CLINICAL TRIALSIN HUNGARY

Cromos Pharma presents this Country Profile“Clinical Trials in Hungary” as one of our seriesof reports about locating your clinical trial in Cromos Pharma's geographic regions.

Clinical Trialsin Hungary

• Hungary is an established EU member state since 2004 and has embarked on an impressive program of economic, regulatory and infrastructural reform in the last two decades.

• Hungary has a positive economic environment focused on attracting international companies and authorities committed to making the country a global leader for clinical research.

• It offers a relatively low-cost base when compared with other EU member states yet at the same time boasts high quality work and results.

• Hungary has a strong pharmaceutical and medical device sector including leading international firms and indigenous companies.

• It has a clear regulatory process and authorities that have been working to improve efficiencies resulting in quick approval periods and expedited timelines.

• The country has a large pool of highly skilled and motivated medical professionals.

• It has a large number of well-equipped medical facilities with experience in running international trials.

• Hungary offers excellent recruitment potential across a wide range of therapeutic areas especially for multi-country trials.

• Its physicians and patients are very favourably disposed to participating in clinical trials as a means of accessing novel treatments.

• Hungary has an excellent track record of producing high quality data as confirmed by positive inspection records from the FDA and EMA.

• Hungary has exceptional experience as a location for clinical trials in oncology, cardiology, vaccine, medical devices and paediatrics.

This Cromos Pharma Country Profile presents a comprehensive overview of the main advantages that make Hungary the right location for your next clinical trial.

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� The country has a centralized health system which assists rapid patient recruitment.

Summary Hungary is a highly attractive location for international clinical trials particularly for sponsors seeking to run multi-country trials for a number of key reasons:

CROMOS PHARMA

Hungary is a landlocked country located in Central Europe with a population of 9.77 million (World Bank, 2019 ). Its largest city and capital is Budapest with 3

a population of 1.75 million. It became a member state of the European Unionin 2004. The pharmaceutical sector is one of the main pillars of the Hungarianeconomy accounting for 7.5% of national GDP (2019 ). There is a strong 4

presence of international pharmaceutical players in the country and a well-developed indigenous sector. Hungary is one of the leading pharmaceuticalmanufacturers in the Central and Eastern Europe. The strength of the sectorhas resulted in a strong knowledge base and skilled workforce in the area .5

In recent years, Hungarian authorities have focused attention on further developing related subsectors where they have experience and know-howand aim to become a global competitor in the areas of clinical trials, developmentof biopharmaceuticals, medical devices and biotech . Parallel to these efforts6

significant investment is being directed at strengthening its national healthinfrastructure and its research and development sector . 7 8

Background

Introduction

CLINICAL TRIALS IN HUNGARY

POPULATION OF HUNGARY

GDP (IMF, 2019)

9.77 MILLION

$12.3 TRILLION

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Cromos Pharma established a representative office in Budapest, Hungary in 2016 and it is staffed by a highly experienced team that consistently delivers high quality results for sponsors. It has developed its presence in the country in line with the company's overall strategy for growth in Central and Eastern Europe. Hungary boasts several advantages for sponsors conducting clinical trials which will be examined in this profile. Hungary is placed 10th worldwide in terms of the number of trials conducted in the country and 4th in Europe1. (based on population- proportional patient numbers). Each year approximately 20,000 patients2 participate in clinical trials in the country. This profile includes general background information about Hungary, an overview of clinical research currently being conducted in the country, particular advantages for international sponsors including information on patient recruitment, the health system and pool of experienced clinical professionals as well as a Cromos Pharma case study of a trial successfully conducted in Hungary.

