Clin Eval 41（2）2013

Interview

Discussion toward the 50th anniversaryof the Declaration of Helsinki─ Interview with Dr. Otmar Kloiber,

Secretary General, World Medical Association ＊ ─
1Otmar Kloiber
Secretary General of the World Medical Association

Interview and translation：
Chieko Kurihara 1）
Takeo Saio 2）
1）Molecular Imaging Center, National Institute of Radiological Sciences2）Fuji Toranomon Health Promotion Center(March 2, 2013, Imperial Hotel Tokyo, Tokyo, Japan)

Abstract
This article is the record of our interview with Dr. Otmar Kloiber, Secretary General of the World
Medical Association (WMA) during his visit to Tokyo for the World Medical Association ʼ s “ Expert
Conference on the Revision of the Declaration of Helsinki” held on February 28 and March 1, 2013, andhosted by the Japan Medical Association (JMA).
We were privileged to have the opportunity to interview with Dr. Kloiber after the Conference, on theimportant topics related to the 2013 revision of the Declaration such as: biobank, compensation forresearch-related harm, research in resource-poor setting, post-study access, vulnerable populations, ethics
committee. Dr. Kloiber shared with us his thoughts and opinions on these topics as well as on the issue of
ethical principle for placebo-controlled clinical trial. He explained the standpoint of WMA on these topics
especially on the 2002 Note of Clarification and the 2008 revision in which the revised version of this Noteof Clarification to the placebo principle was moved into the main text of the Declaration.
The Declaration of Helsinki was first issued in 1964. Next year, 2014, will be its 50th anniversary. The
WMA is now vigorously working on the final version of the current revision, which we hope to be adopted
in October 2013, reviewing all the topics that have been intensively discussed during the past decades.
Key words
Declaration of Helsinki, research ethics, placebo-controlled clinical trial, post-study access, compensation
for research-related injury＊1Japanese translation of this interview is published in()．2013；41（2）：351-72．Citation of thisEnglish version：Kloiber O．Interviewed and translated by Kurihara C，Saio T．Discussion toward the 50th anniversaryof the Declaration of Helsinki ─ Interview with Dr. Otmar Kloiber, Secretary General, World Medical Association ─．
()．2013；41（2）e．
（http://homepage3.nifty.com/cont/41̲2/p351-72eng.pdf）
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just before finalization? And also is it no problem

1．Expert Conference on the
Revision of the Declaration of
Helsinki

to ask some of the delegates of some countriesʼ

Interviewer Thank you so much for accommo-

want. We are an organization that stands for thedating this interview right after the meeting of thefreedom of research and the freedom of publica-

World Medical Associationʼs (WMA) “Expert Con-

tion. That means not only our freedom but yourference on the Revision of the Declaration of

freedom as well.

Helsinki,” hosted by the Japan Medical Association

Interviewer

Medical Associations or speakers about their opinions on the draft?
Kloiber

You are absolutely free to do what you

Thatʼs great. Thank you. So how(JMA), from February 28 to March 1, 2013 inis your impression of the discussion this time inTokyo. As Secretary General of the WMA, we sup-Tokyo compared to the other open discussions heldpose you have a lot of work to do during the confer-in the past?

ence and also after the conference. So we thank you

Kloiber

There was a lot of interest here invery much for this opportunity and for giving us

Tokyo. Actually, it was the biggest of the confer-

your time. It was surprising and remarkable thatences which we have had so far. I think we hadsuch kind of discussion meeting for the revision of

more participants than in Cape Town and Rotterdam.

the Declaration was held open to the public.

That is at least in part due to the work of the Japan

Kloiber Usually we do not publicly discuss our

Medical Association. Everyone seems to have adrafts of the revision of the Declaration of Helsinki.

very strong interest in the issue of subject protec-

Thereʼs nothing secret, but we do not publish drafts

tion. We also have seen quite some interest on theuntil the planned time, because we have experi-question of research in resource-poor settings. We

enced that many of the drafts, actually nearly all of

have heard various arguments concerning biobanks,

the drafts, have received amendments. Often weall pointing to a stronger role for ethics commit-

find that the initial ideas are not sufficient and wetees. There is obviously a stronger demand for pro-want to come to a better product. And we havetection of human-derived material, and there is afound that it is highly confusing when preliminary

demand for compensation for research-related

versions are out.

injuries of subjects. All in all - everyone seems to

On the other hand, we are trying to get expert

be very supportive of our work. So I found these

input to our drafting process. The Declaration of

two days conference here in Tokyo very reward-

Helsinki has received so much public attention. And

ing.
Interviewer

therefore we do a two-step process: We first pro-

It is also important and a goodduce a draft which the Council accepts, and only

idea that editorial work such as creating subhead-

when the Council has decided to have it discussed

ings and arranging the order of the ideas according

publicly we go out with them. And it has turned out

to topics, which we also thought for long timein the past that this is a very beneficial process,should be done. Our journal have had discussions

and therefore we most likely will repeat this with

about the Declaration 1〜3）several times in the past,

the Declaration of Helsinki.

and also published interviews with Dr. Delon

Interviewer Is it no problem to ask you some

Human 4）, when he was the Secretary General ofquestions concerning the draft of the Declaration

WMA, and with Dr. Eitaka Tsuboi 5）, just after his−2−

Clin Eval 41（2）2013
Dr. Otmar Kloiber is currently
Secretary General of the World Medical
Association. He has been engaged ininternational medical relations andspearheaded various health collaborations for more than 20 years. His expertise includes medical ethics, health policy,
government affairs and management ofrelationships with patients, other healthprofessionals, manufacturers and othermedical stakeholders. He has been chief
executive of the WMA since 2005.
Between 1997 and 2005, he served as
Deputy Secretary General and Secretaryof the German Medical Association(GMA). During his tenure in GMA, he
was appointed as Member of the Study
Commission on the Law and Ethics ofModern Medicine of the German BundeDr. Otmar Kloiber, giving speech during the World Medical Associationʼs“Expert Conference on the Revision of the Declaration of Helsinki”,
stag (Parliament), 14th electoral term.
hosted by the Japan Medical Association, February 28 to March 1, 2013,
Between 1991 and 2005, he was also aTokyo.
key liaison to the Standing Committee ofEuropean Doctors, the WMA, the International Conference of Medical Chambers, the European Forum of the World Health Organization and individual national
medical associations. Additionally, for six years, he was the foreign relations adviser to the German Medical Association,
focusing on international health and social policy reforms and construction of the German Health Network.
He holds an MD (1984) and PhD (1986) from University of Cologne, was a postdoctoral fellow in the Department ofBiochemistry at the University of Minnesota, and was a research assistant at the Max Planck Institute for NeurologicalResearch. In 2006, he was awarded an honorary doctorate by the Victor Babes University for Medicine and Pharmaceutics,
Timisoara, Romania. He was appointed Clinical Professor in Health Administration at the Brooks College of Health,
University of North Florida from 2009 to 2013.
Quoted from the web-site of OECD: http://www.oecd.org/health/ministerial/worldmedicalassociationotmarkloibersecretarygeneral.htm

tenure as President of WMA. So you were appointed

tion on the proposed revision and will have a meet-after Dr. Delon Human?

ing in Washington D.C. in August 26-27, and thenfinalize this current revision during the General

Kloiber Yes, Iʼm following Dr. Delon Human in

Assembly on October 16-19, 2013 in Brazil. So

the office.
You have been engaged in WMA

next year, 2014, is the 50th year anniversary of thesince before the time Dr. Human was secretary-

Declaration. What is your plan toward this 50th

general?

year anniversary?

