a dose selection problem. And it\'s a little
bit more complicated than dose selection because it\'s not just a matter
of a little bit more or a little bit less, but at the level of
restricting stuff, one can either restrict pharmacists or restrict the
patient population or restrict the physicians and so on. But it is very
much like the problem that Dr. Temple discussed yesterday and other
people mentioned yesterday of dose selection, can it be done before
Phase III trials and Dr. Temple with his usual wit pointed out, no, you
don\'t know enough before Phase III trials. You can guess, but your
guess may be wrong on the basis of this preliminary data.

And so doing a mere two-arm trial in Phase III really is probably
unwise. Well, here you\'re not talking about doing a two-arm trial.
You\'re talking about doing a one-arm trial. You\'re going about doing,
setting up a risk management scheme, and then on the basis of what that
looks like it should work and at the end of it, yes, that seems to work.
Well, of course, surgeons used to do that and now they do randomized
trials, sometimes. People devising welfare programs used to do that. Now
they do randomized trials, sometimes. People devising patient compliance
schemes do that. Now they do randomized trials and Gerry Faich told us
about earlier today and they sometimes are surprised, they often are
surprised at things that sounded good that they thought were going to
work are actually worthless. And I guess the question is when we\'re
talking about interventions which involve a great deal of both financial
and other resources at stake with benefits being denied because you can
always reduce risk by reducing exposure as someone pointed out this
morning, how long is it going to be that this remains in contention
which has been theoretical today and is going to become much more heated
as it concerns specific products, as this becomes implemented, how long
is that going to go on and I guess Dr. Temple is the one whose
prediction I would most value before it becomes routine to say we are
going to try this in randomized trials. We\'re going to do this in this
part of the country and the other thing over there. Or something of that
kind and if you say oh, no, we can never randomize, how can you deny
people adequate warnings about the drug, well, as Richard Peto has said,
if you know what you ought to do that and you don\'t have to try it and
what he means by that is most of the time you don\'t know what you\'re
going to do. You don\'t know what you ought to do. You just think you
know what you ought to do.

So the question to Bob Temple is how long do you think this is going to
go on in a kind of touchy, feely way which is what\'s being proposed
before randomized trials are not only accepted, oh yeah, that\'s a good
idea, but before a program like those being proposed is simply refused
to file?

DR. SELIGMAN: You are suggesting randomized interventions or randomized
risk management programs?

PARTICIPANT: Yes, absolutely.

DR. SELIGMAN: Anybody want to bite?

DR. TRONTELL: We are lining up for this opportunity. I don\'t think we
intended to imply in the free testing that we described in the
evaluation section which is still clearly formative that we would in any
way exclude in Phase III trials individuals who might be randomized with
some comparator for any number of a different interventions. That is
being done, in some instances, in labeling comprehension. So just
because you\'re pilot testing doesn\'t mean you have either a control
arm and comparison arm.

DR. HOUN: I think it\'s a good time at the end of Phase II meeting if
there is a potential signal in an unknown compound or in a class that
you know fairly well that there might be problems that that can be
proposed on not only what efficacy end points you\'re going to study,
but in terms of safety outcomes as well.

It may not be the 10,000 person trial in terms of the safety health
outcome, but there might be other steps that could be evaluated in terms
of comprehension or appropriate use or people getting the right dose or
getting into the \-- getting the drug at all.

PARTICIPANT: Let me make my analogy to what Bob Temple was talking about
yesterday, perhaps more precise, and that is what Bob Temple was saying
you don\'t have enough \-- you\'re never going to have enough experience
or rarely will you have enough experience in the Phase II trials to know
what you ought to do in Phase III and that\'s why you randomize to dose
in Phase III or why you often should randomize to dose in Phase III.

In the same way, it seems to me, yes, you might very well try to
accumulate pertinent data in Phase III even in a randomized way, much as
Phase II is, after all, randomized. But once again, the reason why
we\'re here, it seems to me, is that at the end of a normal development
program, at the end of Phase III which is not the end of the program
because that\'s what we\'re talking about, at the end of Phase III, at
the time of approval, there is not adequate experience to know exactly
what to do in the next phase. And so just as Phase II gives you a
suggestion to what to do in Phase III, but you still have to shuffle the
cards again. Phase III can, if you do the sort of thing that you\'re
just recommending, give you some suggestion about what to do after
marketing, but you will not have enough experience often, and you have
to shuffle the cards again.

DR. TEMPLE: These things are really hard to do. It\'s not different
entirely from some of the arguments we had about whether statins should
be over the counter. What you really wanted to know was whether in the
end if they were, more people would end up being treated than not.

But how do you do that without making it available OTC, so then maybe
you could possibly do something, but how can you have it be Rx in one
place, one state or something, and OTC in another so that you really
compare or even better, randomize within the same community. Nobody can
figure out how to do it.

