200405 ethics clinical research history

7/29/2019 200405 Ethics Clinical Research History

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SoCRA SOURCE- May, 2004 - 37

OF ETHICAL STANDARDS

David Perlman, Ph.D.

Senior Education Advisor

Glaxo Smith Kline

unc ss s an ro essor

Temple University School of Pharmacy

Abstract: The current regulations for clinical research are based on a combination of

et ica t oug t an istory, some o it eing very tragic. T is artic e presents t e et ica

an istorica un erpinnings o t ese regu ations, inc u ing t e Nurem erg Co e, t e

Dec aration o He sin i, t e Be mont Report, Tit e 21 Co e o Fe era Regu ations (CFR

Parts 50 and 56, 45 CFR Part 46, and the International Conference on Harmonization

Goo C inica Practices. In a ition, t e artic e ig ig ts t e ro e o t e t erapeutic

misconception, w ic occurs w en patients enro ing as researc su jects misinterpret an

perhaps even distort information about the research because they believe that aspects of the

researc wi irect y ene t t em.

e current regu at ons or c n ca

research are based on a combination

o e t ca t oug t an story, some

o t e ng very trag c. T e wor

ethics derives from the Greek,

t os w c means custom or

c aracter. Et cs s contraste w t

mora ty, w c requent y re ates to

ow you were ra se an w at va ues

you earne rom parents, re g on,

cu ture, an ot er n uences. Et css more systematic, as the following

concept on suggests: et cs s t e

systemat c stu y o va ues y w c

a determination of what is the right

an wrong t ng to o s ma e.

Et cs s a so erent rom aw an

regulation, both of which mandate

a certa n way o act ng. T e Un te

States regu at ons or t e protect on

of human subjects provide baseline

n mums w t w c everyone

ust comp y n operat ng an

nst tut ona rev ew oar IRB ,

o ta n ng n orme consent rom

researc su ects, an con uct ng

researc n an et ca manner.

Et ca t oug t as e pe s ape

e regu at ons. But et cs goes

beyond what the regulations require

o nc u e or w at we oug t to o.

Et cs as s, W at oug t I to o?

and What is the right thing to do?

T roug out t e 4,000 year story

of ethics ther have been many

nterest ng t eor es a out w at et cs

oug t to e an w at pr nc p es

should be at the forefront of our

t n ng. In exam n ng an us ng

t ese et ca t eor es, we are try ng to

ust y part cu ar ru es, proce ures, or

out oo s on et cs an w at we oug t

to o. T e c a enge, espec a y n a

pract ca env ronment suc as c n caresearch, is to translate the theoretical

concepts rom et cs nto act on. T e

regu at ons e p us accomp s t s

task.

ETHICAL PRINCIPLES FOR

CLINICAL RESEARCH

A var ety o co es an reports


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orm t e e roc or oun at on

or t e et ca con uct o c n ca

research (Table 1). These codes

an reports ave een trans ate

nto part cu ar pract ces, gu e nes,

and requirements in our current

regu at ons. However, et ca

pr nc p es must e scusse w t n

t e r stor ca context. T ere aveeen many trage es t roug out t e

story o researc nvo v ng uman

su ects, an many peop e were

arme as a resu t o t e r unw tt ng

part c pat on n researc . From

an et ca perspect ve, t oes an

njustice to them to abstract thinking

regar ng t e regu at ons away rom

ts stor ca an et ca context.

The Nuremberg Code

e mo ern story o uman su ect

protections begins with the discovery

o t e atroc t es comm tte y Naz

p ys c ans. For examp e, suc

atrocities included twin experiments,

w ere one tw n was expose to

a pat ogen an t en autops e to

eterm ne t e natura progress on

o t e sease. T e ot er un n ecte

contro tw n was t en sacr ce

to see w at t e erences were. It

may constitute a very interesting

compar son rom a sc ent c

perspect ve, ut suc an exper mentwas wholly unethical and inhumane.

e u ges at t e tr a a no as s

n law by which to judge the Nazi

p ys c ans. T ey eve ope 10

pr nc p es or t s purpose, an t ese

principles formed the basis of what

came to e nown as t e Nurem erg

Co e or researc nvo v ng

uman su ects. H g g ts o t e

Nurem erg Co e nc u e:

Vo untary consent s essent a .