Interviewer

Kloiber Indeed. Iʼm engaged in the association

Kloiber Provided the WMA Council agrees,

since 1991; so actually the time before Dr. Humanwe are planning to have a public consultation dur-came. I have been part of the discussion on theing the summer. After that, the workgroup will

Declaration from the middle of the 1990s until

analyze the comments and critique coming in. Thisnow.

may lead to a new draft to be discussed again in a

Interviewer

After the Tokyo Conference, we

conference we plan for August in Washington D.C..

heard that WMA is going to have a public consulta-

In the end, our aspiration is to have a final draft
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Dr. Kloiber giving a speech on March 1, 2013, at the closing of the Expert
Conference on the Revision of the Declaration of Helsinki.

ready for the General Assembly in Brazil in
October this year＊2

issue, more people participated in the discussion.
Kloiber. However, let me emphasize

The placebo issue was very much

this: Our focus is on the quality of the document,

expert discussions, and we invited all those people

not the timeline. If we donʼt finish this year, we will

who had scientifically published on the methodol-

do it next year.

ogy of using placebos, because we want to makeIn 1964, the Declaration of Helsinki was handed

sure that there is good scientific evidence for theover to the President of Finland. It was a documen-

use of placebos, even if there is already an estab-tation of self-governance and social responsibility.

lished therapy. There are of course such situations

We have asked the President of Finland to again

where you never can replace a drug by a placeboshare this moment with us, celebrating 50 years of

because the drug treatment is essential, and it

the Declaration, and we are proud to say thewould be threatening to the patient to remove such

President of Finland has agreed to do that. So wetreatment. But we learned that there are many

will celebrate 50 years of the Declaration ofother instances and diseases, especially when it

Helsinki next year in Helsinki and we are sure itcomes to symptomatic treatment where we deem itwill get some attention.

now necessary to have the chance to do placebo
studies. So currently I see a trend to use three-arm

2．Issue of placebo-controlled trial

studies ‒ to have a verum arm, to have active comparator, and where necessary also a smaller placebo arm.

Interviewer We supposed that in the meetings

Interviewer

held in the past to intensively debate the placebo＊2

In Japan, there are many psychia-

Postscript by Dr. Otmar Kloiber: The meeting in Washington DC was successful and there will be a final draft.
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Clin Eval 41（2）2013

trists and persons in the field of medicine or medi-

retest whether our assumptions are really correct.

cal ethics who protest against the use of placebo in

The placebo can be very good instrument to doclinical trials. But very recently such trend of psy-that. To ban the placebo completely, we now arechiatrists protesting against the use of placebo issure would in turn be damaging the science, and bychanging because of the increasing number of reviews

that it would most likely harm patients more thanor meta-analysis of research on psychiatric drugs

using the placebo correctly. But ‒ to make that

6〜8）

9）

showingvery clear ‒ this is not about using the placebo asthat there is no significant difference between thea cheaper alternative instead of an active drug. We

test drug and placebo. Yesterday, during a break inare talking scientific, not economic reasons to use

the meeting, we talked to a delegate from anotherplacebos.

for depression, and schizophrenia

medical association. He is a psychiatrist, and heInterviewer The 2008 revision seemed to be

told us very clearly that placebo should be used in

the conclusion of this kind of placebo debate. The

the area of psychiatry.

condition on the use of placebo is that even if there

Kloiber We thought at some point we can iden-

is a proven therapy, placebo can be used when there

tify a “best-proven” therapy for each disease. But

is the scientific reason and it will not subject theif you take for instance the established anti-depres-patient to any risk of serious or irreversible harm.

sants, we now know that many of those drugs turn

These are very well written descriptions. But why

out to be not so effective. Also, we have not yet

was there so much debate raised after this 2008

understood for all the different diseases and thera-

revision and discussed in São Paolo in 2012?

pies, how to select the right drugs for each poten-

A delegate from the Japanese Medical Association

tial subgroup of patients with one disease, because

wrote that the Brazilian Medical Association, on

what we often see is that there are collectives ofbehalf of developing countries, expressed strong

responders and non-responders. We always have toopposition to Paragraph 32 of that time 10）.

Box 1

Provision concerning “Use of Placebo”, in the proposed revisionof the Declaration of Helsinki

33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against thoseof the best current proven intervention(s), except in the following circumstances:
The use of placebo, or no treatmentintervention is acceptable in studies where no current provenintervention exists; orWhere for compelling and scientifically sound methodological reasons the use of any intervention
less effective than the best proven one, placebo or no treatment is necessary to determine theefficacy or safety of an intervention
and the patients who receive any intervention less effective than the best proven one, placebo or
no treatment will not be subject to any additional risks of serious or irreversible harm as a resultof not receiving the best proven intervention.
Extreme care must be taken to avoid abuse of this option.
Comment by WMA: Old paragraph 32.
Excerpt of the proposed revision shown in the version released for public consultation to revise the 2008 version.
Paragraph 32 of the 2008 version has become Paragraph 33. A final decision on this proposed revision would be madeduring the General Assembly of WMA in October 16-19, 2013 in Brazil.

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placebos. We think itʼs necessary to make veryclear to all the lawmakers that indiscriminately
banning placebos is not a good idea because there
is a need for placebos.
Interviewer

So you mean that some scientists

in Latin American countries (especially the Brazil
Medical Association) want to revise the 2008 revision because of that kind of prohibition in the law?
Kloiber

They say 2008 version is not accept-

able to them because the law says they cannot use
the placebos. We now know that this is not correct
because there are good reasons to use placebos inclinical studies.
Interviewer

We heard from someone that

there are some religious people in Latin America
who protested against the use of placebo.
KloiberDr. Kloiber, responding to a journalist during the Press
Conference held on March 1, 2013, after the conclusion of the “Expert Conference on the Revision of the
Declaration of Helsinki”.

I have not heard any religious argu-

ments concerning the use of placebos. I have heard
from some of the activists groups, especially inEurope, who have said that there are placebo studies being done in resource-poor countries, and they

Kloiber After the 2000 revision, there wereare raising the assumption that these studies aremany lawmakers and regulators, especially in Latinbeing done because itʼs cheaper to test against pla-

American countries, who banned the use of placebo

cebos instead of a real medicine. And this is unac-

in clinical trials if there is an established treat-

ceptable for us as well. Placebos must never been

ment. In a number of Latin-American countries

used for economic reasons in clinical studies.

placebo-controlled trials are impossible if there is

However, if you look into those studies that havean active compound to treat with. Of course webeen criticized, you will find that the studies have

could be proud that lawmakers and regulators havebeen done multi-nationally with the same design notfollowed our Declaration, but at this point it

only in poor countries but also in richer countries.

becomes clear why there is a difference between an

So the argument of exploitation does not seem toethical guideline and a law. After the 2000 version

be correct. There may be studies which are being

banning more or less the placebo use, we learnt

done and produced unethically. The Declaration ofthat this was too strict and we have taken the con-Helsinki is exactly about preventing those studies.

sequence to change. But once you have a law or a

3．Note of Clarification for the
principles of placebo-controlled
trial

government regulation, itʼs very difficult to change.
Knowledge grows, sciences changes, new methods
come in. We can revisit ethical principles and therules we derive from them ‒ and so we do. We have
had discussions from 2005 to 2008 about the use ofInterviewer−6−

So before the 2008 revision,

Clin Eval 41（2）2013

Kloiber Yes. That was the idea of the note ofthere was the 2002 Note of Clarification for
Paragraph “29”. It was strange and seemed for us

clarification. But this is history. The 2008 version

a little bit tricky. There was a conjunction “or” inis much stricter. Already in 2000, it was clear to us

this Note of Clarification, that is, “scientific com-that we had to continue the work on the Declaration

pelling reason OR no additional risk of serious orof Helsinki because there were many issues where

irreversible harm for the subjects....”

we thought that this was not final. The Declaration

Kloiber There was one discussion point thatof Helsinki has always been a living document.

we said that there are many studies which are notSome of us were also convinced that the solution

about serious diseases. The idea was that an indi-

for placebos and for the continuation of treatment

vidual person can decide whether they want to takeafter the trials was not perfect. So we made thethe risk of being in a placebo group.

note of clarifications in 2002 on placebo, and inThat is the point raised by Dr.

