carvedilol and the food and drug administration approval process: an introduction

Carvedilol and the Food and DrugAdministration Approval Process:An Introduction

Lloyd D. Fisher, PhD, and Lemuel A. Moye, MD, PhDDepartment of Biostatistics, University of Washington, Seattle, Washington; and Universityof Texas School of Public Health, Houston, Texas

ABSTRACT: We discuss briefly the new drug carvedilol (Coregt), a beta-blocker, alpha-blocker,and antioxidant. This drug was developed for congestive heart failure in a series of trials,four in the United States and one in Australia and New Zealand, briefly summarized inthis document. We also summarize the classical paradigm of the U.S. Food and DrugAdministration (FDA) for drug approval and the FDA’s use of advisory committees.This document serves as background to the discussion of carvedilol’s approval. Con-trolled Clin Trials 1999;20:1–15 Elsevier Science Inc. 1999

KEY WORDS: FDA, advisory committee, carvedilol, beta-blocker, alpha-blocker, antioxidant, randomizedclinical trial

INTRODUCTION

Carvedilol is a drug that recently received approval from the U.S. Food andDrug Administration (FDA). The data, approval process, and issues raisedwere relatively unusual. They brought starkly to the forefront fundamentalissues in the application of hypothesis testing and strength of evidence. Weparticipated in this process and had strong opposite points of view which wegive in the accompanying articles [1, 2]; this joint introduction gives backgroundfor those articles. There were many issues involved in the discussions, and weomit from this introduction some issues not in the following articles. Thesearticles have several purposes: to debate the appropriateness of a rigid adher-ence to the hypothesis-testing paradigm; to give simplified background aboutthe usual FDA approval process; and to illustrate the fundamental role thatbiostatistical considerations can play in evaluating new drugs, biologics, anddevices. To begin with relevant background, we first discuss the illness treated,congestive heart failure (CHF); second, the drug under consideration (knownas carvedilol generically or by its brand name Coregw); and third, the usual FDA

Address reprint requests to: Dr. Fisher, Dept. of Biostatistics, Box 357232, University of Washington,Seattle, WA 98195-7232.

Received April 9, 1998; accepted September 16, 1998.

Controlled Clinical Trials 20:1–15 (1999) Elsevier Science Inc. 1999 0197-2456/99/$–see front matter655 Avenue of the Americas, New York, NY 10010 PII S0197-2456(98)00052-X

2 L.D. Fisher and L.A. Moye

paradigm for drug approval. A discussion of the use of Advisory Committees bythe FDA follows.

This background information sets the stage for a description of the clinicaldevelopment program for the compound and the FDA approval. There weretwo advisory committee meetings that ended with recommendations for theFDA. We must also state for the record that Lloyd Fisher was a paid consultantfor the sponsor, SmithKline Beecham Pharmaceuticals. He had previouslyserved two terms (8 years) as the biostatistician on the Cardiovascular andRenal Drugs Advisory Committee and also reviewed new drug applications(NDA), on an outside appointment to the FDA, for 10 years before this experi-ence. Dr. Moye was the biostatistician on the committee during these delibera-tions (and still serves in that role).

CONGESTIVE HEART FAILURE

CHF results when the heart cannot produce enough blood circulation tomaintain the body in its normal state. Several factors can cause it. For example,a heart attack that kills a portion of the heart muscle diminishes the heart’sability to pump blood. This failure can lead to the buildup of fluid in the bodyand extremities; one standard treatment is thus with diuretic drugs that helpthe body eliminate fluid. Several drugs have been proven useful in heart failure.Angiotensin-converting enzyme inhibitors (ACE inhibitors) have been shownto prolong life, and digoxin reduces the combined incidence of death andhospitalization. Thus, patients are often treated with the triple therapy of diuret-ics, digitalis, and ACE inhibitors. The amount of impairment due to CHF rangesfrom none after appropriate compensation by drugs to the patient’s beingtotally bedridden and incapable of any normal functioning. The most commonsymptoms are shortness of breath (dyspnea) and fatigue. One standard measureof the disease’s severity is the subject’s ability to exercise.

CHF is a problem of tremendous societal importance. There is a prevalenceof approximately 4 million patients in the United States and 6% of individualsover the age of 65. In 1992 it was the single most costly medical problem inthe United States, using 5.4% of the federal health care budget.

