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UNITED STATES OF AMERICA
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
ANTI
-
INFECTIVE DRUGS ADVISORY COMMITTEE
(AIDAC)
+ + + + +
MEETING
+ + + + +
WEDNESDAY
FEBRUARY 20, 2002
+ + + + +
The Committee met at 8:00 a.m. at the Holiday
Inn, Two Montgomery Village Avenue, Gaithersburg,
Maryland, Dr. L. Barth Reller, Chairman, presiding.
PRESENT
:
L. BARTH RELLER, M.D. Chairman
GORDON L. ARCHER, M.D. Member
DAVID M. BEL
L, M.D. Consultant
P. JOAN CHESNEY, M.D. Consultant
STEVEN EBERT, Pharm.D.
Consumer
Representative
MARY GLODE, M.D. Consultant
DON GOLDMANN, M.D. Guest
CATHERINE HARDALO, M.D.
PhRMA Representative
JAMES E. LEGGETT, JR., M.D. Member
CELIA MAXWELL, M.D. Consultant
JOSHUA P. METLAY, M.D., PhD Guest
MARISSA A. MILLER, DVM, MPH Guest
JUDITH R. O'FALLON, PhD Member
JAN A. PATTERSON, M.D.
Consultant
JULIO A. RAMIREZ, M.D. Member
LOUIS B. RICE, M.D.
IDSA Representative
COLEMAN ROTSTEIN, M.D. Guest
DAVID SHLAES, M.D.
PhRMA Representative
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PRESENT: (continued)
CIRO SUMAYA, M.D.
Consultant
GEORGE H. TALBOT, M.D. IDSA Rep
FRANCIS TALLY, M.D.
Cubist Pharmaceutical
JANET WITTES, PhD Consultant
LIANNG YUH, PhD
PhRMA Representative
TARA P. TURNER, Pharm D.
Executive Secretary
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I
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N
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D
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E
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X
Page
Call to Order, Introductions
4
L. Barth Reller, M.D., Chair
Conflict of Interest Statement
6
Opening Comments, Mark Goldberger, M.D.
10
Acting Director, Office of Drug Evaluation IV
Antibiotic Resistance: Update
12
Janice Soreth, M.D.
Developing
Drugs for Resistant Pathogens
22
David Ross, M.D.
Industry Presentation (PhRMA)
41
David Shlaes, M.D.
Catherine Hardalo, M.D.
Lianng Yuh, Ph.D.
Christy Chuang
-
Stein, Ph.D.
Industry Presentation
76
Francis Tally, M.D., Cubist
IDSA Presentation
102
Louis B. Rice, M.D., George H. Talbot, M.D.
Dennis D. Wallace, Ph.D.
Committee Discussion
115
Open Public Hearing
161
Summary and Presentation of Issues
208
Mark Goldberger, M.D.
Committee Discussion
212
Adjourn
267
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P
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1
(8:06 a.m.)
2
CHAIRMAN RELLER: I would like to call
3
today's meeting of the Anti
-
In
fective Drugs Advisory
4
Committee to order and begin the day with introductions.
5
I am Barth Reller, Division of Infectious
6
Diseases, Director of Clinical Microbiology, at
7
University of
--
Duke University. We will begin our
8
introductions, inclusive of all of the tables, and start
9
at my far, far right, Dr. Metlay.
10
DR. METLAY: Josh Me
tlay, University of
11
Pennsylvania, Departments of Medicine and Epidemiology.
12
DR. YUH: Lianng Yuh from Astra Zeneca.
13
DR. SHLAES: David Shlaes from Wyeth
-
Ayerst.
14
DR. TALLY: Frank Tally from Cubist
15
Pharmaceuticals.
16
DR. GOLDBERGER: Mark Goldberger,
Office of
17
Drug Evaluation IV, FDA.
18
DR. ALBRECHT: Renata Albrecht, Division of
19
Special Pathogens and Immunologic Drug Products, FDA.
20
DR. SORETH: Janice Soreth, Division of
21
Anti
-
Infectives at the FDA.
22
DR. LEGGETT: Jim Leggett, oregon Health
23
Sciences
University.
24
DR. SUMAYA: Ciro Sumaya, School of Rural
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Public Health, Texas A&M University System Health Science
1
Center.
2
DR. GLODE: Mimi Glode, Pediatric Infectious
3
Disease, University of Colorado.
4
DR. O'FALLON: Judith O'Fallon, Cancer
5
Center Stati
stics, Mayo Clinic, Rochester, Minnesota.
6
DR. RAMIREZ: Julio Ramirez, Division of
7
Infectious Diseases, University of Louisville, Kentucky.
8
DR. TURNER: Tara Turner, Executive
9
Secretary for the Committee.
10
DR. EBERT: Steve Ebert, Meriter Hospital
11
and
University of Wisconsin, Madison.
12
DR. BELL: David Bell, National Center for
13
Infectious Diseases, CDC.
14
DR. PATTERSON: Jan Patterson, Adult
15
Infectious Diseases, University of Texas Health Science
16
Center, San Antonio.
17
DR. ARCHER: Gordon Archer, Adul
t Infectious
18
Diseases, Virginia Commonwealth University in Richmond,
19
Virginia.
20
DR. CHESNEY: Joan Chesney, Pediatric
21
Infectious Disease at the University of Tennessee Health
22
Science Center in Memphis.
23
DR. WITTES: Janet Wittes, statistician,
24
Statistics
Collaborative, D.C.
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DR. MILLER: Marissa Miller, National
1
Institute of Allergy and Infectious Diseases.
2
DR. ROTSTEIN: Coleman Rotstein, McMaster
3
University, Hamilton, Canada.
4
DR. GOLDMANN: Don Goldmann, Pediatric ID,
5
Children's Hospital, Boston, r
epresenting the
6
Bacteriology and Mycology Study Group of NIAID.
7
DR. TALBOT: George Talbot, Talbot Advisors,
8
representing IDSA.
9
DR. RICE: Lou Rice, Medicine and Infectious
10
Disease, Cleveland VA Hospital and Case Western Reserve,
11
representing IDSA.
12
C
HAIRMAN RELLER: Thank you. Dr. Turner.
13
DR. TURNER: Thank you. The Food and Drug
14
Administration has prepared general matters waivers for
15
the following Special Government Employees: Julio
16
Ramirez, Steven Ebert, Jan Patterson, Celia Maxwell, Ciro
17
Sumay
a, L. Barth Reller, Alan Cross, Gordon Archer, James
18
Leggett, Jr., Joan Chesney, Celia Christie
-
Samuels, and
19
Janet Wittes, who are attending today's Anti
-
Infective
20
Drugs Advisory Committee meeting on the approaches to
21
development of anti
-
microbial agents f
or the treatment
22
of resistant pathogens being held by the Center for Drug
23
Evaluation and Research.