2004 on the post-trial access to care. And it was

Temple and other FDA staff wrote articles 11，12）also clear that we have to bring it back into theabout.

main text of the principle, not as a note of clarifi-

Interviewer

Kloiber Yes, they made a point.

cation. So when I came into office in 2005, I pro-Interviewer The point which seems to beposed immediately that we look into producing a

tricky is that in the Note of Clarification, there is

new revision in order to have a clean text. And thatthe conjunction “or”. Not “and”.

was the purpose for 2008.

Kloiber In the 2008 version, we decided forInterviewer It became very clear to us now.

the stricter version by introducing the conjunction

After 2008, there were some questions remaining.

“and”, which means both conditions must apply.

Were these questions resolved during the meeting

Interviewer Wasnʼt it just a mistake or somein São Paolo, because there was no discussion onvery tricky person inserted this conjunction “or”?

that in Tokyo?

Kloiber The conjunction “or” was put in there

Kloiber In 2008, we saw a strong opposition by

by purpose. The question whether it should besome of our colleagues, especially from Latin“and” or “or” had been discussed. And it was for

America against the placebo rule. The Council told

the reason which I mentioned, that it was made anme: “We take these concerns very seriously, and we“or” at that time. Nevertheless, the WMA Generalwant you monitor the situation and report back to

Assembly in 2008 decided for the stricter version.

us whether the new (2008) version is appropriate

Interviewer If this is an “or”, then the use pla-

or not.”cebo is permitted only for scientific compelling

Interviewer When we saw the note of clarifi-

reason, even if the study may cause serious harm tocation, it seemed strange that the Note of Clarifica-

the subjects.

tion (i.e. placebo-controlled can be allowed if there

Kloiber At no point! It was clear that the pla-is scientific reason, on condition that the Declaration

cebo use should be only permitted if the study

is adhered to) upend the statement of the principles

adheres to all other conditions in the Declaration.

in the main text (i.e. placebo-controlled can be

Interviewer You mean that if the study adheres

allowed only when there is no established method)

to all the other conditions, ethics committee andconcerning placebo use.

the prospective subjects can properly evaluate theKloiber Itʼs probably not. The Note of Clarifi-

risk of harm? Is that what you mean?

cation was made because we thought that we had
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not expressed the principles clearly enough indone for valid scientific reasons and not because

2000. It has never been intended as an opposition tosecond best is cheaper. This is important for all

the principles. However, we found that we hadpatients, not only for those in poor countries.

written a non-working rule. The aspirational rule

4．Post-study access andresource-poor setting

simply saying “no placebos” was just not working.
The principle behind that is non-exploitation or “dono harm”. We must prevent that people are being

Interviewer

subject to exploitation by the use of placebos forNow, letʼs shift the topic to post-

economic reason. But when the use of placebo is

study access and resource-poor setting. How isscientifically necessary, not using placebos may doyour impression of yesterdayʼs discussion on this,more harm.

especially the comment of a delegate from India

Interviewer We understand completely what

about exploitation of subjects in the trial? Some ofyou mean. So how about the next discussion on pla-

the delegates from pharmaceutical companies

cebo? There is no discussion in Tokyo about the

explained something in response to that.
Kloiber

placebo issue; instead the discussion has shifted toFirst of all, itʼs not only a problem in

the resource-poor settings. Actually, I get these

the post-access issue.
Kloiber We think the rule on placebo in 2008

questions concerning the post-trial access to theis correct. We will probably develop a little more

best-proven treatment from rich countries as well.

precise wording, but the rule is fine. We think itʼs

Also, patients in rich countries donʼt necessarily

not only necessary to explain why you use placebo

get the newest drug or the best-proven drug. Even

instead of the best-proven practice or treatment;in the rich countries, payers or regulators tell theweʼll also ask why do you use anything else but thepatients “No, you have to take a cheaper one

best-proven treatment. Sometimes new compounds

because the best-proven, may be 5 percent better,or procedures are not tested against the best-

but we donʼt pay five times more money for that.

proven treatment but tested against the second-

We only pay for the second best.”
A mistake in the 2000 version was that we put

best. We want to make sure that this is only being

Box 2

Provision concerning “Post-trial Access”, in the proposed revisionof the Declaration of Helsinki

34. In advance of a clinical trial, sponsors, researchers and host country governments shouldmake provisions for post-trial access for all participants who still need an intervention
identified as beneficial in the study. This information should also be disclosed to participants
during the informed consent process. All study participants should be informed about theoutcome of the study.
At the conclusion of the study, patients entered into the study are entitled to be informed about theoutcome of the study and to share any benefits that result from it, for example, access to interventions identified as beneficial in the study or to other appropriate care or benefits.
Comment by WMA: Old paragraph 33.
Clarifies and strengthens post-trial access issue.
Excerpt of the proposed revision shown in the version released for public consultation to revise the 2008 version.
Paragraph 33 of the 2008 version has become Paragraph 34. A final decision on this proposed revision would be madeduring the General Assembly of WMA in October 16-19, 2013 in Brazil.

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Clin Eval 41（2）2013

Interview with Dr. Kloiber

the burden on the continuation of healthcare after

changed. I am very happy that many companies now

the end of a study on the sponsor of the study andprovide medicines for post-trial care. I think thatthe researcher. But indeed, this is not their duty.

is already a big win which the Declaration ofItʼs the duty of the states to provide healthcare in

Helsinki may have triggered.

one way or another. It can be a private healthcare

But we also have to come back and say, “States,

system or public healthcare system. It can be aitʼs your business to make sure that there is ahealthcare system by a social insurance. But wehealthcare system; that people get appropriate

believe it is the obligation of the state to make sure

healthcare when they need it and want it.” Mostthat everybody gets the healthcare a person needs;

sponsors of clinical trials ‒ the universities, foun-

to ensure this is not the obligation of a researcher

dations ‒ even many companies are not able to door the sponsor of a study. Of course, what we see

that. They cannot replace the functions of a state.

is that by doing the research and by offering treat-

So we have to step back, and what we say isment in a research program, people may have anthese conditions have to be explained beforehand.

undue inducement to be part of an experiment. That

People have to know what happens with them dur-is unfortunately correct. That is what Dr. Kumar

ing and after a clinical trial; and what that means

described as the treatment naïve people, who arefor their health. People can then decide whether

strongly induced to be part of an experiment

they want to be part of that trial or not. The

because otherwise they donʼt get treatment.

empowerment of patients is probably the mostimportant aspect of this rule.