CARVEDILOL, OR COREG

Carvedilol is unusual in that it has a number of activities that are possiblybeneficial. The rationale for its use is given in the quote below from the briefingdocument that the advisory committee received. It relates the drug’s activityto the hormones that trigger our “fight or flight” reaction and increase theactivity of our cardiovascular system:

Activation of the sympathetic nervous system is one of the most importantpathophysiologic abnormalities in chronic heart failure. Circulating levelsof catecholamines are increased in this disorder in proportion to the severityof the disease, and patients with the highest plasma levels of norepinephrinehave the most unfavorable prognosis. These observations have lead to thehypothesis that sympathetic activation has a major influence on the clinicalstatus of patients with heart failure and plays an important role in determin-ing the rate of progression of the underlying disease. Norepinephrine can

Carvedilol and the FDA Process: Introduction 3

exert adverse effects on the circulation, both directly and indirectly, andinterference with its actions can ameliorate the pathophysiologic abnormali-ties of heart failure and can retard progression of disease in experimentalmodels of left ventricular function.

Drugs that interfere with the sympathetic nervous system, by acting ona-, b1, or b2 receptors, or preferably all three receptors, might be expectedto block these deleterious effects. Alpha-receptor blockers can exert periph-eral and coronary vasodilator effects and may have favorable effects onmyocardial hypertrophy and arrhythmias. Beta-receptors (particularly non-selective agents) can interfere with the toxic effects of catecholamines, mayprevent and reverse the structural changes that occur during the progressionof heart failure, and may reduce the contribution of arrhythmias.

These observations have led investigators to propose the beta-adrenergicblocking drug might be useful in the management of heart failure. Beta-blockers were previously considered to be contraindicated in the disorderbecause of their propensity to produce short-term effects, but studies initi-ated in Sweden more than 20 years ago raised the possibility that long-termtherapy with these drugs might produce hemodynamic and clinical benefits.Controlled trials with several different beta-blockers have shown that thesedrugs can be beneficial in patients with heart failure.

As one would suspect by the rationale above, carvedilol is an a-, b1, and b2

blocker. In addition to the mechanisms of perceived potential benefit, carvedilolis one of the most potent antioxidants ever found. Antioxidant activity (suchas possessed by vitamins C, E, and beta-carotene) may have long-term benefiton the development and progression of coronary artery disease. This is, how-ever, not thought likely to be an important mechanism of action in the settingof CHF.

USUAL FDA PARADIGM FOR DRUG APPROVAL

To have some measure of predictability and order in drug approval, sponsorsof new drugs, biologics, or devices and the FDA must both have a mutualunderstanding of what is expected for approval. (A biologic is a substance thatoccurs naturally in the human body, such as insulin). Because we are studyingthe drug carvedilol, our further discussion refers to drugs; however, the princi-ples are the same for biologics and devices. Consider a situation in which theend point or outcome variable for a favorable drug effect ethically allowsreplication of the results. For approval in this case, a sponsor normally needsto have two randomized clinical trials, double-blind where possible, each ofwhich shows statistically significant benefit of the drug being studied. Thistwo-study paradigm is interpreted in the total experiment context of the drugdevelopment program. If there are more than two studies, then the totalityand consistency of the data are examined. Further, the downside of the drug(usually adverse events or “side-effects”) is examined to ensure a favorablerisk-to-benefit ratio. For rational use of the drug, one needs to provide a labelfor the drug giving physicians information concerning the correct dose ordoses, possible interactions with other drugs commonly used in the illness orphysiologic state (called the indication for use) being studied, and a carefulprecise description of which patients may reasonably be expected to benefitfrom the drug. Still, all in all, one first looks for two positive trials as minimal


evidence of drug effectiveness for a regulatory decision. Note that the one-sided p value associated with two such trials is 0.025 3 0.025 5 0.000625, andthe corresponding two-sided p value is 0.00125.

As stated above, we need objective and commonly understood standardsto allow industry to plan drug development and decision making with a reason-able prospect of success if all works out as hoped. Having standards understoodby both sides also allows the agency (the FDA) not to approve a drug submittedto it. This introduces a fairness into the process.

FDA ADVISORY COMMITTEES

The FDA often uses committees to advise them on the approvability anduse of specific drugs, biologics, and devices and on conceptual issues associatedwith such approval. The agency does not bring all compounds to advisorycommittees, but the division evaluating a drug decides whether or not to solicitinput from one. Different divisions of the FDA use their committees in differentways, but among the more common issues on which the committees meet arethe introduction of the first drug in a new drug class, a new clinical indicationfor an existing drug if it is the first such approval in a drug class, when thereis a “close call” or disagreement within the agency, and the introduction intothe public domain of reasonable standards and methods for developing certainclasses of drugs.

