MPTX 519 Class 3

Bridging Concept

"Bridging Data" = "Korean Data""Bridging Study" = "A trial conducted for the Korean People " Ethnic Factors(Ethnic differences) Intrinsic factor (genetic) Extrinsic factor (culture, environment) evaluation: ethnic sensitivity, foreign clinical data, bridging data

Japanese Submission Strategy

"Typical" Submission Strategy 1.US First 2.EU First 3.US/EU Simultaneous

Service Order 69/2019

"reliance" Simplification of the evaluation of quality aspects based on assessments carried out by regulators of the ICH founding members(US, Europe, Japan): -the DDCM contains at least one Phase III clinical trial, referring to experimental drugs that have all stages of manufacture and have already started the clinical trial in at least one ICH founding member territory; -the investigational drug is identical, without any change in quality aspects, to that from the clinical trial carried out in at least one ICH founding member territory; and-the manufacture of the investigational drug is in accordance with ICH guidelines

UKRAINE

. State medical institutions are moving to a new model of financing by the National Health Service of Ukraine (NHSU), on "money follows patient" principle. A list of medical services that are provided free of charge to the patient under the medical guarantee program is approved. A reimbursement program for medicines has been introduced. The total volume of the Ukrainian pharmaceutical market, including retail and hospital segments, is about 3.7 billion Euro per year. The pharmaceutical market of Ukraine is characterized by strong positions of national manufacturers. State registration is required for import and sale of medicinal products in Ukraine. Since 2005, Ukraine has introduced legislation in the field of medicinal products registration, based on EU legislation. At present, requirements to registration and circulation of medicines in Ukraine are similar to the EU, the procedure is transparent and predictable for international manufacturers.

Medical Device Submission in Japan

1. determine classification ( class 1 general, class 2 specified controlled, class 2 controlled, class 3 highly controlled, class 4 highly controlled.) 2. appoint marketing authorization holder (MAH) to manage your device registration in japan 3. prepare and submit application for foreign manufacturer accreditation 4. implement QMS that complies with PAL and MHLW 5a. class1: submit premarket submission to pharma and medical device agency (PMDA). 5b. class 2 specified: submit pre market certification application to a registered certified body (RCB) 5c. class 2 controlled, class 3 and class 4: pre market approval application and registration dossier in summary technical document (STED) format to PMDA. 6.a some class 1 devices require QMS conformity assessment 6b. QMS audit by RCB 6c. QMS audit by PMDA 7a. self declaration no certificate by PMDA 7b. Pre market certificate by RCB 7c. premarket approval by MHLW (does not expire) 8. begin marketing in japan ** all premarket documentation in japanese

Medical Device Submission in China

1. determine classification (class 1 routine mgmt, 2 controlled, 3 implanted) 2. appoint legal agent and after sales agent located in china to coordinate CFDA device registration 3. if located outside of china demonstrate proof of home country approval using a Certificate of free sale (CFS) or certificate to foreign gov 4. foreign companies submit "proof of qualification of the manufacturer" 5. prepare product standard including technical info. class 2 and 3 include details of additional testing to be conducted. 6. class 2 and 3: submit device to CFDA for testing. pay testing fee 7. Class 2 and 3: clinical trial conducted in china maybe required for some devices. 8. prepare Chinese registration dossier 9. CFDA issues IMDRC. valid for 5 years

Medical Device Submission in Korea

1. determine device classification (1,2,3,4) 2. if you have no local office in SK than u appoint a Korea License Holder to manage the device registration with the MFDS 3a. class 1: prepare premarket notification including basic device info (in korean) 3b. class 2,3,4: prepare general technical file or safety and effectiveness review (SER). include clinical data. may accept clinical data from other markets 4b. submit device for testing to independent lab or submit existing equivalent testing results. 5a. submit pre market notification application to MFDS 5b. get general technical file or SER technical file reviews by the MFDS or a third party 6b. your company and korea license holder must comply with "korea good manufacturing practice (KGMP)" valid for 3 years and includes an onsite audit for foreign mfg facilities. 7b. premarket approval/notification licence by MFDS and does not expire 8. KLH assists with clearing products through south korea customs PMA/notification license and KGMP certification must be present during importation

CR MARKETING AUTHORIZATION

Any proprietary medicinal product is subject to marketing authorisation, which includes an assessment of a dossier with the information on the safety, efficacy, and quality of the product as well as the indications, contraindications, dosage, general classification for supply, and the package leaflet for the patient and proposed texts on the labelling.There are three types of registrations (marketing authorizations):(i) National Registration,(ii)Mutual Recognition Procedure and(iii)Decentralized Procedure. National Registration authorizes the marketing of the product solely in the Czech Republic. The other two authorization types allow for the marketing of the product in other EEA member states as well. In addition, a Centralized Procedure by the European Medicines Agency can also be used; it authorizes the product for all EEA member states. In a limited number of exceptions (drugs prepared in a pharmacy based on a prescription for an individual patient, drugs for research and development, etc.) the requirement for marketing authorization does not apply.Manufacturers and distributors of drugs are required to obtain licenses from the State Institute for Drug Control. A manufacturing license is also required to import drugs from non-EEA states. Distribution licenses issued by EEA member states are recognized in the Czech Republic provided that the distributor submits a notification to the State Institute for Drug Control.Clinical trial authorization from the State Institute for Drug Control is needed to conduct testing on drugs that have not yet been registered. To test drugs that have already been registered, it is sufficient to notify the State Institute for Drug Control of the clinical trial.

Mexico

Article 4 of the Constitution has guaranteed the right to health protection since 1983, while Article 1 recognizes the human rights -including health -declared by the International Covenant on Economic, Social and Cultural rights. Health coverage is achieved through a mix of social insurance schemes, a voluntary public program for the uninsured, and private insurance, which collectively cover about 85% of the Mexican population. The social insurance system is dominated by two national institutions covering formal sector salaried employees and funded by the federal government, employers and employees. Other federal-level schemes cover the army and navy, while state-based schemes cover state bureaucrats.