These questions too, sometimes pose that problem. I mean in theory, you
might want to compare giving it out with a MedGuide, giving it out
without a MedGuide. But once you sort of think there ought to be a
MedGuide, it gets very funny to give it out to some people without a
MedGuide. And a lot of people would object to your doing that. They\'d
say it\'s not ethical to not help people do it right. So it is a
formidable challenge to do those things.

What you can do is test an intervention you haven\'t introduced yet. One
way of dealing with people or requiring, I don\'t know, you could do a
trial where people are very intensely advised, versus a trial where
people are much less intensely advised. And there have been smoking
cessation programs, for example, that did that with and without a
careful program.

I think there\'s no simple answer. Some questions probably can be
approached and other questions, it would be extremely difficult and if
there were sort of face facility to the intervention you were thinking
about, people would be very nervous, randomizing people to not getting
that. They\'d be very nervous. And I think a lot of the things we do
here are based on face validity. How can it be bad to tell the patient
what to expect? It will help them think about whether they should take
the drug or not. Do you really need to test that? Well, Bob\'s probably
right. You probably do need to know how effective you are. I don\'t have
any short answer on how to do it. I think it\'s case by case. But then
we say that over and over again.

DR. SELIGMAN: This is a challenging question. Do others want to comment
particularly on that? Yes, Dr. Kahn.

DR. KAHN: Sidney Kahn. There are complications here. The first one,
it\'s very hard to randomize interventions for the kinds of products for
which we anticipate the higher level of risk management programs because
by definition, as we said previously, products that have substantial
safety concerns that are going to used in large numbers of patients
probably don\'t exist, unless there\'s no therapy alternative, but that
seems fairly unlikely, unless you\'re talking about something like
Alzheimers. But the ability to do any kind of randomized interventional
post approval is I think totally limited by the legal system because I
don\'t believe that you could get away with the liability issues of
randomizing patients into subsets on different levels of intervention
if, in fact, the risk appeared to be such that a risk management program
was required.

Now you could probably try different risk management programs if they
could somehow be shown to be equivalent in terms of the effectiveness,
but then if that\'s what you know up front then what\'s the point of
doing the trial. I see this as an absolute vicious circle that is very
hard to get out of.

DR. MARKS: Lou Marks. This is done all the time in health education. And
the question that we\'re asking isn\'t what is the effect of A versus B.
It\'s what is the effect of A plus B, plus C, plus D. You \-- it\'s very
possible to do a base program nationally and the question we\'re asking
which is a very legitimate question is where is the additive effect of
additional interventions and then you can do randomized small little
pocket studies in which you have additive effects and that \-- actually,
that I think can be very helpful in a risk management sense because we
do not know what is the right level and why not start low and see if
it\'s of value, as along as there\'s some protection for everybody. I
mean Sidney\'s point is quite correct. There has to be some baseline
level for everyone, but we\'re asking for very expensive interventions
and we don\'t know how, what the additive effect is going to be. Why not
test it?

DR. FRANZEN: Tim Franzen from Lilly. Just a thought on what the
implications of moving to by default value dose finding in Phase III may
be. First, it would be a wonderful topic for PDUFA-4. And I say that
because I think it would be a fundamental restructuring perhaps.
Certainly, if one is talking about doing that kind of work in Phase III,
it would presuppose that there is some massive gap in current Phase IIIs
that is creating some sort of major public health issue with all the
current approvals.

I would be very interested to see if there were data to that effect, but
I think many of us would feel that the current mechanisms for proving
safety and efficacy are quite good and quite in keeping with the
standards of what we should to protect public health and expedite access
to medicines and I think to move to a new default approach would be very
complex, very time consuming and to Lou\'s point, we don\'t know what
the positive impact might be. So that\'s talking about making a
tremendous investment of people resources without necessarily
understanding what that yield could or should be. So I guess this is
just a plea for before one proceeds to that point, can we make sure that
the perfect is not the enemy of the good here.

DR. SELIGMAN: Other comments on this particular area before we move on?

Okay. Yes, on this side.

DR. GORMLEY: Glenn Gormley from Astra Zeneca. I\'m only going to link to
Tim\'s comment. If you recall in the presentation that I made yesterday
morning, what we thought PhRMA\'s biggest concern was or the question
that we raised of most concern was on my second slide was whether the
implications of what we were going to be talking about over the next
couple of days were, in fact, going to change the standards for drug
approval. And I think that\'s what Tim was picking up and wondering
whether this was around just maximizing the ability to protect patient
safety, or just getting it right, or whether we were beginning to enter
a round of asking whether there is a different standard now for
approving a drug. It wasn\'t clear what everyone\'s conversation was. I
remember Bob Temple clearly responding back to me at that point saying
no, that was not the intent to change any standards. We were just simply
trying to get it right. I was hoping that that was still the spirit in
which we were discussing it here.

