Clin Eval 42（2）2014

Special Interview

Interview with Dr. Robert Temple
on drug evaluation policy of FDA
─ Ethics, science of placebo-control
1
and comparative effectiveness studies ─＊
Robert Temple ＊ 2
Center for Drug Evaluation and Research
Food and Drug Administration, U.S. Department of Health and Human Services

Interviewer: Chieko Kurihara ＊ 3
Molecular Imaging Center, National Institute of Radiological Sciences (NIRS)(June 13, 2014, Washington D.C., United States)

Abstract
This is the record of an interview with Dr. Robert Temple, Deputy Director for Clinical Science of theCenter for Drug Evaluation and Research (CDER) and also Acting Deputy Director of the Office of Drug
Evaluation I (ODE-I), Food and Drug Administration, U.S. Department of Health and Human Services.
Dr. Temple is one of the key-persons in the international debate on the ethics and science of placebocontrolled clinical trials, who greatly contributed to the ICH-E10 guidelines on the choice of control group,
as well as 2008 revision of the Declaration of Helsinki, for its paragraph of the use of placebo control. In
addition to this subject Dr. Temple has for a long time played a very important role in the establishment of
FDAʼs philosophy and policies on clinical science, and has had an important role in many CDER and ICH
guidances (ICH E-3, E-4, E-5, E-7, E-10, and E-14).
The wealth of ideas about clinical trial design discussed here could contribute to future perspectives
that might contribute to more attention to individualized medicine, shifting the mega-pharma-approach of“one-size fit all.”
Key words
U.S. Food and Drug Administration, placebo controlled clinical trial, comparative-effectiveness study,enrichment study, clinical science
Rinsho Hyoka（Clinical Evaluation）2014；42：539−51.

＊1
＊2
＊3

Japanese translation of this interview is published in. 2014; 42(2): 411-23．
Office of Drug Evaluation I (ODE-I), Food and Drug Administration, U.S. Department of Health and Human Services
Research Center for Radiation Protection, NIRS; Editorial staff, Rinsho Hyoka (Clinical Evaluation)− 539 −

臨 床 評 価 42 巻 2 号

2014

Dr. Robert Temple is Deputy Director
for Clinical Science of the Center for
Drug Evaluation and Research (CDER)
and also Acting Deputy Director of the
Office of Drug Evaluation I (ODE-I) in
the U.S. Food and Drug Administration.
He has served in this capacity formerly
Director of ODE-I since the officeʼsestablishment in 1995.
Dr. Temple received his medical degreefrom the New York University School of
Medicine in 1967 and was a clinicalassociate at the National Institutes of
Health from 1969 to 1972. In 1972 hejoined CDER as a Medical Officer in the
Division of Metabolic and Endocrine
Drug Products. He later moved into theposition of Director of the Division of
Cardio-Renal Drug Products, which heInterview was at the home of Dr. Robert Temple, Washington D.C.,
Maryland, United States, June 13, 2014.
held from 1976-1982.
In his current deputy position, Dr.
Temple participates in the direction of ODE-I, which is responsible for the regulation of cardio-renal, neuropharmacologic,
and psychopharmacologic drug products. Dr. Temple has a long-standing interest in the design and conduct of clinical trials
and has written extensively on this subject, especially on choice of control group in clinical trials, evaluation of active
control trials, trials to evaluate dose-response, and trials using “enrichment” designs.
Source: Web-site of the U.S. Food and Drug Administration (http://www.fda.gov/Drugs/NewsEvents/ucm295045.htm)

1992 for a symposium with other of your colleagues

1．Establishment of FDAʼs policyof FDA 6）(Photo, page 4). There have been a number of publications of Japanese translations of theInterviewer

I greatly appreciate your willing-

FDAʼs guidance since the 1970s.
Templeness to accept this interview. There are two rea-

I remember when Prof. Naokata

sons I regard this as an extremely valuable

Shimizu first invited me to a meeting in Japan,

opportunity: First, I have published some inter-

about 30 years ago. Since then, I have had many

views with key-persons of the debate on ethics ofopportunities to visit Japan.