Romanian Regulators

Medicinal products are regulated in Romania by the Ministry of Health, through the National Agency for Medicines and Medical Devices. The ministry is responsible for setting national priorities in public healthcare and coordinating the allocation of funds, the agency is in charge of regulating medicines and market supervision. Its powers range from the issuance of marketing authorizations, the supervision of clinical studies and the assessment and approval of laboratories to market supervision. However, certain authorizations (eg, for the manufacture of psychoactive substances) also require approval from the ministry. There are no restrictions on the sales and imports of new and refurbished medical devices in Romania. The medical equipment must meet the European certification requirements and have the CE mark.

Brazilian Clean Companies (BCC) Act

Brazil introduced the Brazilian Clean Companies (BCC) Act in 2014. It prohibits companies and their employees from committing various acts associated with bribery anywhere in the world.•The BCC Act sets out the offenses of giving, promising, or offering a bribe. •Unlike the FCPA and the UK Bribery Act, the Brazilian Clean Companies Act does not prohibit receiving a bribe.•Under the BCC Act, companies are held liable for the actions of their employees.

Brazil Healthcare

Brazil's decentralized, universal public health system is funded with tax revenues and contributions from federal, state, and municipal governments. The administration and delivery of care are handled by municipalities or states. All residents and visitors, including undocumented individuals, can access free, comprehensive services, including primary, outpatient specialty, mental health, and hospital care, as well as prescription drug coverage. No application process is necessary. There is no cost-sharing for health care services. Nearly 25 percent of Brazilians, mostly middle-and higher-income residents, have private health insurance to circumvent bottlenecks in accessing care. Private health insurance costs, as well as health-related purchases, qualify as tax deductions.

BULGARIA - CLINICAL TRIALS HUB

Bulgaria ranks top 20 in the world in clinical trials performed, valued approximately $330 Million. All major CROs are present in market collaborating with active Bulgarian Association of Clinical Research (BACR) that is advocating for high standard in conducting clinical trials and adherence to the requirements of the Bulgarian and international standards. Strengths ■ Stable and predictable regulatory environment ensured by the country's EU membership and the harmonization of the national legislation with the EU ■ Highly efficient patient recruitment is one of the strongest positive descriptors of the local clinical trials sector - high level of treatment naïve patients as well as low study drop outs ■ Competent medical personnel (mostly from academia and large hospital systems) guarantees the quality of the conducted trials ■ High quality of data ■ Relatively favorable cost

Central and Eastern Europe (CEE)

CEE is a key emerging region for the multinational pharma companies expansion since the pharmaceutical industry is experiencing a rapid and significant growth in Central and Eastern EuropeHighly diverse market - economic development, the healthcare landscape, internet usage, network coverage, local regulations and restricted access to certain networks, literacy, language, cultural reference and many more.

COFEPRIS

COFEPRIS is a deconcentrated MoHbody charged with sanitary regulation under the scope and limitations outlined by the General Health Law. It has direct control over all public and private health establishments with the important exception of those operated by social insurance institutions. COFEPRIS is also tasked with undertaking health risk assessments and for the development of national policy against health risks. Further, it is responsible for enforcing these policies in health establishments (excluding social insurance establishments) and for regulating medicines and other inputs, organs and tissues, food and drinks, cosmetic products, cleaning products, tobacco, pesticides, toxic substances, biotechnological products, food supplements, and environmental control, occupational health and basic sanitation. COFEPRIS is also charged with formulating and enforcing sanitary regulation of goods, infrastructure and services, with the exception of social insurance institution health establishments and the procurement and processing of organs, tissues and cells, which are the province of specialized agencies.

EAEU REGISTRATION CERTIFICATE

The validity period of a registration certificate for the first time registered medicinal product in the reference state is 5 years. After renewal, the registration certificate is issued without expiry. A registration certificate shall consist of: • The certificate itself; • Normative Document (ND); • Summary of Product's Characteristics (SmPC); • Instructions for use / Package insert / Leaflet; • Package labeling artworks. According to the requirements of the EAEU foreign applicant must have a qualified person responsible for pharmacovigilance in each member state and provide this information in the registration dossier

Pharmaceutical regulation in Brazil

Categories of drugs registered in Brazil: "New" drugs (innovative and others) •Synthetic, semi-synthetic and radio pharmaceuticals •Biologicals •Herbal medicines "Copies" (Synthetic and semi-synthetic drugs) •Generic •Similar ("branded generic") Bio similars(comparable biologics) Focus on prioritizing drug registrations relevant to public health • Pediatric population; • Neglected diseases; • Emerging or re-emerging diseases; • PublicHealth Emergencies; • Serious debilitating conditions; • Vaccines to be incorporated in the National Immunization Program; • First 3 new generics for a given drug.

Medical devices regulation in Brazil

Categories-In vitro diagnosis-Orthopedic implants-Medical equipment-Materials used in health Risk classification I (low risk) to IV (high risk)-Classes I and II subject to notification (cadastro- class II subject to review)-Classes III andIV subject to registration Risk classification based on he intended use, the risk to the patient, operator and/or to any other consumer, and if the product is active or not(operation depends on an electric power source) Timeline: Registration of equipment (also for families)= 250 days Registration of materials (also for families)= 320 days IVD families notification= 150 days IVD families registration= 250 days Class I notification=30 days

Regulatory Authorities and Classification Schemes

China RA- National medicinal products admin Japan Ra- Pharmaceuticals and medical device agency Korean RA- ministry of food and drug safety

Shonin Approval

Class II and III devices without a specific certification standard are subject to the pre-market approval process. This also applies to all Class IV devices. In this case your MAH will file a pre-market approval application with the PMDA and ultimately obtain approval from the MHLW.

