Hungary provides an attractive environment for clinical trials due to its: 1) Strong patient access programs that support high enrollment rates. These include a centralized patient database and satellite GP networks. 2) Supportive regulatory environment with efficient approval timelines under 60 days on average. 3) Established academic research centers that offer therapeutic expertise, trained personnel, and access to facilities like central laboratories and imaging. These support both early and late phase trials across therapeutic areas.

1. Sept 12, 2016
Bela E Toth MD, PhD, MBA
Faculty of Pharmacy, University of Debrecen
MEDIX Clinical & Academic Consulting Network
Multifactorial Approach in Clinical Research
Concept and Practice
in Hungary

2. BACKGROUND
Why the Phase III Clinical Trials Really Consistently Behind Schedule ... ?
ByHarold E. Glass, PhD. Jun 30, 2016 in ACT

3. Globalization of Industry-Sponsored Trials
a) Shift to Pharmamerging markets growth
b) Trends of movement away from traditional destinations (NA, W-Eu)
c) CEE countries continues to dominate highest market share gain over the
last years (e.g. over China with moderate growth ratein this field)
d) The Industry-sponsored product development growth rate of trials in
trends does not necessarily follow product sales growth (1)
Trends in Clinical Research
More complex Regulatory/EC procedures and environment
a) EU regulation
b) FDA guidelines
c) Pharmacovigilance /Risk assessment/PBRER approach
Centralised e-systems, EDC, CTMS, IT, DM and QA
a) High demand for on-site /local input, assigned trained personnel
b) Global remote / and RBM monitoring
c) Access to patient data by Safety and Adaptive Design reasons
(1) Misik (2014) Applied Clinical Research, Clinical Trials & Regulatory Affairs, 2014, 1, 56-66

4. #1 Patient access
• Feasibility by epidemiology related indicators
• Access to patient data in clinical/hospitals
• Information and education for patients: trial
access
• Investigators’ networking
• Supporting primary patients access programs
Attractiveness of Hungary in Clinical Research
#2 Regulatory and the legal environment
• Competent Regulatory (NCA) body (<60days)
• Improved efficiencies with ethics review
process (<45 days of review)
• Within the European Union framework

5. Attractiveness of Hungary in Clinical Research
#4 Study personnel
• Study Experience
• Expertise in therapeuti areas
• Networking within the Scientific Community
• Trained study personnel
• Motivation: financial and scientific benefits
#3 Study start-up and contracting at sites
• Standardised CT procedures in hospitals
• Clinical Reseach Coordinating offices in Academic
sites
• Access, Information and Contact – to fill the gaps
• Straight legal language in clinical trials contracts
• With Reasonable study costs and scientific benefits

6. #5 Clinical Quality: Defined and Maintained
• Regulatory compliance in filing
• Compliance to EU regulations
• Adherence to FDA guidelines
• Access to Risk Based Quality Management
• The „oral and written culture”
• Centralised supportive procedurals to remain competitive
Clinical Quality in Research
Quality, in Clinical Research - should be sufficient to
support the decision making process on medicines throughout the
clinical development and use post-marketing authorisation ensuring:
- Subject rights, safety and welfare
- Plus the robustness of data

7. THE FACTS
About clinical and academic research trials in Hungary

8. Hungary
is one of the most popular countries in EU Trials
(ClinicalTrials.gov Oct/2015.)
Hungary
was ranked
within the
first 3 in
the CEE
region

9. Experiences accumulated in Hungary
„… along with the outstanding scientific quality may enable the country to
maintain the current quality of clinical trials, moreover, it can even increase
it with the utilization of its unique, centralized patient database, which is
considered a major value in Europe…”
“CEE was also the region with the lowest percentage of inspections that
required official or voluntary action… quality standards that are not inferior
to those in Western regions.”
Quality in Clinical Research – Outstanding
FDA Site Inspection Findings over 2008-2015
Region
No Action
Indicated
Voluntary Action
Indicated
Official Action
Indicated
Count of
inspections (n)
Developed Markets 49% 46% 5% 14,580
Emerging Markets 43% 53% 5% 1,962
CEE 59% 39% 2% 264
Hungary 64% 36% 0% 45
FDA inspections data referred by Longtaal Oct 2008 – Sep 2015)
AIPM (2015); Calderon (2012); Dutton, G. (2015)

10. THE CONCEPT
National program aimed to enhance clinical research environment in Hungary

11. The clinical site should be confident to offer:
 Local knowledge and trained field personnel
 Therapeutic Expertise (KOLs) and Academic sites
 Supportive, reliable and rapid feasibility (database, registry)
 Regulatory and procedural guidance (local office + NCA)
 Single step-procedural in Ethics submission (CEC)
 Contracts and budget negotiation guidelines
Success in Start-up – The Concept
Start- up
Contracts
ED packages
Feasibility
Regulatory
1.) Start-up:
Streamlined Start-up Coordination in Place
RESULT:
Readiness for startup procedures
Predictable short timelines
Transparency start-up progress

12. 2.) The Concept:
Therapeutic and Study Experience
Study personnel (PI, Sub-I)
• CV/GCP trainings
• Therapeutic Experience
• Spec. for Clinical Pharmacology*
• Motivational factors
Staff (Study Nurse, St. Coordinators, Data Admins)
• Study Experience
• On board trainings (by Academic sites)
• Study nurse/ study coordinator courses
• Immediate start/ availability
• External Coordination Services/centres

13. 3.) In progress:
Academic Research Centres – a Difference
Success in Patient Access Program
- Satellite GP Network and Patient Database
- Screening Program (SZEBB) within the region
- Patient Education and Information Portal
- Coordiantion Centre for Drug Development
Over 150 phase I.-IV. clinical trials (2015) at Debrecen
University
 Accredited Phase I. unit, (12% trials)
 Medical centres for Phase II.-IV. trials
 Central laboratory
 Central imaging