placebo-controlled clinical trials

1-5）

Interviewer, and you are

I believe that Prof. Shimizu, an

the most important key-person. Another reason is

editorial board member of this journal will bethat I know you have been playing a very important

pleased about this interview. I found in the web-role in the establishment of FDAʼs philosophy andsite of FDA 7） that you have commented on thepolicy of clinical science, the origin of which was

impact of the Kefauver-Harris amendments. The

the 1962 Kefauver-Harris Amendments which

editor-in-chief, Dr. Masanao Kurihara says thatspecified that drug approval should be based on two

you must be very much engaged in the process toor more “well-controlled clinical trials”. From thisrealize this policy in FDA.

second reason, the editorial board members of ourjournal,, invited you to Japan in

TempleBefore the Kefauver-Harris amend-

ments in 1962, there was no legal requirement that− 540 −

Clin Eval 42（2）2014

a new drug be shown to be effective before it could

2．Debate toward 2013 revision of
the Declaration of Helsinki:
Ethics and science of placebo
controlbe marketed. It only had to be shown to be “safe.”(You might ask how a drug that did no good at all
could be safe if it had any adverse effects, but thelaw did not consider that). And people developing
drugs rarely carried out the kinds of controlled
studies that could reliably demonstrate effective-

Interviewer So I would like to start the issue

ness. Of course the effects of some drugs are fairlyof placebo. Since the 1996 revision of theobvious (loop diuretics, many antibiotics) so that

Declaration of Helsinki (DoH), by the World Medical

there were effective drugs even before 1962. But

Association (WMA), there were 4 revisions related

when we looked, as the 1962 law required, at theto use of placebo controls. In 2000 it was changed

pre-1962 drugs, about 1/3 did not appear to work.

by WMA to say that placebo controls could be used

In 1962 the law was changed to require that for

where there was no effective therapy but that theya drug to be marketed, there had to be “substantial

could not be used for any condition if there was anevidence that the drug will have the effect it isavailable effective therapy. FDA and others objected

represented to have under the conditions of use

to this, arguing that although patients could not beprescribed, recommended, or suggested in the pro-denied an available life-saving treatment, if noposed labeling.” Very importantly, the law went onharm would come to patients from not using theto say that “substantial evidence” meant “evidence

available therapy, it was ethical to use a placebo-consisting of adequate and well-controlled investi-

control in a fully informed, non-coerced patient.

gations, including clinical investigations,” by quali-

Moreover, as explained in ICH E-10 8） there were

fied experts that support the conclusion that the

many situations, especially for symptomatic treat-

drug actually had the claimed effect. Well, thisments, where only a placebo-controlled trial couldchanged everything, especially when, in 1970, we

be informative. In those cases comparative or non-wrote regulations describing the properties of aninferiority trials were uninterpretable when theyadequate and well-controlled study.

did not show a difference between the treatments.

The new law completely changed the data we

FDA has recently elaborated on this in its draft

received and since that time we, and much of the

Non-Inferiority Guidance. The WMA 2002 note ofworld, have increasingly applied the well-controlled

clarification attempted to correct this, allowing use

study standard to any treatment, drug, biologic,

of a plabebo for a scientifically compelling reason

medical device, and even many surgical procedures.

OR if there was no additional risk of serious or

I have longbelieved it has been a (maybe the) major

irreversible harm, but that was a mistake. Even acontributor to medical progress in the last half-

valid methodological reason for wanting to use a

century (together, of course, with the development

placebo would not justify denial of a life-savingof the novel and valuable treatments that were put

treatment. This was corrected in 2008, where it

to the well-controlled study test).

said that placebos were acceptable if there was agood reason for a placebo-controlled design AND
patients would not be harmed. I know you believethat ICH-E10, finalized in 2000, had described theproper conditions for use of placebo controls long
− 541 −