T s requ rement s at t e eartof what the Nazis did wrong.

T ey not as any o t e

peop e w o were su ect to t e r

experiments if they wanted to

part c pate.

Researc r s s must e

minimized and relative to the

ant c pate ene ts o t e

researc .

The research must benet

soc ety. It s unet ca tonee ess y en anger t e we

being of human volunteers if

ot er met o s o nvest gat on

ex st. Poor y es gne uman

subject research is unethical from

ts ncept on. I you o not ave

t e stat st ca power to answer

your researc quest on, no IRB

s ou approve t e researc . I

you ave a aw n t e researc

es gn, or you can mprove t e

research design to have a better

r s ene t pro e, you must o

t.

Research must be based on

pre-c n ca stu es n an ma s

an now e ge o t e con t on

under study. Many of the Nazi

exper ments were per orme ust

ecause t e p ys c ans oun

them interesting.

Su ects ave t e r g t to en

t e r part c pat on n researc .

Un ortunate y, t e Nurem erg Co enot ave muc mpact n t e

Un te States outs e o t e sc o ar y

community.

The Declaration of Helsinki

The Declaration of Helsinki is a

v ng ocument t at attempts

to ta e nto account t e evo v ng

nature o sc ent c researc . It was

rst a opte y t e Wor Me ca

Assembly in 1964, and revised

n 1975, 1983, 1996, an 2000.

H g g ts o t e Dec arat on o

Helsinki include:

In researc , t e we e ng o

su ects s ou ta e prece ence

over t e nterests o sc ence ansoc ety.

Severa et ca stan ar s are

art cu ate : respect or persons

an protect on o su ects ea t

an r g ts.

Some popu at ons are vu nera e

(e.g., the physically or mentally

an cappe an requ re spec a

protect ons.

Experimental procedures must

e eta e n a protoco , w c

s su m tte to an et ca rev ew

committee. This statement

represents one o t e rst

art cu at ons o t e requ rement

for a protocol, which includes

t e sc ent c reasons or an t e

purpose o t e stu y, an w at

quest ons t e researc ers ope to

answer y con uct ng t e stu y.

Invest gators must su m t

n ormat on regar ng t e

research (especially monitoring

n ormat on suc as ser ous

a verse events to t e et careview committee.

Assessment o r s s an ene ts

to su ects or ot ers s requ re

before conducting the research.

Su ects must e n orme

vo unteers. I t ey cannot

consent for themselves, then

ega y aut or ze representat ves

must consent on t e r e a .

Su ects ave t e r g t to

sa eguar t e r own ntegr ty

anot er app cat on o t e

pr nc p e o respect or persons .Informed consent must be

ocumente .

e context o o ta n ng

nformed consent is as important

as t e n ormat on presente n

t e n orme consent ocument

tself. If the researcher is also the

TABLE 1

The Foundation for the Ethical

Conduct of Clinical Research

T e Nurem erg Co e

T e Dec arat on o He s n

The Belmont Report

21 CFR Parts 50 an 5645 CFR Part 46

International Conference on

Harmon zat on Goo C n ca

Pract ces


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su ects p ys c an, a p ys c an

not connecte w t t e researc

or the subjects medical care

s ou o ta n n orme consent

to m n m ze un ue n uence.

Research Abuses

In 1966, Henry Beec er, a Harvar

anest es o og st, aut ore anexpos of numerous unethical

exper ments t at a een pu s e

n prom nent me ca ourna s.

Beecher did not furnish names or

re erences to t e researc . H s goa

was not to encourage prosecut on

ut rat er to ncrease awareness o

roa er et ca pro ems n uman

exper mentat on. He wante to

e g ten awareness t at unet ca

activities in the United States were

very s m ar to w at appene n

Naz Germany. H s art c e a amajor impact on the development

o t e regu at ons. H s conc us ons

nc u e :

Unethical treatment of human

su ects was not con ne to t e

ar ar sm o t e Naz s.

Informed consent is a goal. It

s somet ng we may never e

a e to ac eve, ut we s ou

strive for it.

It s not enoug to ment on

t at consent was o ta ne ;

su ects must e n orme anun erstan t e r s s.

ere s ou e a secon

sa eguar : an nte gent,

nformed, conscientious,

compass onate, respons e

nvest gator.