24
A copy of the waiver statements may be
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obtained by su
bmitting a written request to the agency's
1
Freedom of Information Office, Room 12A
-
30 of the Parklawn
2
Building.
3
Unlike issues before a committee in which
4
a particular product is discussed, issues of broader
5
applicability such as the topic of today's meet
ing involve
6
many industrial sponsors and academic institutions.
7
The Committee members have been screened for
8
their financial interests as they may apply to the general
9
topic at hand. However, because general topics impact
10
on so many institutions, it i
s not prudent to recite all
11
potential conflicts as they apply to each member.
12
FDA acknowledges that there may be potential
13
conflicts of interest, but because of the general nature
14
of the discussion before the Committee, these potential
15
conflicts are miti
gated.
16
With respect to FDA's invited guests, there
17
are reported interests which we believe should be made
18
public to allow the participants to objectively evaluate
19
their comments.
20
Dr. Don Goldmann owns stock in Pfizer and
21
Merck. He is also a consulting
contractor with
22
BioSynexis and receives consulting fees from a law firm
23
representing Novartis on a legal case.
24
Dr. Joshua Metlay lectures and is a
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scientific advisor for Aventis.
1
Dr. Coleman Rotstein serves as a researcher
2
and has contracts and grants
from Pfizer, Merck, ICOS,
3
Schering, Wyeth and Fujisawa. In addition, Dr. Rotstein
4
consults for Merck, Schering, Pfizer and Pharmacia. He
5
also lectures for Pharmacia, Pfizer, Bayer, Merck and
6
Fujisawa.
7
In addition, we would like to note for the
8
record
that Doctors Catherine Hardalo, David Shlaes,
9
Liangg Yuh, and Chrisy Chuang
-
Stein from PhMRA, and Dr.
10
Francis Tally from Cubist Pharmaceuticals are
11
participating in this meeting as industry representatives
12
acting on behalf of regulated industry. As such,
these
13
participants have not been screened for any conflicts
14
of interest.
15
Also, Doctors George Talbot, Dennis Wallace,
16
and Louis Rice are participating in this meeting on behalf
17
of the Infectious Disease Society of America. As such,
18
these participants ha
ve not been screened for any
19
conflicts of interest.
20
I have one announcement. If you wish to
21
enter a statement for the record, comments on this meeting
22
topic may be submitted to Docket No. 02N
-
0047 titled
23
"Development of Antibiotics for Resistant Pathoge
ns."
24
We have prepared a handout which is available
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at the registration table. It's a blue handout. Thank
1
you.
2
CHAIRMAN RELLER: One reminder. When you
3
speak, tap the button on the bottom of your microphone
4
that lights up the red ring.
5
If you are
not at the table and already have
6
introduced yourself, please give your name and position,
7
if you come to a microphone for the comments from the
8
group later.
9
Next we shall have an update on antibiotic
10
resistance presented by Dr. Janice Soreth, Director,
11
Division of Anti
-
Infective Drug Products at the FDA.
12
DR. SORETH: But first Dr. Goldberger will
13
make some opening comments, I think.
14
CHAIRMAN RELLER: Ah, indeed, he will. Dr.
15
Goldberger.
16
DR. GOLDBERGER: Well, in the interest of
17
that, I will make
my remarks particularly brief today.
18
Basically, we would again like to extend our
19
welcome to Advisory Committee participants, invited
20
guests, consultants, and members of the audience.
21
As I said yesterday, and it's certainly still
22
true today, the goal
that we have is to ensure that there
23
is adequate antimicrobial therapy to meet the therapeutic
24
challenges that we face. In this case today, we will
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be focusing on primarily resistant organisms and, I think,
1
some of the serious infections that they are of
ten
2
associated with.
3
Again, I want to emphasize, we view this
4
meeting as the beginning of a process. This meeting will
5
be followed by a docket that will be open, I think, for
6
at least 120 days for additional public comment, and that
7
will be followed the
n by at least one other subsequent
8
meeting to discuss perhaps in more detail both some of
9
the issues that have been raised here, as well as the
10
issues that have been raised in the docket, and other
11
information and comments that we receive from other
12
groups
.
13
I think we certainly believe that it is
14
appropriate to be flexible in the approach to products
15
that add value, particularly in more serious diseases
16
and, certainly, oncology drug development and HIV drug
17
development certainly are good examples of that,
and we
18
believe that the development of agents for resistant
19
infections clearly falls into that area.
20
We do think that, as we consider ways to
21
expedite the development of such products, we must also
22
consider what approaches might be appropriate that woul
d
23
preserve the value of these products. Fundamentally, we
24
would like, if possible, to restrain a little bit the
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built
-
in obsolescence that does seem at times to be a
1
component of many new antimicrobials that are developed.
2
There are clearly a number of a
pproaches to
3
developing drugs for resistant indications. There are
4
a number of situations that occur ranging from drugs that
5
are fairly toxic, intravenous only, that are probably
6
ideal for fairly limited situations to oral and IV or
7
oral only broad spectr
um agents that would be effective
8
against resistant organisms as well as many others.
9
The approaches that one might take to the
10
development of products like that differ widely. At
11
today's meeting some of the suggestions we will be
12
presenting will focus
on a couple of aspects of this,
13
probably initially more on an intravenous, more toxic
14
type of drug.
15
We do not want to give the impression that,
16
by any stretch, that is the only way to proceed. We do
17
feel, however, that that may be the best way to initiat
e
18
the discussion, with the understanding that subsequently
19
in forums like this as well as in interactions with
20
industry, there will need to be discussions of the broader
21
range of possibilities.
22
Thank you.
23
CHAIRMAN RELLER: Thank you, Dr. Goldberger.
24
Dr. Soreth.
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DR. SORETH: Good morning. Leo, if I could
1
have the first slide, please.
2
I wanted to give an update this morning on
3
recent developments and history within the FDA Center
4
for Drugs for developme
nt of products for antibiotic
5
resistance.
6
By way of overview, I would like to briefly
7
summarize some of the meetings that we have had within
8
the Center that come largely in two flavors, both general
9
meetings on antibiotic resistance and drug development,
10
as well as specific product meetings, talk about some
11
of the important lessons learned within those meetings,
12
and finally talk briefly about what's new in 2002.
