Word - Food and Drug Administration

echinoidclapΒιοτεχνολογία

1 Δεκ 2012 (πριν από 4 χρόνια και 8 μήνες)

623 εμφανίσεις




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


1


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






S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


2

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





S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


3


I
-
N
-
D
-
E
-
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




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


4


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

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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


5

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.

25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


6



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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


7

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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


8

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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


9

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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


10

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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


11

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.

25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


12



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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


13

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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


14

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.

25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


15



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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


16

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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


17

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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


18

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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


19

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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


20

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.

25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


21



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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


22

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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


23

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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


24

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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


25

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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


26

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.

25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


27



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,

25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


28

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.

25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


29



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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


30

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.

25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


31



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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


32

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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


33

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.
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


34

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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


35

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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


36

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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


37

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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


38

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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


39

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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


40

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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


41

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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


42

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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


43

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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


44

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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


45

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.

25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


46



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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


47

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
25




S A G CORP.

202/797
-
2525

Washington, D.C.

Fax: 202/797
-
2525


48

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