CROMOS PHARMA

According to the health care statistics of 2019 , the average life expectancy at birth9

for males is 72 and for females is 79 years. This is significantly lower than the EUaverage life expectancy of 80.9 years (83.5 years for females and 78.3 for males).10

Hungary takes 5th place for the number of deaths per 100,000 inhabitants per year in the EU region (Eurostat, 2016 ). Based on the results of 2018 Hungarian health 11

statistics and 2016 European health statistics, the two leading causes of death aremalignant neoplasms (Hungary takes 1st place for the incidence of colorectal and lung cancer in the EU ranking list ) and ischemic heart diseases. Based on 201612

Eurostat figures Hungary had the highest cancer mortality rate in the EU (OECD,2019 ).13

Ischemic heart disease (hypertensive heart diease - 6th in EU, cardiomyopathy)

Malignant neoplasms (lung cancer - 1st in EU, colorectal cancer - 1st in EU,breast cancer)

Cerebrovascular diseases (stroke, Alzheimer's Disease)

Liver diseases (cirrhosis and hepatitis)

Pulmonary diseases (COPD, asthma, pulmonary emphysema, bronchitis)

Acute myocardial infarction

Intentional self-harm (7th in EU)

Motor vehicle accidents

Source: HealthData.org

National health profile

Figure 1: Leading causes of deaths in Hungary (based 2017 figures)

CLINICAL TRIALS IN HUNGARY

Two-thirds of over 65s in Hungary report having at least one chronic disease (+12% compared to the EU average) and onein six report having a condition that limits their daily activities (OECD, 2019 ). According to the most recent OECD health report 14

on Hungary, its population has higher rates of “risky health behaviors” than the EU average including high rates of smoking (3rd in EU), high alcohol consumption (average 11.1 liters vs 9.9 liters in EU), as well as growing rates of obesity in both adultsand children (OECD, 2019 ).15

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CROMOS PHARMA

Hungary boasts several key advantages for sponsors considering the country as a location for clinical research. Its membership of the EU, high standards in education (in particular clinical and medical training), recent national programsaimed at developing a strong medical research sector, and general economic initiatives aimed attracting international investment all mark Hungary out as an attractive location for international sponsors. Furthermore, Hungary has a longstanding reputation as a good location for clinical trials due to a strongclinical infrastructure, centralized healthcare system, a highly skilled workforce,naïve patient populations in a diverse range of clinical indications, solid recordfor producing high quality data (based on positive inspections e.g. FDA) and16

physicians positively predisposed to clinical trials. In this section, we look at some of the key advantages on offer to sponsors considering Hungary as thelocation for their next clinical trial.

Hungary has a centralized health care system, with four medical universities (Budapest, Debrecen, Szeged, Pécs) and over 160 governmental hospitals (approx. 100 active treatment centers and several specialized/rehabilitationinstitutions). Eighteen of them are specialized in conducting phase I studies(four of them are phase I oncology centers). There are 66 private health care providers, the majority are engaged in clinical trials, most of them utilizing sitemanagement organization (SMO). Several SMO networks are present in Hungary that are specialized in conducting clinical studies. Relative to its size, Hungaryalso has outstanding number of hospital beds per 1000 habitant in the world(6th in EU, 2017 ). Hungary has a tax-funded universal health care system 17

organized through the National Health Insurance Fund . There is also a wide18

range of private health insurance schemes available to citizens. The centralized nature of Hungary's health care system assists rapid patient recruitment.

Hungary has a notable naïve patient population in a wide range of therapeuticareas. Its patient population is well disposed to taking part in clinical trials inorder to get access to novel and advanced treatments which may not be available to them through the national health system notably in the area of oncology. Patients in general display a high degree of trust in clinical professional who themselves view participation in clinical trials in a positive manner. Thesefactors help to make Hungary a good location for rapid patient recruitment.

As noted above, clinical staff in Hungary are in the main positively disposed totaking part in clinical trials. The primary motivation for participation of theinvestigators in trials is opportunity to provide novel and effective treatmentsfor their patients. Other motivating factors include the advantages to them of gaining experience in state-of-the-art medical innovations while ensuring theimprovement of the overall Hungarian health care system . Due to the national 19

financial therapeutic protocols, access to some newest or the most expensivetreatments is limited to certain patient populations, so the physicians are motivated to participate in clinical trials where their patients can receive thesetreatments in clinical trial settings. Another advantage for participating in a trialas an investigator is to further improve their scientific knowledge in thetherapeutic area. Taking part in clinical trials is also attractive due to the higherfinancial compensation investigators receive in comparison to what they mayearn in the Hungarian health system.