But this is a general problem, not only a problem
in resource poor settings. In my country (Germany)

We also say there has to be a sharing of theten years ago, if you had macular degeneration, theresults, and that can be that a pharmaceutical com-only way to get an effective treatment was topany provides drugs after the trial. It can be that

become part of a study because the healthcare sys-

information is being given to the community andtem would not pay for the drug. Things havethat the whole community has a win from that. Very
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often we find patients who are very willing to take

5．Obligation of states to assure
health for nations

part in a trial even though they know that they
themselves will not benefit from it. Think about
cancer treatments. Very often patients clearlyInterviewer

understand that they may not be saved from a trial.

You said that “post-study access”

But they well know that the knowledge that is being

is an obligation of the state. So which kind of obli-

generated may help the future patients. In the end,

gation? Is it correct to say ethical obligation?
Kloiber

we had to come to a more realistic wording but alsoItʼs a human right. Health is a humana wording that puts the obligation to ensure health-right. The states, in one way or another, have tocare back to the states without prescribing a spe-

provide a functioning healthcare system.
Interviewercific type of health care system.

Itʼs a very important suggestion.

Interviewer Itʼs a very important point. Another

There is also another point: post-study access ispoint is that too much emphasis on the post-study

very much a monetary issue, same as compensation

access can bring some harm to the patient. There isissue and ancillary care. Ancillary care is not

one example ‒ post-study access includes the prob-

included in this Helsinki Declaration, but is verylem of expanded access.

much discussed in the U.S. by bioethicists.
Kloiber

Kloiber You are absolutely correct.

Ancillary care is part of the health-Interviewer In Japan, a new molecular-tar-care that has to be provided by the health caregeted cancer drug gefitiniv (Iressa Ⓡ) was approved

system in general. Now, for a functioning clinicalearlier than in the U.S. or Europe. Such case was

research environment you need functioning ancil-

very rare in Japan at that time. But soon after

lary care. Because you cannot do any drug study on

approval, and also before the approval, many of thesubstances on blood pressure regulation when yournewspapers or other media released information

people are starving or are not being taken care of,about the drug, and many patients got the drug

and so far, it is part of a good clinical practice. But

through the scheme called “Expanded Accessthis is also an ethical dimension that reaches into

Program” which is not legally well-defined system

the other questions of the human right, that is, toin Japan. And then so many adverse events came

have proper health care.
People tend to read the Declaration of Helsinki

out and lawsuits were raised by patients groups in

as a solitary document. It is not. Itʼs part of ourJapan.
Yes, that is a problem. Unfortunately,

policy compendium. In our policy compendium, we

the rule in the 2000 version of the Declaration did

also have a Charter on Patientʼs Rights which

not take in account that a single clinical trial nearlyclearly states that persons have a right to appro-

never ever gives you a definite result. Usually, sev-

priate and timely treatment. Thereʼs the Interna-

eral trials in different places are needed. Second,tional Code of Medical Ethics; the Declaration of

if a new drug is being tested in a trial, and even if

Geneva; the Declaration of Lisbon on Patientʼs

itʼs been found more beneficial than an old one, it

Rights. The Declaration of Helsinki is not in a vac-does not mean that you have a marketing authority

uum.

Kloiber

for that. The marketing authority may take anothertwo years to come. So that was why we finally foundthat the rule in 2000 version was unrealistic.
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Clin Eval 41（2）2013

issue is included in the CIOMS but not in Declara-

6．Resource poor setting andcapacity developmenttion of Helsinki. Capacity development is very
important but a little bit tricky if it becomes asubstitute for post-study access. Itʼs like saying, “IWe regard that a very importantam sorry we cannot give you continuing therapy but

characteristic of the Declaration of Helsinki is

we can provide you with capacity development

research ethics, human research. So letʼs go backopportunity.” If it is true that they cannot provide

to another point of resource-poor setting. When I

continuing therapy but they could contribute in(Kurihara) visited the University of the Philippines,

capacity development, it could be welcomed.

Interviewer

I discussed with the members of their ethics com-

Kloiber But we think itʼs not an “or”. Itʼs an

mittee about the north-south issue and ethics of“and”. So both have to be achieved. But we also13）

. We dis-believe that CIOMS and WMA are not apart. We

cussed about the comparison between the Declara-

think that the participation in research is extremely

14）.

important for the development of healthcare sys-

Comparing the Declaration and CIOMS, the word-

tems. Having a perspective for academic develop-

ings on placebo issue became almost the same after

ment is a strong incentive for the retention of

the 2008 revision. Healthcare needs issue and post-

health personnel in those countries. Currently thestudy access issue are also the same.

rich countries of this world are stealing the healthinternational clinical research (Table 1)tion of Helsinki and the CIOMS guideline

professionals from the poor countries of this world.

The only difference is that capacity development

Table 1

Obligation of the researcher in collaboration with resource-limited community
Declaration of Helsinki

CIOMS

Placebo or no treatment control
32. Placebo or no treatment control may be acceptable
when it will not be subject to any risk of serious or
irreversible harm.

Placebo or no treatment control
11. Placebo or no treatment control may be acceptable
when it would not add any risk of serious or irreversible harm to the subjects.

Health needs
17. Research involving a disadvantaged or vulnerable
community is only justified if the research is
responsive to the health needs of this community.

Health needs
10. The Research in communities with limited resources
should be responsive to the health needs of thecommunity.

Post study access
14. The protocol should describe arrangements forpost-study access by study subjects to interventions
identified as beneficial.
33. At the conclusion of the study, patient participants
are entitled to be informed about the outcome of thestudy and to share any benefits that result from it.

Post study access
10. Any intervention or product developed will be madereasonably available for the benefit of that community.

Capacity development
20. The research projects should contribute effectively
to national or local capacity to design and conduct
biomedical research, and to provide scientific andethical review and monitoring of such research.
Quoted from reference No. 13. Numbers of provisions of the Declaration of Helsinki are from 2008 version.

− 11 −

臨床評価41 巻 2 号

2013

And if we want to have healthcare in the resourceand human research volunteers are very much pro-poor countries as well, there have to be researchtected. Also sometimes this kind of early phase

opportunities as well. Capacity building is extremely

clinical trial on patient can show efficacy. But thisimportant. But it must not be at the expense ofkind of situation is far from the assurance of post-

safety or correct ethical behavior. Both have to

study access to best proven treatment.
Kloibercome together.

I think the future markets for drug

Interviewer In the description of CIOMS, I

development, and the future demands for drug

think their idea is the same as yours. Both should

development are coming from those big countries

be kept together. But in the description of CIOMS,

which right now people have no proper or do notthey say that even if it is very difficult to provide

yet have full access to the available drugs: China,

the new therapy after the completion of the study,

India, but also Philippines, Indonesia, and many

it would be acceptable if the conduct of the study

African and South American countries. As I said

helps in capacity development.

before, we strongly believe that those communities

Kloiber Well, if you read our document thatshould be part of the scientific development as

would not be in contradiction with that because

well. If it is okay to have such a study being done

what we are saying right now is that it has to be

in Japan, it should also be okay to be done in the

explained what is happening after that and that thePhilippines, provided that the technical and ethicalbenefits have to be shared. But there is no guaran-safeguards are absolutely the same.
Again, when it comes to the post-trial access, we

tee for anything automatically.
Although we are 49 years further now, thesay the benefits have to be shared, in one way or

Declaration of Helsinki in the beginning was a doc-

another, itʼs not clear what that has to mean in eachument that has been made to enable research inindividual case. But people have to be told what

humans, to make research acceptable. And we still

happens to them afterwards, so that people cansay, health research, clinical research is necessary

decide whether they want to be part of that. Whatand has to be done in order to advance medicine andwe donʼt accept is that people are being paid forto save people and to prevent disease and to allevi-

clinical studies. That is an undue inducement.

ate the suffering. And we always stress that we

But then again, we are convinced that bringing

believe that health research has to be brought toresearch to a country, in many cases will, increase

all people, all communities, and all professionals.

or improve the health care situation in general.