14. Success in Patient Access Programs
Examples of 1.5x - 12x enrolment rate
9.54
0.89
1.25
3.47
0.12
0.81
0
2
4
6
8
10
12
Dental Pain Paed. Hypertension Migraine
Pts/site/month
CEE
ROW
14 Sites
1 Site
11 Sites
4 Sites
4 Sites
0
5
10
15
20
25
30
UK Germany Poland Hungary France
1.86
2.36
0.27
0.14
0
0.5
1
1.5
2
2.5
NSCLC Breast Cancer
Pts/site/month
CEE
RO
W
47 Sites
14 Sites
12 Sites
2 Sites 1 Site
3 Sites
0
50
100
150
200
250
300
350
UK Poland Australia N. Zealand Hong Kong Taiwan
14
Colorectal Cancer, Phase III,
Cumulative Enrolment by Country (N=700 Patients)
Lung Cancer, Phase II,
Cumulative Enrolment by Country (N=47 Patients)
CNS /pain
Cumulative Enrolment by Country
Oncology
Cumulative Enrolment by Countries

15. NEW RESEARCH STRATEGIES - SNAPSHOT

16. Academic Research – Translational Medicine
Translational Medicine
in Hungary
University of Pécs – Centre for Translational Medicine
Institute & Department forTranslational Medicine
INTERNATIONAL LEADERS:
Curtesy of Prof Peter Hegyi MD, DSc,
head of Institute & Department for Translational Medicine

17. The concept of
Translational Medicine
MEDICINE
20152000198519701955
BASIC
BASIC
BASIC
BASIC
CLINICAL
CLINICAL
CLINICAL
CLINICAL
Translational Medicine
CLINICAL TRIALS
PHARMACOLOGY
University of Pécs – Centre for Translational Medicine
Institute & Department forTranslational Medicine
PATHOPHYSIOLOGY
Curtesy of Prof Peter Hegyi MD, DSc,
head of Institute & Department for Translational Medicine

18. Academic – Translational Medicine Approach
Success in Scientific Networking
- Hungarian Pancreatic Study Group (HPSG)
- Network to CEE, W-EU and USA
- Prospective International Clinical Trial
- Connect high quality clinical science and research
Success in Patient Access
- Patient database and case registry
- Clinical trials organised and conducted by HPSG:
PINEAPPE
Prospective studies in AP

19. Hungarian Pancreatic Study Group – Magyar Hasnyálmirigy Munkacsoport
EASY
Academic – Translational Medicine
Clinical Trials Organised by HPSG
322
420
820
1230
1590
1750
4
9
16
26
34 35
14
23
25
0
10
20
30
40
50
60
0
200
400
600
800
1000
1200
1400
1600
1800
2000
Dec 2012 Feb 2013 Feb 2014 Nov 2014 Jul 2015 Nov 2015
Number of patients
Hungarian institutions
Foreign institutions
Massive dataset available for scientific approach and re-evaluation

20. MEDICAL/DIAGNOSTIC DEVICE RESEARCH

21. Medical Device Research Projects
in Hungary
Examples for ongoing research projects:
• Evaluation in Rehabilitation
• Early prognosis of risk of fall (elderly people) by the
combination of accelerometry and posturometry
• Drug safety modell evaluation on body sway and FFT/FA
• Efficacy of Medical Device by Environmental health

22. Combined Medical and Device
Evaluation in Rehabilitation
Somogy Megyei Kaposi Mór Oktató Kórház
Rehabilitation Development Program
by Prof. Ferenc Nagy and Jozsef Tollar
Semmelweis University
Sensimotor Adaptation Laboartory
Dr Laszlo Simon
Rehab Training
program
Posturometry
4F- FFT theory
MED-EVAL LTD, Academic partner
Diagnostic Device for objective eveluation
of clinical sites of trail subject
Posturometry
diagn. device
SM-KMMK+ PTE + SE
Rehabilitation: Prosp Clinical Trial
Jozsef Tollar and Dr. NF and Dr. NK
Comparative
efficacy

23. Combined Medical and Device
Evaluation in Rehabilitation
Trial subjects:
• Parkinson’s
• Post-Stroke
• MS
• Under
rehabilitaion
Tests:
EQ-5D-5L, PDQ-
39, Schwab and
England
MDS-UPDRS,
M-EDL, TUG
+ posturometry
Prospective study: analysis at base + 3 weeks
Normal population
After rehab* training
Without training
Results:
(35-)51% gain
in body sway index
TUG: from 16,8
to 10.6 sec

24. SUMMARY

25. Well characterized „national” patient profile
 Population - high # access of patients
 National Healthcare
 National Insurance system
 National Therapeutic guidance
 Standard list of pharma products
 Strong patient relationship and trust
Startup and study conduct
 Advanced EU-conform Regulatory
 Central EC process
 Descriptive start-up procedures
 E/Z access due to geography
 EU logistics and procedures
 Trained and qualified monitoring
 Short, predictable timelines
In summary
Hungary: an „Incubator” for clinical trials
Hungary in Central and Eastern
Europe

26. In summary
Hungary: Present and Operational
QC and Trusted Approach
Supportive Legal and
Regulatory environment
National Training Program
Facilities, Offices
• Local knowledge
• Patient access
• Trained personnel
• Scientific approach
• Procedural expertise
• Contracts
• MotivationQualified* Phase I. Units
Therapeutic Expertise in
Phase II.-IV.

27. Multifactorial Approach in
Clinical Research Practice in Hungary