Hungary's experience in clinical trials has led to the development of a highlyskilled clinical workforce which has gained a reputation for producing high qualitydata. These high standards are demonstrated by the results of international inspections for example, between 2008-2020 the US Food and Drug Administration(FDA) carried out a total of 42 inspections. The results of which were 28 No ActionIndicated, 14 Voluntary Action Indicated and no Official Action Indicated.

Hungary as a locationfor clinical trials:advantages

Centralized healthcare system

Significant naivepatient population ina wide range of clinicalindications

Highly motivated clinical staff

Skilled staff with astrong track record forproducing high qualitydata

CLINICAL TRIALS IN HUNGARY

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CROMOS PHARMA

The cost of research in Hungary is very competitive when compared to20

neighboring western EU countries and other emerging economies, at thesame time the quality of the collected data is exceptional. In addition,investigator grants, supplementary vendor / service costs are also highly competitive when compared worldwide.

In 2018, the total number of authorized studies in Hungary was 290, and in2019 this increased to 315 .The average duration of clinical trial conducted21

in Hungary is 1-3 years. The number of authorized phase I studies in 2018-2019 was 46 (incl. pediatric studies) .22

Clinical trials in Hungary include studies on a wide range of therapeutic areas.The largest number is in oncology (55 in 2018 and 38 in 2019) with neurology,gastroenterology, dermatology, metabolic and cardiology also featuring strongly.Alongside these areas, it should also be noted that a number of trials with raredisease indications were initiated including Ewing's sarcoma, neuroblastoma, hereditary angioedema, Sjögren's syndrome, Pompe's disease, systemic lupus erythematosus, or paroxysmal nocturnal hemoglobinuria, and Wilson'sdisease. This demonstrates the breadth of experience of investigators in Hungary.

Competitive cost of research

A snapshot of clinicaltrials in Hungary2018-2019

Indications

Figure 2:FDA Inspections(2008-2020)

Figure 3: Clinical Trialsin Hungary 2018-2019by therapeutic area

CLINICAL TRIALS IN HUNGARY

Source: Inspections databaseFDA

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CROMOS PHARMA

As a European Union member state since 2004, Hungarian laws and regulationsare EU harmonized (e.g. EU CTD, GDPR). The relevant authorities with regardto the regulation of clinical trials are the National Institute of Pharmacy and

23Nutrition (NIPN) [Országos Gyógyszerészeti és Élelmezés-egészségügyiIntézet (OGYÉI)] working with the central ethics committee, and the MedicalResearch Council (MRC) [Egészségügyi Tudományos Tanács (ETT) ]. The24

authorization process is well regulated including specialized regulations for Phase I, GMO, medical device and non-interventional studies. For instance, in case where a clinical trial is conducted with a GMO IMP, the Committee ofHuman Reproduction of MRC will also be involved in the initial authorizationprocess.

Regulatorybackground

Figure 6: Outline of clinical trial submissionprocedure

Figure 4 and 5: ClinicalTrials in Hungary 2018and 2019 by phases

CLINICAL TRIALS IN HUNGARY

Source: (OGYÉI)National Institute of Pharmacy and Nutrition

Applicant Applicant

Central EC : ETT-KFEB

• Refusal by EC results in total refusal• Deadline for authorization: 75 days• Deadline to response to request for further information: 15 days

2 copies Decision withethical opinion

OGYÉI

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CROMOS PHARMA CLINICAL TRIALS IN HUNGARY

During the clinical trial authorization process the NIPN/OGYÉI asks for the Specialized Authority Position Statement from the Medical Research Council in parallel with its own review of the package and will only authorize the trialwhere the central ethics committee provides a positive opinion (i.e. a supportive Specialized Authority PositionStatement).

The Ethics Committee for Clinical Pharmacology•

The Committee of Human Reproduction•

The Scientific and Research Committee•

The System of Regional Committees•

The local, or regional ethics committees do not authorize studies, they are responsible for local oversight of the trials andneed notification of the study start-up, close-out and about the local SAEs.