DR. SELIGMAN: Yes. It\'s still the operative spirit, but John, I\'ll let
you \--

DR. JENKINS: I would just like to comment on that because as part of the
group from FDA who was involved in the PDUFA 3 discussions and I know
Tim Franzen was very involved from industry. It is true that the risk
management program component that\'s part of PDUFA 3 was primarily
suggested by industry, but I think we all agree at the table that the
goals of that program were to improve how we managed the risk of drugs
after approval, and that the activities that occurred prior to approval
on risk management activities would not interfere with a drug that
otherwise would have been approved under the usual standards.

I mean we\'ve always had risk management activities that have been
invoked for certain drugs before approval, and the idea was that the
things that were here in addition to what we had previously done would
not stand in the way of approval or raise the limits or raise the bar
that you needed to surpass to get your product approved. And I think
that\'s the spirit that we\'re trying to work under.

A risk management plan may or may not be able to help you get a drug
that would previously not have been approved. I mean that\'s going to be
a case by case scenario. The idea was that a lot of these activities
were going to be studies such as utilization studies, how effective were
the labeling recommendations that would occur after approval that
wouldn\'t interview with the actual approval. And Tim may want to
comment on that, but I think we all felt confident that the way we had
set this up is that we weren\'t adding a new bar that you had to get
over for approval, but we were trying to do a better job of linking the
safety information that we had at the time of approval, understanding
what the gaps were in that information and trying to collect even more
useful information and ensure that the drug was used safely and
effectively after approval.

DR. SELIGMAN: Flo?

DR. HOUN: And also as part of that, in looking at the drug\'s life cycle
as a continuum, once you\'re approved, once the product is on the
market, new information that allows if you\'re coming in again for
developing in a different indication, different population, different
use, finding a risk during marketing and wanting to test it in a Phase
III study for this expanded indication or for different uses, that\'s
something we should be talking about because if there\'s different ways
to, I don\'t know, develop the PPI, develop an educational tool or a
nursing intervention, those are things that we would be interested in
talking just again to see if there can be a better way to implement
management of a particular risk that was found.

DR. SELIGMAN: Yes, Bob.

DR. TEMPLE: I am not sure what Tim was responding to, but I don\'t think
Bob Fenishall was suggesting that all this ought to be worked out
pre-marketing. He was saying are we ever going to learn what really
works. And as Gerry said, if you read [The Lancet]{.underline} which
seems to specialize in these things, they have something every week
about comparing one way of practice with another way of practice.
Usually, there isn\'t much difference, actually. But every once in a
while there is, although it\'s small. And it goes from how to
communicate with people, whether to have a special nurse doing
something, all kinds of variety of things and they\'re tested in
community-based, randomized trials. So it\'s not out of the question,
but it\'s not always so easy to think of what the trial will be in the
cases we\'re talking about.

DR. SELIGMAN: Yes, on this side.

PARTICIPANT: Alex Abramo from NCI Regulatory Compliance Practice. I
wanted to touch upon critical success factors for risk management plan
and I agree with what Dr. Kahn mentioned in his presentation talking
about pragmatic, specific and measurable. I want to add coordinated to
this list and that\'s something which I think needs to be included. I
can bring a couple of examples. One of them is counterfeit drugs. I\'m
not sure that this issue was really brought up and there was a figure
that was quoted earlier today that 97 percent of risk management can be
handled through PIs may not include all the gray areas and all the areas
which are outside of the illegal drugs which are handled through the
pharmacy in the legal way.

Coordination of efforts in risk management with preventing counterfeit
drugs reaching consumers is an important issue. Another one is
coordinating as a risk management initiative which FDA announced, for
instance, in February which is risk based approach to enforcement of 21
CFR Part 11 with 20 signatures. When we are working with the industry,
we always look for the best practices when the risk management programs
are coordinated and looking for multiple objectives and that way it\'s
ensured that all the risks are included and not overlooked. We know good
examples and examples outside of our specific industry is a very
significant effort which U.S. government makes in risk management with
foreign nations as a whole through U.S. Patriot Act and other pieces of
legislation.

So my question, is there any other level of coordination with an agency,
whether it\'s operational or at least ideological in approach to risk
management which would look into initiatives which we\'re discussing in
this room in addition to risk based approach as described in a recent
guidance, or changes in ways that our good manufacturing practices are
evolving over the last, I would say, six months?

DR. SELIGMAN: Any takers? This is a question related to coordination
within the Agency on various activities associated with managing \--

PARTICIPANT: Risk management.

DR. SELIGMAN: Risk management.

PARTICIPANT: That\'s correct.

DR. TRONTELL: I\'ll have to confess to a somewhat parochial view on this
standpoint and there may be programs of which I\'m not aware, but
certainly we confront within the Agency different components, call it
different aspects of the programs risk management, but we are certainly
aware that there are such programs in the area of GMPs and there are
certainly ones in the area of compliance. But I think we\'re trying to
again work on risk-driven principles in terms of setting priorities and
making strategies. At this point, we have friendly relationships, but I
think we\'re probably still at the very early information sharing. We
welcome your suggestions on how that might be done more efficiently.