13
The reduction in morbidity and, here,
14
mortality from infectious diseases in the United State
s
15
in the past century is certainly one of the great public
16
health success stories. However, recent trends are
17
somewhat concerning. Next slide, please.
18
We know that bacteria wisely adapt to
19
pressures, one of them being the use of antibiotics.
20
So that t
he rise in resistant pathogens shown here
21
threatens to thwart or wipe out the gains that we have
22
realized in the previous century by leading to untreatable
23
infections.
24
So we've met and met again almost on a yearly
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basis, sometimes twice yearly since 1998
. When we began
1
in July of '98 a dialogue, a workshop, a word I heard
2
a lot about yesterday, the '98 July meeting was a meeting
3
between FDA and largely with industry to get input on
4
approaches to developing new products for resistant
5
pathogens and to try
to talk very seriously about
6
streamlining that process.
7
In October of '98 we expanded the discussion
8
to members of this Anti
-
Infective Advisory Committee,
9
to academia, to other public health agencies, as well
10
as other regulatory bodies and the industries
whom they
11
regulate, to define antibiotic resistance, to discuss
12
the use of information like pharmacokinetics and
13
pharmacodynamics in drug development, to talk about
14
prudent use of antibiotics so that we might preserve or
15
maintain those agents that we alre
ady have on the market
16
that we wish to be able to use for many years to come.
17
Finally, in October of '99 we had our last
18
general meeting on antibiotic resistance, and this dealt
19
with a guidance, in this case a guidance on
20
catheter
-
related bloodstream inf
ections which are often
21
associated with resistant pathogens, with the intent to
22
encourage development of products in this arena.
23
From the product
-
specific meetings
--
Let
24
me just go back to that slide, Leo, please. From the
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product
-
specific meetings be
ginning with Synercid in
1
1998, Levaquin in October of '99, Zyvox in April of 2000,
2
and finally AugmentinES, January a year ago, I think we
3
gained a lot of knowledge, and the deliberations of the
4
Committee were certainly important in helping us to reach
5
con
clusions and come to an action that led to the
6
registration of each of these products some months after
7
the Advisory Committee meeting. Next slide, please.
8
What were some of the important lessons
9
learned, both from the general meetings on resistance
10
as
well as the product
-
specific meetings?
11
I think that we have found that regulatory
12
tools may encourage development and facilitate
13
registration. I think, particularly in the Synercid
14
deliberations, the use of surrogate markers in the
15
clearance of bacterem
ia were an important tool, part of
16
Subpart H David Ross will go into a little bit more, that
17
it enabled us to reach a conclusion that this represented
18
substantial evidence that would lead to the registration
19
of Synercid for treatment of vancomycin
-
resistan
t
20
enterococcus faecium infections.
21
I think that we recognize fully that greater
22
flexibility is something that we all need to have when
23
therapeutic options are limited and when there are no
24
approved drugs on the landscape.
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Novel approaches to study desi
gn need to be
1
considered always. The traditional way that antibiotics
2
for routine infections are developed don't easily apply
3
here, don't readily and quickly enable companies to amass
4
data to support resistant pathogens.
5
What are some of these novel app
roaches that
6
we have used in the registration of the products in the
7
previous slide? Well, I think with the development of
8
Pharmacia's linezolid or Zyvox, we had the luxury in the
9
anti
-
infectives of having a dose response trial, again
10
in the setting of va
ncomycin
-
resistant enterococcal
11
infections, when at the time of that product's development
12
there were no proof comparators, where we learned that
13
historical control is really difficult and that we might
14
gain an important body of data by employing what I th
ink
15
in non
-
anti
-
infective realms of drug development might
16
be used more commonly, the dose response trial. But it's
17
not a one
-
size
-
fits
-
all gain.
18
We recognize that, if one has a product with
19
a very narrow safety therapeutic margin, something like
20
a dose
response trial probably isn't feasible.
21
Furthermore, I think there are ethical
22
considerations that can be raised with dose response
23
trials, for the key in a dose response trial is to pick
24
pharmakinetically distinct enough doses that one can hope
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to show
a difference, while at the same time picking a
1
lower dose that is not a thinly veiled placebo.
2
Enrichment strategies can help, and I think
3
we have seen this strategy work, particularly in the realm
4
of otitis media and the development of products for
5
p
enicillin
-
resistant Strep. pneumoniae.
We've
6
talked at committee meetings like this about what some
7
of those enrichment strategies are in otitis, studying
8
children under the age of two, studying children with
9
a history of difficult to treat or many prior
infections
10
with otitis, studying children with siblings, children
11
in daycare, etcetera.
12
Those strategies have helped, but again it's
13
not one
-
size
-
fits
-
all for all indications, because I
14
think, on the other hand, in the realm of community
15
acquired pneumon
ia, enrichment strategies haven't worked
16
or they haven't worked as well, as readily as they have
17
in developing drugs for otitis.
18
Overall, we know that the total body of
19
evidence and everything that's in the package is helpful,
20
and that includes experienc
e from susceptible isolates.
21
They are an important part of the overall picture, and
22
tell us something about how a drug performs as an
23
anti
-
pneumococcal agent, as an anti
-
staph agent.
24
A strategy of what we like to think of as
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working backwards has helped
, certainly in the arena of
1
MRSA, methizone
-
resistant staph aureus infections, where
2
a product's development may include site specific
3
protocols, a pneumonia protocol, a skin and skin structure
4
protocol.
5
That's augmented by another umbrella or
6
catchall p
rotocol that would work backward from positive
7
cultures to the patients represented to have those
8
infections for overall augmentation of experience with
9
a particular isolate. Next slide.
10
While regulatory tools have helped, it is
11
still a challenge to acc
rue organisms. We hear that time
12
and time again from colleagues in the pharmaceutical
13
industry, and great resources are spent to develop a drug
14
for resistant pathogens, great resources both when the
15
claim is an in
-
class claim as well as out of class.
16
I think we need to think about that and, as
17
we recognize resources are limited, decide is that is
18
a direction that is wise to continue to go in.
19
As I mentioned, historical controls can be
20
used when there is no proof comparator, but they may be
21
--
they us
ually are problematic.
22
Finally, more data do not necessarily equal
23
better data. At the end of the day, if we have 1,000
24
patient experience, a 1500 patient experience, but we
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really can't form a conclusion about what those data mean,
1
it's a very difficu
lt position to be in, both for drug
2
developers, the investigators who participated in the
3
trials, the patients who were exposed to the medication,
4
and we as regulators.
5
Bottom line, very simply: We recognize that
6
new drugs are still needed, as is preser
vation of the
7
already marketed ones. The pipeline is not bursting with
8
new products. We need to maintain what we have as well
9
as try to encourage development of new. Next slide.