Biologics (Service Order n°45/2018)

Clinical and Technical evaluation Companies must submit all documents according to regulations in place Detailed assessment report issued by FDA and EMA (centralized procedure) Leaflet(same indication and posology to FDA and/or EMA) Stability studies, transport qualification, summaries of quality, efficacy and safety Questions issued byFDA and/orEMA with their answers and post-approval commitments with the FDA and/or EMA must be provided

Clinical trials regulation in Brazil

Clinical trial can only commence after the sponsor, the designated contract research organization(CRO), or the sponsor-investigator receives clinical trial application(Drug Clinical Development Dossier-DDCM) approval from ANVISA. •The principal investigator(PI) must also obtain approval from institutional ethics committee(CEP). •Some applications require an additional review and approval by the National Research Ethics Commission(CONEP). •The sponsor or the designated CRO is required to obtain an import license from ANVISA for the shipment of the investigational product to be used in the trial. Some of the current challenges: -Gaps in the legal and regulatory framework that define clear timelines and operation procedures for the import of experimental drugs -Post-trial access policies not sufficiently clear to allow for proper planning and that differ from international standards

Korean Healthcare system

Compulsory National Health Insurance (NHI) System: -National single payer system -Has covered entire population from 1989 -Government administers funds, coverage, coding, payment and pricing

Ukraine New Registration

Depending on the type of medicinal product, indications for use, market authorization status and other characteristics, various types of Applications and different expert evaluation periods are used. Although Ukraine follows the harmonization procedure with the EU, it still has own independent legislation and expert evaluation procedure. For each type of a medicine, the legislation stipulates certain requirements for the content of the registration dossier, the timing of the expert evaluation and other issues. Registration procedure begins with the submission of the Application form to the single-window system of the Ministry of Health, and ends with the signing of the Order of the Ministry of Health and receiving of the hard original Marketing Authorization Certificate. Both MAH and competent authority must follow strict timelines as soon as the Application form is submitted. If the MAH does not perform a specific action, or submits the necessary documents not in the full amount, or the documentation is filled incorrectly, then the registration procedure may be canceled, and all paid state fees will not be returned. Registration includes several payments to the accounts of state bodies, including: • payment of the state fee for a medicinal product registration to the account of the State Treasury of Ukraine; • payment of the cost of expert works to the account of the State Expert Center; • (if necessary) payment of the cost of laboratory quality control of a medicinal product samples to the account of an authorized laboratory.

Ukraine Duration of New Registration

Duration of expert evaluation of the registration depends on the type of Applications and chosen registration route: •210 business days for full Application medical immunobiological products and biosimilars •90 business days for other types of medicines (generics, etc) •45 working days for orphan products and treatments of socially dangerous diseases (HIV, viral hepatitis, tuberculosis, cancer etc.); •10 business days for medicines registered by the competent authorities of the USA, Switzerland, Japan, Australia, Canada as well as by the competent authority of the EU according to a centralized procedure; •5 business days for medicinal products subject to purchase by specialized international organizations. The indicated timelines are duration of expert evaluation of materials, and do not include: •period of the initial assessment of the Application and registration forms; •period for payment of state fees and receiving payment confirmation; •period for answers on the deficiencies; •time needed for import of samples and standards, labs (if required); •finalizing actions after expert evaluation (verification/proofreading of draft of registration certificate and its annexes); •signing the Order of MoH on the registration of a medicinal product. The realistic timelines of the registration procedure includes the expert evaluation period, plus several months for the mentioned actions

Russian Medical Devices

Fast growing market Heavily dependent on imports - about 80% of the total market. Foreign-made high-end medical equipment, sophisticated medical devices and many medical products and supplies in the majority of cases do not have national analogs. US is the second leading supplier of medical equipment. Registration of a medical device is a two stage process: STAGE 1 - Determining the risk class and the type of medical device in accordance with the nomenclature classification - this is one of the main criteria affecting the content of the registration dossier documents. The EAEU rules require the inclusion of a risk analysis file for all products, including those of the 1st risk class. Compliance of the list of documents in the registration dossier to the required minimum. STAGE 2 - registration and examination of a medical device

Generic pricing (SK)

First year after patent expiration: 30% reduction in the price of originator, 85% of which (59.5%) is set for the price of generics-Second year after patent expiration: 53.5% of originator price (10% reduction from the year 1) for all generic medicines, regardless of the order of entry

Ukraine REGISTRATION PROCESS

For import and sale of medicines on the territory of Ukraine it is required to obtain the state registration and fulfill specific requirements regarding quality and safety. The general requirements for documentation and expert assessment procedures are similar to the EU, but there are many national features that significantly affect all regulatory processes. The definition of "medicinal product" includes finished medicinal and immuno-biological products as well as Active Pharmaceutical Ingredients (APIs). Currently there are three different registration procedures for medicines: • The general requirements for the registration of medicines, including simplified (accelerated) registration of products for the treatment of socially dangerous diseases (Order No. 426); • A simplified registration procedure (so-called "recognition") for medicines registered by the competent authorities of the USA, Switzerland, Japan, Australia, Canada, and medicinal products registered under a centralized procedure by the competent authority of the EU (Order No. 1245); • The registration of medicinal products that are subject to purchase by specialized international organizations (so-called "authentication") (Order No. 721)

CEE DOMINANCE OF GENERIC MEDICINES

Generic drugs have been the strongest segment of national pharma sectors historically. Generic drugs are viewed as the only source of hope in the current economic environment and appear to be the main beneficiary of reduced purchasing power of consumers and government spending, as well as government import substitution and pharma industrial policies. Generics are and will continue to be the key growth segment of local pharma markets. Building new facilities to produce generic drugs and biosimilars attracts most of investment.

ROMANIA

Healthcare in Romania is dominated by the public sector, which owns most of the hospitals and provides national health insurance to almost all Romanian citizens. The drug pricing environment pose considerable risks for drug makers and limiting the market attractiveness. Access to medicines is poor, with a severe lack of public healthcare financing shifting the burden of costs onto patients.

BULGARIA

In per capita terms, the Bulgarian pharma market is one of the smallest in EE.All Bulgarian pharmaceutical companies manufacture generics - cannot afford development of the innovative drugs. The Bulgarian Ministry of Health (MoH) is responsible for the overall supervision of the healthcare system, drafting health legislation, developing national health policy and implementing programs aimed at improving the health of the population, budget and financial control.

CEE LEGISLATION

In the CEE countries members of EU laws and procedures for pharmaceutical regulation have been updated in line with those already established in the EU, introducing procedures for mutual recognition of licensing, pharmacovigilance, and improved exchanges of information among national regulatory agencies. All drugs on the market must conform to EU requirements on good manufacturing practice and drug information. In most CE countries Pharmaceutical Law relies on all the principles of Directive 2001/83/EC, which are further detailed in Regulations approved through Minister of Health Services.