臨 床 評 価 42 巻 2 号

2014

Templebefore this.
8）

You are quite right. The 3-arm design

provides adoes not allow use of a placebo when denying avail-very clear description of the ethics of placebo-con-able therapy would be unethical because that would

trolled studies. As for the Declaration of Helsinki,cause harm. The design, including both a placebo

almost everybody agrees with the 2008 revision. If

and an active control (in addition to the test drug)

you want to study a new drug in a life-threatening

helps interpret a study showing no difference between

condition where there is some existing therapy, you

test drug and placebo by showing whether the trial

have to compare the new treatment with the exist-

had assay sensitivity, i.e., could distinguish an

ing therapy; you canʼt deny it to patients. You caneffective from an ineffective drug. In other words,

show superiority to the other treatment or non-it helps interpret a negative (no drug-placebo differ-

inferiority. But for symptomatic conditions, youence) study: did the test drug fail or did the study

can ask people if theyʼre willing to be in the study

fail? If the active control did not beat placebo it

and be randomized to placebo, because whatever

indicates that the study could not tell us actual

happens to them is temporary, i.e., discomfort, but

drug from placebo. It also can help interpret a com-

not harm, and a patient can choose to accept that.

parative study; one would not expect to see a dif-Interviewer I know your articles 10, 11） on thatference between 2 treatments if they could not be

TempleI believe that ICH-E10

point. I know that FDA changed its regulations on

distinguished from placebo.

using foreign clinical studies not conducted under

3．Standard care issue

an IND (investigational new drug application) to
support a marketing application in 2008 to removereferences to the Declaration of Helsinki. Was that
because of the placebo-control issue?
TempleInterviewerItʼs good to be able to hear youropinion like that. So how about the standard of

It was not a direct response. What we

care issue. If there is an existing therapy in therealized was that a reference in any regulations toUnited States only, can you use a placebo control

a document that we had no control over (such as thein developing countries?

Declaration) was not prudent. So we referredinstead in the regulations to the ICH ‒ good clinicalpractice guidance, ICH E-6

12）

TempleI think it depends on whether thetreatment can be used in those countries and on the, which notes thatspecific circumstances. There was tremendous con-many of its principles had their origin in thetroversy over an HIV study carried out in develop-

Declaration.

ing countries, mainly in Africa. The study was toInterviewer Itʼs nice to hear that you agree

see if an AZT regimen using only a single treat-with 2008 revision, which is compatible with ICH-

ment would be effective in preventing fetal trans-

E10. I also believe ICH-E10 is almost perfect, but

mission. It was already known that the “076

there is one thing I feel some concern. It describes

regimen,” which involved treatment before, during

a three-arm design as one that may resolve ethicaland after delivery, was effective. The new study

problem 13）, but even if you can decrease number ofcompared a single dose AZT regimen to placebo,

subjects assigned in placebo, it is not ethical if it

not to the 076 regimen. Many people wrote about it,

may cause serious, irreversible harm, althoughe.g., Dr. Harold Varmus 14）, Director of NIH, andthree arm study may be better benefit/risk ratio

people from Public Citizenʼs Health Researchfor study population.

Group, Drs. Sidney Wolfe and Peter Lurie. There− 542 −

Clin Eval 42（2）2014

were 2 reasons for the design (specifically use of a

had any effect at all. So, to see if it had an effect,

placebo control). First, the 076 regimen could notthey needed a comparison with placebo.

be used in the regions where the study comes to be

Although some, notably Wolfe and Lurie 15）, said

carried out because there was no way to get all 3

you have to compare the single dose to the standard

AZT regimens to patients in the treatment environ-regimen on ethical grounds, that would not havement. But second, and even more important, there

served the communityʼs interest in finding a treat-

was good reason to think that although the single

ment they could actually use and that was at leastdose regimen would not be as good as the 076 regi-

somewhat effective. The reduced regimen, com-men, it might have an effect and it was critical topared to placebo was found to be effective, proba-know whether this treatment worked at all. If they

bly not as good as the 076, but it was effective.

had compared it to the 076 treatment and it worked

This issue came up at a WMA meeting in Brazil

less well, they would not be able to tell whether ita couple of years ago; there was agreement that in

Photos at the time of symposium titled Clinical and statistical aspects of drug approval commemorating
20 years anniversary of Controller Committee. The lectures were published in. 1992; 20 Suppl 6.