DR. GALSON: We\'re also working on an Agency-wide strategic planning
effort that has as one of its goals risk management and I think when
that process is done it will be a lot more clear to the outside world
what we really mean by risk management from the Agency perspective, but
these activities definitely fall under that rubric, as do a lot of other
activities as Anne mentioned like the GMPs and a lot of food safety
activities as well.

DR. SELIGMAN: Yes, right here.

PARTICIPANT: My name is Steve McCombs and I\'m from PPD Medical
Communications and I just have a comment that perhaps you could comment
on. I know that FDA acknowledges that all products have some degree of
risk associated with their use and I know that FDA recognizes OBRA and
supports the development of MedGuides to better improve information to
patients.

So I\'m really curious as to why patient education and outreach doesn\'t
have the status of being a Level 1 intervention because it seems like it
would really be fundamental across the board to any risk management
program, you know, even the simple ones for which a structured program
was not necessary and then at Level 2, you may have targeted education
if there are specific risk factors that are identified, specific to the
product.

It just seems like this is being completely overlooked as a Level 1
intervention and I don\'t understand why.

DR. TRONTELL: I think you make a fair point and we had, as you have just
described well, thought of targeted patient risk information such as
would occur with medication guidance and patient package inserts.

The Agency certainly has some input into the other forms of patient
information that are distributed by Pharmacists, but we don\'t formally
regulate that. And you make a good point. I think the question is at
what level might education be just so basic that we consider it as a
given. Our thinking, though not maybe so articulated in this document
was for the education for cause apart from issues of how to take the
product appropriately, store it, and other things that obviously have
very important impacts on the benefit-risk profile.

PARTICIPANT: But I would just say at a very basic level that is risk
management as well.

DR. SELIGMAN: There is no doubt that that\'s risk management. I agree.
Bob?

DR. TEMPLE: Well, the rules we wrote for ourselves on when we would
actually write a MedGuide are very clear. There has to be special
circumstances with very great risk that patients would need to know
about or something bad that they could manage if they knew more or
something crucial they need to know about how to use the drug properly.
Of course, all other drugs come with patient information handed out by
the Pharmacist. So that is part of Level 1, in fact, but it\'s not
written by us, unless it meets the higher test.

DR. HOUN: We can certainly take comments. I don\'t think these levels
\-- I know we\'ve gotten feedback that they\'re confusing and that they
may put a black eye on some drug that\'s a Level 3 rather than a Level 2
and everyone wants to be a Level 1. And so I would really welcome your
thoughts. I think that education is really, really important and if we
have a narrow view of only MedGuide we\'re calling education because
that\'s FDA approved, you know feedback to us on your need to look at it
differently. The other thing too is someone brought up the marketing
forces on the Pharmaceutical industry and is that education or is that
promotion? Or should that be educational, so I\'m interested in hearing
people\'s advise and comments on those issues, too.

PARTICIPANT: I think when I said MedGuide, I was really thinking about
not the patient package inserts which I think are FDA-sanctioned, but I
was thinking more about the informational leaflets that FDA has taken a
stance on trying to standardize and you know, have a certain percentage
of drugs covered within certain time frames and acknowledging the value
of interactive communication by Pharmacists and other health care
professionals as a supplement to the printed leaflets or whatever one
offers the ultimate user of the product. I think all that would comprise
a very important part of risk management at a very basic and fundamental
level.

DR. SELIGMAN: Point well taken. Yes?

DR. HAAS: Joanna Haas, Genzyme Corporation. Sponsors developing gene
therapy products are now being asked to provide a 15-year long-term
follow-up program for any new studies under any INDs existing or new.

I wanted to know how you see that [de facto]{.underline} requirement as
fitting into this program, particularly in terms of validated standards
and expectation that there will be a measurable outcome?

DR. TRONTELL: It might seem that with such a lengthy period of follow up
in a defined population exposed to the product, you have an opportunity
to do a form of enhanced pharmacovigilance, however you might term it.
Whether in our nomenclature that falls into what we considered an active
intervention I think is something that is worthy for us to consider, but
perhaps you could elaborate a little bit more in the nature of the
follow up. Is this really largely monitoring for unanticipated adverse
events or is this, in fact, some ongoing intervention to optimize
benefit-risk.

DR. HAAS: First of all, let me say that the programs, regardless of
vector, regardless of aging, regardless of indication, and the details
are not out. You have to propose the program. It looks at new
malignancies, deaths, new neurologic disorders. I believe new
immunologic disorders and other events of interest.

DR. WEINSTEIN: Clearly, this is an area that is new and needs, we need
information in order to develop these programs and get a clear idea of
what the risks are. Right now, it appears that that \-- what you are
talking about is this notion about collecting information in order to
integrate into a risk management program. But it is part of our thinking
about trying to manage the risk of these products, clearly.