Interviewer So how do you think of Singapore

That is a benefit, and itʼs not an incorrect benefit

as an example? There are many Phase 1 studiesof having that. The rich countries have enjoyed thisbeing conducted in Singapore. They very much wel-

benefit for all the last decades.

come global pharmaceutical companies to come and7．Compensation forresearch-related harms

conduct Phase 1 study, even if it is not assured that
all the successful studies will proceed to later
phases in Singapore. These later phases may be
conducted outside Singapore, in other countries

Interviewer

So, how is your opinion on thewhere many patients can be recruited in large hos-compensation issue? It must be very important but

pitals in a short period of time. In these days, mostseems very difficult to include such issue in thisof the early phase clinical trials are not so risky,kind of ethical guidelines. Theoretically, “no-fault”− 12 −

Clin Eval 41（2）2013

Box 3

Provision concerning “compensation for research-related harms”,
in the proposed revision of the Declaration of Helsinki

15. Adequate compensation and treatment for subjects who are harmed as a result of participating in the research must be ensured.
Comment by WMA: New paragraph. It reflects the obligation to ensure that subjects
who are harmed will receive compensation and treatment.
Excerpt of the proposed revision shown in the version released for public consultation to revise the 2008 version. In
the 2008 version, paragraph 14 included the statement: “The protocol should include information regarding funding,sponsors, institutional affiliations, other potential conflicts of interest, incentives for subjects and provisions fortreating and/or compensating subjects who are harmed as a consequence of participation in the research study.”
A final decision on the above proposed revision would be made during the General Assembly of WMA in October
16-19, 2013 in Brazil.

compensation needs legal bases. Because tort-law

trial conducted by pharmaceutical companies underor civil law grants people the right to be compen-

the pharmaceutical affairs law, and the investiga-sated on the bases of negligence liability of the

tor-initiated clinical research which is under the

person who is responsible for the harm. So grant-

guidelines. In the cases of clinical trials conducted

ing “no-fault” compensation is difficult withoutby pharmaceutical companies in Japan, the amountlegal bases, even if ethical principles require it.

of compensation provided for research-related

Kloiber It was not that difficult, we have

injuries are higher compared to trials in otheralready included this request in the 2008 revision.

countries. On the other hand, in investigator-initi-

The question is ‒ do we have to get a little bit

ated trials, the clinical research guidelines require

stricter on that? We believe it is necessary that the

only that experimental trial of drug or device toresearch subjects are protected against any adverse

prepare for compensation, but for other type ofeffect of the study. Some countries have compensa-

research (e.g., interventional, but not using drugs

tion funds for patients. Some countries use insur-

or devices) it is allowed only to say that researcher

ance systems. The nations have to find out how thathas to explain to the patients whether there is or

should be done. What we want is certainly that any

not the compensation.

researcher, any physician, is aware that there has

Kloiber Our approach is different. We say

to be some mechanism of a proper compensation if

there has to be a compensation, not you can explain

damages occur caused by the research.

whether there is or there isnʼt.

We understand the ethical prin-Interviewer This seems to be an idea coming

ciple that a person who worked for a social benefit,

from Europe because some of the European coun-taking the risk of participating in an experimenta-

tries have laws to provide no-fault compensation

tion, should be compensated for an injury that he/

for research-related injuries, or not only research-

she sustained even if the injury resulted without

related but also medical-related injuries.

Interviewer

the fault of the other person. This idea was written

Kloiber Yes.

in the report in 1982 of the U.S. Presidentʼs com-

Interviewer But in U.S. the situation is dif-mission15）

ferent.

. However even now, the U.S. still does

Kloiber Yes, I know. Itʼs different because

not have a system of providing “no-fault” compen-

there is no legal regulation on that.

sation for research-related injury.

Interviewer How is the debate on this point? I

In Japan, there is a discrepancy between clinical− 13 −

臨床評価41 巻 2 号

2013‒ and not just telling people you will not get com-mean the debate with the U.S. delegates.
Kloiber No, I see the American Medical

pensation. It will mean there has to be a system for

Association is with us. There has to be a mecha-

compensation. If there is no compensation mecha-

nism for compensation. That is part of the Declara-nism, the study has not followed the Declaration oftion of Helsinki already, and they fully subscribe to

Helsinki and we demand from editors not to accept

that.

such studies for publication.
Interviewer

8．FDA and AMA, ICH-GCP and
Declaration of Helsinki

So your idea is that the Declara-tion of Helsinki has such power.
KloiberWell, many journals ask the research-ers to show that they have followed the Declaration
Interviewer One more interesting issue wasof Helsinki. Whether they will and can test for eachthat FDA changed their policy to include Declara-

and any detail, I doubt. They will have to trust thetion of Helsinki in their regulation for the clinicalinvestigator to a large extent.

trials conducted outside U. S. . They changed to

9．Biobanks and broad consent

ICH-GCP. That may be the reason why they canagree very easily. This is very cynically saying.
Kloiber No, thatʼs not cynical. The one thing isInterviewer

the FDA is a government authority. If they think

So another topic, in this Tokyo

meeting, a new upcoming issue is biobanks.

they can go to lower ethical standards, thatʼs their

KloiberWell, biobanks are not really a newdecision. The AMA has not done so. The AMA

issue. We have been discussing this with theupholds high ethical standards. And that is some-Government of Iceland in the end of the ʼ90s whenthing I would like to stress here. It is the govern-

they started their project with DeCode Genetics.

ment which has lowered the standards, not the

And we have discussed it with governments in

AMA. Very important.

Estonia and in Sweden. We have seen similarInterviewer So you think that even if the FDA

Biobanks being installed in other countries.

exclude the Declaration of Helsinki, it is no prob-

But concerning the rules of the Declaration oflem if AMA does not do it. The Declaration says

Helsinki, we also anticipate experiments being donethat “No national or international ethical, legal orin simulation, without any physical material or per-regulatory requirement should reduce or eliminate

sons; just with data. Therefore, already the 2000

any of the protections for research subjects set

revision of the Declaration of Helsinki covered notforth in this Declaration.”

only experiments in real persons but all research

Kloiber No, they have not excluded it. They

with identifiable samples and/or data.

have only said that they are not demanding it fromThe strict application of the Declaration of

the studies from outside. We still ask all physiciansHelsinki in the 2000 version limited further use ofin this world to obey the Declaration of Helsinki.

specimens in biobanks because you cannot give

And we also expect that, for instance, publishers,

informed consent to experiments which you do noteditors ask for compliance with the Declaration ofknow. One solution that is currently being dis-Helsinki before results are accepted for publica-

cussed may be the broad consent. Iʼm not suretion. And this would include also the question

whether the World Medical Association will say

whether there has been a system for compensation

this is enough. We have heard yesterday from the− 14 −

Clin Eval 41（2）2013

After the interview, from the left - Dr. Kloiber, Kurihara, Dr. Saio.