Trends in New Legislation

Increased Transparency: New bill introduced in Ireland that would make the country's transparency reporting obligations for payments made to HCPs and HCOs legally required, and would increase complexity and level of detail required:• New legislation in Germany, France and Catalonia in Spain make transparency of lobbying activities required by law. • Transparency Register of EU lobbying activity strengthened in 2021 by European Parliament bringing requirement for greater transparency on lobbying activities. Data Protection Laws: • China - Personal Information Protection Law• Makes it harder to transfer individual personal data outside of China especially to other enforcement agencies• Australian review of Data Protection Laws• Brazil - New data privacy laws in force• Singapore - updated it data privacy laws Greater focus on compliance programs: • CPIA - Chinese Pharmaceutical Industry Association release the "Compliance Guidelines" for Pharmaceutical companies operating in China - • Sapin II in France -has been reviewed after 5 years in force and recommendations made for strengthening France's anti corruption system • DOJ in US stress the importance of strong compliance program which are not just paper based but where the compliance function is embedded in the business.

POLAND CLINICAL TRIAL ADVANTAGES

Large population of patients in comparison with neighboring countries.•High motivation for patients to be involved in clinical trials due to access to innovative treatmentsSpecialized medical centers - academia and large hospital systems, clustered around main cities (e.g. Warszawa, Wrocław, Kraków, Poznań, Szczecin, Gdańsk, Lublin, Bydgoszcz, Rzeszów). •These centers have well-qualified specialists and provide access to patients in all therapeutic areas, particularly oncology, rheumatology, cardiology, and pediatrics.Highly interested, qualified and motivated investigators and site staff - possibility to test new treatment standards, exchange information with foreign experts, financial benefits, and an opportunity to have co-authored publications in respected professional journals.High quality of clinical research data - over 25 years of experience No Polish investigator is present on the FDA's list of disqualified investigators.•A strategic advantage - much lower cost of conducting clinical trials (nearly 30% less) than in the U.S. - high rate of patient recruitment and retention along with excellent quality of data, leading to a reduced number of rejected clinical trial recordings and time-efficient proceedings.

Medical devices regulation in Mexico

Marketing authorization requirements for medical devices depend on the level of risk involved in their use, according to a three fold classification: •ClassI: products that are well known in medical practice and for which safety and efficacy have been proven. They are not usually introduced into a patient's body; •ClassII: products that are well known in medical practice but may have material or strength modifications. If introduced, they remain in a patient's body for less than 30 days; •ClassIII: products either recently accepted in medical practice or that remain in a patient's body for more than 30 days. Categories •Medical equipment: Appliances, accessories and instruments for medical use; •Prosthetics, orthotics and functional aids; •Diagnostic agents; •Dental supplies; •Surgical materials; •HygieneDevice

MEDICAL DEVICE CLASSIFICATION IN EAEU

Medical device classification differs significantly from the EU classification regarding the first risk class. EU has a more detailed categorization of low-risk medical devices, while in the EAEU medical devices are generalized The average terms are as follows: • Class 1 - 9-10 months; • Classes 2a and 2b - 10-12 months; • Class 3 - 12-15 months.

Clinical trials regulation in Mexico

Mexico has a decentralized registration process forResearch Ethics Committees (REC)operating through theNational Bioethics Commission. •REC -Research Ethics Committee and RC -Research Committees approval is required for each trial site where a study is being conducted, and when applicable,Biosafety Committees (BC)approval is required as well •Research Committees (RCs)andBiosafety Committees (BC)within each health institution must register with theFederal Commission for the Protection Against Sanitary Risks (COFEPRIS)where the study is being conducted •REC must approve the informed consent document and evaluates the technical quality and scientific merit of the proposed research. •The BC is responsible for determining and regulating the use of ionizing radiation or genetic engineering techniques within the health institution (not always necessary) •The REC and COFEPRIS reviews may not be conducted in parallel.

Mexico Regulatory Approval

Mexico offers a pre-assessment evaluation that helps to facilitate COFEPRIS's review. Rather than submitting the application directly, the applicant may first choose to obtain a pre-assessment evaluation of the application through an Enabled Pre-Assessment Support Unit (Unidad Habilitada de Apoyoal Predictamen-UHAP).

UKRAINE - COMPETENT AUTHORITIES

Ministry of Health of Ukraine The central executive body that implements public health policy Ministry of Economic Development, Trade and Agriculture The central authority responsible for technical regulation State Expert Center of the Ministry of Health The competent authority responsible for conducting expert work at the registration of medicinal products, and for pharmacovigilance State Administration of Ukraine on medical products and control of narcotics The competent authority responsible for the quality control of medicinal products and medical devices

REGISTRATION OF MEDICINES IN RUSSIA

Necessary documentation for the submission to MoH: 1) Application form with the attached documents: • legalized Power of Attorney from the applicant to the representative; • legalized copies of the Manufacturer's Authorizations for manufacturing sites from competent authorities of countries-manufacturers; • legalized copies of GMP Certificates for all manufacturing sites issued by the competent Authorities of countries-manufacturers; • certified copies of Conclusions of Compliance to the GMP requirements for all manufacturing sites issued by one of the competent Authorities of the member state of the Union (if available) or certified copies of the Eurasian GMP Certificates for all manufacturing sites issued by one of the competent Authorities of the member state of the EAEU (the procedure of issuance of these documents may be conducted in parallel to the procedure of registration after submitting the Application for registration); • legalized copy of registration certificate from authorized body of applicant and/or manufacturer's country or justification of its absence; • certified list of the countries where the medicinal product is registered/re-registered/cancelled with indication of dates, numbers and validity of the registration certificates/dates and reasons of cancelling; • proposed samples for the market of the Russian Federation; • legalized copy of Certificate of Pharmaceutical Product or Free Sale Certificate (if available), etc. 2) Registration dossier in the format of the common technical document (CTD); 3) Samples of medicinal product and standard samples. The Ministry may request additional information and/or documents. This is individual for each instance. DURATION OF REGISTRATION PROCESS Registration should be conducted within 210 days without considering the time required for preparation of responses to remarks. In reality depending to the requests from MoH registration may last 12-18 months without time required for responses to remarks