Before considering a drug at such a meeting, the committee members typi-cally receive a briefing document prepared by the sponsoring drug company(in this case, SmithKline Beecham); FDA review documents, both clinical andbiostatistical, or one document integrating both types of review; and questionsto be asked of the committee at the meeting. The questions direct the committeeto issues and questions considered important by the agency. The carvedilolmeeting questions are given in Appendices A and B as further background tothe considerations at the two advisory committee meetings for carvedilol. Bydesign, the committee members deliberate in public and are not allowed totalk to one another about the upcoming review before the meeting. The agencystaff makes this clear and certainly do not allow such discussions in theirpresence (e.g., when a review is to take place the second day of the meeting).If a committee member has questions that the sponsor could answer, she orhe can contact the sponsor through the executive secretary of the committee;the sponsor usually answers promptly. The agency requires all committeemembers to report conflicts of interest and can, and does as deemed appropriate,disqualify members either from voting or from voting and participating in thedeliberations. Conflicts of interest can arise not only from involvement withthe sponsor but also from involvement with a company with a competing drug.More minor conflicts of interest can be announced but still allow a committeemember full participation in deliberations and voting if it is deemed in thepublic interest. Public announcements about the conflicts are made at the begin-ning of the meetings; the meetings are announced in the Federal Register andare open to all interested parties. In addition to representatives of patientgroups and medical and commercial members of the audience, stock analystsoften attend.


Tab

le1

End

Poin

tsfo

rth

eC

arve

dilo

lSt

udie

sE

ndpo

int

Des

crip

tion

Com

men

ts

Mor

talit

yA

llca

use

mor

talit

y.6-

min

corr

idor

wal

kd

ista

nce

Rec

ord

edis

the

dis

tanc

eth

atca

nbe

wal

ked

As

CH

Fim

pair

sth

eab

ility

toex

erci

se,a

nin

crea

sein

6m

in.

inex

erci

seab

ility

isco

nsid

ered

bene

fici

alto

pati

ents

;atl

east

inth

esh

ortt

erm

,bet

a-bl

ocki

ngd

rugs

low

erth

em

axim

alex

erci

sere

spon

se.

9-m

intr

ead

mill

dis

tanc

eT

hed

ista

nce

wal

ked

ata

cons

tant

spee

don

atr

ead

mill

in9

min

.M

axim

alex

erci

seto

lera

nce

Tim

eon

atr

ead

mill

,ac

cord

ing

toa

def

ined

prot

ocol

,unt

ilth

epa

tien

tca

nnot

cont

inue

any

long

er.

New

Yor

kH

eart

Ass

ocia

tion

CH

FC

lass

I—N

olim

itia

tion

:or

din

ary

phys

ical

Thi

scl

assi

fica

tion

sche

me,

alth

ough

rela

tive

lyfu

ncti

onal

clas

s(N

YH

Acl

ass)

acti

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doe

sno

tca

use

und

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tigu

e,cr

ude,

cont

ains

cons

ider

able

info

rmat

ion

dys

pnea

,or

palp

itat

ion.

abou

tth

epa

tien

t’ssu

rviv

alst

atus

and

the

Cla

ssII

—Sl

ight

limit

atio

nof

phys

ical

acti

vity

:ab

ility

tod

oph

ysic

alac

tivi

ty.

Itis

the

mos

tsu

chpa

tien

tsar

eco

mfo

rtab

leat

rest

.co

mm

only

used

clas

sifi

cati

onsc

hem

efo

rC

HF.

Ord

inar

yph

ysic

alac

tivi

tyre

sult

sin

fati

gue,

dys

pnea

,or

angi

na.

Cla

ssII

I—M

arke

dlim

itat

ion

ofph

ysic

alac

tivi

ty:

alth

ough

pati

ents

are

com

fort

able

atre

st,

less

than

ord

inar

yac

tivi

tyw

illle

adto

sym

ptom

s.C

lass

IV—

Inab

ility

toca

rry

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ysic

alac

tivi

tyw

itho

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scom

fort

:sy

mpt

oms

ofC

HF

are

pres

ent

even

atre

st.

Wit

han

yph

ysic

alac

tivi

ty,

pati

ent

expe

rien

ces

incr

ease

dd

isco

mfo

rt.

