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To share or not to share It’s your call !. Are we living in Splendid Isolation ?. Island of Neutropenia. Michael Angelo Petrone. How did this idea start ?. AITL a remarkable response to Thalidomide. Clinical Trials - Problems. Selectivity Bias Not good for ‘VULNERABLE’ groups - PowerPoint PPT PresentationTRANSCRIPT
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To share or not to shareIt’s your call !
Are we living in
Splendid Isolation ?
Island of Neutropenia. Michael Angelo Petrone
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How did this idea start ?
• AITL a remarkable response to Thalidomide
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Clinical Trials - Problems
Selectivity Bias Not good for ‘VULNERABLE’ groups
• children, elderly, pregnant, developing world risk of OBSOLESCENCE Regulation Bureaucracy Cost
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CASE REPORTS - Problems
CASE REPORTS• POSITIVE OUTCOME PUBLICATION BIAS• EDITORS DISLIKE CASE REPORTS
• SOFT PUBLICATIONS• DEVALUE THE JOURNAL• HIGHLY SELECTIVE
• CANNOT BE EASILY/REGULARLY UPDATED• NOT UNIFIED INTO A SINGLE DATABASE• UNSTRUCTURED
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CONVENTIONAL REGISTRIES - issues Denominator is all patients with the
disease in a defined territory. Disease incidence, prevalence and
outcomes on a population wide basis Most of the effort (99%) in data
collection is ‘uninteresting’ with respect to investigational therapies.
Global scope is essential.
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Comparison table
RTC REGISTRY CICEROGLOBAL NO NO YESFOCUSSED ++++ NO ++++PUBLICATION BIAS YES NO NOSELECTION BIAS ++++ NO ++BUREAUCRATIC YES NO NO
RTC REGISTRY CICEROGLOBAL NO NO YESFOCUSSED ++++ NO ++++PUBLICATION BIAS YES NO NOSELECTION BIAS ++++ NO ++BUREAUCRATIC YES NO NO
CASE REP TRIALS REGISTRY CICERODATA QUALITY ++ ++++ + ++GLOBAL + ++ + ++++FOCUSSED ++++ ++++ - ++++PRE-PUB APPROVAL - + - ++++PUBLICATION BIAS ++++ ++ - -SELECTION BIAS ++++ +++ - ++ONLINE SEARCH + + + ++++I.A. MODELLING - - + ++++VUL. GROUPS ++ + +++ ++++BUREAUCRATIC + ++++ + +EASY TO UPDATE + ++ +++ ++++REAL TIME + + ++ ++++
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Summary so far
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Summary so far
Existing sources of data are flawed. Inadequate for clinical needs - especially for
patients with• rare diseases• relapsed/resistant disease• children• pregnant• elderly• diseases specific to developing countries
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Evolution or Revolution
If I asked my customerswhat they wanted, they would have said:
“FASTER HORSES”
Henry Ford
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INVENTION“You look at things and ask - Why ?
But I dream of things that never were, and ask -
Why not ?”
George Bernard Shaw
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CICERO
MARCUS TULLIUS CICERO
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CICERO
C ollection I nvestigational C ase-reports E lectronic R egistry O utcomes
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CICERO - Key features 1
Database/Journal to record outcome data to Investigational Therapies of Interest
Using the Internet to Record Existing Work Systematically
Open Access Global
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CICERO - Key Features 2 Peer Reviewed: Data And Contributors Trustworthy
• Professionally controlled• No vested interests• Not-for-profit
Low Cost Low Bureaucracy Easy to Update/Edit Free from publication bias
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Free from Publication Bias ??