Approval Time for NDA

New chemical entity (working days) •Required for safety & efficacy evaluation : 70 days •Required for Specification & test method : 55 days •Required for Pharmaceutical equivalance: 55 days •Required for GMP : Drug product 90 days, Drug substance 60 days •Required for DMF evaluation : 120 days MFDS can request supplement data only twice during one review cycle. •Sponsor response time •The First request : 60 calendar days •The Second request : 10 working days •Sponsor can extend their response time. Pharmaceutical Affairs Consultation

POLAND REGULATORY AUTHORITIES

Office for Registration of Medicinal Products, Medical Devices and Biocidal Products (URPL)- central government administrative authority responsible for the marketing authorization of medicinal and biological products, medical devices, clinical trials and cooperation with EU. Main Pharmaceutical Inspectorate (GIF) -supervises the conditions for the manufacture and import of medicinal products, medical devices, veterinary medicinal products and active substances as well compliance with pharmaceutical law and cooperates with the competent Pharmaceutical Inspections of third countries. National Health Fund (NFZ) -Is financed by citizens' compulsory health insurance payments and is responsible for providing health services and reimbursing the cost of medicines. The President of the NFZ is appointed by the Prime Minister at the request of Minister of Health ,which also supervises the NFZ. There is an NFZ branch in each of the 16 provinces of Poland. The Ministry of Health.The Ministry of Health is responsible for reimbursement of medical products, medical devices and food stuffs for particular nutritional uses, the performance of medical professions, implementation of health programs, organization and supervision of the State Medical Rescue service (ambulance system) and sanatorium therapy (therapy in facilities for long-term illnesses).

SLOVAKIA

One of the most developed device and pharma markets in the CEE region. Compliant with international requirements for approvals and intellectual property protection. The country has a long tradition of medical device manufacturing, but it is increasingly difficult for domestic production to compete with Western quality and innovative imports.Slovakia is compliant with international requirements for approvals as well as intellectual property protection.A foreign producer that would like to export medical devices into Slovakia must first establish a contract with a local importer, which can help the company fulfill regulations such as the CE mark, Declaration of Conformity, translation of directions and manuals into Slovak, and a guarantee that the product has been approved by the Ministry of Health.

National Health Insurance Service (NHIS)

Part of the ministry of health and welfare ▪Contribution Collection ▪Provider Payment ▪Negotiation for Fee schedule with providers

Health Insurance Review and Assessment (HIRA)

Part of the ministry of health and welfare ▪Review Claims ▪Quality Assessment ▪Benefit Management

regulatory hierarchy of drug approval

Pharmaceutical affairs act (1953) regulation on safety of pharmaceuticals regulation on pharmaceutical approvals, notification and review korea pharmacopeia guidline for industry and reviewer * PICS joined 2014 and ICH joined 2016* Medical device act 2004 cosmetics act 2000

PHARMACEUTICALS HUB IN POLAND

Pharmaceutical exports, especially to WE, have been strong and on the rise. Opportunities for new medicine development, infrastructure and entry/ expansion. Established solid reputation and the fundamentals in the manufacture and marketing of pharmaceutical products. Strengths include generic prescription drugs (both branded and non branded) and branded over-the-counter (OTC) products. Several modern manufacturing plants are operating in the sector, with skilled labor that is competitive with specialists from other countries and are situated in attractive locations to serve Western, Central, and Eastern European geographies. Since early 1990s Poland was regarded as one of the largest clinical trials markets in CEE

POLAND

Poland is an attractive market for the pharmaceutical industry because country is a member of the European Union, which ensures stability and a predictable regulatory environment. Pharma market size - $11 billion Both pharmaceutical sales and consumption are on rise and the outlook to 2025 remains robust driven by strong pharmaceutical market fundamentals. The market is the largest in CE and the 6th largest in the EU.

EE - MARKET OVERVIEW AND SEGMENTATION

Prescription drugs account for up to 68% of sales in value terms depending on the market. Patented drugs claim a usually low share of sales (11%-29%) as they are most expensive. The drug market is predominately generic (about 70%), that provides a less expensive alternative to the state healthcare programs. OTC drugs are traditionally strong because of more affordable prices, better customer awareness and tendency for self-treatment (32%-41% of sales).

Privacy

• Regional differences in treatment of Privacy-US: HIPAA -patient privacy; State Consumer Privacy Laws-EU: GDPR - all EU citizens • Affects collection, processing, storage, and reporting of data• Most pharma/device companies require Data Privacy Officer

Corruption Red Flags

Requests for Unusual contract terms or payment arrangements, such as requests for payment in cash, bearer instruments , "upfront payments," or excessive or unusually high compensation, commission rate, or fees.Requests for payments in third countries or to third parties.The role or function of an agent, consultant or middleman is not clear.Lack of adequate facilities or qualified staff.Use of shell or holding companies.Lack of experience or "track record" with the product, field or industry.Allegations related to integrity or reputation for impropriety or unethical or illegal conduct; Violations of local law.Requests to perform services without a written agreement.Close social or business relationships with government officials.Entertaining government Officials or their family membersRecommendation by a government official or government customer to use a particular representative or consultantMisrepresentations or inconsistencies in the application or the due diligence process.Involvement of a high-risk country.

Small Molecules (Service Order n°70/2019)

Restricted to the clinical evaluation Detailed assessment report issued by FDA & EMA (centralized procedure), after their approval Leaflet (same indication and posology to FDA and/or EMA)

EASTERN EUROPE

Russia, Ukraine, and Belarus have inherited their pharma sectors from the Soviet Union. EE has historically been an importer of drugs, predominantly from the Central and Western Europe.Each former republic had a different economy structure, but pharmaceutical sector is fairly well-represented in all of them.Over the last two decades, Russia's pharma market was among 10 world's largest pharma markets.Strong global representation with first COVID-19 vaccine Sputnik-V regulatory approval Russia and Belarus are part of EAEU

RUSSIAN PHARMACEUTICAL MARKET CHALLENGES/OPPORTUNITIES

Russians' preference for western quality and brands, aging population and untapped growth potential, positioned it as one of the most attractive emerging markets for international pharma manufacturers. The pharmaceutical sector is one of the priorities for the Russian government. Unfortunately, a dysfunctional health care system and political issues frustrate big drug makers In the short- to medium-term, the generic drugs market will continue its growth due to incentives from the Russian government, as well as population's preference for cheaper drugs Two major problems of the Russian pharmaceutical industry: 1. Short-term - Inability to provide the population with a standard range of state-of-the-art treatments, produced entirely in Russia. 2. Long-term - Low-level innovation and technology used to design and manufacture drugs. This common problem of the Russian economy is especially crucial for the pharmaceutical industry. However, pharmaceutical market has a great potential for investments and launches of new products Driven by import growth; a heavy reliance on imports has resulted from the lack of locally-manufactured innovative pharmaceuticals.