10
Well, what is new in 2002 with regard to
11
resources, surveillance, education, and future
12
approaches, which I will only touch on briefly as the
13
final bullet is the subject of Dr. David Ross's talk.
14
We have received at the FDA Center for Drugs
15
resources ear
marked specifically for antimicrobial
16
development and resistant issues, and we intend to
17
increase our staff who can deal with these.
18
We plan to augment our access to surveillance
19
information, in collaboration with colleagues at the
20
Centers for Disease Co
ntrol as well as with the private
21
sector. The goal here is to better approach
22
anti
-
microbial drug development and usage.
23
As far as education is concerned, we know
24
that we have to target both the health care professional
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as well as patients, and we plan
to address antibiotic
1
resistance and prudent use in product labeling, and
2
anticipate an impact on promotional material.
3
We are cognizant of the fact that more
4
information in package inserts are not the sole solution
5
to getting information out about antib
iotic resistance
6
and antibiotic utilization, but feel for us it's an
7
important first step.
8
In September of 2000, the
Federal
Register
9
had a proposal to amend regulations that would require
10
all systemic antibacterial products intended for human
11
use to con
tain additional labeling information about the
12
emergence of drug resistant bacteria.
13
The intent here is to encourage physicians
14
to prescribe antibiotics only when they are clinically
15
necessary, and to counsel their patients about the proper
16
use of antibi
otics and taking them as directed.
17
At this point the proposed rule has received
18
comments. I believe those comments are in the process
19
of being collated, as we anticipate an issuance of the
20
final rule. Next slide.
21
A CDER effort is underway to develop
22
advertisements on the prudent use of antibiotics, and
23
we envision a variety of media to do this, both in print
24
advertisements in professional journals, patient
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leaflets, and public service announcements, again in
1
collaboration with other agencies like CDC
who have
2
already been doing this for a number of years. Next
3
slide.
4
As to future approaches to anti
-
infective
5
development for resistant pathogens, we recognize fully
6
that they require creativity and flexibility on our part.
7
We are cognizant of the limi
ts of resources, patients,
8
time and money, that go into developing an antimicrobial
9
product, period, especially an antimicrobial product for
10
resistant pathogens.
11
As Dr. Turner mentioned at the outset of this
12
meeting, we welcome your comments, written co
mments, on
13
approaches to anti
-
infective development for resistant
14
pathogens, and you may submit them to Docket 02
--
I left
15
out the N for Nancy
--
0047. Next slide.
16
In summary, I think we have made some progress
17
in getting antimicrobial products registe
red for patients
18
with resistant pathogens, but clearly more are needed.
19
We also need to preserve the antibiotic treasures that
20
we do have, through education, through prudent use.
21
Finally, we recognize the need to strike a
22
balance between available resou
rces for performing
23
clinical trials and level of certainty in determining
24
effectiveness.
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I thank you, and will turn the podium over
1
to Dr. Ross.
2
CHAIRMAN RELLER: Dr. David Ross is a Medical
3
Team Leader at the Division of Anti
-
Infective Drug
4
Products a
t FDA, and will speak to us about developing
5
drugs for resistant pathogens: problems and
6
possibilities.
7
DR. ROSS: Good morning. I am going to be
8
speaking this morning about problems and possibilities
9
in terms of developing drugs for resistant pathogen
s.
10
I think one thing we want to emphasize is that this is
11
what is the continuation of a wide ranging discussion
12
about how to deal with this extremely serious public
13
health problem.
14
Let me first mention my colleagues in the
15
Office of Drug Evaluation who
have been working on this
16
area with me: Dr. Edward Cox from the Division of Special
17
Pathogens; Dr. Brad Leissa who is now working on
18
bioterrorism issues; Dr. Jean Mulinde; Dr. Janice Soreth
19
from the Division of Anti
-
Infective Drug Products; Dr.
20
Renata Alb
recht from the Division of special Pathogens
21
and Immunologic Drug Products; and Dr. Mark Goldberger
22
from the Office of Drug Evaluation IV. Next slide,
23
please.
24
What I would like to do is talk briefly about
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some trends in antimicrobial drug resistance, re
view
1
briefly some of the problems in developing drugs for
2
resistant pathogens
--
and I know we will hear more about
3
this from our colleagues in industry and from our
4
colleagues at the IDSA
--
and then talk about one
--
and
5
I want to emphasize one
--
possib
le solution which is
6
focused development.
7
It is not the intent that this serve as the
8
template for all future efforts to develop drugs for
9
resistant pathogens, but as one potential element. Next
10
slide, please.
11
I've just listed here some resistant bact
eria
12
that are of public health concern. This is not intended
13
to be an all inclusive list, but it's some organisms that
14
clearly represent a problem: Methicillin
-
resistant
15
staph aureus; methicillin
-
resistant coagulase
-
negative
16
staph; VRE; multidrug
-
resista
nt Klebsiella and
17
Pseudomonas as well as other gram negative rods; and in
18
the community setting penicillin
-
resistant strep pneumo
19
and multidrug
-
resistant nin
-
typhi salmonella.
20
I think it's important to remember that there
21
is interchange between these two
environments. So these
22
categories are somewhat artificial and will continue to
23
blur. Next slide, please.
24
These are just some prevalence and incidence
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estimates of various resistant organisms. Just as a note
1
of clarification, I want to mention that th
ese bloodstream
2
estimates represent my own quick calculations from a paper
3
by Edmond that was published in CID a few years ago using
4
a figure of 250,000 bloodstream infections per year.
5
The point I want to make is that these numbers
6
may seem at first gla
nce low, but the impact of these
7
infections on the public health is extraordinary, because
8
we don't have effective treatment or what we regard as
9
very good treatments for a lot of these patients, and
10
these are, obviously, transmissible pathogens.
11
In the
briefing package I also presented some
12
very, very, very crude estimates drawn from Dutch data
13
of the burden of disease due to resistant pathogens.
14
One thing I would like to emphasize is these are almost
15
certainly, as are these, extreme underestimates, and
we
16
look forward to more definitive robust analyses from our
17
colleagues at CDC.
18
I think, even given the conservative nature
19
of these estimates, this is clearly a bad problem. Even
20
when you have a low prevalence
--
for example, for
21
fluoroquinolone
-
resist
ant gonococcus
--
this translates
22
into a substantial public health problem. Next slide.
23
It is not a static problem either. We all
24
know it's getting worse. This is a slide that people
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have seen not only in this presentation but in a number
1
of others a
variety of times. One thing I want to point
2
out that's missing from this slide, which is gram
-
negative
3
rods. I would like people to keep that in mind as one
4
component of the resistance problem that we need to
5
address as we move forward in our discussions
. Next
6
slide.