Car

dio

vasc

ular

hosp

ital

izat

ions

Hos

pita

lizat

ion

for

aca

rdio

vasc

ular

caus

e.Pa

tien

t’sgl

obal

asse

ssm

ent

Poss

ible

answ

ers:

mar

ked

lyim

prov

ed,

Such

‘‘glo

bal

asse

ssm

ents

’’in

man

yse

ttin

gsar

em

oder

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yim

prov

ed,m

ildly

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oved

,no

inse

nsit

ive

mea

sure

s.U

sing

them

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isof

ten

chan

ge,

slig

htly

wor

se,

mod

erat

ely

wor

se,

dif

ficu

ltto

show

trea

tmen

tch

ange

s.an

dm

arke

dly

wor

se.

(con

tinu

ed)


Tab

le1

(con

tinu

ed)

End

poin

tD

escr

ipti

onC

omm

ents

Phys

icia

n’s

glob

alas

sess

men

tSa

me

asab

ove.

Sam

eas

abov

e.L

eft

vent

ricu

lar

ejec

tion

frac

tion

,L

VE

FT

hees

tim

ated

prop

orti

onof

bloo

dpu

mpe

dL

VE

Fan

dN

YH

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ass

are

extr

emel

ypr

ogno

stic

orE

Fou

tof

the

left

vent

rica

l(t

hepu

mpi

ngin

dic

ator

sfo

rsu

rviv

al;

how

ever

,d

rugs

that

cham

ber

ofth

ehe

art)

dur

ing

ahe

art

beat

.ch

ange

LV

EF

wit

ha

resu

ltin

gch

ange

insu

rviv

alha

veno

tbe

enad

equa

tely

stud

ied

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low

itto

bem

ore

than

asu

rrog

ate

outc

ome

vari

able

.L

VE

Fis

anex

trem

ely

impo

rtan

tsu

rrog

ate

end

poin

tat

this

tim

e.M

inne

sota

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wit

hH

eart

Failu

reA

ques

tion

nair

esp

ecif

ical

lyd

esig

ned

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owQ

uest

ionn

aire

chan

gein

CH

Fsy

mpt

omat

olog

y.It

had

not

prev

ious

lybe

enus

edas

apr

imar

yen

dpo

int

befo

reth

eca

rved

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prog

ram

.


Tab

le2

Sum

mar

yof

Car

ved

ilol

Stud

ies

Plan

ned

Pati

ent

Follo

w-u

pSt

udy

Sele

cted

Pati

ent

Elig

ibili

tyC

rite

ria

Prim

ary

End

Poin

t(m

o)

U.S

.Pro

gram

220

LV

EF

<0.

35N

YH

Acl

ass

II–I

VC

hang

ein

exer

cise

dis

tanc

efr

omba

selin

e.B

oth

6-m

inco

rrid

or6

CH

F6-

min

corr

idor

wal

kw

alk

dis

tanc

ean

d9-

min

trea

dm

illte

st.

dis

tanc

e15

0–45

0m

221

LV

EF

<0.

35N

YH

Acl

ass

II–I

VC

hang

ein

exer

cise

dis

tanc

efr

omba

selin

e.B

oth

6-m

inco

rrid

or6

CH

F6-

min

corr

idor

wal

kw

alk

dis

tanc

ean

d9-

min

trea

dm

illte

st.

dis

tanc

e15

0–45

0m

239

LV

EF

<0.

35N

YH

Acl

ass

II–I

VC

hang

ein

exer

cise

dis

tanc

efr

omba

selin

ean

dM

inne

sota

qual

ity

6C

HF

6-m

inco

rrid

orw

alk

oflif

esc

ore.

dis

tanc

e,

150

m24

0L

VE

F<

0.35

NY

HA

clas

sII

–IV

Clin

ical

prog

ress

ion

ofhe

art

failu

re,

def

ined

asd

eath

due

to12

CH

F6-

min

corr

idor

wal

kC

HF,

orho

spit

aliz

atio

nfo

rC

HF,

orw

orse

ning

CH

Fre

quir

ing

dis

tanc

e.

450–

550

min

crea

sing

back

grou

ndm

edic

atio

nsby

50%

for

atle

ast3

0d

ays.