researchers that they say broad consent may be aconsent in the end means rubber stamping every-

part of it but it will not be enough to protect peo-thing, and this is not an informed consent. This isple. So there must be broad consent and there must

worth nothing. In the end, such procedure will seri-also be some governance structure in order to pro-ously damage the image of research.

tect the individuals. And I think that is a very, very

Interviewer Is there any background, sometricky question. Currently, we have a rule that tokind of ethical or legal background on that in yourme is very realistic, requiring consent by an ethics

country?
Kloiber Well, there have been court decisionscommittee when individual consent cannot be

about informed consent for medical treatment. And

achieved.
But many of the U.S. people seemthe decisions have always stressed that an informed

to regard that if the researcher provide enoughconsent has to be very specific, it has to be direct

explanation about what is the broad consent, and if

to the point, and there cannot be any blanket

the subject accepts it, it is enough. We translated

informed consent. So you cannot go to a patient andRobert Amdurʼs “IRB Handbook” 16）, which is very

say, we operate you tomorrow, and then theremuch well used in the U.S.. The author describedmaybe the danger that the anesthesia doesnʼt work,

such kind of idea in a persuasive way.

that your heart stops and that you may die. This isInterviewer

Kloiber Maybe. Maybe not. I think people can-not enough. They have to be very precise and they

not imagine what can come out from this data or

have to be clear to the point. And the same is true

specimen experiments. The quoted suggestion

for research.

seems to be a very simplistic view and in my coun-

Interviewer This kind of explanation would be

try this probably would not be enough. A broadnecessary for some surgery or something or medi− 15 −

臨床評価41 巻 2 号

2013

the conditions to allow broad consent.

cal care. But in case of providing human samples, isKloiberit the same?

Currently, it is for secondary use of

Kloiber Well, if there is a potential danger

samples or data whether they are in single reposi-

falling back to the participant, yes. You may, fortories or biobanks or medical data banks. The broad

instance, learn about a disease you have, that can-consent is not an issue for the Declaration of

not be treated. You may end up in a disease group

Helsinki because it has only the informed consent

that is stigmatized or you may receive knowledge

and it does not accept the broad consent currently.

that makes your future insurance more expensive

And then maybe that if we go in dealing withor even impossible. The future research may entail

biobanks separately apart from the Declaration of

ethical or commercial aspects you donʼt agree with.

Helsinki.
Interviewer

A blanket consent cannot cover the unforseeable

Declaration of Helsinki doesnʼt

and therefore does not provide protection to theallow broad consent but since the 2008 revision it

individual giving that consent.

already allows research without informed consent

Interviewer Itʼs a very important point. I

when it is not realistic or impossible to obtain such

(Kurihara) once wrote an academic article with myconsent. You mean that if the ethics committee

colleagues to propose Human Research Subject

authorizes such research after considering minimal

Protection Act. In this proposal, we included

risk or significant importance of the research and“broad consent” with the requirement that the sum-other things, such exceptional case is acceptable,

mary of the categories of possible future researchalthough broad consent is not acceptable?
Kloibershould be described. There would be one option toYes, the difference to the broad con-explain that the researcher should declare thatsent is the decision by ethics committee, which will

future research would be in the range of socially,

be able to weigh risks and benefits. Such a consid-

ethically acceptable one. This kind of declaration

eration is excluded by a solitary broad consent.
Interviewer

would avoid the situation where the sample is usedOkay. In Japanese guidelines,

for unethical research or activity, such as researchbroad consent is allowed on condition that theon human cloning. Another option, which is included

expected subject is explained that the future indi-

in the Japanese clinical research guideline, is avidual research is to be discussed by future ethics

statement saying that future ethics committee willcommittee and allowed only when the committee

discuss about each future research. This is one ofgives authorization, so I think our guidelines are

Box 4Provision concerning “biobank”, in the proposed revision of the Declaration of Helsinki
32. For medical research using identifiable human material or data, such as research on material
or data contained in biobanks or similar repositories, physicians must normally seek consent for
the its collection, analysis, storage and/or reuse. There may be exceptional situations whereconsent would be impossible or impracticable impractical to obtain for such research or would posea threat to the validity of the research. In such situations the research may be done only after
consideration and approval of a research ethics committee.
Comment by WMA: Old paragraph 25.
Excerpt of the proposed revision shown in the version released for public consultation to revise the 2008 version.
Paragraph 25 of the 2008 version has become Paragraph 32. A final decision on this proposed revision would be madeduring the General Assembly of WMA in October 16-19, 2013 in Brazil.

− 16 −

Clin Eval 41（2）2013

have been developed, especially focusing iPS cells.

compatible with the principle of the Declaration.
Then how about to say biobank is not a research

Kloiber The iPS cells raise the question on

project but biobank itself is project, including many

whether the reprogrammed cells can be seen as

kinds of research projects?

embryos themselves, and if that is the case thenKloiber Exactly. That may be the case. Our

they would have the same problem as any embry-

solution is if you cannot ask the persons themselves

onic stem cell research. As in the start, iPS cells

whether you can use their specimen for an unfore-

are somatic cells and no embryo has to be sacri-seen secondary use and an informed consent is

ficed to win them and most people will find them

impossible or impractical, then it should be done

more acceptable than embryonic stem cells. Con-

with the permission of an ethics committee.

cerning the Declaration of Helsinki and the research

Listening to our conference, I think we will find aon that, I donʼt think that there has to be a specificsolution which maybe a combination of broad con-edition to that. They will fall under the Declaration

sent plus a governance structure, like ethics com-of Helsinki like any other experiment.

mittees, in order to put in safeguards. But justInterviewer Many people may think that iPS

broad consent doesnʼt seem to be acceptable.

cells can be replaced with embryonic stem cells,
destroying embryo. But one very serious ethical

10．Issues of marginal or out of
the scope of the Declaration of
Helsinki:

problem of iPS cells is that if it is possible to cre-

iPS cells; disease kidney/uterustransplantation; neuro-ethics;
dual use

ethical debate is not in the Declaration of Helsinki

ate embryo from iPS cells, it may cause humancloning to become very easy. I think this kind of
but in some other documents, such as, European
Council, UNESCO.
Kloiber Yes, but World Medical Association

iPS cellalso has spoken out against reproductive cloning.
You are very much experienced

But this is a specific research matter. And regard-

and also has deep insight for ethical analysis of theless whether you are against or for cloning, if you

difficult issues so we would like to ask you several

produce a new embryo then the question of humankinds of ethical questions on the issues discussed indignity applies to that embryo as well.

Interviewer

Japan.

