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

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.

Basel

Almost 200K inhabitants;

Located where the Swiss, German and French borders meet

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

Basel

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

Critical Measurements in CTs

Time

Budget

But there are also:

Data quality

Outcome Probability / Predictability (prove

work hypothesis)

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)

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)

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

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)

“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)

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!)

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?

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

CTs in CEE

Evans A, Tse T, Emerging Market Trends for Europe, 2008, Applied Clin Tr. OL

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)

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…

FDA International Inspections

Ayalew K, FDA Perspective on International Clinical Trials, 2013

Since 2007 the number of CEE inspections by FDA remained constant

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

CTs in CEE

AMAKEL Clinical Research Consulting, 2011

Average Number of Clinical Trials per 100,000 in 2000-2007

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

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

Time

Time

Time

Time

Time

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

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?”

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

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

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

THANK YOU!

julian.platon@gmail.com