From the right: Late Dr. Yorio Sato (Founding member ofController Committee/Clinical Evaluation), Dr. Robert Temple(FDA), Dr. Robert T OʼNeil (FDA), Dr. Stuart J. Pocock (London
School of Hygiene and Tropical Medicine), Dr. Satya D. Dubey(FDA). This photo was previously published in. 1992; 20
Suppl 6.

Dr. Temple and
Dr. Naokata Shimizu,
editorial board member.

Second to the left: Dr. Temple; right: Dr. Masanao Kurihara,
editor-in-chief

Dr. Temple, Dr. Kurihara and Tatsuo
Kurokawa, editorial board member, who
was at the Ministry of Health, now
professor of Keio University.

− 543 −

臨 床 評 価 42 巻 2 号

2014

a country that lacked an important treatment, andwhether itʼs really effective.
Interviewer

where there was no way the treatment could be

There are some bioethicists say-used in that country, a placebo-controlled trial of a

ing that “instead of” or “in addition to” post-trial

usable regimen was ethically acceptable.

access, there should be “fair benefit”. For example,

For a poor country that doesnʼt have the best

Dr. Ezekiel Emanuel and his African colleagues

therapy and you really do want to know whether

wrote a paper 17） to propose a concept of “fair ben-something less than optimal works or not, thatefit”.

seems perfectly reasonable.

TempleThis is a difficult question; if thereʼs

too much benefit, maybe itʼs an inappropriate

4．Post-trial accessinducement to join the trial. And suppose the condition is chronic. If you do an anti-depressant trial inInterviewer So how about the issue of post-sion for their whole lives? I donʼt have answers

trial access ?
Templea poor country, do you have to treat their depres-We do not require that it be provided,

here but it is difficult.

but a lot of companies make it available. I donʼt

5．Comparative effectiveness study

think that should be a requirement, and the current
Declaration doesnʼt say it is a requirement

16）. Whatit now says is you should tell people whatʼs going toInterviewer

Thank you for your comments on

happen. In the 2008 revision it said at the end of

the Declaration of Helsinki. I have read many of

the study everybody should get the drug if itʼs

your papers, power point slides, and interview talks,effective. But you donʼt know whether itʼs effective

so itʼs really great to be able to see you and discussat the end of the study; you havenʼt done the analy-

this topic. So I would like to move to some othersis yet; and you probably need two studies to know

aspects of clinical trial design. First, I would like− 544 −

Clin Eval 42（2）2014

federal funding, under 45CFR46 “human subject

to discuss comparative effectiveness studies.
TempleOkay in most areas we do not see very

protection” regulations, do you mean?

many good studies.

Temple Well, where patients have to receive

Interviewer

treatment, e.g., with anti-coagulant in atrial fibril-

It is not mandatory for thelation or anti-platelet drugs in acute coronary

approval of the drug.
Definitely not, unless there is an exist-

artery disease, you of course do see comparative

ing treatment that affects serious (generally irre-

studies. But where they are optional, I donʼt thinkversible) morbidity or mortality. In that case thethere are that many, even funded by the govern-

only ethical studies will usually be comparative

ment, although ALLHAT 19） and CATIE 20） arestudies, either to show non-inferiority or superior-clearly examples of such studies. If the federal

ity, or studies that add the new therapy to the stan-government, rather than a commercial enterprise

dard of care (add-on study). Certainly we see many

funds the trial, using marketed drugs, no IND issuch trials in oncology and in serious cardiovascu-

needed. But if a drug company supports the trial,

lar disease (atrial fibrillation treatment with anti-

the intent is fairly clear to include it in labelingcoagulants, treatment of acute coronary syndrome).

and an IND is needed under the IND regulations.

TempleInterviewer

But after approval, for a Phase 4Interviewer Could there be a clinical trial

trial, if the pharmaceutical company intended towhere the pharmaceutical company is the sponsor

conduct a study to show superiority and include

but there is no intention of new label or no inten-

this claim into the label, or promotion, it should betion of promotion? Can you imagine such kind of

conducted under the FDAʼs regulations

18）

trial?