PRE-TREATMENT APPROVAL
‘INTENTION TO PUBLISH’ ANALYSIS
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The Process
C o ntr ib u to r su pp lies ou tco m e da taa t a gre ed in te rva ls
P O S IT IV E o r N E G A T IV E
C a se a cce p tedT re a tm en t sta r ts
C a se re jec ted
C o ntr ib u to r su bm its case to C IC E RO be fo re tre a tm e n t s ta r ted
P a tie n t co n se n ts to p u b lish o u tco m e o n C ICE R O
C lin ic ia n /con trib u to r a nd pa tie n ta g re e o n a n inv es tiga tio na l tre a tm e nt
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THE PROCESS Suitable case arises Clinician obtains informed consent Clinician submits case for pre-approval Approval given on condition that:
• regular outcome updates at agreed intervals• until agreed endpoint• outcomes may be positive, negative or neutral• reports of any adverse effects• patient identity anonymised
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Comparison table
RTC REGISTRY CICEROGLOBAL NO NO YESFOCUSSED ++++ NO ++++PUBLICATION BIAS YES NO NOSELECTION BIAS ++++ NO ++BUREAUCRATIC YES NO NO
RTC REGISTRY CICEROGLOBAL NO NO YESFOCUSSED ++++ NO ++++PUBLICATION BIAS YES NO NOSELECTION BIAS ++++ NO ++BUREAUCRATIC YES NO NO
CASE REP TRIALS REGISTRY CICERODATA QUALITY ++ ++++ + ++GLOBAL + ++ + ++++FOCUSSED ++++ ++++ - ++++PRE-PUB APPROVAL - + - ++++PUBLICATION BIAS ++++ ++ - -SELECTION BIAS ++++ +++ - ++ONLINE SEARCH + + + ++++I.A. MODELLING - - + ++++VUL. GROUPS ++ + +++ ++++BUREAUCRATIC + ++++ + +EASY TO UPDATE + ++ +++ ++++REAL TIME + + ++ ++++
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CICERO versus CONVENTIONAL REGISTRIES
CONVENTIONAL REGISTRIES• Denominator is all patients with the disease in a defined territory.• Disease incidence, prevalence and outcomes on a population wide
basis• Most of the effort (99%) in data collection is ‘uninteresting’ with
respect to investigational therapies.
CICERO• Denominator is the treatment episode.• Concentrate on the first hundreds/ one thousand/ two thousand
patients treated worldwide with a new therapy. • Global scope is essential.
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CICERO versus RCT’s
CICERO is not an alternative to RCT’s Data quality CICERO < RCT’s Selectivity CICERO < RCT’s REPRESENTATIVENESS CICERO > RCT’s ?
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Where does CICERO fit in ?
PHASE 3CASEREPORTS
CICERO
IV -> -> -> III -> -> -> II > -> -> I EVIDENCE LEVEL
PHASE1 AND 2
EXPERT OPINIONS
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WHAT IS A SUITABLE CASE ?
INVESTIGATIONAL THERAPY AVAILABLE• DRUG - UNLICENCED/OUTSIDE OF LICENSE• PATENT EXPIRED• NON-DRUG BIOTHERAPY, IMMUNOTHERAPY, CELLULAR• VACCINE, COMBINATION
NO CLINICAL TRIAL AVAILABLE LOCALLY PATIENT REFUSES ENTRY TO TRIAL PATIENT EXCLUDED FROM TRIAL PATIENT FULLY INFORMED AND CONSENTED
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Real Examples
Response rate for: • Mycophenolate in resistant ITP
Match patients with following characteristics:• HCL female; age 58; DCF Resistant• What treatments have been tried and what were
the crude response rates ? Side effects of MabCampath: age > 70 yrs
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Early detection of adverse events
• Existing systems have problems– Case reports and case series (publication bias)– Clinical trials (selection bias, power)– Yellow card systems
• (poor compliance, geographically restricted)
• We need a system which can:– Detect infrequent but serious adverse events– Detect them early – (1000-2000 exposures)– Detect them wherever they happen (global coverage)– Offers incentives to contribute– Targets new drugs, and new indications.
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POTENTIAL USES CRUDE OUTCOME RATES EARLY DETECTION OF ADVERSE EVENTS FOR THE FUTURE
• NON-HAEMATOLOGICAL MALIGNANCY • NON-MALIGNANT CONDITIONS• NEW INTERVENTIONAL PROCEDURES• NEW SURGICAL TECHNIQES• CELLULAR THERAPIES
SPECIAL GROUPS• RARE DISEASES, CHILDREN, PREGNANCY, ELDERLY
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CICERO and RARE DISEASES Clinical Trialists tend to ignore rare diseases But in a way - all diseases are becoming rare ! AML is now stratified - for instance. Lymphoma is becoming stratified according to:
• New DIAGNOSTIC modalities• Application of PROGNOSTIC INDICATORS
Therapy is becoming ‘tailored’• MRD STATUS• RATE OF ACHIEVEMENT OF CR• RATE OF ATTAINMENT OF PET NEGATIVITY
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GIVE ME AN EXAMPLE !
