Professor Yuji Sato MD PhD 

Centre for Clinical Research

30th September 2008

Th  8th Kit t H d S i Centre for Clinical Research

Keio University School of Medicine, JapanThe 8th Kitasato‐Harvard Symposium

d f l b l ld f l b l lEducation  in preparation for global trialsEducation  in preparation for global trials

Issues and Challenges from ongoing global trialsIssues and Challenges from ongoing global trials

Suggestions for futureSuggestions for future

P i i fP i i f d ti f l b l t i ld ti f l b l t i lProvision of Provision of  education for global trialseducation for global trials

Three different levels

Undergraduate medical students

Postgraduate junior doctors and investigators

IRB members and other executives

d d di l d id d di l d i1. Undergraduate medical education1. Undergraduate medical education

I d   h i l  di iIntroductory pharmaceutical medicine

As a part of pharmacology course (3rd year students)As a part of pharmacology course (3rd year students)

As a part of public health/social medicine course(4th year students)As a part of public health/social medicine course(4 year students)

– Clinical trials

– How to develop a new drug

– Drug lag issue

2 P t d t2 P t d t d tid ti2. Postgraduate 2. Postgraduate  education education 

Hi h   d i     li i l  hHigher education on clinical research

Introductory course (twice annually)Introductory course (twice annually)

Advanced course(twice annually)

Biostatistics and study design(two series per annum)

Attending basic course 

to be mandatory to all investigators

3 Faculty development3 Faculty development3. Faculty development3. Faculty development

For senior professionals

Special executive crush course twice per annum

IRB members, Ethics committee members

Joint course with the University of Minnesota(7th Feb 2009)

Issues and Challenges from ongoing global trialsIssues and Challenges from ongoing global trialsg g g gg g g g

General issues for conducting trialsGeneral issues for conducting trialsGeneral issues for conducting trialsGeneral issues for conducting trials

C t  it ti   f  l b l t i lC t  it ti   f  l b l t i lCurrent situation of global trialsCurrent situation of global trials

Hurdles for global trial participationHurdles for global trial participation

l i f li i l i l il i f li i l i l i

Enrollment difficulty

General issues of clinical trials in JapanGeneral issues of clinical trials in Japan

Enrollment difficulty

Enrollment per site is limited, in particular at teaching hospitals

Time consuming site set‐up & slow study progress

Complicated in‐house rules

Interdepartmental coordinationInterdepartmental coordination

Investigators: availability & capacity for trials limited

Expensive trials despite limited incentives for investigators

O i l b l i lO i l b l i l K iK iOngoing global trialsOngoing global trials at Keioat Keio

An investigator‐initiated global trial in gynaecological An investigator‐initiated global trial in gynaecological 

oncology

Sponsored global trials

A global trial in haematology

A  l b l t i l i   ti iA global trial in septisaemia

As an investigational site

As a coordination center for the investigational sites in 

Japan

l b l l d f d l l dl b l l d f d l l dGlobal trials: Identified issues & lessons learnedGlobal trials: Identified issues & lessons learned

Diffi l i   d  h ll  iDifficulties and challenges in:

L  1. Language 

C i i   di i   ll b i2. Communication, coordination, collaboration

P i  j d   d d i i   ki3. Perception, judgment and decision making

C ff i   f4. Cost‐effectiveness, cost‐performance

Ti     i  i tiTime, manpower, experience, incentives

ff l d h ll ( )ff l d h ll ( )Difficulties and challenges(1): LanguageDifficulties and challenges(1): Language

E li h d （ l      f  b h   )English documents（protocol, case report form, brochure etc)

Acceptable to many physicians/specialists in teaching hospitalsp y p y / p g p

Other staffs with varying degree of experience/exposure

Interaction, discussion with global centre for trials

T l f  &  iTeleconferences & meetings

Urgent inquiry, protocol amendmentsg q y p

Negotiation, clarification and compromise

Difficulties and challenges(2): Difficulties and challenges(2): Communication, coordination &collaborationCommunication, coordination &collaboration,,

Local sponsor Global HQSite

AdminIRBScientist

MD

Scientist

MD

Investigator CRC CRA

MD

Regulatory

QCCRA

MD

Regulatory

QC

Data Manager

QC

Data Manager

QC

Pt Pt PtSales Reps Marketer Sales Reps Marketer

Many players, manifold processes, complex reporting lines, unclear accountability