Diseased kidney transplantation

First of all, we want to ask you about iPS cells
issue. At the press conference, some media person

Interviewer In Japan, there is a doctor who

asked you a question about iPS cells issue, althoughconducted very peculiar kidney transplantation

it was not discussed at the meeting. I think it is notsurgery: from a patient who is to undergo surgery

necessary to describe specifically about iPS cells

to remove kidney because of kidney disease toin the Declaration of Helsinki, but some people inanother patient who wants to be a recipient of kid-

Japan may think that including iPS cells issue into

ney transplantation. We call this “diseased kidney

Declaration of Helsinki is a good idea because atransplantation”. This very outstanding doctor, avery peculiar situation in Japan is that there is nopractitioner rather than a researcher conductedcomprehensive law for human research, but very

this surgery in several patients, but the academic

recently laws to regulate regenerative medicine

society did not like that, so there were several− 17 −

臨床評価41 巻 2 号

Box 5

2013

Provision concerning “Unproven Interventions”, in the proposed revisionof the Declaration of Helsinki

37. In the treatment of an individual patient, where proven interventions do not exist or have beenineffective, the physician, after seeking expert advice, with informed consent from the patient or alegally authorized representative, may use an unproven intervention if in the physicianʼs judgement it
offers hope of saving life, re-establishing health or alleviating suffering. Where possible, tThis
intervention should subsequently be made the object of research, designed to evaluate its safety andefficacy. In all cases, new information should be recorded and, where appropriate, made publicly
available.
Comment by WMA: Old paragraph 35.
Intended to clarify the intent of this paragraph. Strengthens requirement
to make the intervention the object of subsequent research.
Excerpt of the proposed revision shown in the version released for public consultation to revise the 2008 version.
Paragraph 35 of the 2008 version has become Paragraph 37. A final decision on this proposed revision would be madeduring the General Assembly of WMA in October 16-19, 2013 in Brazil.

debates and the society said that it should be eval-

Uterus transplantationuated in the academic society, and at this time such

InterviewerItʼs a very interesting idea. Therekind of surgical procedure should be conducted as

is also another issue. There are some people with“research”, and not practice. I think the Declaration

gender identity disorder who donʼt want to haveof Helsinki also say that such experimental prac-uterus for bearing children. On the other hand,tice can be done by a physician but it should bethere are some women who have some disorder inmade subject of research program.

their uterus but wish to have a child. Recently,

Kloiber Yes, thatʼs right. As for the “disease

there is an emerging experimentation of uterus

kidney transplantation”, in the beginning it sounds

transplantation. There are some cases wherein the

odd and very difficult to accept. However, you haveuterus is transplanted from mother to daughter.

to ask questions. For instance, can you exclude thatHow do you think about transplantation of uterus

you transplant the cancer into the next person. Or

from a person who can agree to removal of thatis it a cancer that is very slowly growing so that itorgan to another who want to receive it, for exam-

does not affect the lifetime of that patient. We, forple, a person with gender identity disorder or a

instance, in my country we have a program which ismother who already has child and donʼt to wish tocalled “old for old”. Usually only organs of younger

have more.

people are being transplanted ‒ under 50, under 55.

Kloiber

We have not made policy on that, andAnd now we have a program where we transplantI think that is something that we first would haveorgans from people aged 60+ to people of age 60+.

to look into. And the question in the end may be: is

So if you can exclude any additional risk to that

this medically indicated or not. And it would beperson, ethically that may be possible. I would havemedically indicated if you consider the desire, ato look into that. If you endanger that patient, it

medical need of that person.

comes under the rule “do no harm” and that is not

Interviewer

acceptable.

The woman who want to have achild. Is it a medical issue or quality of life issue?
KloiberYes. Children are a natural event, andI think that is what we should deal with in medicine− 18 −

Clin Eval 41（2）2013

as a natural event, not as an artificial and not as a

Kloiber We have clear statements on that. Not“social accessoire”. It is our role to overcome med-in the Declaration of Helsinki but in other declara-

ical problems, the problems of illness and disease.

tions. Our answer is “no”. No physician should be

And as far as that is being done, I think there is a

involved in the development of weapons, and that

medical justification for it. There is no medical jus-applies also to any research physicians may betification for doing things which go beyond that.

involved in. It is something different to look into

One problem is that sometimes

research on the medical treatment for the effects

this comes to be undue influence (mother, sister, orof weapons. That has to be done because we have torelatives may feel pressure to donate utero). And atreat patients which have been harmed by weapons.

better way is donation from the brain-dead case. I

And I agree this is sometimes very tricky because,

think European people tend to think organ donation

you cannot 100 percent separate the use of thatshould be from dead people, not from living peo-

information from the development of new weapons.

ple.

Physicians should not get involved in the develop-

Interviewer

Kloiber There is a lot of organ donation fromment of weapons.

living people as well ‒ kidney, liver parts. I donʼt

11．Laws and ethical principles

think there is a very easy judgment. With a living
donation, there is always a problem of exploitation
behind that. People are being forced to give some-Interviewer Another thing which was very

thing. There may be family pressure, individualmuch discussed in the Tokyo meeting was the rela-pressure. There may be payments, if recipient andtionship between law and ethics, which varies indonor know each other. But as long as there is freeeach country. The Declaration says that each coun-

will behind that ‒ including the necessary informa-tryʼs legal regulation should not be broken down bytion about the risks involved, itʼs ethically okay.

the Declaration (“No national or international ethical, legal or regulatory requirement should reduce

Neuro-ethics
Interviewer

or eliminate any of the protections for researchsubjects set forth in this Declaration.”). In some of

And another issue is how about

the European or international documents, theneuro-ethics.
Kloiber Yes, we have discussed neural enhance-

European Council, UNESCO, thereʼs a description

ment at an earlier conference in Rotterdam. In thethat every county should have some law that pro-end, we found that this is a general topic for thetects human subjects.

Declaration of Helsinki but not a specific one which

Kloiber This is being done very differently in

we want to address. So most likely the workgroupdifferent countries. Let me give you an example.

will recommend not to address it separately.

Austria and Germany are very similar countries
culturally, but their approaches to the question are

Dual use

fundamentally different: In Germany, every insult
So on another topic different

to the body of another person is a criminal offense.

from human research, we would like to ask your

Even an invasive medical treatment in the beginning

opinion about “dual use” issue. This means thatis an offense. You will not be punished for this if

medical research outcome may be used for develop-

the patient is informed and the patient wants it andment of weapons.

if the practitioner is licensed to perform medicine.

Interviewer− 19 −

臨床評価41 巻 2 号

2013

Austria starts from the opposite direction, by that

instances, the soft law approach, the self-regula-any medical act by the doctor is

not a crimi-

tory approach, is much more effective than thenal offense. Very different approaches. Now inother ones. But as I said there are things where

Germany, if you do something wrong in treating a

you have to say “Stop - this is criminal”. But again

patient in a trial because you do not give thethis is very different from country to country; for

informed consent, you do not work according to thedifferent cultural, legal, and technical reasons.

professional rules, you are in most cases producing

12．Impression of Japana criminal act automatically. So you donʼt need an
extra rule for that. It is already in the law. But I

Interviewer

agree, there should be laws protecting people in

So through these discussions, I

every country. But then it comes to the details andwould like to ask you how is your impression of

to the different principles. The placebo issue is aJapanese researchers, Japanese health professional

good example. If the law will go into details, thecommunity. Could you please advise or comment

risk of mistakes increases. Thereʼs room for ethi-

based on your experience of this time visiting

cal rules that do not necessarily have to be fol-

Tokyo for this meeting.
Kloiberlowed up by state attorneys, and courts, and

Oh, I am biased because I have beenworking with a lot of Japanese colleagues in thecriminal punishment but by ethical supervision.
Interviewer In Japan, there are various opin-

past. Japan is one of the leading research nations inions on that. Someone say that it is necessary tothis world. We all know that the Japanese medicine

develop laws to protect human subjects. But on theis the highest developed. You are playing inother hand, there are scholars who says “soft law”

research in healthcare in the top league. And if you(guidelines not without legal bases; ethical princi-

look in the outcome, what you produce for yourple, professional code, etc.) is suitable to regulate

people, and I think you have the best results.

research. These people say that Japanese research-

Everybody gets healthcare. You have an unsur-

ers are very much obedient to guidelines so “legal”

mounted longevity. This is a fantastic result. I

regulation is not necessary. It is correct to say thatthink you can be proud of that. And you get it for a

Japanese researchers are very much obedient tovery low price. So you just look to the numbers andguidelines; however at the same time, there are

the numbers speak for themselves.

several researchers who act against rules ＊3.