I don\'t know if that\'s quite \--

DR. HAAS: I guess the question has been really trying to ask whether
this program, which is a really fairly \-- it is a major undertaking for
those involved with it. It\'s a killer for sponsors who are from
academia since they only have perhaps five years of funding and have to
think about how they\'re going to handle something over 15 years, but
particularly in terms of the interpretability of the kind of information
that might one might derive from such a heterogeneous operation and of
course, many of those programs where we don\'t know if they\'ll survive
or die, but how usable that kind of information might be.

It\'s a one size fits all.

DR. SELIGMAN: Yes.

DR. FULLER: Yes, David Fuller. I\'m VP of Medical Affairs for Ortho
Medical and part of my responsibility is I\'m one of the people here
after the Zyrone risk management program which I now see as being an
exclusive club. Sounds like Level 4.

The first thing I\'d like to comment on is the terminology and before I
go on, I\'m both a Pharmacist and a physician, so I\'ve had practice
communicating risk both in pharmacies and in clinical practice.

I think the first thing I\'d like to say is risk management program, I
think the concept of risk is poorly understood. Most patients, most
people have trouble understanding what a risk is, so I would encourage
an alternative terminology, something along the lines of targeted safety
programs or targeted safety enhancement because that\'s what we\'re
really talking about is targeting safety and improving it.

I think most people understand safety much more easily than they do
risk. That\'s a personal view.

The other thing I\'d like to comment on is that everything is relative
in these levels. I\'m going to ask a question. Could a product used
appropriately under a Level 4 risk management program have less risk
than something used inappropriately under Level 1?

And this is just a philosophical comment.

What we\'re really talking about is communicating risk through the whole
pharmaceutical distribution process and what we\'re talking about is
doing no harm or a more cynical, slightly harder \-- do as little harm
as possible.

Now this is something that we do every day. My wife was going to have a
medical procedure and she got an individual consent for that procedure.
It started with a leaflet and then when she went in, the doctor sat down
and customized the consent procedure to her specifically. She was
interested in something, she wasn\'t interested in others. And that\'s
why I\'m concerned about and I understand very much from the procedural
point of view people wanting consistent systems and the same thing for
everything. I think the moment you dilute the message it takes away from
customizing the message and I think that\'s something I haven\'t heard
today. It\'s not the tools of communication. It\'s the message that
needs, the testing and the qualification.

I think out of that comes we need better communication tools. People
need to be trained to how to communicate better. That means I\'m not
sure that Walgreens is the best place to be taught about a risk
management program, with Shirley being paged to checkout 4 and the kids
are screaming in the background.

Some practical things, the risk management programs are currently
handled in different divisions. It would be really useful to the
industry, I think, to have a central point of contact, someone who we
could talk to meaningfully. You have the total perspective. Only the FDA
has the overview of all these programs at the moment.

I think we could be braver and take a stand. Why not pre-qualify some of
these tools? I mean do we really have to justify the use of the patient
leaflet to communicate a message? I think you could say these could be
acceptable tools to use.

Your making an emphasis is post-innovation.

The final point I\'d like to make is in my 30 years in the industry,
I\'ve seen a history of increasing drug regulation and I\'m moved to be
a little more conservative. So I now see risk management programs coming
in, being formalized, becoming part of drug submissions and I think the
philosophy is great. Do no harm, reduce the risk.

However, the safety always is a dynamic process. We need to make sure
the process is dynamic and remains dynamic, not having outdated safety
data. We need to make sure it gets updated. And the other thing I would
like, my question to the FDA is with the introduction of risk management
programs or safety enhancement programs, will the FDA commit that maybe
if a drug has been under one for five years that they\'ll remove the
requirement because I get this feeling begin to creep up rather than
down or away.

DR. TRONTELL: You have asked a very difficult question. There\'s the old
joke about the person who is tearing a paper and he\'s asked what are
you doing? He said I\'m keeping elephants away. Well, what do you mean?
There\'s no elephants around here. He said but of course, it\'s working.

So by extension, the challenge would be if we have a highly effective
program, how might you ever imagine removing components of it. It\'s
much like we do in optimizing therapy for an individual. You\'ve
titrated your anti-hypertensive patient. At what point do you back down?
I think it\'s a very difficult question to ask. It would \-- some of the
designs that Dr. Moore has described where you may at some point try at
institution comparisons of A versus A plus B, versus A plus B plus C,
might, in fact, give you some insights where you\'re adding value with
each individual tool. But you ask a fundamental question that is really
quite difficult.

On your other question which was quite provocative which is might a
Level 4 program, in fact, enjoy greater safety than a product at Level 1
or Level 2 that doesn\'t have the same level of restriction, I think we
may be able to go back to the difficulties in comparing risks and
benefits across class. We may, for instance, in the case of Thalidomide
take comfort that pregnancy exposures appear to have been very well
managed by that program, but I don\'t know how to compare that to the
risk of hypo- or hyperglycemia with a particular therapeutic agent.
Again, we\'re in a apples and oranges arena. And some of that
individualization relates to the disease state being treated as
therapeutic alternatives and so forth.