. Right?

TempleTemple Studies to support labeling claims or

Well, I guess anything is possible, but

promotion do need to be conducted under an IND.

I would argue that such a trial always needs to be

And such claims would generally have to be sup-done under an IND. And thatʼs a good idea for otherported by controlled studies, probably two of them.

reasons. We can help a manufacturer understandItʼs not common to seek such claims but it does

what design the trial needs to get a claim. For

occur. We have two angiotensin receptor blockers

example, suppose you compare your drug to a dose

(ARBs), for example, that did studies comparingof another drug that too low; i.e. itʼs not the fullthemselves with other ARBs, and they did have adose. We had a manufacturer of an angiotensin

larger blood pressure effect and the drug label

receptor blocker (ARB) that wanted such a claim,says that. Of course many oncology drugs will be

but the first study they did they used too low atested against the standard of care, usually seeking

dose of the comparator drug. So we told them thisto show superiority, or as add-on to the standard

would not support the superiority claim. They thentreatment. Some anti-coagulants and anti-platelet

had to do two more studies using a full dose. In

drugs have shown advantages over the standard

case of cancer drugs, studies often show that new

drugs they were compared to.

drugs beat the standard of care, so you see that all

Interviewer You say itʼs not common, do you

the time. But, as I said, once you leave that area,

mean that it is uncommon within the range of FDAʼs

itʼs fairly unusual to see comparative studies.

regulations? I think that there are many clinical

Thereʼs no antidepressant that has a claim that itʼstrials of head-to-head comparison using 2 or more

better than another one, for example.

approved drugs. Most of them are conducted by− 545 −

Interviewer One of the reasons why people臨 床 評 価 42 巻 2 号

2014

want to see comparative studies that the FDA

on how to do a non-inferiority study. It is, of course,

approved many drugs that are not very effective

perfectly all right to do a comparison of 2 drugs in

because many of these were compared with pla-

addition to a placebo comparison.

cebo.
Temple6．Enrichment study

Well, that goes to another whole ques-tion, one that is addressed in our draft non-inferiority guidance 9）and ICH E-10 8）. How can you showthat a drug is effective without a placebo-controlledInterviewer

So, how about enrichment study?

Do you think it should be promising approach?

trial? You have to do a formal, rigorous, non-infe-

TempleWell, we have a draft enrichment guid-21）

riority study, and these are done where outcomesance also

are well-defined for the control drug; e.g., we know

maneuvers, and some could relate to comparative

the effect of CoumadinⓇ in preventing stroke inclaims. One interesting one is to take non-respond-

atrial fibrillation or of clopidogrel in preventing

ers to previous therapy and randomize to a newheart attacks in people with acute coronary syn-drug and to the failed drug. It would be of great

drome; we know the effects of antibiotics in a range

interest to practitioners to know how to treatof diseases; we know the effects of anticancer

patients who fail standard therapy. But only 4 tri-

treatments. In those cases a non-inferiority study

als like this have ever been done, as far as I could

can be done because we know the effects of thetell, and 3 were successful. They allowed drugs

control drug. But for symptomatic treatments, it isthat would not have been approved otherwise

very hard to know the control effect, so that doing(because of toxicity) to be approved. We would

a non-inferiority study in a symptomatic condition

never have approved clozapine (with its 1.5% rateis almost impossible, and you will need a placeboof agranulocytosis) unless it was better than thecontrol. As I noted, we have a whole draft guidancealternative drugs in people who failed the other− 546 −

. It describes a variety of enrichment

Clin Eval 42（2）2014

treatment. In the critical study, they took people

conducted 2 pivotal studies in Japan of active-con-

who had failed to respond to haloperidol, then ran-trol (because placebo control used to be very diffi-

domized to a drug like haloperidol or to clozapine

cult at that time) and failed to show non-inferiority.

and clozapine was far better.

