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Synevo Clinical Research Symposium – 9th Edition
2017, November the 17th – the Intercontinental Hotel, Bucharest, Romania
Dr. med. Julian V. Platon, Basel, CHPLATON STRATEGIES & OPERATIONS
R`nD & MA CONSULTING
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Disclaimer
The opinions expressed in this presentation are my own (as per November 2017).
The content does not necessarily represent the views or policies of any companies for which I worked or work.
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Basel
Almost 200K inhabitants;
Located where the Swiss, German and French borders meet
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Basel: Pharma-“Mecca”
Pharmaceutical Companies with Headquarters in Basel:
Novartis (Sandoz) Actelion
Hoffmann-La Roche Basilea Pharmaceutica
Abbott Pharmaceuticals Straumann
Bayer Consumer Care about 900 pharmaceutical and medtech companies
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Basel
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Agenda
Start up Planning for Multinational Studies
Critical Measurements in CTs
Planning
Facts about CTs in CEE
Why to combine developed and emerging countries / Why “Go East!”?
Conclusions
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Critical Measurements in CTs
Time
Budget
But there are also:
Data quality
Outcome Probability / Predictability (prove
work hypothesis)
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Time
Depending on:
Design (e.g. cross-over)
CRO (e.g. slow/fast, existing personnel)
Administration, NA, IEC [e.g. serial applications, duration to
decision (as a negative example the ANMDM), No. of needed
countries]
Recruitment (e.g. No. of patients under management by site)
No. of needed sites (e.g. training ressources)
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Budget
Depending on:
Design (e.g. adaptive design = need for independent safety
committee)
CRO (!, do not pay for CRO’s name but for the name of the
project manager)
Administration, NA, IEC (expensive vs. acceptable costs,
“Nordrhein Medical Chamber”, No. of needed
countries/translations)
Recruitment (e.g. high vs. acceptable investigators fees)
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Data Quality
Depending on:
Design (e.g. statistical power vs. multiple primary parameters)
CRO (e.g. SOPs, monitoring visits, data entry)
Administration, NA (get scientific advise from NA/CA, esp
when phase II/III, NDA relevant)
Recruitment (e.g. No. of patients per site, adequate ethnicity)
Central Lab (standardization = quality) – it helps also re Time,
Budget and Outcome Predictability
NA/CA = National Agency / Competent Authority
NDA = New Drug Application
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Outcome Predictability
Depending on:
Design (e.g. is the design adequate to answer your question or just “quite in”?)
Administration, NA (discuss but make your(!) own decision)
Risk Assessment (team! medical, clinical, pharmacologist, statistician, etc)
Literature research vs. singular KOL advise (esp. for predictability of comparator)
Pilot Study (impact on time and budget)
No. of Patients (within budget)
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“Sponsors’ Dilemma”
Since ages Clinical Development and Medical Affairs
are handled as serial stations in products life cycle
Increased time pressure leads to “effectiveness”
increase ambitions and communications cuttings
Lack of communication between data generation
(ClinDev/ClinOps) and data utilization (MedAff,
SciCom)
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Planning of Study Start up
Sites selection criteria (given ICH-GCP and national laws conformity):
Require communication of ClinOps and MedAff and split between
(i) Sites for predominant data advocacy and communication and
(ii) Sites for predominant data generation
(both should be included in publication!)
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Planning of “Multinationality”
Does a split between centers in (i) “established markets”
and centers in (ii) Central and Eastern Europe improve
the results of the critical measurements in Clinical Trials?
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CTs in CEE
The CEE is a heterogeneous group of countries with
different
Legal Systems (imperative!)
Habits, mentalities and cultures
Level of centralization of healthcare systems
Level of focus from the pharmaceutical and medical devices
companies
Level of coverage by CROs
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CTs in CEE
Evans A, Tse T, Emerging Market Trends for Europe, 2008, Applied Clin Tr. OL
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Overall Clinical Trial Costs
Kaitin K, Tufts Center for the Study of Drug Development, 2008
Ayalew K, FDA Perspective on International Clinical Trials, 2013
The cost of conducting Clinical Research in Russia is less than half the cost to the
US (manpower, rental, IT & operational costs)
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Increase Rate for FDA Regulated
Investigators Around the Globe
Ayalew K, FDA Perspective on International Clinical Trials, 2013
During 10 year period, the % of total for US based investigators declined by 20%
Western Europe remained constant (4% increase)
LATAM and Asia increased 7 times
CEE increased by 20 times…
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FDA International Inspections
Ayalew K, FDA Perspective on International Clinical Trials, 2013
Since 2007 the number of CEE inspections by FDA remained constant
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FDA CI International Inspections*