IS CLL BECOMING A RARE DISEASE ?• OUR COMMMONEST LPD• SLOW DISEASE • TRIALS LASTING >10 YEARS TOO SLOW NOWADAYS• DIAGNOSIS STRATIFIED A/C PROGNOSTIC INDICATORS
• CLINICAL STAGING, WCC DOUBLING TIME,• SERUM MARKERS, CD38, IgVH STATUS, ZAP70 Cytogenetics
• TAILORING OF TREATMENT• Drug sensitivity testing, P53, CD38 expression, microarrays • MRD detection by FLOW or BM immunohistochemistry
• INVESTIGATIONAL THERAPIES OF INTEREST• Purine analogues, HDMP, MOAB’S, ABMT, ALLOBMT, MiniALLO• Splenic irrad, Radioimmunoconjugates, proteasome inhibitors, anti-angiogenesis agents,
cyclin dependent kinase inhibitors (Roscovitine)
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What about children, pregnancy and the elderly ? Paediatricians generally prefer to offer
standard therapy or a new investigative therapy - but outside of the confines, and restrictions of a clinical trial.
They are already doing the clinical work of participation in clinical trials, but they are no better off, as they do not record and share the outcome data.
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What about children, pregnancy and the elderly ? New therapies are licensed often excluding
these important population groups. CICERO offers the opportunity to at least
partially redeem the situation, gathering information after the event perhaps, but better to do this than nothing at all.
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WHY NOW ? ONLINE TECHNOLOGY NOW MATURE AND ACCEPTED PROBLEMS WITH TRANSLATION OF RESEARCH NEW WAYS TO STRATIFY DISEASE
• DIAGNOSIS• RESPONSE
NEW MODALITIES OF THERAPY BUREAUCRACY SURROUNDING
• CONDUCT OF CLINICAL TRIALS• PUBLICATION TO PAPER JOURNALS
NEW OPPORTUNITY TO CONTRIBUTE TO THE KNOWLEDGE BASE - WITHOUT THE BUREAUCRACY
THE PROBLEM OF RARE ENTITIES
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THE REWARDS
CONTRIBUTING CLINICIANS• A NEW WAY OF CONTRIBUTING TO THE KNOWLEDGE BASE• SERIES OF CASES ( >5 ?) COULD BE REWARDED WITH A
CITATION ON MEDLINE OR PUBMED• CME POINTS • REWARDS SCHEME FOR SpR’s
PATIENTS • DECISION SUPPORT TOOL
• May help guide treatments for new patients• May help inform design for future RCT’s
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POTENTIAL PROBLEMS WITH NEW PROPOSAL TECHNOLOGY FUNDING/SUPPORT MIS-USE OF DATA
• MANIPULATION OF INPUT DATA ? MIS-INTERPRETATION OF DATA
• SUB-GROUP ANALYSIS ETHICS
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WHO SHOULD PAY ?
PHARMA INDUSTRY ?• PER CASE ?• PER COMPANY ?• PER INDUSTRY ?
NHS /GOVERNMENT ? CHARITIES ? NATIONAL LOTTERY ? CONTRIBUTORS ?
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WHO SHOULD CONTROL IT ? THE PROFESSION - WHY ?
• DATA HAS TO BE TRUSTED• FREE FROM VESTED INTERESTS
IMPLICATIONS• WILL HAVE SIGNIFICANT COSTS• WILL HAVE TO BE PROPERLY REGULATED• WILL REQUIRE CO-OPERATION FROM COMMUNITY• WILL REQUIRE DISCIPLINE
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Potential Sanctions for Misuse
Cases/Contributors removed • when input data are inaccurate• when input data are not regularly updated
Cancellation of credits Editor’s decisions are final ?
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CICERO SUMMARY ONLINE DATABASE PROFESSIONALLY REGULATED OUTCOMES TO CASE REPORTS PUBLICATION PRE-APPROVAL REGULARLY UPDATED BY ACCREDITED CONTRIBUTORS DECISION SUPPORT TOOL FOR THE FUTURE LOW COST TO CONTRIBUTORS AND USERS NOT-FOR PROFIT FREE FROM VESTED INTERESTS LOW BEUREAUCRACY
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To Share or not to ShareHow Do We Plead ? Guilty or Not Guilty
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To Share or not to Share
Guilty ? Misdemeanour or Felony ? What is the cost of complacency ? Who has the solution ?
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WAITING FOR A MIRACLE
You can either take action or you can wait for a miracle.
Miracles are great - but they are so unpredictable.
The best way to predict the future is to create it.
Peter F Druker
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CICERO Key Messages
Existing systems for sharing data are inadequate for clinical needs.
The technology to make things better already exists.
You need to declare your support for this type of proposal - otherwise it will not happen.
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To share or not to share ?It’s your call !
I’m a clinician
Get me out of here !
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CICERO your next step
• Submit a comment www.CICER.Org• E-mail a friend • Help select a pilot• Give it your support• Advertising• Funding