MR. FULLER: The comment was made in relation to changing level of risk
management based on the fact our drug got approved with a very small
data base and it\'s understandable that people were concerned with the
safety data base of 500, what if, what if? I\'m particularly interested
to know when we get to 20,000 and we haven\'t seen some of these
theoretical concerns is the door open to come back and say with the hard
data, look, we really think \--

DR. TRONTELL: There is perhaps one example. I\'m not sure if directly
extentisble to the case of Zyrone, but certainly with Clozapine. You
know, initial blood level monitoring was done on a weekly basis and
based upon results shown over time that individuals were experiencing no
increase with consistent monitoring. That was, in fact, relaxed for
individuals on long-term therapy to two weeks. And I think there are
even further considerations about whether it might be further relaxed
for individuals who have been on this product for years.

So it is a possibility. Good data, in fact, make it possible and in that
tightly regulated systems and perhaps with yours as well, if you have
good registration of your patients and ability to ascertain the
outcomes, you may, in fact, be in a better position to roll back from a
Level 4 than perhaps a Level 3 could go to a Level 2.

PARTICIPANT: Thanks very much.

DR. SELIGMAN: Just agreeing with you. I think we and sponsors really
have a responsibility to evaluate these programs, particularly the ones
that are very restrictive or that are causing human samples to be
collected. A lot of them involve collecting data and I think we really
have responsibility to revisit them periodically and determine, if we
can, and it\'s not always going to be possible how effective they are.

MR. ARIANA: Felix Ariana, Pharamaceia. I just wanted to comment that
I\'ve heard a couple of people saying before, giving the impression that
whenever a drug is put on the market, basically we haven\'t got a clue
of what the safety profile of a drug is going to be which I don\'t think
is completely accurate.

It is true that the final safety profile of a drug is not known, but at
least some good information is available and I wanted to highlight
something or a methodology that I haven\'t seen described in the paper
which is simulation.

In other industries, for example, aviation, nobody would think once of
allowing a pilot to actually fly a plane without actually putting him or
her into a simulation and the same thing can be done with drugs. There
are a number of data bases available by which, for example, the
Framingham database where you can actually create a fictitious cohort of
patients and study what happens when you elevate one millimeter of
mercury in diastolic blood pressure for X amount of time and how many
days do you have? And you can actually test the interventions, positive
of negative that you can have with a drug.

It is usually fascinating to see that the \-- all individuals react to
drugs in very different ways, populations don\'t. They\'re extremely
predictable and we also have to be reminded that this is important
because most of the risks that have actually resulted in drugs being
withdrawn recently are very well known Pharmacology 101 risks, not the
fancy hypersensitivity reaction which exists in 1 in a million, the
contraindication that has not been fulfilled, etceteras.

In fact, in ISPE, we are having a simulation workshop in August in
Philadelphia.

DR. SELIGMAN: Thank you for that comment. Yes?

MR. CAMPBELL: Bill Campbell. This is an issue that has been alluded to,
touched on and really it comes up in CERTS a lot, but more recently and
more intensively perhaps in the drug safety and risk management advisory
committee and that is if we are going to move toward a system where
research on the on-going and active research a contingency of approval,
that is approval is contingent upon conducting effectiveness studies of
risk management programs, then it creates a unique type of public trust,
I think. We\'re not exactly human subjects to say that all the
prescribers, all the Pharmacists, all the patients are subjects that
need to be consented, but they are subjects in some sense, generating
research for all of us to learn from.

And if that\'s true, the reporting of that information creates a special
obligation, it seems to a lot of us. And so the argument would be not
just conducting the research, but an affirmative requirement to require
reporting of that information to all the constituencies of interest.
This discussion gets difficult at that point because at one extreme this
information is all proprietary and the only requirement should be to
report back to the Agency and it should be maintained in confidence. The
other extreme is to say that all the data then should be in the public
domain and it should be completely available even in raw form.

But I think we need to draw a line some place between those two points
to say that the learnings from the effectiveness studies of risk
management programs become broadly and generally available in an
appropriate manner to the various constituencies of interest because
we\'ve heard either the impression or the reality that many studies are
intended to take place and may, in fact, take place, but the reporting
back is either very, very slow or not existent to all of us.

So is it possible, one of the tools, perhaps, should also be a reporting
back tool.

DR. TRONTELL: Excuse me, are you suggesting that the reporting back be
done by FDA or by the company undertaking the research? If you could
just clarify your last point.

MR. CAMPBELL: By the company, by the sponsor, but in fact, truly a
reporting back to all the constituencies.

DR. SELIGMAN: I think it is both reporting back as well as access to
that information once it comes into the hands of the FDA, to a wider
domain and wider audience.