Foreign Drug Requirements in Russia

Since 01.09.2010 clinical trials in Russia for all drugs at the registration stage are mandatory. One exception - if similar product has been registered in Russia for over 20 years and it is impossible to conduct study of bio equivalence. A clinical trial conducted on an international basis will be acceptable if it was conducted with the participation of Russian patients. There is a provision that clinical trials conducted outside Russia will be accepted on the basis of mutuality in accordance with international agreements with RF, but no such agreements exist at the moment. Preclinical studies do not have to be conducted in RF, it is enough to provide own reports (not a literature review) of studies outside Russia

SLOVAKIA - REGISTRATION

Slovakia's medical device manufacturing sector has a long history, particularly in the area of orthopedic and dental equipment. At present, Slovak companies largely produce single-use medical equipment, most of which (except orthotics) is exported to markets such as the Czech Republic and other Eastern European counties. The Slovak State Institute for Drug Control is the main entity that regulates medicines, biologists and devices in the county. Potential registration specifics beyond European Union registration regulations and laws can be found on this website.

EAEU REGISTRATION BY THE DECENTRALIZED PROCEDURE (PARALLEL PROCEDURE)

This procedure allows submitting a medicinal product for registration simultaneously in the several EAEU member states chosen by the Applicant. The country to which the Application and the full registration dossier are submitted is referred to as the "reference" country. The regulatory authority of this country is primarily responsible for the review of the registration dossier, making a decision on approval or refusal of registration. Other countries, also selected by the Applicant, are referred to as "countries of recognition". The registration dossier is submitted to the reference country in full (Modules 1-5 of the EAEU CTD format), taking into account the type of medicine and the type of Application. For each selected country of recognition, the Applicant (MAH) additionally submits Module 1 with national documentation (instructions, layouts, brief description of product properties), according to the language requirements

EAEU REGISTRATION BY MUTUAL RECOGNITION PROCEDURE (sequential procedure)

Stage I: registration of the medicinal product in the reference country. The Applicant (MAH) independently selects the EAEU Member State for registration according to the procedure approved by the Decision of the Council of the EAEU of November 3, 2016, No. 78 A full registration dossier is submitted for registration, according to the type of Application and the specifics of the medicinal product, in the format of the Common Technical Document (CTD), in 5 modules. During the registration process, an inspection may be required. The duration of the procedure should not exceed 210 calendar days, not including the clock stops required to respond to comments. Stage II: Registration through the mutual recognition procedure in other countries. The Applicant (MAH) chooses one or several countries of recognition. For mutual recognition, Module 1, as well as SmPC, instructions and labeling in the language of the recognizing member states should be submitted. The duration should not exceed 90 calendar days, not including the clock stops to respond to comments. A consistent registration procedure allows the Applicant to focus on the registration in the reference country, then expand the list of countries through a fast-track recognition procedure.

ANVISA

The Brazilian Health Regulatory Agency (ANVISA) is responsible for regulating, monitoring and inspecting(surveillance) all the activity related to products and services subject to the Brazilian sanitary fields. ANVISA is one of the Agencies subordinated to the Brazilian Ministry of Health, but administratively independent. The institutional purpose of ANVISA. is to promote the health protection of the population by regulating all actions related. to the products and services that affect the public health. ANVISA's administration is subject to a Management Contract. This type of Contract is predicted in the Constitution and, in the case of ANVISA, it is agreed between the Agency's President and the Ministry of Health. The objective is to establish performance goals to allow the evaluation of the Agency's administrative and technical performance. The evaluation occurs based on a work plan agreed between the parties

Ukraine Registration Dossier

The CTD format has been introduced since 2005 and is still submitted in paper form. In some cases parts of the dossier are allowed to be submitted in electronic form. New registration documentation for the standard procedure includes: • National Application form; • Registration form (legal and administrative documentation amending the Application); • Registration dossier in CTD format consisting of 5 Modules (Modules 2-5 comply with ICH CTD requirements); • Translation of specific parts of the registration dossier into Ukrainian or Russian; • Specific national documents: • expert reports on non-clinical and clinical data, prepared according to national forms and recommendations; • MQC - methods for quality control of a medicinal product • instructions for use - information on the use of a medicinal product (leaflet) • text for the package labeling - a description of the information printed on the primary and secondary packaging. The following documents are submitted in the Ukrainian language: • Application form; • all documents from Registration form; • Module 1 (translation); • parts of Module 2, in required; • parts of Module 3.2.P;

CZECH REPUBLIC

The Czech Republic has a high standard of healthcare, is one of CEE's most high-performing healthcare systems, and one of the region's leading economies. Several multinational companies are setting up regional hubs and service centers in Prague, as well as centers of excellence for research and clinical trials in key therapeutic areas such as oncology. The main authorities with jurisdiction over drugs, biologicals, and medical devices in the Czech Republic are the Ministry of Health and the State Institute for Drug Control , which regulates every aspect of business, from pricing to packaging, from clinical trials to advertising. High degree of foreign ownership - one of the most attractive markets in the CE for investment by multinational drug makers. Extremely strict and complex regulatory environment along with the State regulation of pharmaceutical prices, resulting in limited margins. Increasing demand for healthcare and burden of disease, a strong economic outlook will contribute to healthy growth in the short - and long-term.

