Download Antibiotics - The Perfect Storm - D. Shlaes (Springer, 2010) WW PDF

TitleAntibiotics - The Perfect Storm - D. Shlaes (Springer, 2010) WW
TagsMedical
LanguageEnglish
File Size1.6 MB
Total Pages110
Table of Contents
                            Antibiotics: The Perfect Storm
Front-matter
	Title page
	Copyright
	Dedication
	Contents
1 The Perfect Storm
2 The Miracle
3 Resistance
	The Basics
	Antibiotics for Animals and Crops Lead to Resistance for People
	In Our Hospitals, Things Are Getting Critical
	Antibiotic Resistance Plus Toxin Production Equals Death
	Our Communities are Not Spared
	Resistance Summing Up
4 The FDA
	We Need Them, but They Have Become Part of the Problem
	The FDA Increases Clinical Trial Design Stringency and Costs. Companies Abandon Antibiotic Research
	Mild Infections Require Placebo-Controlled Trials Industry Balks
	New Antibiotics for Mild Infections Are Forced from the Market While Generic Antibiotics Are Still Approved in the Absence of Placebo-Controlled Trials
		The Ketek Scandal
	Pneumonia The New Frontier. New Trial Requirements for Pneumonia Will Make Approval Much More Difficult and Costly and Sometimes Simply Infeasible
	The FDA Can Change Its Requirements After Completion of a Trial and then Require New Trials for Approval
	The FDA is Regulating Itself Out of the Antibiotics Business
	We Need Balance and Perspective from the FDA
	The FDA Makes It Difficult for Them to Obtain Good Advice
5 Europe
6 The Industry
	Antibiotics Form a Cornerstone of the Pharmaceutical Industry
	Resistance Should Create Opportunities
	Industry Consolidation Reduces the Effort in Antibiotics
	Antibiotics Are Not Financially Attractive in the Consolidated Industry
	Industry Takes a Risk-Averse Approach to Its Clinical Trials, but Deprives Us of the Most Important Information
	Discovery of New Antibiotics Is Becoming Harder
	The US Market Share is Stagnant or Shrinking. Will the Industry be Able to Prioritize Ex-US Territories?
	Research and Development Costs Increase, but Approvals Are Down
	Some Good News for Everyone
	Antibiotic RD in Biotech Is Stymied by Late Stage Clinical Trial Costs
	Biotech Is Still a High-Risk Proposition
7 Modest Proposals
	The Role of Government
	Government Loves a Task Force
	Government Can Play Several Important Roles
	The Transatlantic Taskforce on Antimicrobial Resistance
	Government-Sponsored Research and Research Tools Are Required
	Industry Incentives Will Probably Also Be Required. Europe Is Leading the Way in Thinking Here
	The FDA (and EMEA)
		The FDA and EMEA Both Must Adapt a More Balanced Approach to Antibiotics. Required Trial Designs Must Be Feasible
		Do We Want New Antibiotics for Mild Infections? Is Bacterial Bronchitis in the Setting of Chronic Lung Disease a Mild Infection?
		The FDA Must Modify Its Guidelines for Clinical Trials in Community Acquired Bacterial Pneumonia
	The FDA Has to Stop Moving the Goal Posts in Mid-Stream
	The FDA Has to Level the Playing Field with Generic Antibiotics
	Congress Needs to Step Back from the FDA Especially Where Science Is Concerned
	Our Government Needs Access to the Best Advice it Can Get
	How About a Totally New Approach to Drug Development?
	Communication Between the Industry and Physicians Is Required, but is Becoming More and More Restricted
	What Should the Industry Be Doing?
	The Current Large PhRMA Model Is not Viable. These Giants Need to Divide Themselves into Bite-Size Portions to Survive
8 Conclusions
Back-matter
	Bibliography
	Index
                        
Document Text Contents
Page 2

Antibiotics

Page 55

48 4 The FDA

before the minimum length of therapy, the data could not be used since for either the
experimental drug or the comparator. The treatment has to be long enough that we
can evaluate whether it was successful or not. HIV infected patients might be harder
to treat since they might not have a normal immune system. These all may be good
reasons for excluding our hypothetical patient, but they also explain why trials are
not real life.