7
Well, in response to this, the Public Health
8
Service convened a task force chaired by CDC, NIH and
9
FDA with input from other Federal agencies and other
10
stakeholders to deal with this crisis. There's a number
11
of components to this action p
lan.
12
There is prevention, research, surveillance,
13
and product development. Under each of these elements
14
there are a number of action items, and I want to just
15
cite two for product development.
16
One action item, 82, calls for streamlining
17
the regulatory process. I'll just mention here that the
18
action plan is
--
The report and the action plan are
19
available on the CDC's website and on the FDA's website,
20
if people would like more details.
21
Another
action item that's quite important
22
is identifying ways to promote the development of priority
23
antimicrobial resistance products, Action Item 80. This
24
includes incentives. While we will not explicitly be
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discussing incentives today, that's clearly one com
ponent
1
that needs to be considered in any response to this
2
problem. Next slide, please.
3
What are the regulatory tools that we have
4
at hand right now to implement the product development
5
aspect of the response to resistance? Well, briefly
6
these are
--
a
nd I'll go into these in more detail
--
7
Subpart E, Subpart H, fast track, and market exclusivity,
8
and I'll talk about what each of these mean in a minute.
9
10
I want to make the point that these are
11
intended to deal with
--
These are written in a fairly
12
ge
neral way that allows us to apply them to antimicrobial
13
resistance. They are not, in and of themselves, explicit
14
economic incentives except for market exclusivity. Next
15
slide, please.
16
Subpart E
--
and I'll forgo citing the CFR
17
section, although that is
really one of the joys of being
18
a bureaucrat
--
is intended to address life threatening
19
and severely debilitating illnesses. It calls for
20
utilizing risk
-
benefit analysis in the decision making
21
process.
22
It promotes early consultation between the
23
FDA a
nd pharmaceutical sponsors as well as increased
24
communication, which can be crucial in a successful
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development program and, finally, provides for earlier
1
approval in the drug development process than one
2
traditionally sees. Next slide.
3
Subpart H, which
is also known as accelerated
4
approval, addresses serious or life threatening diseases
5
and targets agents that provide a meaningful therapeutic
6
benefit over existing therapy.
7
One major feature of Subpart H is the use
8
of surrogate endpoints as the basis
for accelerated
9
approval, and this refers to surrogate endpoints that
10
are reasonably likely to predict clinical benefit.
11
I'd like to just take a minute to talk about
12
that, because one focus of the discussion yesterday was
13
on surrogate markers that cou
ld be useful in development
14
of drugs, and I would like people to keep in mind that
15
these markers have both strengths and weaknesses.
16
They may allow us to develop drugs much, much
17
more rapidly. A classic example is the use of HIV viral
18
load in developmen
t of antiretrovirals, and that's been
19
extraordinarily successful.
20
It's important to keep in mind that
21
surrogates are just that. They are not direct evidence
22
of clinical benefit, and you can go wrong sometimes or
23
get fooled. Another classic example occu
rred as the
24
cardiac arrhythmias back in the late Eighties.
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It was noted that there was increased
1
mortality in post
-
MI patients who had an increased number
2
of ventricular premature contractions, and it made sense
3
that if you suppressed those VPCs, you w
ould reduce
4
mortality. This led to the cardiac arrhythmia
5
suppression trial in which patients who had been shown
6
to respond to these drugs were randomized either to the
7
drug or to placebo.
8
t was argued actually that this might not
9
be an ethical trial, t
hat this was becoming the standard
10
of care, consensus standard, and therefore, it wasn't
11
ethical to a trial where everyone knew that this was the
12
thing to do.
13
In fact, the patients who were treated with
14
anti
-
arrhythmics had a markedly increased mortali
ty rate
15
as well as cardiac arrest rate due to arrhythmias, and
16
this trial showed that VPCs as a surrogate marker were
17
not predictive of benefit. Just the opposite.
18
So we need to be careful about using surrogate
19
markers. They can be very helpful, but th
ey are not
20
clinical benefit or evidence of clinical benefit in and
21
of themselves. For that reason, Subpart H calls for
22
post
-
marketing confirmatory trials.
23
If a clinical benefit is not shown, there
24
are provisions for expedited withdrawal. In addition,
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Subpart H also calls for prior submission of promotional
1
materials and carries the potential for restricted
2
distribution and use. Next slide, please.
3
Fast Track designation, which is part of the
4
FDA Modernization Act, combines Subparts E and H. It
5
inc
ludes a provision to accept for review a portion of
6
a marketing application prior to submission of the
7
complete package.
8
A final regulatory tool that is available
9
to us is market exclusivity. Without going into the
10
economic aspects of this in great deta
il, essentially
11
this is protection of a product from identical products
12
being introduced in the market, and represents an
13
incentive for companies to spend the money to develop
14
a drug and get their investment back.
15
There's a number of different forms of t
his:
16
Orphan Drug exclusivity which applies to agents intended
17
to treat a condition affecting 200,000 patients per year
18
or less. This represents seven years of stand
-
alone
19
marketing exclusivity for each indication for which it
20
is approved.
21
Pediatric exc
lusivity: If a sponsor
22
performs studies requested by the agency, six months of
23
exclusivity can be added onto other forms of exclusivity,
24
such as patent protection.
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Then finally, there's a form of exclusivity
1
called Waxman
-
Hatch that provides for three t
o five years
2
of marketing exclusivity. Next slide.
3
Now our job at the agency is to look at the
4
data and say do we think this drug is safe and effective?
5
But we cannot ignore the fact that, as Dr. Andriole said
6
yesterday, drugs are developed by drug com
panies.
7
What are some of the considerations that a
8
sponsor looks at when they develop drugs, and I'm going
9
to talk about this very briefly. I know that again our
10
colleagues from industry will be talking about this more.
11
Some obvious things to look a
t are market
12
potential. How many patients have got the condition that
13
you are studying the drug for, and how long will they
14
be receiving the drug? There's a big difference between
15
giving an agent for two weeks versus giving it for the
16
rest of a patient's
life, an antibiotic versus a
17
cholesterol lowering agent.
18
What's the feasibility of doing a study?
19
How long will it take? How many patients do you have
20
to screen to get there?
21
How complex is the trial? How many patients
22
do you have to accrue? How h
ard is it to accrue them?
23
How do you document the diagnosis? One thing to remember
24
is that, as opposed to many other therapeutic areas in
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infectious diseases, the diagnosis is generally
1
established during the trial. It's not like, for
2
example, colon car
cinoma where patients may come in with
3
the diagnosis already established.