REGISTRATION PROCEDURE

The Holder of the registration certificate (MAH) can be any legal entity, a resident or non-resident of an EAEU Member State. The legislation defines several types of procedures for registering a medicinal product in the EAEU: Procedure for bringing the registration dossier to EAEU requirements; Registration by mutual recognition procedure (sequential procedure); Registration through a decentralized procedure (parallel procedure). Despite similar terminology - registration procedures in the EAEU differ significantly from procedures in the European Union. Regardless of the procedure chosen, the competent authority of a member state is involved in the assessment of a medicinal product for the purpose of registration in a certain country. The competent authority evaluates the registration materials uploaded to the common electronic database and during the registration process has the right to ask questions (give comments) as well as to refuse to register a medicine in the member state.

The New Molecules Committee

The New Molecules Committee New drugs or new indication registration are considered "new molecules", therefore require a pre-submission meeting before the New Molecules Committee (NMC) from COFEPRIS. The NMC can issue an approval (positive opinion) or a rejection (negative opinion). What is in the scope of the NMC: •An active ingredient or drug not approved world-wide (new molecular entity) •An active ingredient or drug already available in other countries but with limited clinical experience or disputed information, without approval in Mexico •A drug which is a non-marketed combination of two or more active ingredients •An active ingredient or drug already available in the market, but to be marketed for a new therapeutic indication. There was a restructuring of the Committee in 2021 to allow for: •Prioritization for product related to: COVID-19; high impact health products; orphan drugs. •Greater transparency: the applicant is informed of the day and time for the session; publication of technical opinion in real time. •Structural simplification: weekly ordinary sessions; extraordinary sessions in case of emergency use, virtual sessions; simplification of the regulation; streamlining the process for drugs approved by other recognized regulatory agencies; the subcommittees and the Committee meet at the same time to expedite procedures. Requirements for a meeting: Scientific technical information - administrative documentation; summaries; quality; preclinical; clinical

SINGLE REGISTRATION AUTHORITY

The drug market in the EAEU has common regulations, procedures, and requirements, but today there is no single registration authority for all the states that are members of the Union. To bring drugs to the EAEU markets, the manufacturer must either consistently carry out the examination and registration procedure separately for all five member countries or send the documents to the registration authority of one of the member states, and then apply for their recognition in other member states. The approvals procedure is different in each country. In some, the applicant company might wait for years for a response. With mutual recognition, even if the registration report in one country is positive, they may not agree with it in another, if, for example, they already have a similar drug. The new regulator - a single regulatory supranational body - is needed to warrant a centralized testing and registration of drugs.

Essential Elements in Clinical Trials

The protocol approval by MFDS •Only at the MFDS designated clinical trial institutions •Qualified investigators•Protection of the rights and safety of subjects•Informed consent before enrollment of subjects

EAEU LANGUAGE REQUIREMENTS

The registration dossier is submitted in Russian, or in English with the translation of the following parts into the Russian language: Module 1: all, except sections 1.6.3, 1.10.1, and 1.10.3. The general description of a medicinal product, instructions for medical use and package layouts must be submitted in the national language of each country. Module 2: all sections should be translated or submitted in the Russian language; Module 3: may be submitted in English, but multiple sections must be translated into Russian: Module 4: allowed to submit in English; Module 5: allowed to submit in English

Ukraine Medical Devices

The total volume of the Ukrainian market for medical devices, including retail and hospital segments, is about 1 billion Euro per year, import is ~ 80%. New products can enter the Ukrainian medical device market if they conform with technical regulations based on the EU Directives for medical devices. The following are requirements for Ukrainian medical device registrations: • Foreign registrants must appoint an Authorized Representatives based in Ukraine • Expanded list of documentation and sample submissions required for registrations • Manufacturing site inspections for Classes I, IIa, IIb, and III • Special symbols of national conformity are required for medical devices imported into Ukraine (CE mark is not enough) • National conformity certifications are valid for five years Documentary expertise, on-site manufacturing inspections and testing of samples of medical devices is being performed by national authorized bodies (notified bodies in the EU).

EAEU Registration Dossier Procedure

This procedure is a route to obtain a registration certificate according to the EAEU requirements on the basis of previous national registration in one or more member states and is used to move from fragmented national registrations to a common certificate under the new rules. The Applicant (MAH) of existing registration must submit a dossier corresponding to the format of the Union. The dossier is assessed and a registration certificate of EAEU is issued. The reference country for filing is chosen as the one in which the medicinal product is already registered. To bring the registration dossier in line with the EAEU requirements, the Applicant may choose to submit an Application for registration only in those countries where the drug is already registered. In the future, the list of countries may be extended by the procedure of mutual recognition. CTD format is used for filing, Modules 1, 2 and 3 shall comply with the EAEU CTD requirements, and Modules 4 and 5 may be presented without bringing them to the requirements. The duration of the procedure should not exceed 100 calendar days, not including the clock stops required to respond to the comments (deficiencies) and an unscheduled inspection (if needed). As a result of this procedure, a registration certificate will be issued: • for 5 years in the general case,

HUGARY

To get the market access, manufacturers must comply with regulations of Hungary's National Institute of Pharmacy and Nutrition (OGYEI). There are very stringent regulations, language barriers and the complex regulatory procedural challenges.The main activity of OGYÉI is to provide the public with safe, effective and quality medicines. OGYÉI is the national organisation of official drug controlling tasks and it is also the methodical and research institute of Hungary. There are four types of procedures to issue the marketing authorisation in Hungary - as it is common in the EEA:•centralized procedure: the documentation of the new product is assessed by the EMEA-CHMP, the authorisation is issued by the European Commission;•decentralized procedure (DCP): the new product has not been authorised in any EU countries; the OGYÉI is entitled to assess the documentation and to issue the marketing authorisation;•mutual recognition procedure (MRP):the new product has been authorised at least in one EU country; the OGYÉI is entitled to assess the documentation and to issue the marketing authorisation;•national procedure: assessment is carried out by the OGYÉI; the marketing authorisation is valid in Hungary.

US Foreign Corrupt Practices Act (FCPA)

Two Main Provisions•Anti-Bribery Provisions: Prohibits the offering or paying of a bribeor anything else of value to a foreign government or political party official in order to obtain or retain business or secure any improper advantage.•Books and Records Provisions: Requires companies that trade on U.S. exchanges to make and keep accurate books, records and accounts of all payments, and to devise and maintain reasonable internal accounting controls for preventing and detecting FCPA violations.

