Ethical dilemmas in research quality assurance

DOI: 10.1002/qaj.344

Ethical Dilemmas in Research QualityAssurance

Hans Lucas*

Quality Assurance Unit – PECD, NV Organon, P.O. Box 20, 5340 BH Oss, The Netherlands

Summary

In this essay three examples of ethical dilemmas in research quality assurance arepresented. For one of the examples, dealing with the use of placebo control groupsin bio-medical research on humans, the balance between ethical and scientificconsiderations will be evaluated on basis of a critical review of the applicablestandards and/or regulations, such as the Declaration of Helsinki and the currentGood Clinical Practice (GCP) regulations. Copyright # 2005 John Wiley & Sons, Ltd.

Key Words: ethics; bio-medical research; Declaration of Helsinki; GCP regulations; placebo;

ICH

Introduction

This essayy deals with ethical concerns in three

separate areas of research: pre-clinical research,

bio-medical research on humans, and animal

health research. Its objective is to identify one

ethical issue in each of the three research

areas and to briefly describe the opposing

viewpoints with reference to ethical principles

or values. In addition, a critical evaluation is

provided for the topic ‘bio-medical research in

humans – placebo-controlled clinical trials’ on

how the applicable laws, regulatory require-

ments and guidelines address public concerns

and the extent to which these legislations and/or

guidelines achieve a balance between ethics and

science.

Ethics

The Oxford learner’s dictionary [1] describes

ethics ‘as the moral principles that control or

influence a person’s behaviour’. In Stedman’s

Medical Dictionary [2] ethics is described ‘as the

branch of philosophy that deals with the

distinction between right and wrong, with the

moral consequences of human actions’. One

might say that ethics guides us in our decision

and understanding of which actions are good

and which actions are wrong. This guidance can

be provided by four basic ethical principles.

Principles of ethics

The principles of ethics, as described by Pur-

chase [3], are:

* Beneficence (do good): actions should be

aimed at creating some good or benefit.* Non-malfeasance (do no harm): the moral

obligation to avoid causing harm.* Autonomy (respect individual’s decision): the

capacity to deliberate on and make decisions

for oneself.

*Correspondence to: Hans Lucas, Quality Assurance Unit– PECD, NV Organon, P.O. Box 20, 5340 BH Oss, TheNetherlands. E-mail: [email protected] essay has been written as part of the first moduleof the ‘MSc in Quality Management course’ organisedby the British Association of Research Quality Assurance(BARQA) and the Anglia Polytechnic University (APU),UK.

Copyright r 2005 John Wiley & Sons, Ltd. Qual Assur J 2005; 9, 265–272.

* Justice (be fair): the moral obligation to be

just or fair.

Although these principles are clear and

obvious, they do not always help us in answer-

ing ethical dilemmas. Especially in those situa-

tions when two or more of the principles are

conflicting and difficulties arise on deciding

which principle outweighs the other(s). Under

these circumstances, the use of moral theories

(e.g. utilitarian ethics, right-based ethics, virtue-

based ethics or duty-based ethics) might be

helpful to rationalise whether an action is

good (ethical) or wrong (unethical). Examples

of the use of moral theories in ethical dilemmas

have been published by Purchase [3] and

Gluck [4].

Ethical Dilemmas

Pre-clinical research: toxicologicalevaluation in animal studies

The legitimisation of animal studies in the

toxicological evaluation of potential drugs has

been a subject of debate for a very long time.

For the proponents of animal experimentation

the legitimisation is founded on the ethical

principle of beneficence. Society as a whole will,

in the end, benefit from new medicines that will

result from the research and developments

(R&D) programs running within the pharma-

ceutical industry. Performing toxicological stu-

dies on animals, which are an integral and

essential part of the whole R&D process, is

therefore regarded as ethically acceptable.