Another disconnect between clinical trials and life on the wards is the fact that
most, probably 70–80%, of initial antibiotic therapy is empiric. By that I mean that
either the physician does not know the bacteria he/she is treating or, sometimes,
doesn’t even know the site of the infection (lung, urinary tract, etc). He/she just
knows that the patient has a fever or other signs of infection that needs treatment.
Usually, such a patient will be treated expectantly with an antibiotic or even more
than one antibiotic to make sure that all the likely bacterial pathogens are treated.
Only later, if a bacterial pathogen is identified or the site of infection declares itself,
might the antibiotic therapy be more specifically tailored to the specific infection at
hand. When I was consulting at the VA hospital, more often than not, if the patient
had responded to the broad-spectrum therapy that was used initially, there was a
great reluctance to change to a more specific therapy even when a specific pathogen
had been identified. There is always a lingering doubt that maybe what was identi-
fied is not the entire answer. I frequently get the feeling that the FDA has lost sight
of these issues and they actually believe that the trials they require reflect clinical
practice. We will return to this subject in Chapter 7.

The FDA Makes It Difficult for Them to Obtain Good Advice

The FDA works closely with advisory committees. The FDA’s Office of
Antimicrobial Products has a Anti-Infective Drugs Advisory Committee (fondly
known as AIDAC) that it uses to help its reviewing divisions with decisions around
approvals, withdrawals, questions of trial design and other important issues that
require public airing. There is also a strict conflict of interest policy that limits or
bans the participation of individuals with a financial interest in the particular deci-
sion or decisions the committee confronts. The guidance actually speaks about a
$50,000 limit that, in my view, is too generous. In its application of these policies I
think the FDA has at times gone so far as to limit the expertise of its anti-infectives
committee. The problem is that industry, like the FDA, needs outside advice. If folks
in industry had no one to speak with other than themselves, I’m not sure we would
ever have any products. These same experts can also provide valuable advice to the
FDA. The anti-infectives world is a very small one and shrinking all the time. I once
complained to the director of the anti-infectives reviewing division at FDA about the
quality of the anti-infectives advisory committee. I felt that very few on the com-
mittee were experienced in antibiotics per se and especially in clinical trial conduct
and design for antibiotics. These topics were almost always part of the committee
discussions. She did not disagree with me and asked me for recommendations for

Page 56

The FDA Makes It Difficult for Them to Obtain Good Advice 49

new committee members. She said they could not work with people in industry out-
side the single non-voting member that is a part of every advisory committee. She
wanted nominations for women, professionals of color, and people from regions
other than the Northeast. As I considered the people I thought had the experience
and expertise the FDA needed at the time, I came up with a list of names – almost
all white men from the East coast. None were appointed.

This discussion reminds me of a recent set of news articles noting that Senator
(retired) Tom Daschle works for a lobbying firm tied to the health insurance industry
while he is simultaneously a close advisor to President Obama on health care reform.
Is this an apparent conflict of interest? Sure. Is President Obama able to put this in
perspective when discussing things with Mr. Daschle? Of course. FDA scientists and
reviewers are not stupid, either. They know how to sift advice. As long as everyone
discloses his or her potential conflicts, a conversation can take place.

The FDA still works with outside stakeholders such as PhRMA and the Infectious
Diseases Society of America and others. Unfortunately, good advice from all is
frequently ignored.

What has happened to the FDA since 2000? The FDA was leaderless for most
of the last 9 years. Either the appointed commissioners did not last long or there
was an acting commissioner for most of this time. In the anti-infectives group, there
has been a significant loss of key individuals in leadership roles who understood
the more practical problems of trial design and struggled in tandem with industry to
achieve both the FDA’s charge of assuring efficacy and safety of marketed products
and industry’s goals of doing so in a feasible way. With a new and dynamic com-
missioner, I hope we will see a more balanced approach to antibiotics such that we
will be able to have them when we need them.

See the Chapter 7 for suggestions on possible ways forward for us all.

Page 109

Index

A
Acinetobacter, 20, 22–23
Agriculture, 29, 77
Aminoglycosides, 58–60, 74
Amoxicillin, 21, 40, 59
Ampicillin, 21, 25–26
Animal use, 26
Antibiotics, 1–7, 9, 12–13, 15–49, 51, 55,

57–61, 63–75, 77–89, 93–96
Arsenic, 9
Astellas, 45, 65–66
Augmentin, 21–22, 40, 59, 63
Azithromycin, 6, 19, 39

B
Bactrim, 5, 17, 25–27, 57, 60
Beta-lactamase, 21, 59
Beta-lactamase inhibitors, 59–60
Bronchitis, 7, 34, 37–41, 45–46, 54, 73, 82,

84–85, 88

C
Cancer, 64, 67, 89, 93–94, 97
Carbapenem, 17, 20–23, 60, 73
Cellulitis, 10, 12
Centers for Disease Control (CDC), 20, 24,

27, 77–80, 91–92
Centers for Medicare and Medicaid

Services, 78
Cephalosporin, 17, 19–21, 23, 26, 58–60, 65
Cerexa, 65–66, 74
Chronic Obstructive Pulmonary Disease