Algeria** 1
Argentina 19
Australia 9
Austria 6
Bahamas 1
Belgium 26
Brazil 13
Bulgaria 1
Canada 151
Chile 8
China 7
China, Taipei 3
Colombia 1
Costa Rica 8
Czech Republic 7
Croatia 3
Denmark 13
Dominican Rep. 1
Ecuador 1
Egypt 1
Estonia 5
Finland 15
France 51
Peru 6
Philippines 4
Poland 29
Portugal 2
Romania 1
Russia 35
Serbia 3
Singapore 1
Slovenia 1
South Africa 26
Spain 17
Sweden 28
Switzerland 2
Thailand 4
Turkey 6
U. K. 91
Ukraine 4
Venezuela 2
Yugoslavia 3
Zambia 1
*Conducted for FDA/CDER
from 1980 through 08/8/07; total: 810
**data reviewed in U.S.
Gabon 1
Germany 59
Greece 2
Guatemala 2
Hong Kong 5
Hungary 10
India 6
Ireland 1
Israel 5
Italy 36
Japan 3
Kenya 1
Latvia 5
Lithuania 2
Malawi 1
Malaysia 4
Mexico 14
Netherlands 24
New Zealand 4
Nigeria** 1
Norway 5
Panama 2
FDA, Lepay D, Toth-Allen J, APEC GCP Inspection Workshop, 2008
CI = Clin. Investigations
CDER = Center for Drug Evaluation and Research
APEC = Asia-Pacific Economic Corporation
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CTs in CEE
AMAKEL Clinical Research Consulting, 2011
Average Number of Clinical Trials per 100,000 in 2000-2007
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Population CEERussia (European) 107.2
Ukraine 46.7
Poland 38.5
Romania 22.3
Belarus 10.3
Czech Republic 10.2
Hungary 9.9
Bulgaria 7.4
Slovakia 5.4
Georgia 4.6
Moldova 4.5
Bosnia & Herzegovina 4.5
Croatia 4.5
Lithuania 3.6
Albania 3.6
Latvia 2.3
Macedonia 2
Slovenia 2
Estonia 1.3
Total 290.8
http://www.cia.gov/cia/publications/factbook/geos/it.html
Total EE population 290.8 Mio.
Russia (European)
UkrainePoland
Romania
Belarus
Czech Rep.
HungaryBulgaria
SlovakiaGeorgia Moldova
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Weaknesses
Only 4% of the registered global studies are
running in CEE (in the last 5 years)
Romania ranking #6 within CEE
Defined weaknesses Romania: (i) Long
evaluation time of the NA (25 w.) – with
declining character since 2011 (254) -> 2016
(161) and (ii) outdated hospitals equipment
KPMG, Studiile Clinice in Romania, Report, December 2016
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Time
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Time
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Time
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Time
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Time
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ANMDM Position
Continuous efforts to recruit highly qualified personnel – however, non-competitive salaries vs. sponsors and CROs + subsequent forced (i) personnel cuts and (ii) frozen positions
Doubling of amendments (clock-stop)!
Despite tremendous efforts the existent resources can not solve the problem
MoH (as escalation responsible) & Prime Minister have been repeatedly informed
Dr. Nicolae Fotin, personal email from November 16, 2017
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Pt. Compliance (Data Quality)
No data but by own experience…
Physician to the patient:
“You please take this pill 3 times per day!”
German Pt: (thinks) let’s see what the package insert and the internet are saying
US Pt: (thinks) let’s see what my lawyer is saying
Romanian Pt: “before or after the meal, doctor?”
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Strengths
Clinical Trials market size Romania (2015) -
€ 98 Mio. (WWMS – € 111 Bio. 2014)*
Patients compliance and willingness
No. of physicians / 100k inhabitants
High data quality (due to (i) sites interest, but
also (ii) “CRAs engagement”)
Offering patients a better general medical
care (except investigational drug)
*KPMG, Studiile Clinice in Romania, Report, December 2016
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Solutions
ANMDM (MoH/Prime Minister!) to actively increase efficiency and respect legislation
Increase transparency and patients information (e.g. discussions pros & cons in mass media) – as negative publicity goes on its own…
Simplified, standardized contracts for CT sites
Implement and improve monitoring educational tools (and general GCP understanding)
When outdated hospitals equipment -> use central lab
Cooperation / Working Group ARPIM, ACCSCR, ANMDM, IEC, Study Sites, Patients Advocacies, etc
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Conclusions
When it comes to planning CTs ClinOps and
MedAffs need to become a team
Plan for multinational studies start up to
combine “data generation” with “outcome
advocacy” sites and countries
Use existing geographical opportunities in
order to achieve given goals
For Authorities: Respect legislation and the
country you are expected to serve