The opponents approach the action, i.e. the

execution of animal studies, from the animals’

point of view. In their opinion, animals do have

rights and performing animal experimentation is

unethical because of the following arguments:

* The animals themselves do not benefit from

the results from the experiments. This com-

promises the principle of beneficence.* The animals are exposed to stress and suffer,

which is in conflict with the non-malfeasance

principle.

* The animals are eventually sacrificed which,

in combination with the previous two argu-

ments, may be considered as not fair and a

compromise of the ethical principle of justice.

Bio-medical research: placebo-controlled clinical trials

The ethical concerns of the use of placebo-

control groups in clinical trials have been

addressed in numerous publications. The objec-

tions, from an ethical point of view, are related

to the well being of the subjects in terms of

autonomy, beneficence and non-malfeasance [5].

With respect to autonomy, subjects are not

informed whether they will be treated with the

experimental drug or a placebo. The omission of

this information is vital to the study but abstain

the participant from his autonomy. Further-

more, it cannot be stated that the individual

subjects in the placebo control group benefit

from the treatment. It might even be the case

that during the period of no-treatment the

condition of subjects deteriorates. This is in

controversy with the non-malfeasance ethical

principle.

The arguments for the use of placebo-con-

trolled clinical trials are mainly based on

scientific grounds. One of these is that by means

of this design the efficacy and the side effects of

the experimental medication can be determined

more exactly. It goes without saying that the

advocates of the (placebo-controlled) clinical

trial furthermore adhere to the ethical principle

of beneficence.

Animal health research: use ofantibiotics

In this section, the controversy of the use of

antibiotics in the animal husbandry sector is

being exemplified. Antibiotics are being used by

the farmers as growth promoters and are fed to

the livestock to accelerate the process of gaining

weight. The benefit for the farmer is obvious and

is of economic concern. From the animals’ point

of view, one might assume that the livestock might

be more protected to infections (beneficence).

266 H. Lucas


The opponents, however, fear for the future

health risks associated with the practice of

deliberately introducing antibiotics into the food

chain. There is increasing scientific evidence [6]

that drug-resistant bacteria strains are present in

meat products and that these bacteria are

dangerous to public health. Therefore, the

opponents propose to prohibit the use of any

antibiotics in animals that may adversely affect

humans. In addition, they propose to ban the use

of antibiotics as growth promoter.

This would decrease the risks of exposure to

drug-resistant bacteria (non-malfeasance) by

humans through the food chain and ultimately

benefit the health of the world’s population.

The Use of Placebo Control Groups inBio-medical Research: Ethics andRegulations

Ethics and science are inextricably bound in bio-

medical research involving human subjects. In

fact, most of the current Good Clinical Practice

(GCP) guidelines and legislations refer to ethical

standards that have been published as early as

the fifties. How ethical standards and regula-

tions have balanced the scientific and ethical

concerns regarding the use of placebo control

groups in bio-medical research over time will be

exemplified by critically reviewing the history

and current status of these standards and

regulations.

The ethical standard: The Declaration ofHelsinki (1964 – 2004)

The most widely respected and referenced

ethical standard is the Declaration of Helsinki

(DoH) [7], which describes the ethical principles

for medical research involving human subjects.

The first version of the DoH was published by

the World Medical Association (WMA) in 1964.

Since then, several updates have been published

(e.g. 1975, 1983, 1989, 1996, 2000, 2002 and

2004) reflecting the modernisation of ethical

principles from that time forward. In the

October 2000 version, the stance of the WMA

towards the use of placebo control groups was

more explicitly expressed. Provision 29 of the

declaration states:

‘The benefits, risks, burdens and effectivenessof a new method should be tested againstthose of the best current prophylactic, diag-nostic, and therapeutic methods. This doesnot exclude the use of placebo, or notreatment, in studies where no proven pro-phylactic, diagnostic or therapeutic methodexists.’

This provoked a new wave of debate on this

matter, not only in the scientific community, but

also between the WMA and the regulatory

authorities of the United States (US) and the

European Union (EU).