The NIPN/ OGYÉI and the MRC have a reputation for being responsive during the clinical trial submissions and authorizationprocesses as compared to other neighboring countries and several other regions of the world ensuring highly collaborative and supporting regulatory environment as an additional competitive edge of running clinical trials in Hungary.

Currently there are two ways for the initial authorization of a trial via:

• National Authorization

• Voluntary Harmonization Process (VHP)

In general, using the national process is more favorable in the case of single country trials. The VHP can be used in multi-country trials involving at least two EU countries. VHP is a procedure which makes it possible to obtain a coordinated assessment of an application for a clinical trial that is to take place in several European countries . It harmonizes the 25

approval timelines of key documents, like protocol, IB, IMPD among the participating countries. Hungary has actively taken part (since 2009) in the VHP process, the Hungarian competent authority is often involved as the reference country,therefore it has significant experience with this authorization procedure.

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The MRC has the following ethical committees

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For human clinical trials the initial submission fee is 580 000 HUF (appr. 1750 EUR)and the authorization procedure takes 60 calendar days, with an additional 15calendar days available in case of any questions arise during the review. Thewhole process including the central ethics committee review takes up to 75calendar days with the national submission process.

Hungary is currently participating in the VHP+Pilot project where the ethics review 26

is done in parallel with the central part of the VHP, ensuring authorization in VHPprocess occurs without significant delay. In summary the VHP+Pilot timelines arethe following: central VHP and Hungarian central ethics committee review takes up to 60 calendar days (preauthorization period), and country authorization periodtakes up to additional 15-20 calendar days.

The authorization of a trial with GMO investigational product takes up to 90 calendar days (72 days for the MRC statement, and 18 days for the authorization). In the case of xenogeneic cell therapies, the authorization timelines are extended(up to 365 calendar days: 335 days for the MRC statement, and 30 days for theauthorization).

The submission fee for the substantial amendments is 110 000 HUF (appr. 340EUR), and the approval takes up to 60 calendar days (including the centralethics committee evaluation, if applicable). Submission of a non-substantialamendment is free of charge, and the acknowledgement takes only up to 20 calendar days.

National Authorization

VHP+

GMO

Amendment fees and timelines

CLINICAL TRIALS IN HUNGARY

Figure 7: HungaryAverage Start-UpPeriod Duration

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week 9

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INDIVIDUAL STAGES

Translation of docs and submission dossier preparation 35 5 1,2 1 1 1 1 1

Review & approval by National Institute of Pharmacy (NIP) 77 11 2,5 1 1 1 1 1 1 1 1 1 1 1

Review & approval by the Central EC* 63 9 2,1 1 1 1 1 1 1 1 1 1

Review & approval by local ECs** 0 0 0,0

Negotiating & signing study agreements 119 17 3,9 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

Obtaining import/export licenses, importation & distribution of IMP*** 28 4 0,9 1 1 1 1

SUMMARY

From submission till study approval 70 10 2,3 1 1 1 1 1 1 1 1 1 1

From submission till first site initiation 105 15 3,5 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

From start of work till first site initiation 140 20 4,6 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

* Submission is performed to NIP only (forwarded by NIP to the Central EC);

duration of review is irrelevant; done in parallel and within the timeframe of the RA review

** Local ECs are not involved into the study documents review and approval process

*** No importation license needed if imported from the EU

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CROMOS PHARMA CLINICAL TRIALS IN HUNGARY

Authorization timelines based on Cromos Pharma-managed trials (2018-2020):

• Initial submission preparation: average 30 calendar days after the receipt of core documents in English (incl. preparation of the submission package with customization and preparation of the Clinical Trial Application (CTA or Annex I) form, translations and customization of ICF, PIS, patient card, label, synopsis, patient diaries, and questionnaires/PROs).

• Authorization of an initial submission: average 59 calendar days.

• Authorization of substantial amendments: average 32 calendar days.

• Acknowledgements: average 5 calendar days.

The EU Clinical Trial Regulation (Regulation (EU) No 536/2014) is expected to come into effect at the end of 2021 andwill implement a VHP-like centralized authorization process for all EU member states. Hungary is in a good position toadapt to this new system having gained significant experience in the VHP process in recent years.

