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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