US Food and Drug Administration (FDA)regulations (as from 1980)

In 1979, the National Commission for the

Protection of Human Subjects of Biomedical

and Behavioural Research (US) presented the

Belmont Report in which a summary of basic

ethical principles were documented [8]. This

Report formed the key document for clinical

trials work in the USA. Both the Belmont Report

and the DoH were used as the basis for the

establishment of the FDA GCP regulations

published under Title 21 Code of Federal

Regulation (CFR) Parts 50, 54, 56, 312 and

314 in the period from 1980 till 2000.

In these GCP regulations the use of a placebo

control group was not prohibited unless

‘administration of placebo or no treatment

would be contrary to the interest of the patient’

(21 CFR 314.126 Adequate and well controlled

studies). This is in line with the ethical principles

in the Belmont Report and previous versions of

the DoH. In practice, the FDA regards clinical

design containing a placebo control group as

the ‘gold standard’ for the development of new

treatments [9]. It has even been reported that on

at least one occasion, the approval of a new drug

in the US market was denied by the FDA

because the drug was not tested against a

placebo [10]. In March 2001, the FDA pub-

lished the Guidance for Industry ‘Acceptance of

Ethical Dilemmas 267


Foreign Clinical Studies’ [11]. By explicitly

referring to the 1989 version of the DoH, the

FDA emphasises the different stances of the

WMA and FDA, regarding the placebo group.

A more recent example, which corroborates

the diverging viewpoints of the FDA and the

WMA, is found in the latest proposals of the

FDA in the update of the provisions of Section

312.120 ‘Human Subject Protection; Foreign

Clinical Studies not Conducted under an In-

vestigational New Drug Application’ of the 21

CFR 312 regulations. In the current rule, foreign

study data may be used for an IND or marketing

approval under the condition that the studies

have been conducted in accordance with the

DoH. In the proposed rule, the reference to the

DoH in Section 312.120 will be completely

eliminated, and replaced by the statement that

the foreign study must have been ‘conducted in

accordance with GCP, including review and

approval by an independent ethics committee’

[12]. In the opinion of the FDA the reference to

the GCP principles [13] is more appropriate

since these principles:

* adequately address the ethical concerns of

clinical investigations,* provide sufficient detail on how these clinical

investigations should be conducted,* document the responsibilities of the persons/

organisations involved in clinical studies.

On the basis of this, the quality and integrity

of foreign study data can be adequately assured.

The DoH does not provide the above-

described detailed information. In addition,

revisions of the DoH are independent from

FDA authority. To avoid any inconsistencies

between the US legislation and the DoH, due to

future revisions of the latter, the disconnection

of the regulations and the DoH is proposed by

the FDA.

EU regulations (as from 1975)

The Council Directive 75/318/EEC [14] issued

on 20 May 1975 was an important document in

which clinical standards and protocols were set

for the testing of proprietary medicinal products

within the European Union. It is written in Part

3, chapter I (2), how a trial should be conducted:

‘Clinical trials must be carried out in the formof ‘controlled trials’. The design of the trialswill vary from case to case and also willdepend on the ethical considerations; thus itmay, in some instances, be more pertinent tocompare the therapeutic effect of a newproprietary medicinal product with that ofan established medicinal product of proventherapeutic value rather than with the effectof a placebo.’

As in the US the use of a placebo is allowed by

the EU legislation. However, the latter does not

specifically indicate the boundary conditions for

the use of a placebo control – or the no-

treatment group. Furthermore, the directive did

not address the rights of the subject nor was

referenced to an ethical code such as the DoH or

other relevant standards at that time.

On 19 July 1991, the text of Council Directive

75/318/EEC [14] was amended with the issuing

of Council Directive 91/507/EEC [15]. In this

Directive, the term ‘Good Clinical Practice’ was

introduced, as well as a reference to the ‘current

version of the DoH’, which was held up as an

example for the ethical principles. In addition,

the freely given informed consent of each trial

subject was mentioned. With respect to the use

of placebo control groups the Directive has not

been modified. Even the use of a ‘no treatment’

control group has been addressed (91/507/EEC,

Part 4, C 3(d)).