Experiments are ethical or

not et ca at t e r ncept on,

exper ments o not ecome

ethical or unethical afterwards.

I you es gn t e researc

proper y, you s ou ave an

ethically conducted protocol as

ong as a equate protect ons are

u t nto t e protoco to protect

uman su ects.

Beec er was correct. T e sa est

examp e n our country o a

research abuse was the so-called

us egee Syp s Stu y 1932-

1972 . In 1972, T e New Yor

Times pu s e art c es expos ng

et ca atroc t es assoc ate w t

a Public Health Service study on

e natura progress on o syp s

n poor an arge y une ucate

frican-American men in rural

us egee, A a ama. T e stu yas on y suppose to ast a out s x

onths but the researchers were

gett ng goo ata an ec e

o cont nue t. In t e 1940s, w en

penicillin became widely available,

esearc ers w t e treatment rom

e men.

ese reve at ons spurre

Congress ona ear ngs. T e

esu t ng Nat ona Researc Act

n 1974 authorized the formation

o t e Nat ona Comm ss on or

e Protect on o Human Su ects

of Biomedical and Behavioral

Researc . T e Comm ss ons c arge

nc u e exam nat on o t e con uct

of all federally sponsored human

su ect researc n t e Un te

States an eve opment o t e

philosophical and ethical principles

at s ou govern sc ent c

esearc w t uman e ngs as t e

est subjects. The Commission

pro uce many reports, t e mostn uent a o w c s t e Be mont

Report.

The Belmont Report

e Be mont Report art cu ates

hree core ethical principles:

Respect for persons: T s

pr nc p e concerns t e a ty

of a person to direct his/her

own act ons. T e requ rement

to o ta n n orme consent

from prospective subjects is

t e pract ca trans at on o t set ca pr nc p e. Capac ty to

consent is also important. You

must ensure t at t e person you

are as ng to un ergo a c n ca

tr a as t e capac ty to ree y

aut or ze s er part c pat on.

Benecence: T s pr nc p e

requ res a a ance etween

m n m z ng arms y goo

study design and maximizing

any ene ts t at m g t accrue

to stu y part c pants.

Justice: This principle asks

us to ta e a roa er v ew o

t e researc . T ere s ou

e an equ ta e str ut ono ene ts an ur ens, w t

equ ta e su ect se ect on.

Somet mes mp ement ng t s

principle can be daunting due

to entrenc e soc a nequa t es

an spar t es t at ex st n our

country and in the world.

Eac o t ese pr nc p es s trans ate

into specic requirements in all

current regu at ons o t e Foo

an Drug A m n strat on FDA ,

the Department of Health andHuman Serv ces DHHS , an

t e Internat ona Con erence on

Harmonization (ICH).

Respect or persons s trans ate

into the requirement to obtain

n orme consent rom su ects

e ore t ey part c pate n researc .

T ere are t ree components o a

va n orme consent process:

n ormat on, compre ens on,

an w u vo unteer ng. T ere

are severa quest ons re ate tot ese components. How muc

n ormat on s ou e sc ose ?

We all know how long and

comp cate consent orms can e.

Most are suppose to e wr tten

between a sixth- and eighth-grade

eve ; I ave seen ew n orme

consent ocuments wr tten at t at

level. How should complex medical

n ormat on regar ng r s s e

presente to su ects? T e manner

and context in which information is

conveye n uences compre ens onan can e as mportant as t e

n ormat on t se . T e su ect must

ma e a ree an uncoerce ec s on

to part c pate e.g., not to e pus e

y am y mem ers, y t e prospect

of receiving reimbursement for

part c pat on, y ree access to


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nvest gat ona rugs, or y o ers o

ree me ca care .

The principle of benecence asks

us to a ance t e r s s an ene t s.

Everyone nee s to e nvo ve n

thisthe investigator, the IRB, and

su ects.

e nvest gator must eterm newhether the research design

s soun , an w et er t ere

are ot er ways to ac eve t e

benets of the research. Such

eterm nat ons requ re t n ng

outs e o t e c n ca researc

ox. T e IRB can o ten e

a goo source o n ormat on

ecause t as seen so many

protoco s.

he IRB must determine whether

t e r s s are ust e .

e su ects ave aresponsibility to decide whether

to r s any o t e poss e

arms t at are ment one n t e

nformation presented to them.