Additionalconsiderations forsponsors

Figure 8:Standard ContractingTimelines*

Private practices: 1-4 weeks

Regular hospitals: 4-8 weeks

University clinics: 4-6 weeks

*in case of no/minimal legal and budget questions

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As outlined above the authorization process and study start-up periods in Hungary are in general well defined, predictable and fast moving. Other considerations include the site contracting process and budgeting procedures. The investigator budget needs to be negotiated prior to the initial CTA submission since the budget split (hospital-investigator) is part of the submission package. If the contract negotiation is initiated during the NIPN evaluation, it can be signed-off during the authorization process, but the contract will be valid only upon study approval receipt. In order to mitigate the risk of delays arising from these factors Cromos Pharma advises sponsors to start contract negotiations as soon as possible after site selection. Both multiple contracts and single institutional contract models are used in Hungary, depending on the site's preferences and structure. Cromos Pharma has developed various contract templates for each case and we support sponsors with our local expertise in this area.

In Hungary the patient reimbursement and compensation is well regulated by local legislation. Due to taxation and data privacy concerns of the reimbursement process, specialized third party companies are regularly involved, who provide cost-effective and EU data protection (GDPR) compliant services. Cromos Pharma has established relationships with such vendors, to provide clear and easy reimbursement systems for the sponsor and the patients.

CROMOS PHARMA

In 2018, Cromos Pharma was contracted to rescue an ongoing phase I/II multi-country clinical trial in the field of neurology with recruitment difficulties. Hungaryand Russia were selected to support the recruitment and Hungarian sites demonstrated an exceptional contribution by providing more than 50% of enrolled subjects.

Following a quick start-up period (~4.5 months from start of submission preparation to first site initiation visit), the study accrual increased significantly meeting the enrollment goal ahead of the client's expected timelines.

Hungary has a longstanding reputation as an advantageous location for international clinical trials. It has a solid track record in producing high qualitydata delivered by a large pool of highly motivated, skilled and experienced clinical personnel. Hungary offers sponsors an ideal location for rapidrecruitment of patients from naïve populations in a range of therapeutic areas and a well-defined regulatory environment to provide competitive costs andtimelines from submission through initiation and management of studies.Cromos Pharma has an experienced team on the ground in Budapest who effectively manage regulatory and contracting processes to ensure that studiescan get up and running in the quickest time possible. We recruit highly educatedand experienced personnel to guarantee each trial managed by our team in Hungary produces the exceptional quality data and results.

For more information about running your clinical trial in Hungary pleasecontact:

Zsolt Kocsis Country Head HungaryOffice 102, Rubin Business Centre, 3 Dayka Gábor st, 11th district,Budapest 1118, Hungary +36 20 457 1688 [m] +36 1 808 8078 [o] zsolt.kocsis@cromospharma.com

Conclusion

CLINICAL TRIALS IN HUNGARY

The actual timelines for the study were the following:

Site selections:

November 2018

Regulatory

submission:

December 2018

Regulatory

approval:

February 2019

Site initiation

visits:

April 2019

First subject

inclusion:

April 2019

(one week

after SIV)

Enrollment

completed:

Dec 2019

(several months

ahead of the

planned timelines)

The involvement of Hungary as a location in this clinical trial made significant contributions to the successful enrollment of thestudy.

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Case Study

CROMOS PHARMA

Cromos Pharma provides tailored and effective clinical trial services tosupport the development of drugs that transform healthcare. It is aninternational CRO with over 15 years' experience in offering fullyintegrated services and delivering all aspects of clinical trials in allclinical phases and a range of therapeutic areas. Cromos Pharmadelivers rapid recruitment and excellent patient retention as well as expert study design and management. Cromos Pharma has strongregional experience in Central and Eastern Europe. Its US base isin Portland, Oregon with additional operations in South Florida andits European HQ is situated in Dublin, Ireland. Find out more by visiting www.cromospharma.com.

About Cromos Pharma

References

CLINICAL TRIALS IN HUNGARY

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