4
Then finally, what's the development time?
5
How long does it take to develop the drug, and what is
6
the regulatory review clock? Next slide, please.
7
In terms of market potential, I just wanted
8
to briefly talk about this. The point I want to make
9
--
This is just a summary of data from IMS Health
--
about
10
15 or so classes of drugs account for half of all drug
11
sales in this country.
12
Antimicrobials
--
a
nd this excludes
13
antiretrovirals
--
account for about four percent of all
14
sales. So this is a small but critical portion, but
15
clearly, there are many other therapeutic areas that a
16
pharmaceutical company may choose to invest its time,
17
money and resources
in.
18
Furthermore, if you blow up this four percent
19
or you expand this four percent, I should say
--
next
20
slide. This is data from Linda McCaig and James Hughes
21
at CDC
--
the majority of prescriptions are written for
22
upper respiratory tract infections,
and Dr. Thompson
23
showed this slide yesterday. Again, this is from ten
24
years ago.
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The situation is probably about the same or
1
more extreme today. The sort of serious infections we're
2
talking about, meningitis, endocarditis, nosocomial
3
pneumonia, repres
ent a much smaller portion of this pie.
4
Next slide.
5
In terms of feasibility, I would like to show
6
some results from a recent trial of community
-
acquired
7
pneumonia. This is not necessarily typical, but I think
8
it's illustrative.
9
This trial enrolled 74
5 patients. 561 of
10
these completed the protocol. 191 of these had a pathogen
11
isolated. 146 of these patients had pneumococcal
12
pneumonia or what we thought was pneumococcal pneumonia
13
on the basis of sputum and blood culture data.
14
In terms of who we rea
lly felt sure had
15
pneumococcal pneumonia, there were 54 patients who were
16
bacteremic, who had what we regard as definitive evidence
17
of invasive pneumococcal disease. None of these patients
18
had a highly resistant pneumococcal isolate.
19
So does this mean t
hat those patients aren't
20
out there or this isn't a problem? Of course not. What
21
it means is that clinical trials that are being conducted
22
have difficulty capturing these patients, and it's easy
23
to understand why.
24
If there is a requirement that patient
s not
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be exposed to antimicrobials for a prolonged period of
1
time before entry, well, that's one major risk factor
2
for pneumococcal resistance.
3
So even large controlled trials for common
4
indications
--
Dr. Powers mentioned yesterday that
5
there's about 4
million cases of CAP in this country a
6
year
--
may not be sufficient to obtain the sort of data
7
we would like to get about treatment of infections due
8
to resistant pathogens. Next slide.
9
In terms of dealing with these problems, I'd
10
like to consider four
broad categories of drugs, and these
11
are not the way that we look at things from a regulatory
12
perspective but just
--
this is a convenient way of
13
classifying drugs as far as their applicability to the
14
problem of resistant pathogens.
15
What I'd like to do
is focus on new
--
that
16
is, unapproved
--
drugs that are targeting a narrow range
17
of indications, category 3. I want to emphasize, this
18
is not the only possible category that could help address
19
the resistance problem. We are going to focus on it
20
today,
but drugs in the other categories could also be
21
quite useful. Next slide.
22
What we would like to throw out for
23
consideration is looking at category 3 drugs, those that
24
have not been
--
are not on the market yet and have a
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potential narrow range of indica
tions as candidates for
1
focused development.
2
What do we mean by that? Development
3
specifically for serious indications due to resistant
4
pathogens. Why focused development? This is called for
5
or mentioned in the action plan, and it may allow marketing
6
of agents that would not otherwise be developed, either
7
because of toxicity concerns or market considerations
8
or other reasons.
9
The safety profile of the drug may preclude
10
a broader program, and approval of these agents may rely
11
on Subpart H, using surro
gate markers and confirmatory
12
trials with restricted distribution and labeling. Next
13
slide.
14
What are some of the characteristics of a
15
candidate agent for focused development? Obviously, it
16
should have activity against the resistant pathogen.
17
There sho
uld be an absence of alternative or comparable
18
therapy for the pathogen, subject pathogen and subject
19
indication.
20
The subject pathogen and subject indication
21
should represent an important public health problem, and
22
the safety information on the drug's ri
sk profile should
23
support an acceptable risk
-
benefit profile, assuming that
24
there's going to be a limited population exposure.
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That's why we are targeting specifically category 3 drugs.
1
Next slide.
2
I think it's helpful to quote here from the
3
rule for S
ubpart H that was published in the
Federal
4
Register
, which states that "these procedures"
--
that
5
is Subpart E
--
"generally reflect the recognition that
6
physicians and patients are generally willing to accept
7
greater risks or side effects from products t
hat treat
8
life
-
threatening and severely debilitating illnesses
9
than they would accept from products that treat less
10
serious illnesses"
11
It's a tradeoff. We are willing to accept
12
more risk if there is evidence of added benefit,
13
especially when there are n
o therapeutic alternatives,
14
or few therapeutic alternatives. Next slide.
15
What would a development program for
--
our
16
focused development program look like? Well, Phase I
17
would look similar to the traditional program, with dose
18
ranging studies, pharmaco
kinetics performed by either
19
traditional or sparse sampling techniques, and special
20
population studies in the elderly and patients with renal
21
and/or hepatic impairment. Next slide.
22
I think the real differences arise in Phases
23
II and III. A program woul
d call for dose finding, to
24
find an optimal dose, and proof of concept that the drug
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can treat serious infections due to a resistant pathogen,
1
and the data would have to demonstrate safety and
2
efficacy.
3
If there was sufficient data from controlled
4
trials
, then the traditional strategy of adequate and
5
well controlled trials could be followed, combined with
6
enrichment strategies, as Dr. Soreth mentioned.
7
If there's insufficient data from controlled
8
trials, which is the situation that we are confronting,
9
what do we do then? Well, then we might want to look
10
at clinical data with historic controls, keeping in mind
11
the problems that historic controls can give rise to.
12
Data from infections with susceptible
13
organisms may be helpful. If we don't think that
there's
14
a difference in virulence between susceptible and
15
resistant pathogens, then efficacy against infections
16
caused by susceptible pathogens could be supportive.
17
There's a couple of important caveats to
18
this, the major one being that the population
s of patients
19
with susceptible organism infections and resistant
20
organism infections would have to be comparable or at
21
least one would need to try and adjust for differences,
22
since that could affect outcome.