Therefore, they conducted a placebo-control ran20）

study?

domized withdrawal study. A regulator gave them

CATIE was a large comparative study

this idea saying that this design may mitigate thethat NIMH (National Institute of Mental Health)ethical dilemma, as it is explained in ICH-E10,

researchers conducted. They studied 5 antipsy-

which was just being finalized at that time. They

chotic drugs, looking at dropouts and the cause of

conducted a withdrawal trial for the acute phase

dropouts (was it because of intolerance or because

patients of major depression 24）. It means that they

the drug did not work?). Olanzapine was better thanproved only relapse prevention for non-responders

the others with respect to dropouts for lack ofin the acute phase. However, it was allowed to claim

effectiveness but it had more dropouts for toxicity,

more general effects for depression, seeing sub-e.g., weight gain.

stantial foreign data. In the brochure of post-mar-

Interviewer
TempleHow about the CATIEThe enrichment design using the non-responders,keting survey, it was written that the drug could

and randomizing to the failed and new drug, is

not show non-inferiority to other active drugs.

really of interest. Even if your drug isnʼt better

Therefore an association of clinic psychiatrists

overall, if there are some people who respond bet-

worried it may cause law suits claiming that they

ter to it than to the other drug, you can detect thisprescribed a less effective drug. Once they boycot-

in such trials and it would be important to know. Of

ted this drug, but then after some struggle, thiscourse, drugs donʼt always work in people who faildrug came to be used commonly. This is a somewhat

other therapy. Weʼve had a lot of public discussions

funny story.

about non-steroidal anti-inflammatory drugs, andⓇ

their toxicity. Vioxx

Temple Iʼm not sure I follow all of this, but a(rofecoxib), you recall, was

few points. We would never consider a comparative

removed from the market because it caused antrial of an antidepressant that showed no differ-increased rate of heart attacks. Merck then did aence from a control to be evidence of effectiveness.

study in which they took people who had failed to

You need a placebo group. We have to date expectedⓇ(celecoxib) and randomized

evidence of effectiveness in acute depression tothem to Celebrex or to Vioxx. I would have bet that

support a claim for treatment of acute depression

Vioxx would be better for those people, because(and sertraline has such studies). We very much

rheumatologists believe that people are individual-

want to see maintenance studies as well, showing

ized in their responses to these drugs. But thethat continued use decreases the rate of recurrent

study showed no difference between the two drugs

depression. To date no one has received approvalat all.

solely for maintenance (i.e., prevention of recurrent

respond to CelebrexInterviewer

I agree with you concerning thedepression), but it is a possibility.
Interviewer I wanted to ask you about approvalissue happening in U.S.. So in Japan, there was one
22, 23）of ICH-E10, whichof valsartan (one of ARBs) for heart failure. Moremay be one of the misuses of an enrichment study.

than 80 countries, including of course U.S.,

Sertraline was approved in Japan in 2006, 15 years

approved new indications of heart failure or ther-later than in the Western countries. The company

apy after heart attack, based on GCP trials 25, 26）,

interesting misuse case− 547 −

臨 床 評 価 42 巻 2 号

2014

was less than the full dose. But in the 7 percent of

including double-blind placebo control trials.
TempleWell, valsartan has the heart failure

people who couldnʼt tolerate an ACE inhibitor- i.e.,valsartan versus placebo- (which was only 300 peo-claim.
Interviewer Except Japan.

ple), there was a 50 percent reduction in mortality.

TempleSo we gave them a claim for people who canʼt toler-

The study was somewhat unusual. The

trial was designed to add valsartan to an ACE

ate ACE inhibitor.

inhibitor and show added benefit. But not every-

Interviewer

body in the trial could tolerate an ACE inhibitor.

Itʼs very interesting, but in Japan

this type of study may be difficult to conduct.

So they tried to put you on an ACE inhibitor but 7

TempleWhy?

percent of the population couldnʼt take an ACE

Interviewer

There are some reasons. First, ininhibitor. In that 7 percent, the trial was therefore

Japan it is difficult to conduct placebo-controlledvalsartan versus placebo. In the group that got thetrials of authorized drugs.
TempleACE inhibitor, valsartan seemed to add somewhat

Well, being on an ACE inhibitor saves

to the effect but when you looked closely, it added

your life, so we too would not allow a trial of val-

most clearly when the dose of the ACE inhibitor

sartan versus placebo in everyone. But in these− 548 −

Clin Eval 42（2）2014

people who couldnʼt tolerate an ACE inhibitor and

ANPRM 28）.

who were on a diuretic, and a beta-blocker, we
would allow it.
Interviewer

Temple Yes, it is the huge rule. It touches ondozens of topics.