Some ten years later, the GCP legislation in

the EU was further modernised. On 4 April

2001, the EU Directive 2001/20/EC was pub-

lished [16]. With this Directive, a legal basis was

created for the conduct of clinical trials in the

EU. Yet, the DoH was still seen as an example

rather than the standard for the ethical princi-

ples and most peculiarly, the Directive specifi-

cally referred to the 1996 version of the DoH

instead to the current version. This explicitly

demonstrates the differences in the stances

of the EU and the WMA with respect to

placebo-controlled trials. The position of the

268 H. Lucas


EU regarding the use of placebo control groups

has not changed in this update of the EU

legislation.

With the publication of the EU directive 2005/

28/EC [17] we have ended up with the latest

modernisation of the EU GCPs. This directive

has been published on 8 April 2005 and EU

Member States are obliged to implement these

new regulations in their national laws by 29

January 2006 at the latest. The differences with

respect to the ethical principles is that the 1996

version of the DoH has now been adopted as a

standard and will, as member states implement

this Directive, become law.

International Conference onHarmonisation GCP guideline (as from1996)

In 1996, the GCP guideline (E6) of the Interna-

tional Conference on Harmonisation (ICH) was

issued [13]. This document provides a unified

GCP standard and describes the technical

requirements for registration of pharmaceuticals

for human use in the European Union, the

United States and Japan. As an international

standard for ethical principles, the DoH is cited

in this guideline. Remarkably, it is not referred

to a specific version of the DoH. Because this

document has been established in cooperation

with representatives of regulatory authorities

and industries of the EU, US and Japan, it is not

surprising that in the ICH GCP guideline the use

of a placebo-controlled study design is also

addressed (see Chapter 6.4.2).

In addition to the ICH GCP guideline, the

ICH published a document entitled ‘Choice of

control group and related issues in clinical trials’

(ICH E10) in 2000 [18]. This guideline describes

the general principles in choosing a control

group in clinical trials in relation to the ethical

issues involved. In the opinion of the ICH, the

use of a placebo control group is ethically

unacceptable ‘in cases where a treatment is

available known to prevent serious harm as

death or irreversible morbidity’. In all other

cases the use of a placebo control group is

considered ethical under the prerequisite that the

subjects have been fully informed on their

participation in the placebo-controlled trial,

including the possibility that they may be

recruited in the placebo-arm and the conse-

quences thereof. Moreover, according to ICH

E10, the final acceptance of a placebo-controlled

clinical trial should rest at the investigator, the

patients/subjects and the judgement of the

institutional review board (IRB)/independent

ethics committee (IEC).

It is obvious that the ICH E10 guideline [18]

does not refer to the ethical principles as laid

down in the DoH.

Evaluation

In light of the above, it can be concluded that the

publication of the 2000 revision of the DoH

created a split between ethical standards and the

regulations. It is not totally unexpected that this

split occurred. Different opinions with respect to

the use of placebo groups have always been

present, as can be derived from the considerable

attention this matter received in the scientific

literature. The examples of unethical placebo

studies as published by Rothman et al. [10] and

the discussions related to the zidovudine trials

on the African continent [19] have been the

impetus for the WMA to sharpen their princi-

ples. This initiative was welcomed by Brennan

[20], who feared a shift in the ethical code in

favour of the scientific arguments over the moral

obligations of the investigator to the patient.

Considering the main objective of the WMA,

being the protection of the patients, provision 29

is nothing more or less than the translation of

this objective into the current thinking of the

WMA, with respect to placebo-controlled trials.

This, to the dissatisfaction of the proponents of

the placebo-controlled studies.

Laughren [9], an employee of the FDA,

reacted on a personal note to the revisions of

the DoH. He claimed that the use of a placebo

control group is the appropriate design to

elucidate whether a new treatment is efficacious

or not. This is especially the case in the field of

research directed towards new psychotropic



drugs. He acknowledges the concerns of the

opponents and emphasises that certain

conditions need to be fulfilled before a placebo-

controlled study may be executed. These condi-

tions are specified in the ICH E10 [18].