23
The use of surrogate endpoints could be very
24
h
elpful. Bacterial eradication of
--
or serialization
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of the CSF meningitis was mentioned yesterday. Again,
1
we need to make sure that this is a surrogate marker that
2
is reasonably likely to predict clinical benefit.
3
One example that was mentioned yesterday was
4
the use of clarithromycin in treatment of MAI where
5
eradication of the organism from the blood did not
6
correlate with survival. In fact, it showed just the
7
opposite.
8
Then finally, as we will hear about,
9
pharm
acokinetics and pharmacodynamic data may be very
10
helpful in supporting the clinical data. Next slide.
11
What sort of data requirements would be
12
needed in a focused development program? Well, I think
13
one crucial point is the quality of the data is more
14
im
portant than the quantity in this situation.
15
It may be that relatively small databases
16
of 300 to 500 patients could sufficient as opposed to
17
the typical NDA database where one sees upwards of 2,000
18
patients.
19
For conditions that are known to have a high
20
mortality
--
for example, VRE or MRSA, endocarditis
--
21
a small number of successes could suffice if one sees
22
an acceptable cure rate.
23
It's important to remember the tradeoff with
24
a small database. Limited data may mean limited
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availability, because aga
in we are targeting and focusing
1
development on a specific indication. Next slide.
2
Let me just contrast traditional and focused
3
anti
-
infective development in terms of how I've outlined
4
it. Traditional development looks at many indications.
5
Focused dev
elopment would concentrate on one or perhaps
6
a few indications.
7
There would be a large Phase III database
8
in traditional development and a small Phase II/III
9
database in focused development. In traditional
10
development controlled trials are pivotal to ef
ficacy
11
demonstration. Other data is supportive but not central.
12
13
In focused development, safety and efficacy
14
would be examined using clinical data, surrogate markers,
15
data from infections from susceptible pathogens,
16
historical controls and PK/PD.
17
In
traditional development a toxicity
18
profile may preclude further development, because if one
19
is targeting a broad set of indications, toxicity may
20
mean that the risk
-
benefit balance is not there. In
21
focused development the toxicity would be weighed versus
22
the benefit and would not necessarily preclude
23
development.
24
Finally, as I've mentioned, one is looking
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at broad availability for a wide range of indications
1
in traditional development, and focused development would
2
look at limited availability for a narr
ow set of
3
indications. Next slide.
4
Some of the questions that such a program
5
would raise include the following: At what point should
6
a drug enter focused development? At what point do we
7
know enough to say this drug is a candidate?
8
If there are pote
ntial toxicities, what
9
populations should be studied? If one is trying to look
10
at, for example, susceptible pathogen data and there's
11
alternative therapies, it may not be ethical to expose
12
patients to a toxic agent when there are less toxic agents
13
availab
le.
14
Finally, is the incentive of focused
15
development with smaller databases and potentially lower
16
costs and shorter development times worth a limited
17
market? Next slide.
18
So in summary, focused development may
19
increase market incentives by decreasing t
he costs and
20
increasing return on investment; increase the feasibility
21
of clinical trials; decrease the complexity of drug
22
development; and decrease clinical development time.
23
I think that it's important to emphasize that
24
this is just the beginning of th
e discussion about these
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sort of strategies, and there are many other potential
1
solutions. Next slide.
2
Just by way of illustration in terms of what
3
we are looking for, this is
--
People probably know this,
4
but this is "C.C," the world's first cloned cat
. I think
5
I'd just like to use this briefly as an illustration of
6
what we are looking for.
7
It took 190 attempts to clone this cat. So
8
we are looking for something that we recognize is going
9
to require a lot of work, is going to make us feel good,
10
but a
lso represents real science, and hopefully, it's
11
not just a ball of fluff.
12
So let me stop there, and I thank you for
13
your attention.
14
CHAIRMAN RELLER: Than you, Dr. Ross. We
15
will have the industry presentation now by Dr. David
16
Shlaes, and then we will
take some questions if time
17
remains before our break at 9:30 or thereabouts. Dr.
18
Shlaes.
19
DR. SHLAES: Thank you. I am glad to be able
20
to be here today. I'm David Shlaes. I run the
21
antimicrobial discovery group in the therapeutic area
22
for infectious
disease at Wyeth
-
Ayerst, and I'm here
23
today to represent PhRMA.
24
I did spend about 16 years in academic
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medicine where I had a research interest in antimicrobial
1
resistance. So this is a topic near and dear to me and,
2
of course, I took care of patient
s during those years.
3
So today I'm here represent PhRMA
--
and is
4
there a pointer? Thank you
--
and PhRMA's Antimicrobial
5
Working Group. Next slide, please.
6
The Antimicrobial Working Group of PhRMA
7
offers a forum for exchange of scientific informatio
n
8
among PhRMA companies with R&D commitment to
9
anti
-
infective drug products.
10
It provides industry's scientific
11
perspective in response to proposed rules, draft
12
guidances, and relevant issues affecting anti
-
infective
13
drug products. Next slide.
14
This is
just a list of the companies who have
15
been participating in the Antimicrobial Working Group,
16
in at least this recent past. All of these companies
17
contributed to the presentation that I am making right
18
now. Next slide.
19
So PhRMA's Working Group applauds
the efforts
20
of the Interagency Task Force. I think the Interagency
21
Task Force could be a model for a way forward to improve
22
communications not only within the different agencies
23
within HHS, but between Departments in the Federal
24
government and between the
se agencies and industry and
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academia. So I think this has been at least a positive
1
step forward.
2
Obviously, there's room for improvement
3
here, but I think this is a very positive step forward.
4
As Dr. Ross and Dr. Soreth just pointed out, the action
5
items from the Public Health Action Plan included efforts
6
to stimulate the development of priority prod
ucts to treat
7
antimicrobial resistance, a streamlining of the
8
regulatory process, and to identify ways, financial and
9
other incentives, to promote the development of new
10
antimicrobial agents, and we applaud these efforts.
11
Next.
12
Now one of the things tha
t I don't know how
13
much you are aware of, but it is extraordinarily difficult
14
to find or to discover new antibiotics that can actually
15
be used successfully in people.
16
There have been a lot of companies working
17
on this for a very long time, and this is
extraordinarily
18
difficult. The resources required to come up with an
19
NCE that will successfully make it to the marketplace
20
are large.
21
Now when you talk about the problem of
22
resistance, we are talking about generally low incidence
23
pathogens. Obviously,
if we want to anticipate the
24
emergence of resistance, then this is going to be a special
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problem in that regard, especially if, for example, you
1
start out with something like the glycopeptide
2
intermediate strains of
Staph aureus
now, which are very
3
low inc
idence, and you want to be sure that
--
or try
4
and be sure that you have a compound that is active against
5
those strains in the clinic. You know, how will you do
6
that in any kind of trial setting?