(COPD), 37, 85
Ciprofloxacin, 19–20, 22, 25–26, 60
Clavulanic acid, 40, 59
Clindamycin, 27
Clostridium difficile, 23–24
Colistin, 3–4, 22–23

Committee for Medicinal Products for Human
Use (CHMP), 51

Crops, 15–17, 19, 77, 80
Cubicin, 57, 72
Cubist, 66, 70–74

D
Dagenan, 10–11
Daptomycin, 17, 26, 57, 65–66, 70–72, 74
Deconsolidation, 1, 95
Diabetes, 11, 29
Diarrhea, 17, 23–24

E
E. coli, 16–17, 19, 23, 25–26, 59
Enterobacter, 23
Enterococcus, 17, 20, 27
Erysipelas, 10, 12
ESBL, 23
ESKAPE, 22–23, 52–53, 79, 81, 98
Europe, 17, 19–21, 23, 28, 39–40, 46, 51–57,

65, 67–68, 81–85, 89–90, 97–99
European Medicines Agency (EMEA), 21, 40,

51–52, 54–55, 84–85

F
Faropenem, 73–74
Fluoroquinolone, 19–20, 26, 60
Food and Drug Administration (FDA), 1, 3–4,

6–7, 29–49, 52, 54, 57, 63–65, 73–74,
77–81, 84–90

Forest, 65–66, 73–74

G
Genomics, 71, 89
Glaxo Smith-Kline (GSK), 62, 67, 73, 94–95

H
Heavy metals, 9

105

Page 110

106 Index

I
Infectious Diseases Society of America, 12,

20, 22, 31, 33, 41, 49, 81–82, 99
Innovation, 52, 59, 74, 98
Interagency Task Force, 77–78, 80

K
Ketek, 38–40, 42, 45, 88
Klebsiella, 20–23
KPC, 21–22

L
Lilly, 34, 60, 62, 71–72, 74
Linezolid, 5–6, 17, 26, 57, 65–66, 69–71, 95
Lipopeptides, 57–58

M
Macrolides, 19, 58
Merck, 4, 6, 11, 61–62, 90, 92–93
Mercury, 9
Methicillin, 16, 20, 26, 60
Mortality, 10–13, 22, 24, 28, 37, 41–46, 85, 92
MRSA, 5–6, 16, 20–22, 26–27, 60, 63, 65–66,

70–71, 79–80

N
National Institutes of Health (NIH), 2, 13, 37,

77–80, 82, 98
Net present value (NPV), 63, 83
Nitrofurantoin, 26
Non-inferiority, 33, 38, 65–66, 87

O
Otitis media, 35–36, 46, 84

P
Penicillin, 5, 9, 11–13, 15–17, 21, 23, 26–27,

29–30, 33–34, 36, 38–42, 57–60, 87
Pharmaceutical Research and Manufacturers of

America (PhRMA), 33–34, 44, 49, 67–68,
86–87, 93–96

Pneumococcus, 92
Prontosil, 9–10
Pseudomonas aeruginosa, 3, 20

Q
Quinolone, 25, 36, 38, 42

R
Replidyne, 45, 73–74, 87
Resistance, 1–2, 5–7, 15–28, 34, 36, 38–39,

42, 52, 54–55, 59–61, 70, 72, 77–81, 83, 93

S
Salmonella, 17–19, 59
Salvarsan, 9, 33
Sinusitis, 7, 34, 36–41, 45–46, 54, 73,

84–85, 88
SmithKline Beecham, 62, 67
Special Protocoal Assessment (SPA), 45
Spin-off, 95, 99
Staphylococcus, 5, 10, 16, 20, 26, 60
Streptococcus pneumoniae, 35, 42, 92
Streptomycin, 16–17, 59
Sulfanilamide, 9, 29
Sulfonamides, 9–13, 26, 30, 33–34, 41–42,

57–58, 87

T
Task Force, 25, 77–78, 80–81
Telavancin, 65, 74
Telithromycin, 38
Tetracycline, 5, 15–17, 21, 23, 26–27, 32,

58–59, 74
Theravance, 45, 65–66, 74
Tigecycline, 2, 23, 34, 64, 95
Trimethoprim, 57–58, 60

U
Urinary tract infection (UTI), 16, 25–26, 46,

59, 79

V
Vagelos, 92–93
Vancomycin, 17, 20–22, 24, 26–28, 42, 60–61,

63, 65–66, 71

Z
Zithromax, 6, 39
Zyvox, 5, 57, 70, 72

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