DR. HOUN: I think for the programs that have a lot of restrictions,
sponsors are anticipating public discussions of results, such as the
Lotronex program, you know. We had a very public venue for trying to
discuss the recommendations for implementing it and the results, people
are very interested in, and so I think we have a few, again, there are
very few Level 4 type programs and those we are very interested in
getting public input on. This is what we\'re seeing for outcomes, is it
good, is it bad? Because again, we are \-- these judgment values on
risk-benefit are public decisions that we need public input to make
those decisions.

So I\'m imaging we will hear many \-- there\'s a lot of opportunity in
advisory committees, as well as if the disarmed group, you know, wants
to specifically hold discussions on outcome measures or on tools or
methodology, those things can be shared.

DR. TRONTELL: I think Flo has made excellent suggestions of ways that we
may be able to enable the feedback for many individual sponsors
experienced to the larger community. The challenge is how that
information can best be shared. I suspect that the successes will be the
champion perhaps more than the failures and sometimes, I don\'t know, I
learn probably best and most painfully from my own mistakes. We\'d like
to avoid more than one person having to make the same one.

But I think the mechanisms that Flo has described are one very good
mechanism and I would also invite you and others here to think of
creative ways where this information might be shared in the arena of
actually the Level 2, in fact, where the majority of products would fall
given our proposed scheme at Level 1 and Level 2. In fact, there\'s
substantial information there that I think we would greatly benefit from
hearing from companies and from others. If, in fact, we\'re going to
presume many products are handled through some level of risk
communication, I think there\'s great strides we can make for it and how
that might be able to be done most effectively, and I would hope that
information would be shared as well.

DR. SELIGMAN: Yes, Bob?

DR. TEMPLE: I noticed a lull, so I have a question about the levels,
sort of, in response to what Flo invited before. I guess I\'m waiting
for the day when people report to the SEC that their drug was considered
Level 1 and expect the shares to go through the roof.

(Laughter.)

The question is this, as I understand it, you don\'t have a risk
management program if you\'re Level 1, so that evaluating things, you
don\'t have to evaluate things, or at least that\'s how I read it. Is
that not true?

DR. HOUN: Yes, the Level 1.

DR. TEMPLE: That\'s just labeling.

DR. HOUN: Yes, that labeling requires you to have made risk-benefit
determinations on what should go into contraindications. Should it be
bolded?

DR. TEMPLE: I know that.

DR. HOUN: Level 1 is a risk management program.

DR. TEMPLE: My question is what about afterward? The other ones come
with some attempt to evaluate the success of the additional things
you\'ve done, whatever it is, the MedGuide or whatever. Level 1 doesn\'t
seem to come with something like that. So my question is this, a lot of
times my guess is we\'ll put something into contraindications and we
won\'t write a MedGuide or do anything in particular. Might it not be of
interest to know how you\'re doing even with a Level 1 program? So I\'m
just wondering whether you might want a Level 1.5 or something where you
actually do look into the success of the various risk management
components of your labeling. That\'s my question.

DR. HOUN: I guess the current practice is that you have a labeling that
is approved. You do post-marketing, pharmacovigilance surveillance. You
get reports. Maybe you have a signal. You assess it. And then you decide
whether your labeling was adequate and then you revise labeling because
maybe it wasn\'t adequate, maybe it didn\'t clearly state the
contraindication. We need to bold it or highlight it. So that\'s
happening. Is it a formal evaluation program where there\'s an agreement
with the sponsor that after use in 500,000 people we are going to
reevaluate? Those kinds of agreements are probably more clear in terms
of one year of surveillance reassessed than some of the higher level
programs, but I\'m thinking what we do all the time is part of
evaluating whether the labeling is working or not.

DR. TEMPLE: So that would be triggered some kind of events, adverse
events or something like that?

DR. HOUN: How it\'s picked up now is a possible signal on the
post-marketing.

DR. TEMPLE: Right. One could also ask whether people are understanding
something. That\'s a little more like the other kinds of evaluations and
if they weren\'t, you might decide to put in a box or something like
that. So that seems like it ought to be at least an option.

DR. HOUN: Yes, I think that should be something that sponsors and FDA
should be able to discuss. If everyone is happy with labeling, but there
is concern that there needs to be \-- either labeling isn\'t said
concisely or clearly or is there something else that has to accompany
the label, those things can be discussed.

DR. SELIGMAN: I think we\'ll take one final comment before we wrap up
today?

DR. PEREZ-GUTTHANN: It is for clarification. Following up this
discussion, I just wanted to make sure that if a company as part of a
pharmacovigilance plan is indeed trying to evaluate whether the labeling
works either through the evaluation of spontaneous reports that was
indicated or through the drug utilization studies in which we make sure
that drug A and Y are not co-prescribed, that that is not going to bump
the drug into the Level 1.5 risk management program as it was indicated.

DR. HOUN: I see now the extreme sensitivities of the labels, the levels.
We\'ll have to call them, \"Betty\", \"George\" and \"Pete.\"

Okay, we\'ve got that.

DR. SELIGMAN: Of course, in the course of public comment we\'re willing
to accept any or we\'re willing to consider any categorization schemes
or approaches to defining various levels or classes of risks that might
be appropriately contained in such a guidance.