Aus

tral

iaN

ewZ

eala

ndSt

udy

223 E

arly

phas

eH

isto

ryof

dys

pnea

atre

stor

Max

imal

exer

cise

tole

ranc

eon

trea

dm

illpl

ustw

ohe

mod

ynam

ic6

fati

gue

atre

stw

ith

EF

,0.

45m

easu

rem

ents

(LV

EF

and

the

LV

inte

rnal

dim

ensi

ons)

.N

YH

Acl

ass

IVw

asex

clud

edL

ater

phas

eSa

me

asab

ove.

All

caus

ed

eath

and

all

caus

eho

spit

aliz

atio

n.(T

his

was

only

18–2

4cl

arif

ied

late

rin

the

stud

y.)

(con

tinu

ed)


Tab

le2

(con

tinu

ed)

Num

ber

Ran

dom

ized

and

Impo

rtan

tSe

cond

ary

End

Poin

tsD

rug

Dos

age

Use

d

U.S

.Pro

gram

Phys

icia

nan

dpa

tien

tgl

obal

asse

ssm

ent;

NY

HA

func

tion

alcl

ass;

CH

Fsy

mpt

omp

584

;c6.

25m

g5

83;

220

scor

e;ca

rdio

vasc

ular

hosp

ital

izat

ions

;EF;

9-m

inw

alk

dis

tanc

e;qu

alit

yof

life

c12

.5m

g5

89;

scor

es.

c25

mg

589

221

Phys

icia

nan

dpa

tien

tgl

obal

asse

ssm

ent;

NY

HA

func

tion

alcl

ass;

CH

Fsy

mpt

omp

514

5sc

ore;

EF;

qual

ity

oflif

esc

ores

.c

25m

g5

133

239

Min

neso

taL

ivin

gw

ith

Hea

rtFa

ilure

Que

stio

nnai

reas

am

easu

reof

the

Qua

lity

p5

35of

Lif

e.c

25m

g5

7024

0Ph

ysic

ian

and

pati

ent

glob

alas

sess

men

t;N

YH

Afu

ncti

onal

clas

s;C

HF

sym

ptom

p5

134

scor

e;ca

rdio

vasc

ular

hosp

ital

izat

ions

;EF;

9-m

inw

alk

dis

tanc

e;qu

alit

yof

life

c25

mg

523

2sc

ores

.

Aus

tral

iaN

ewZ

eala

ndSt

udy

223 E

arly

phas

eN

YH

Afu

ncti

onal

clas

sp

520

8C

linic

alst

atus

(doi

ngve

ryw

ell,

wel

l,fa

iror

poor

)c

520

7L

ater

phas

eN

/A

(All

dat

aea

rly

and

late

incl

uded

inlo

nger

term

follo

w-u

pan

alys

es.)

p5

208

c5

207

p,pl

aceb

o;c,

carv

edilo

l.


COREG (CARVEDILOL) STUDIES

We do not discuss here all of the carvedilol data but only the primary trialsthe sponsor offered as proof of efficacy and a satisfactory risk-to-benefit ratio.At the time the carvedilol trials were designed, the standard end point fordrugs being studied in CHF was improvement in ability to exercise. Onestandard test is to see how far the subjects can walk during a prespecified timeinterval. The sponsor considered mortality as an end point, but sample-sizecalculations suggested studies that were too large and expensive. Further,although some persons viewed the potential for a survival benefit as possibleor even likely, others viewed it as fairly remote. Beta-blocking drugs will bluntexercise response in the short term (because the body is less able to stimulatethe cardiovascular system), and therefore ability to exercise would not seemthe most promising end point for such drugs, at least in the short term. Never-theless, the main thrust of the drug development program was to use exerciseas the primary end point with one exception in the United States. Very briefdescriptions of the end points (Table 1) and of the important studies (Table 2)follow. The program in the United States had four component studies identifiedas studies 240, 221, 220, and 239. Table 2 summarizes the design characteristicsand other features and uses a number of secondary end points that we describeand summarize in Table 1.

REFERENCES1. Fisher LD. Carvedilol and the Food and Drug Administration (FDA) approval

process: the FDA paradigm and reflections upon hypothesis testing. Controlled ClinTrials 1999;20:16–39.