Not only the placebo issue, it isInterviewer There are several topics speciallyalso difficult for Japanese researchers to conduct

Japanese people are interested in: risk-based

sound scientific phase 4 studies. The second reason

approach; broad consent; central IRB; and expand-is that in Japan there are two different sets ofing the scope of the regulations.

regulations for clinical trials: GCP under theTemple We encourage use of central IRBs to

Pharmaceutical Affairs Law and governmental

promote efficiency 29）, but people really want their

guidelines for clinical research. There is a tremen-local control, so they are not widely used.

dous discrepancy between these two sets of regula-

Also we issued a guidance on risk-based moni-tions. This tremendous discrepancy affects the cost

toring 30）. Thatʼs already permitted under ICH-E6.

of trials. So the number of academic researcherʼs

It says the amount of on-site monitoring needed

GCP trials is very small, although it is increasing

depends on the study and you might not need any.

thanks to the efforts of many peopleʼs. This is com-

But companies fear that we would find errors if

pletely different from U.S. situation where many of

they fail to monitor extensively.

academic researchers conduct IND trials using

Interviewer Thank you that you provide such

public or private funding. For Japanese companies

comments. So could you provide your future per-also, it is much too expensive to conduct phase 4spectives, near future? What is your most impor-trials under GCP. Therefore, companies provide

tant job at FDA?

unrestricted funding to academic researchers andTemple Well, I have two jobs. Iʼm called dep-

these researchers conduct clinical trials. Some ofuty center director for clinical science. So thatʼsthese reports may be based on manipulated data, or

one thing. I am very involved in quite a lot of guid-at least, biased data. Many of the company persons

ance, e.g., the guidances on enrichment designs andassist Japanese researchers in writing their manu-

non-inferiority studies, multiplicity, and adaptive

scripts to be submitted to top journals. These inap-

design. You know weʼre very interested in using

propriate relationships have been well known for amore efficient designs and thinking about what thelong time but only recently came to be “socially”

endpoint should be. Iʼm also still deputy director of

criticized after the Novartis scandal 27）. In Japanwhatʼs called ODE-I. ODE-I has cardiovascular,

the culture of conducting sound science, especiallyneurologic and psychiatric drugs. So it keeps me in

ethical phase 4 studies is very much immature.

touch with the real world.

TempleInterviewer I greatly appreciate you for giv-Thatʼs interesting. Such kind of trials

are being done all over the world now. I mean thatʼs

ing your precious time for this interview.
Temple Okay. I enjoyed the conversation.

really quite striking.

7．ANPRM and future perspective

Acknowledgement
This interview was conducted during Kuriharaʼs visit

Now I would like to ask you forto U.S. as the part of following task force. Ministry of

your perspective on the proposal of new rule fromInterviewer

Health, Labor and Welfare, 2014 fiscal year research

the Department of Health concerning what you call

fund: Foreign regulatory frameworks related to Japanese− 549 −

臨 床 評 価 42 巻 2 号

2014

regulations concerning PET diagnosis using PET drugs

sium commemorating 20th anniversary of Controller

produced by in-house PET drug synthesizer.

Committee.

. 1992; 20 Suppl

VI.

The interviewer appreciates Dr. Akiko Suzuki, Center

7）Meadows M. Promoting safe and effective drugs forfor Biologics Evaluation and Research, Food and Drug

100 years. FDA Consumer magazine. The Centennial

Administration, to assist to realize this interview with

Edition/January-February 2006. Available from: http://

Dr. Temple.

www.fda.gov/AboutFDA/WhatWeDo/History/Product
Regulation/PromotingSafeandEffectiveDrugsfor100
Years/

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