With that, let me turn back to Dr. Anne Trontell to provide a wrap of
today\'s discussion before I conclude today\'s workshop.

DR. TRONTELL: Thank you. This has been a very interesting and very
stimulating day. I don\'t know about how many of you might feel
similarly overstimulated by the large number of very important comments
that we\'ve received.

As I\'ve sat here, I\'ve tried to keep a list, sort of the good news/bad
news list of themes that have emerged for me, a theme is if more than,
at least two people have described it. Let me give you the bad news
first because I like to end with the good news.

I think we have seen any of a number of areas where we, as an Agency,
and I hope in conjunction with your commentary here and in the future,
where we need to clarify what we\'ve said in this concept paper as we
take it forward to draft guidance to elaborate on it or where, in fact,
there are concerns that we really need to continue our thinking. And
these include certainly in the area of definitions and the naming of
terms around which there\'s clear boundary issues and where we have some
sensitivities that I think have been well articulated here.

In a number of areas, I\'ve heard a cry for criteria to be set forward
for decision making, whether that be on what\'s an appropriate tool,
what\'s an appropriate level or even our most basic question which is
are you in the realm of what \-- of a Level 2 program or the need for a
risk management program being put into place.

Similarly, I\'ve heard a number of you describe a need for some explicit
consideration of dialogue points to occur between FDA and industry and
certainly any of a number of other stakeholders who have been named
here, for us to discuss these processes and how we move forward in
making decisions on them.

We have also heard very legitimate concerns that we don\'t restrict
access to beneficial drug products in our efforts to make sure that
they\'re used safely and we will take that into consideration.

And similarly, as part of that that we need to come to struggle, perhaps
not in this document or at this iteration, I won\'t be able to give you
a solution today, with the issue of benefit characterization. We\'re
looking at the other side of the benefit-risk balance in terms of how we
might be able to work on that side and maybe have a more positive tone
to the interventions that we hope, we\'ll be designing together.

Now maybe before I go too, the comment \-- I think the picture on the
levels is clearly very mixed and we obviously need to go back and do
some further thinking, but we also have heard, perhaps to the name of
some of the areas of consistency and agreement, some appreciation by a
few parties as being the CERTS. There is some value to trying to move
towards some standard nomenclature, whether this is the one is obviously
something to be determined. And those get me into the very fruitful
areas where we have some agreement and commonalities among the many
parties who have spoken to us today. I think I\'ve heard only uniform
agreement of the need for continuous life-cycle approach to risk
management and that life-cycle approach has been likened in our paper,
although not highlighted today, to a clinical development program
setting up risks in such a fashion in parallel with efficacy, may allow
us to achieve an integrated and coordinated approach which is again yet
another commonality I\'ve heard.

Clearly, I\'ve heard a request that all three guidances develop under
PDUFA 3 speak well to each other and that we find some mechanism to make
the hand offs and overlaps seamless, perhaps through further discussion
and through some overriding document to unify them all.

Similarly, we have the opportunity to coordinate, integrate with the
disciplines of quality improvement and certainly in disease management
and I think we look again to these other disciplines that might be able
to give us valuable instruction.

And with all of you who are partners and some of the partners who
haven\'t been represented here today, we see an expressed interest in
integrating and collaborating and coordinating approach with other
partners in therapeutic decision making, whether they be Pharmacists,
the industry, providers. And the parts of care which were not well
represented here today.

The interest in collaboration and consistency in risk management program
tools, I think, are expressions that we\'ve heard and which we\'ll do
our very best to act upon and lastly, the desire for a systems-based
approach so that we ourselves don\'t fall victim to unintended
consequences that individual well thought actions don\'t, in their
aggregate wind up having an effect that we really didn\'t want to
happen.

In light of those themes, let me express my gratitude and that of the
working group for a very fine discussion today. To those individuals who
spoke here and to those of you who will be speaking in the coming weeks
to the docket that, we will look very eagerly to examine for further
assistance in moving forward with this paper.

Thank you.

DR. SELIGMAN: Thank you, Anne. Are there any other comments either from
the working group or from the steering committee?

If there are no additional comments, tomorrow morning we will begin at 8
o\'clock to deal with the third concept paper on risk assessment of
observational data, good pharmacovigilance practice and
pharmacoepidemiological assessment. The Commissioner of the FDA, Dr.
McClellan will be joining us tomorrow morning, so don\'t sleep late. It
will hopefully offer the opportunity to hear what the Commissioner\'s
viewpoints are on this particular issue as was mentioned yesterday.

Again, I also want to extend my thanks to all of you for a very lively
and robust discussion today and especially to the speakers for coming
forward and we look forward to all of your comments.

Thank you and have a good evening.

(Whereupon, at 4:17 p.m., the workshop was adjourned, to reconvene
tomorrow, Friday, April 11, 2003 at 8:00 a.m.)