2. Moye L. Endpoint interpretation in clinical trials: the case for discipline. ControlledClin Trials 1999;20:40–49.

APPENDIX A

FDA Questions, 2 May 1996, for the Cardiovascular and Renal DrugsAdvisory Committee (with slight editorial changes)

COREGe (carvedilol), an approved agent for the treatment of hypertension,has been investigated as a treatment for moderate (90% New York Heart Associ-ation, NYHA, II–III) chronic congestive heart failure. In support of this indica-tion, the sponsor has submitted the results of four well-controlled U.S. multicen-ter studies plus a well-controlled Australia–New Zealand multicenter study ina population with less severe disease. In addition, there are three shorter termand smaller double-blind, placebo-controlled, single-center studies. If carvedilolwas to be approved for improvement of morbidity in congestive heart failure,it would be the first agent with that claim.

The Advisory Committee has received summaries of these data in the formof a briefing package prepared by the sponsor and a medical and statisticalreview. The two are in substantial agreement with regard to what happenedin these trials; the issues relate to how the results should be interpreted.

In discussion of the findings from these studies, it will be important todistinguish which analyses attributed worst rank to subjects who died or with-drew and which analyses propagated the last measured value. One of thequestions asks for a comparison of the two approaches.


The carvedilol development program collected much clinically relevant data,and much of that data, viewed broadly, is supportive to benefit. The problemis the identification of specific benefits a patient with congestive heart failurecan expect to receive. If it is only in the global gestalt that the benefits aremanifest (i.e., if no single benefit is established to conventional standards ofproof), then what should the indications be for use?

1. Was there a mortality effect in study 220? If so,1.1. Describe the statistical analysis that leads to that conclusion, including

1.1.1. Correction of the estimated p value for multiple interimanalyses,

1.1.2. Correction of the estimated p value for multiple prespecifiedprimary and secondary endpoints, and

1.1.3. Reasons for ignoring at least one potential analysis (retrospec-tively conducted by the FDA: page 21 of the combined medical/statistical review) that denies a treatment effect (p . 0.05 fora random-effects model analysis of mortality plus near-mor-tal events).

1.2. Was this mortality effect confirmed by other studies individually(particularly study 221) or in combination?

1.3. Was such an effect expected on the basis of known effects of otheragents in this pharmacologic class or this agent in other settings?

1.4. If carvedilol were approved for the treatment of congestive heartfailure, should its approval include a claim for prolonging life? If not,what should be done to obtain such a claim?

Unlike mortality, worsening heart failure (a combined end point of sudden-or heart failure-related death, heart failure-related hospitalization, or increasedheart failure medications) was a primary hypothesis tested during the develop-ment program in study 240. The sponsor and reviewers performed very differ-ent analyses, neither of which were exactly what was prespecified.

2. Was there an effect of treatment on worsening heart failure in study 240?2.1. The sponsor’s analysis of study 240 indicated a treatment effect that

was highly statistically significant (p 5 0.003).2.1.1. Was the analysis plan a reasonable one?2.1.2. Was the analysis amenable to verification?2.1.3. How were missing medications data handled?

2.2. The reviewers analysis of study 240 (page 97 of the combined medi-cal/statistical review) indicated a treatment effect that was marginallystatistically significant (p 5 0.04). However, missing medications dataled to exclusion of 60% of subjects from the analysis. Was this areasonable analysis plan? If so, what weight should be given anapparent treatment effect when so large a fraction of the study popula-tion was excluded from the analysis?

2.3. Were the findings in study 240 confirmed by other studies? Cite theconfirming studies and analyses.

2.4. If carvedilol were approved for the treatment of congestive heartfailure, should its approval allow a claim for reducing the rate of


progression of chronic moderate heart failure? If not, what shouldbe done to obtain such an indication?

3. The following are other prospectively defined primary or secondary endpoints for the five multicenter efficacy studies:

• Exercise tolerance by 6-min corridor walk test• Exercise tolerance by 9-min treadmill test• Quality of life (21-question set)• NYHA classification• Ejection fraction• Subjects’ global assessment (single question)• Investigators’ global assessment (single question)• Total cardiovascular hospitalizations• Hospitalizations for heart failure• Heart failure symptoms (7-question set)• Cardithoracic ratio

3.1. For each, address the relative merits of analyses based on3.1.1. Last value carried forward;3.1.2. Assignment of a low score to deaths and withdrawals.

3.2. For which end points are the data to support a benefit of treatmentsufficiently compelling to warrant inclusion?3.2.1. As part of the indications for use?3.2.2. As part of the clinical pharmacology?