Miscommunication& Miscommunication& DiscommunicationDiscommunication

Suggestion from HQ

perceived locally as unquestionable demand or reprimand

forwarded on  to site as an nonnegotiable imperative 

Rapidly evolving clinical issues: need urgent handling

Sense of clinical urgency: difficult to convey and interpret

Diffi lti d h ll (3)Diffi lti d h ll (3)Difficulties and challenges(3):Difficulties and challenges(3):Perception, judgment, decisionPerception, judgment, decision‐‐makingmaking

Perception gap ~ discrepancy in frame of reference

Concern and sensitivity towards details & minutiae as opposed to big picture

Japanese minimalism: a double‐edged sword, risk of degrading into trivialismJ p g , g g

• Upside: better data quality, fewer protocol violations & deviations

D id  M  ti   d      k  d  lit• Downside: More time and energy, manpower, overwork and over‐quality

Decision making & clinical judgmentg j g

Modus operandi different across cultures and countries

ff l d h ll ( )ff l d h ll ( )Difficulties and challenges(4): CostDifficulties and challenges(4): Cost

C ff i   fCost‐effectiveness, cost‐performance

High‐quality data, often swift enrollment despite large N of sitesg q y , p g

Offset by most expensive study budge

Why expensive?  

M  f       i    i i  (d  f  i di   )Most fees go to sites, not investigators (de facto indirect expenses)

Actual workload and manpower not well reflectedp

Local rule (‘point’ calculation system) at work

H t i ti i i ti tH t i ti i i ti tHow to incentivize investigators How to incentivize investigators 

Participation in global research per se  of academic valueParticipation in global research per se: of academic value

Exposure to global standard researchp g

Helpful to improve local research activities

Access to novel pharmacotherapy

tangible clinical advance, benefit for Pts

Financial incentive

So far very limited in Japan

Comparison of two budget systemsComparison of two budget systems

Basis Correlation with actual

Investigator fee

In-house distribution

Comparability with overseas

workload trials

EstimationEstimation Points Poor Ca 30% at best Defined in advance •No clear breakdownsEstimation Estimation by ‘points’by ‘points’

Points calculation based on hitherto defined format

Poor(points rely heavily on lab test items rather than

Ca 30% at best (limited by the point system)

Defined in advance by contract

No clear breakdowns•Only comparable as total sum

format rather than complexity and workload)

GlobalGlobal Summation of Good In proportion Not restricted by the •Globally comparable Global Global budget budget calculationcalculation

actual cost per patient per visit

with enrollment, study complexity

contract per se; freely defined at investigators’ discretion

with respect to details•Transparent

Perceptions among physicians & hospital managementPerceptions among physicians & hospital managementUrgency of implementing global trials to improve drug lagUrgency of implementing global trials to improve drug lag

Necessity to improve infrastructure

Higher education in clinical research methodologies, ethical considerations and related regulationsg

More urgent issues to attend: management crisis

Fi i l  i i l    f  hi  h i lFinancial critical status of teaching hospitals

Medicolegal litigiousness

Mounting workload: lack of primary/specialist care distinction 

teaching hospitals  as mere health care providerg p p

Exodus of experienced physicians  manpower crisis

Challenges for both academia & industry Challenges for both academia & industry Global standard operation & business practice  Global standard operation & business practice  

Timeline & efficiency‐consciousness

Timely and clear decision making and swift operation

Global perspective versus local preference and customsp p pBig picture against local trivialism and micromanagement

Risk taking, positive mindset as opposed to risk‐averse  conservatism

Transparent, equal partnership as opposed to subservienceSeparation between clinical research and sales/promotion aspectsSeparation between clinical research and sales/promotion aspects

Substantial recognition for conflicts of interest

cf. Eli Lilly: First Pharmaceutical Company to Disclose Physician Payments c . y: st a aceut ca Co pa y to sc ose ys c a ay e ts

Pfizer Japan: abolishes unrestricted study grant

h ll d l dh ll d l dChallenges and critical issues at academiaChallenges and critical issues at academiaMorale of investigators, CRCs and other staffs: major, and often only, Morale of investigators, CRCs and other staffs: major, and often only, 

motivation and driver for clinical trials

Mounting procedural, operational issues in carrying out global trials: 

unknown to most investigators & CRCsunknown to most investigators & CRCs

Understaffed, underfinanced

How to ensure  manpower, time, infrastructure required in the face of 

worsening shortage of experienced physicians at teaching hospitalsg g g

Institutional Review Board: to meet global requirement

Training, quality, international accreditation