The stance of Laughren was not only sup-

ported by the FDA but also by the EU regulatory

authorities. The European Medicines Agency

(EMEA) Committee for Proprietary Medicinal

Products (CPMP), now called Committee for

Medicinal Products for Human Use (CHMP),

published a position statement [21] on 28 June

2001 in which they disassociate from the DoH

with respect to the ethical principles as for-

mulated in provision 29 of the DoH 2000

version. In their belief ‘the judicious use of

placebo remains essential to demonstrate the

value’ of new medicinal products. A more

detailed explanation of the EMEA CPMP’s

stance has been published by Lewis et al. [22].

Furthermore, the WMA was blamed for being

the ‘ethical police’, and that they lacked insight

into the complex situation in Africa in relation

to their comments on the zidovudine trials [23].

These critics made the WMA decide to discuss

the implications of the 2000 revisions with an

expert working group. The outcome of these

discussions was that in October 2002, a note of

clarification was added to provision 29 of the

DoH stating:

‘The WMA hereby reaffirms its position thatextreme care must be taken in making use ofa placebo controlled trial and that in generalthis methodology should only be used in theabsence of existing proven therapy. However,a placebo-controlled trial may be ethicallyacceptable, even if proven therapy is avail-able, under the following circumstances:

* Where for compelling and scientifically sound

methodological reasons its use is necessary to

determine the efficacy or safety of a prophy-

lactic, diagnostic or therapeutic method; or* Where a prophylactic, diagnostic or thera-

peutic method is being investigated for a

minor condition and the patients who receive

placebo will not be subject to any additional

risk of serious or irreversible harm.

All other provisions of the Declaration of

Helsinki must be adhered to, especially the need

for appropriate ethical and scientific review.’

With this addition to the DoH, the balance

between the scientific and ethical concerns seems

to be restored for the use of placebos in clinical

research as a result of a better agreement between

the declaration and the GCP regulations. None-

theless, Weijer [24] regretted this action of the

WMA and considers it as a sacrifice of the rights

of the human being over the interests of science

and society. The discussion is not over yet.

In summary, the debate on the ethical

concerns of placebo-controlled trials is very

complicated and typical of one that cannot be

understood solely on the basis of the four ethical

principles. Both the opponents and proponents

give valid arguments as to why or why not

placebo-controlled trials need to be performed.

They all consider their own perspectives and

particular circumstances when justifying these

arguments. The latter is, according to the author,

the reason that consensus is difficult to reach,

since ethics is ‘deciding which actions are

right and which are wrong in a particular

circumstance’ [3].

It is also the belief of the author that principles

should be made for general situations and not for

the exception (i.e. particular circumstance). If we

relate these things to the split in the regulations

and the DoH, the author agrees with Weijer [24]

that adding the note of clarification to provision

29 was a debatable action. There is nothing

wrong in striving towards the highest possible

standard (i.e. no placebo). Moreover, the addi-

tion of the note of clarification to the 2000

version of the DoH did not contribute to a better

acceptation of that version by the regulatory

authorities as can be concluded on basis of the

most recent updates of both the EU and US

legislations. While the EU still refers to the 1996

version of the DoH in their law, a disconnection

of the DoH from legislation is being proposed in

the US. This in itself is a curious phenomenon in

view of the ongoing activities towards global

harmonisation of pharmaceutical legislation by

organisations such as the ICH.

270 H. Lucas


Nevertheless, by reading the articles on this

issue, the author has been made aware of the

great number of variables that should be

considered in trying to decide and understand

whether a placebo controlled study is ethically

acceptable or not. Furthermore, the author is

confident that in general, the scientific and

ethical concerns are adequately balanced in

today’s regulations.

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272 H. Lucas


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Ethical dilemmas in research quality assurance