3.3. If any of the secondary end points were thought to show a compellingtreatment benefit,3.3.1. Was any adjustment necessary because of failure to show an

effect of treatment on the cited studies’ primary end points?3.3.2. Was any adjustment necessary because of the multiplicity of

secondary end points?3.3.3. Was any adjustment necessary because the blind was compro-

mised by treatment effects on vital signs?4. If carvedilol were to be approved for use in heart failure,

4.1. What initial dose should be recommended? Cite the rationale anddata to support a choice.

4.2. What target dose should be recommended? Cite the rationale anddata to support a choice.

5. Should carvedilol be approved for the treatment of congestive heart fail-ure? If so,5.1. Should its use be restricted to patients with symptomatic heart

failure?5.2. What should be said about its use in patients with NYHA class IV

heart failure?5.3. Are there other characteristics of populations that should be specifi-

cally included or excluded?6. Comment on the following as strategies for drug development programs

in chronic congestive heart failure. For each, what are the implicationsfor the certainty with which one will likely know a real benefit exits?


• Prespecify primary and secondary end points. Use secondary endpoints only in interpreting treatment effects on primary end points.

• In round one, prespecify every end point of potential interest. Use theend points for which a treatment effect appears evident as primaryend points in confirming studies.

• Prespecify every end point of potential interest. Seek approval for thosedemonstrating a benefit of treatment.

APPENDIX B

FDA Questions, 27 February 1997, for the Cardiovascular and Renal DrugsAdvisory Committee (with slight editorial changes)

In May 1996, after consideration of the data and analyses that were availableat that time, the Advisory Committee recommended nonapproval of carvedilolfor the treatment of heart failure. Since that time, long-term follow-up fromone study (study 223) and new analyses of all multicenter studies have becomeavailable. These new data are all, to some degree, supportive of benefit fromtreatment with carvedilol. This matter is once again brought to the AdvisoryCommittee, so that all available data can be brought to bear on the final recom-mendation of the Committee.

The Advisory Committee’s initial decision was based in part on the positionthat one cannot reach definitive conclusions about secondary end points froma study that fails to demonstrate effectiveness using its primary end point. Thisposition requires careful consideration, as it is consistent neither with pastAgency actions nor past Advisory Committee recommendations. For example,in 1993, the Advisory Committee recommended approval of enalapril for thetreatment of asymptomatic left ventricular dysfunction on the basis of a singletrial in which there was little evidence for support of benefit on the primaryend point, mortality (p 5 0.3), but fairly strong evidence for a benefit of oneof eight prespecified secondary end points, time to first hospitalization forcongestive heart failure (p , 0.001, with no statistically significant differencefor all-cause hospitalizations). The Advisory Committee’s recommendation ofapproval with regard to enalapril was somewhat controversial, but it wassustained by Agency action; prevention of hospitalization for congestive heartfailure was added to the Indications section of enalapril’s labeling.

In reconsidering carvedilol, the Committee is reminded that federal lawpertaining to approval simply calls for evidence of effectiveness, from adequateand well-controlled clinical trials, that is convincing to experts. Regulations donot specify two-sided p , 0.05 on the primary end points in each of two studies,and some Agency approval decisions involving end points of irreversible harmor rare conditions have not had two such studies. Regulations also do notspecify that the end points in such studies be the same. One effect of relyingon 2 (out of 2) studies with p , 0.05 on their primary end points is that thelikelihood of incorrectly identifying a treatment benefit is ,0.0025 [sic]. Thedegree of clinical confidence in the treatment benefit is often further enhancedby the observation of apparent treatment effects on prespecified secondary endpoints and other study data, where these observations support a mechanism


of action or are otherwise expected in association with favorable effects on theprimary end point.

The questions that follow assume that the Committee does not wish torecommend a change in the standard of approval, in the sense of specifying adifferent level of type I error rate. Instead, the questions are intended to solicitthe Committee’s judgment about how the data from the carvedilol developmentprogram might support a regulatory decision with a degree of confidenceequivalent to the usual standard. The first three questions suggest alternativestrategies by which specific benefits might be said to have been established bythe carvedilol development program. Failing that, the Committee is asked, inquestion 4, if nonspecific benefit should be the basis for approval.