7
The other issue is that these strains are
8
not generally
limited to a single infectious disease
9
indication. So you may get one case in a skin infection,
10
one case in a pneumonia. They are in a variety of
11
infections.
12
As you pointed out
--
As the agency has
13
pointed out, the development timelines can be long. t
hey
14
are uncertain, and this is in spite of a current and
15
projected public health need. Next slide.
16
I think issues for the future, no matter how
17
we look at this, I think fewer companies are going to
18
be developing novel antibacterial agents. The reason
19
f
or this is market concerns and the difficulty in actually
20
discovering new agents that we have all experienced over
21
the last decade or so.
22
This means that fewer new antibiotics will
23
be developed, especially parenteral antibiotics. So the
24
very products th
at you would like, I would view as being
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less likely to be developed, because
--
partly because
1
the patients that are available for treatment with such
2
agents tend to be limited.
3
Other issues: The development costs
4
continue to rise as the size of databa
ses required for
5
efficacy and safety are increased. So this is another
6
issue. Along with this, therefore, because of continued
7
reliance on older classes of antibiotics, resistance is
8
going to continue. I think the incidence will be low
9
to be well studie
d in traditional indications, but clearly
10
VRE is going to continue.
11
I think multiply resistant Gram negative
12
bacilli, as Dr. Ross mentioned, is the threat over the
13
horizon, and there is very little in the pipeline for
14
these organisms. I can only think o
f one compound in
15
the pipeline that would address these organisms.
16
Kind of bottom line, novel breakthroughs are
17
going to be few, unless we can identify adequate
18
incentives for these high risk and limited gain
19
indications. Next slide.
20
Now I'm not going
to spend too much time on
21
this, because this has already been covered. But one
22
of the points I wanted to make is that clinical trials
23
are not "real life" We've discussed this a little bit
24
yesterday, but the fact is that the entry criteria that
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we use fo
r clinical trials are actually very artificial
1
compared to the patients that one sees on the wards and
2
in everyday setting.
3
This leads to situations where, in spite of
4
the fact that resistant organisms may be not so uncommon
5
in clinical practice, they ar
e very uncommon when you
6
try to enroll patients into clinical trials.
7
So one of the things that I think we all need
8
to think about as a group is how can we make clinical
9
trials more "real world"? Is there a way that we can
10
--
Instead of thinking about
the traditional clinical
11
trial design, is there a way that we can design approaches
12
to this that would more adequately reflect real life,
13
and we have a couple of suggestions that we will talk
14
about. Next slide.
15
Now one of the issues that I think the age
ncy
16
is touching on is the fact that right now there's not
17
really much of a balance. There are fewer companies in
18
R&D for antibiotics. There's an emphasis within the
19
industry on blockbuster drugs.
20
There are limited agents now for novel
21
targets, novel
bacterial targets with known safety
22
profiles, and one of the issues that's come up lately
23
is that the patent protection that you might have might
24
be taken away from you in the case of a public health
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emergency.
1
Other things that have been discussed: Mor
e
2
restrictive labeling; prudent use of novel agents, which
3
is something that we all, I think, would support, prudent
4
use of novel agents; and more safety requirements.
5
Obviously, nobody wants to widely market a drug that's
6
not safe.
7
These all kind of ma
ke it more difficult.
8
It makes the risks higher and actually the return on
9
investment lower. At the same time, we have growing
10
resistance problems, and I will emphasize the Gram
11
negative resistance here. Fungal resistance is another
12
consideration, and t
he growing cost of studies as safety
13
and efficacy requirements increase lead to a lack of
14
balance in our approach to this problem. Next slide.
15
So what is needed? I think an early
16
definition of regulatory guidance which include
17
reasonable barriers to en
try for new compounds is
18
something that we have to aim for.
19
We need to define mutually acceptable
20
registration strategies such that efficient and cost
21
effective development programs for very small but
22
significant public health needs can be identified,
and
23
we need to facilitate registration of safe and effective
24
antibacterial agents.
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Another thing we need to do is we need to
1
identify incentives to develop antimicrobial agents to
2
treat niche indications, and this is something that,
3
obviously, you just t
alked about, but I'd like to expand
4
that a little bit.
5
Clearly, exploring supportive data in
6
addition to clinical trials, the issue of patent
7
protection and exclusivity
--
I think one of the points
8
I wanted to make was that the market exclusivity for
9
rel
atively small products has not been enough of an
10
incentive for industry in the past. I don't think it
11
will be enough of an incentive in the present.
12
The other issue is that, when you correct
13
for inflation, those later years are heavily discounted.
14
So t
hat it's just not going to be enough of an incentive,
15
I think, to get us where we would like to go. So I think
16
other incentives need to be considered. Next slide.
17
So we need to strike a better balance. We
18
need to actually reduce the cost of developmen
t and
19
maintaining licensure. We need to protect intellectual
20
property. We need to maintain a level playing field,
21
and we need to reduce barriers to entry into this arena.
22
At the same time, I think the prudent use
23
of novel agents can be supported and, i
n fact, the PhRMA
24
companies have been supporting prudent use campaigns and
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antibiotic resistance awareness campaigns since the early
1
1990s.
2
We also need to encourage better
3
postmarketing surveillance for safety, and I would say
4
for efficacy as well. I t
hink the current requirements
5
for postmarketing surveillance for resistance is to be
6
commended.
7
These kinds of approaches may lead to an
8
acceptable risk for reasonable overall return on the part
9
of the companies, and may ultimately lead to more
10
effecti
ve and timely responses to emerging public health
11
needs, such as the fact that you might have a pipeline
12
of the antibiotics that we can turn to, which is what
13
I think we desperately need. Next slide.
14
So we've put together a few proposals for
15
consideration, some of which you have also mentioned.
16
Clearly, acceptance of PK/PD data as evidence of efficacy
17
is going to be a linchpin of our ability to bring these
18
products forward.
19
As we talked about yester
day, these studies
20
are increasingly utilized in academia and industry, but
21
have not yet been accepted as evidence for approval.
22
Also, we in infectious disease in antibacterial
23
infections have a number of well understood animal models
24
of infection that can
be a useful source of evidence for
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approval.
1
Obviously, surrogate endpoints such as time
2
to clinical response, rate of progression, surrogate
3
endpoints as we talked about yesterday and this morning
4
such as resolution of bacteremia all are approaches tha
t
5
might allow us to move things forward more quickly and
6
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