Interviewer

We really appreciate your saying

Kloiber One thing is that you can sanction

such generous comments. However, we discussed

ethical deviations, usually much easier than a crim-with some of the delegates and they say that ininal procedure. For a criminal case, you needJapan there are some problems, for example, in theextremely hard evidence. I think for most of thepsychiatric area, poly-pharmacy is a serious prob-＊3

During the Conference, Kurihara discussed with some participants who said that clinical trial regulations in the U.S.
and Japan are the same, and corrected this idea saying that Japanese law on clinical trial covers only those aiming
at new drug application (NDA) and introduced 3 prominent cases that violated the no-legally-bound guidelines:
Announcement of fabricated research results on iPS cell clinical research at the academic meeting; extraction anduse of human samples for research without informed consent; retractions of publications based on fabricated resultsof multicenter clinical trials of the antihypertensive drug, valsartan. (There are many other cases that violate theguidelines.)− 20 −

Clin Eval 41（2）2013

lem. He knows it very well. And when we visitedcourse a very important one. But we are dealingsome psychiatrists in Taiwan, we found that they

with different questions right now. And one of theknow such problem in Japan very well. Many psy-things we are very much working on and very muchchiatrists in the world know very well about theinterested is the question of social determinants ofJapanese poly-pharmacy. They also know well about

health. We traditionally look for the pathophysio-

long-term hospitalization in Japan. One of ourlogical causes of diseases, by that we are often notinterviewees said that this is because Japan is acoming to the real causes which lie in the causes ofrich country. This is problem of the rich.

the causes, the ways how we are being born, how we

Kloiber Sometimes we have problems because

live, how we work and how we die.

we are rich, and thatʼs true. Sometimes we have

Of course we are not social engineers as physi-problems because the ways how things are being

cians but I think we have an obligation to tell soci-financed determine the use. And there are prob-

ety, if there are underlying mechanisms. And if youlems in any healthcare system of the world, and I

look to the big non-communicable diseases in thisam sure in Japan as well. However, but if you see

world, which are related to tobacco, wrong diet,

this in the international comparison, your problems

working conditions, we think itʼs very important

are luxury problems.

that we tell society, tell lawmakers that there are

Interviewer

Yes. But we would like to say

underlying conditions which they have to change,that itʼs quasi-rich, because you know that thewhich we have to change, in order to make a differ-

Japanese government has many debts.

ence.

Kloiber Yes, Japan has a very high debt rate,

The human resources for health are another big

but your debt is internally. The debt you have isproblem in this world because we are pulling humanmoney that the Japanese government has bought

resources from poor countries to rich countries.

from the Japanese people. Now that is something

And thirdly, we are very much concerned about

different than in my country or the United Stateshuman rights violations in healthcare. We see that

where the money has been bought from other coun-

there are more attacks on health personnel, directtries. So if you look to the net balance in who Japanor indirect. We think that human rights also of theowns, you own your country. Our country may behealth professionals and the patients they are car-owned by somebody else. So thatʼs a big difference.

ing for are now violated more often than we have

Although the debt of the Japanese state is muchseen in the past. These three issues are topics wehigher, I think you can sleep better with that thanare especially intensively dealing with currently.

the Americans or the Germans.

Interviewer It is very much an important task.
We appreciate very much your answering so many

13．Important issues relating to
WMAʼs activities

questions and you have explained in significant
details the important mission of WMA to promote
ethical conduct of research involving humans forInterviewer

better health in the world.

So you are working as secretary-general of WMA, not only working for Declaration

It is fascinating that you answered very clearlyof Helsinki. What is the very important topic in

our questions and described fundamental principles

WMA, aside from the Declaration of Helsinki?

and conflicting issues surrounding it. We believe
this interview will enlighten many Japanese people

Kloiber Well, the Declaration of Helsinki is of− 21 −

臨床評価41 巻 2 号

2013

who are not so familiar with background philosophy

lent norms created by wisdom of the world special-of WMA and will support them to consider how toists.

manage actual problems according to these excel-

unrealistic ‒ and with the effect that a non-answer

Additional questions
in August 2013

within the short return times equals a positive
decision, this may be even dangerous.
Interviewer

We also would like to ask forInterviewer We came across your article pub-your comment concerning a serious issue in Japan.

lished in the World Medical Journal (Vol. 59, No.

Recently in Japan, there have been a number of

1, page 1). In this article, you wrote that WMA

issues involving scientific misconducts resulting insubmitted objections to the proposed revision ofretractions of academic research articles involving

the EU Clinical Trial Directive. Especially, it isfabricated data. One of the most serious cases isvery important to say that there is no explicit

the data fabrication scandal surrounding Novartisʼ

description about ethics committee review in thatantihypertensive drug valsartan.

proposed revision. We have thought about that pro-

The results of the post-marketing multi-center

posal also, and we believe that the intention of thisclinical trials (Prospective randomized open blinded

proposal is to have “one ethics review in one multi-

end-point (PROBE) design) conducted by researchnational clinical trial in EU”. In the proposed revi-groups in five different universities concluded thatsion of this EU Directive, there is no explicit

this drug seemed to include fabricated data, anddiscussion about this kind of “joint-review” issue

some of the publications were retracted. This drug

(one ethics review in one multi-center/multi-

was developed as an antihypertensive, but thenational clinical trial). So could you please provide

results of these studies showed effectiveness in

us with your opinion on this point?

preventing cardiovascular events. At least at thisKloiber We were disappointed that the require-

moment, six articles written by one of the researchment of seeking the approval of an ethics committeegroups (Kyoto Heart Study) were retracted, while

before the beginning of a clinical trial was no lon-the other articles are under scrutiny. As for thisger in the draft of the proposed regulation. In the

Kyoto Heart Study, the university involved in themeantime, the parliament inserted as well a request

trial conducted its own investigation, and thefor hearing on ethics committee as well as several

results of their investigation suggested a strong

references to the Declaration of Helsinki into thepossibility that data fabrication may have been

proposal. However, we would like to read that andcommitted.

ethics committee has to approve ‒ not only read ‒It was also found that a statistician of Novartis

the protocol. Furthermore, we are worried that a

was engaged in all these five multi-center clinicalsponsor can shop around, looking for the country

trials in question. It was alleged that Novartis had

with the weakest ethical standards. We donʼt thinkprovided substantial monetary donation to thethat this is acceptable. Another problem is theinstitutes of these five research groups, but not

extreme short time frames for the work the appli-

directly to the research, so there was no disclosure

cations have to be processed. They are simply

of conflict of interest in the published articles.
− 22 −

Clin Eval 41（2）2013

memorial event in 2014.

Novartis has generated huge financial profit bymaking use of these articles containing fabricated

REFERENCES

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We cannot ask for your comment on this specific

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Thank you for your comment. We

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臨床評価41 巻 2 号

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2010；36（3）：504-9．

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