1. Most approvals are made on the basis of p , 0.05 for primary end pointsrepresenting clinical benefit in each of two adequate and well-controlledstudies. A case can be made that carvedilol meets that standard withstudies 240 and 223.1.1. Study 240 had a primary end point of time to the first event of sudden

death, death from progression of heart failure, hospitalization forworsening heart failure, or sustained increase in a specified groupof heart failure drugs. Elimination of the medications component ofthe end point from either the sponsor’s analysis (which includedcause-specific mortality and hospitalization) or the reviewer’s analy-sis (which included all-cause mortality and hospitalization) greatlyincreased the p value (from 0.003 to 0.029 and 0.04 to 0.378, respec-tively), suggesting that most of the statistical power lies in the medica-tions component. What effect does this observation have on the clini-cal interpretation of the results of study 240?

1.2. With regard to Study 223,1.2.1. What clinical benefit was the primary end point in the short-

term phase?1.2.1.1. Identify the words in the protocol leading to that con-

clusion.1.2.1.2. What analysis leads one to conclude there was a treat-

ment benefit?1.2.2. What clinical benefit was the primary end point in the long-

term phase?1.2.2.1. Identify the words in the protocol leading to that con-

clusion.1.2.2.2. What analysis leads one to conclude there was a treat-

ment benefit?1.2.3. For what baseline prognostic factors should one adjust?1.2.4. What adjustment in p values is indicated for multiplicity of

end points?1.3. With appropriate consideration of the supporting evidence from pri-

mary and secondary end points of these and other clinical trials,should carvedilol be approved for the treatment of heart failure onthe basis of p , 0.05 on the primary end points in each of two adequateand well-controlled studies?


2. If not, carvedilol might be approvable on the basis of compelling evidence,from prespecified secondary end points, of a specific benefit. The promo-tion of a secondary end point to the status of a primary end pointand a potential bias of approval carries with it some implications withregard to the overall type I error rate. Below is a list of the prespecifiedsecondary end points of clinical benefit for which the sponsor’s analysesyielded a nominal p , 0.05 in at least one adequate and well-con-trolled study:

• Physician’s global assessment• Patient’s global assessment• NYHA class• Hospitalization for cardiovascular causes• Heart failure signs and symptoms

2.1. For each study end point, how should the nominal p value be ad-justed for?2.1.1. The number of the study’s primary end points?2.1.2. The number of the studies prespecified secondary end points?

2.2. For which secondary end points and studies, if any, is the evidenceof benefit as convincing as the observation of p , 0.05 for a primaryend point analysis?

2.3. With appropriate consideration of the supporting evidence from pri-mary and other secondary end points of these and other clinical trials,should carvedilol be approved on the basis of compelling evidenceof clinical benefit in some specific secondary end point or some combi-nation of such end points?

3. If not, carvedilol might be approvable on the basis of compelling evidence,from retrospectively defined end points, of a specific benefit. The promotionof a retrospective end point to the status of a primary end point anda potential basis of approval carries with it some presumably more seriousimplications with regard to the overall type I error rate. Below is a listof some retrospective end points of clinical benefit for which analysesyielded a nominal p , 0.05 in at least one adequate and well-con-trolled study:

• Heart failure mortality and hospitalization for heart failure• All-cause mortality• All-cause mortality and hospitalization for heart failure• All-cause mortality and hospitalization for cardiovascular causes• All-cause mortality and all-cause hospitalization

3.1. For each such study and end point, how should the nominal p valuebe adjusted for?3.1.1. The number of the study’s primary end points?3.1.2. The number of the study’s prespecified secondary end points?3.1.3. The number of the study’s other retrospective end points?

3.2. For which retrospective end points and studies is there evidence ofbenefit at least as convincing as the observation of p , 0.05 for aprimary end point analysis?


3.3. With appropriate consideration of the supporting evidence from pri-mary, secondary, and other retrospective end points of these andother clinical trials, should carvedilol be approved on the basis ofcompelling evidence of specific clinical benefit with respect to somerespectively defined end point or some combination of such endpoints?

4. If not, carvedilol might be approvable on the basis of compelling evidenceof clinical benefit, without naming the specific benefit. For example, onemight conclude that, overall, some set of measurements pertaining tosymptomatic heart failure was indicative of benefit, but one might beunable to conclude that any specific benefit measurement met standardsthat would permit it to be named as the expected benefit of treatment.4.1. What analysis pertains to the assessment of overall benefit?

4.1.1. What weight was given to the primary end points?4.1.2. How did that analysis adjust for each study’s multiple prespeci-

fied end points?4.1.3. How did that analysis include retrospectively defined end

points?4.2. Should carvedilol be approved on the basis of compelling evidence

of an overall clinical benefit?

carvedilol and the food and drug administration approval process: an introduction

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