T e eterm nat on must e a

avora e r s ene t assessment.

There is no one formula for

con uct ng a r s ene t assessment,

an eterm n ng t e a ance s

frequently difcult. In addition,

nvest gators an su ects may

con use t e sever ty o arm w t t epossibility of harm. There are ve

actors to cons er n ma ng a r s

ene t assessment:

1. Brutal/inhumane treatment is

never ust e .

2. R s s must e m n m ze . As

w et er uman su ects are

even nee e . Tec no ogy m g t

a ow t e use o n v tro mo e s,

computer so tware mo e ng, or

tissue samples instead of human

su ects.

3. A g pro a ty o arm mustbe justied.

4. Invo vement o vu nera e

popu at ons must e ust e .

5. he relevant risks and benets

must e presente n t e

n orme consent ocument.

Just ce requ res a r an equ ta e

proce ures n t e se ect on o

research subjects. Achieving justice

n c n ca researc s somet mes

cu t. Invest gators s ou not

offer benecial research only to some

n v ua s an se ect un es ra e

su ects or more r s y researc .

To soc ety, a u ts are pre erre assu ects e ore c ren, an some

c asses o su ects e.g., t e menta y

, peop e w o are nst tut ona ze ,

and prisoners) may not participate

un ess certa n con t ons perta n.

T e Be mont Report notes t at we

may not be able to eliminate deeply

entrenc e soc eta n ust ces, ut

e orts s ou e ma e to target as

wide an audience as possible.

TRANSLATION OF

ETHICAL PRINCIPLES INTOREGULATIONS

Sect ons 111 o ot t e FDA an

DHHS regulations for the protection

o uman su ects out ne cr ter a

t at t e IRB must cons er w en

eterm n ng w et er researc can e

approve Ta e 2 :

1. R s s are m n m ze t roug

a soun researc es gn. T e

IRB can frequently help with

researc es gn. Invest gators

s ou respon to IRB researc

design suggestions as part oft e IRBs m ss on to ensure

protect on o uman vo unteers,

not as interference in the science.

Hav ng someone w o s am ar

w t researc es gn to e p cra t

the protocol is also a good idea;

sponsors are genera y goo at

es gn ng t e r protoco s. In

addition, IRBs should have at

east one mem er w t researc

es gn expert se.

2. R s s are reasona e re at ve to

ant c pate ene ts t e pr nc p e

o ene cence .

3. Se ect on o su ects s equ ta e

(the principle of justice).

4. In orme consent w e

o ta ne an ocumente . W o

will obtain informed consent?

How w t e ocumente ?

W at sort o sa eguar s w

e put nto p ace so t at peop e

know the tests for which they are

vo unteer ng?

5. Data sa ety mon tor ng s

adequate.

6. Pr vacy an con ent a ty

prov s ons are a equate.

7. Appropr ate sa eguar s arenc u e or vu nera e su ects.

In t e ac groun o eac o t ese

cons erat ons are pr nc p es rom

the Belmont Report, the Declaration

o He s n , or t e Nurem erg

Co e. S nce t e IRBs ocus s to

protect human subjects, including

n ormat on a out eac o t ese

requ re e ements n a u ete st

within a protocol should make the

IRBs o eas er.

TABLE 2

rans at on o t ca r nc p es

nto Regulations

R s s are m n m ze t roug a

soun researc es gn

R s s are reasona e re at ve to

t e ant c pate ene ts

Se ect on o su ects s equ ta e

In orme consent w e

obtained and documentedData sa ety mon tor ng s

a equate

Privacy and condentiality

prov s ons are a equate

Appropr ate sa eguar s are

included for vulnerable subjects

Informed Consent Requirements

Legally effective informed

consen

No coerc on or un ue n uence

Language un erstan a e to t e

su ect

No excu patory anguage w ere

su ects wa ve or appear to wa ve

ega r g ts


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TABLE 3

The Therapeutic

sconcept on

Denition:

e t erapeut c

m sconcept on occurs

when patients enrolling as

researc su ects m s nterpretan per aps even stort

n ormat on a out t e

researc , suc t at t ey

e eve t at aspects o t e

researc w rect y ene t

them

Causes:

Human nature: we ear on y

what we want to hear

e trenc ant not on o

persona care n c n ca

medicine: confusion of roles

o p ys c an as c n c an anas researc er

he confusing methods of

sc ence ran om zat on,

use o a stu y protoco , use

o p ace os, n ng, an

contro groups

T e pr nc p e o respect or persons

is translated into requirements for

n orme consent Ta e 2 . Lega y

e ect ve n orme consent means

ensuring that subjects have the legal

r g t to consent or t emse ves or

t at an appropr ate ega y-aut or ze

representative is used when the

su ect cannot consent or mseerse . In recru tment, nvest gators

and study coordinators must ensure

t at t ey ntro uce no coerc on or

un ue n uence n t e r presentat on

o t e n orme consent n ormat on.

Language must e un erstan a e

to t e su ect an must not nc u e

excu patory anguage w ere a su ect

either waivers or appears to waive

a ega r g t to w c t ey wou

ot erw se e ent t e .

A wr tten consent ocument srequ re . It must e n anguage

un erstan a e to t e su ect or

t e su ects ega y-aut or ze

representat ve an s gne y t e

su ect or t e ega y-aut or ze

representative). A copy of the

n orme consent ocument must e

g ven to t e su ect, w o must ave

an opportunity to read the document

e ore s gn ng t.

THE THERAPEUTIC

MISCONCEPTIONT e t erapeut c m sconcept on can e

a vexing ethical issue for obtaining

va n orme consent Ta e 3 .

T e t erapeut c m sconcept on

occurs w en pat ents enro ng as

researc su ects m s nterpret an

per aps even stort n ormat on

a out t e researc , suc t at t ey

believe that aspects of the research

w rect y ene t t em, or t at

t ere s a ene t at a . T e term

rst appeared in the literature in

1987, w en Pau Appe aum an

co eagues pu s e Fa se Hopes

and Best Data: Consent to Research

an t e T erapeut c M sconcept on

n t eHastings Center Report. T e

information in this article is based on

t at pu cat on.

T e t erapeut c m sconcept on s

very common n P ase 1 onco ogy

trials. It is rare for people to benet

rom a ose-esca at on tr a . W en

you as researc su ects, even

in Phase 1 studies, why they are

enro ng, t e terature on t erapeut c

m sconcept on n cates t at t ey

requent y m sconstrue t e erenceetween researc an treatment an

wrong y e eve t at t ey w rect y

ene t rom t e r part c pat on n t e

Phase 1 study.

T e t erapeut c m sconcept on s

caused by a variety of factors.

Human nature (we hear

only what we want to hear):

For example, people only

ear access to cutt ng-e ge

ntervent ons an ree me ca

care, not scientic research

stu y.

The trenchant notion of

personal care in clinical

medicine (confusion of roles of

physician as clinician and as

researcher): Any c n c an w o

conducts a clinical trial must

o ow t e protoco , n w c

t e not on o persona care must

usua y e a an one n or er to proper y o ow t e ctates

o t e sc ent c protoco .

The methods of science

(randomization, use of a study

protocol, use of placebos,

blinding, and control groups)

These concepts can be very

con us ng to su ects t ey

are not exp a ne a equate y.

The notion of personal care is

t e p ys c ans rst o gat on.

T e p ys c an ma es ec s ons,

with the patients input, that

w ene t t e pat ent most.

T e app cat on o t s s are

ec s on-ma ng mo e s not

necessar y t e case n a c n ca

tr a . Moreover, t e met o s

o uman exper mentat on

listed above may inhibit the

app cat on o persona care

n c n ca researc n t e

following ways:

o ere s a ways a c ance

t at t e su ects nterestsmay become secondary to

t e nvest gators sc ent c

nterests; an

o Randomizing subjects for

t e sa e o goo sc ence

negates t e concept o

persona care t e

p ys c an cannot eterm ne

w c treatment a su ect

rece ves. Su ects w o w

be randomized often think

t ey w get t e treatment,

not t e p ace o.

Appe aum an s co eagues

o serve n orme consent

transact ons on severa psyc atry

protoco s. T ey oun t at

researc su ects systemat ca y

m s nterprete t e r s ene t rat o

200405 ethics clinical research history

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