Key Healthcare Laws

US Law•FDA Laws, Regulations, and Guidance•Privacy Rule of the Health Insurance Portability & Accountability Act (HIPAA) •Foreign Corrupt Practices Act (FCPA) •False Claims Act •Anti-Kickback Statutes•Pharmaceutical Marketing & Disclosure Laws (Federal & State) International Counterpart•EMEA; Various country regulatory authorities•GDPR/Data Privacy Laws (US has treaties with EU and Switz.)•UK Anti-bribery Act; Every country has anti-bribery laws•Gov't funded healthcare regulations•Most countries have laws and/or ethics codes governing interactions with HCPs•International transparency laws

UKRAINE - CHALLENGES & OPPORTUNITIES

Ukraine is a big market with great potential - 42.7m inhabitants, of which 70% live in urban areas. • Government's funding of healthcare is reduced, most of drugs and other health related expenses are paid for by individuals. • The market is under pressure resulting from the economic and political difficulties, devaluation of the local currency, falling incomes and growing tariffs. • Investments in the pharma industry are estimated to have reached approximately USD 200 million over the last 5 years. • Ukraine was facing huge challenges with COVID-19 vaccination - government refused to register Russian vaccine and public in general is hesitant to get cheap vaccines from Asia. • A national manufacturer of vaccines, Biolik company in Kharkiv is technically capable of producing a vaccine against coronavirus, but only with its state registration in Ukraine

Drug Evaluation department

Under the national institute of food and drug safety evaluation. drug review management division, bio equivalence evaluation division, oncology and antimicrobial products division, pharmaceutical standardization division, etc.

Anti-Corruption Enforcement

United Kingdom•Updated guidance from the SFO on criteria for Deferred Prosecution Agreement. •Focus on importance of compliance program both at time of offense and after•Importance of monitoring to uncover wrong doing and co-operating with SFO including self reporting and sharing internal investigations China Pharmaceuticals sector listed as a priority sector for enforcement action in China.•China's Ministry of Finance issued fines for violation of accounting laws to 19 Pharmaceutical companies including Wanbang BioPharmaceuticals Haosen Pharma and Sanofi - for false expenses for meetings and seminars.

Ministry of Food and Drug Safety (MFDS)

a regulatory authority. Clinical(Pre-clinical) Premarket approval Postmarket audit. ▪Scope in responsibilities Food, Dietary Supplements, Drugs, Bio-pharmaceuticalsKorean traditional(herbal) medicine, Quasi-drugs, Cosmetics, Cosmeceuticals, Medical devices ▪Organization •Headquarters: 7 Bureaus, 46 Divisions•National Institute of Food and Drug Safety (NIFDS)•6 Regional FDAMFDS: Facts and Figures ▪Staff (1,762) •Headquarters: 577•NIFDS:: 406•Regional KFDA(6): 774

Ministry of Health and Welfare (MOHW)

a regulatory authority. Distribution Retailing (dispensing) Classification Insurance (HTA, coverage)

Compliance and Ethics Program

a strategy adopted by the board of directors to assure legal and ethical compliance; overseen by chief ethics and compliance officer; consist of→ Due Diligence, Risk Assessment, Effective Training Programs

Elements of an Ethics and Compliance Program

code and policies train and communicate monitor and enforce •Purpose of Board Involvement-To reduce risk of company misconduct -To avoid personal liability for company misconduct by understanding:-What "reasonable oversight" means?-What to do when something is reported to the board?-Actions to take if the misconduct involves a board member-To avoid liability for individual conduct by understanding key personal risk exposures:-Conflicts of Interest-Confidential Information/Insider Trading-Media Relations-Gifts, hospitality, favors -Independence-Antitrust•3 Questions the Board and Execs should be able to answer:1.Is the Compliance Program well designed?2.Is it applied in good faith ?3.Does it work?

Data Requirements of NDA

nonclinical pharmacology ADME Toxicology Clinical phase 1,2,3 Bridging submitted through CTD

Pharmaceutical safety bureau

pharmaceutical policy division. pharmauetical management division narotics policy division. Pharmaceutical quality

Why choose Korea for Clinical Trials

reforms include implementation of GCP guidlines from 1995, the introduction and separation of IND from the NDA review process, reduction of the IND approval timeline to 30 working days and support for participation in multi regional clinical trials

CEE IP PROTECTION

the level of IP protection is still concerning. Problems that are commonly raised include a lack of transparency in IP procedures and the lack of effective enforcement.

Ukraine REGULATION AND STATE INVOLVEMENT

• Certification lead times are usually lengthy, but regulations are changed to improve this. • Drugs holding international patents should be registered by national authorities before they can be sold in local markets. • Due to economic challenges, government established "essential drug list" to regulate prices. • Government finance drug purchases for the hospitals -10% to 40% of total market volumes, the rest is covered by the consumer. Language and labeling The only official language in Ukraine is Ukrainian. Suggested text for labeling and instructions for use are submitted for expert evaluation in Ukrainian language. The labeling information and instructions for use are assessed during the state registration and approved as the annexes to the registration certificate. Other languages (for example, Russian, English) may also be presented on the packaging and in the instructions provided the complete identity of the information to the Ukrainian text.

EURASIAN ECONOMIC UNION (EAEU)

• For EAEU (Russia, Belarus, Kazakhstan, Armenia, Kyrgyzstan) Single Drug Market is a key focus. • The estimate of overall volume of the pharmaceutical market in EAEU countries is ~ 17 billion dollars. • Fundamental regulations were adopted in 2016 - they are in line with best practices & cover manufacturing, registration, clinical trials, sales & control of drugs. The main legislative act regulating the registration of medicinal products in the EAEU Member States is the Decision of the Eurasian Economic Commission No. 78 of November 03, 2016 "On the rules of registration and expertise of medicinal products for human use". Registration of medicines under the unified rules of the Union becomes mandatory from January 2021. At the same time, all medicines registered under national procedures must be brought into compliance with the rules of the EAEU by the end of 2025. • All procedures for registration of medicines in the EAEU are aligned with the process of drug registration in Russia, which has the most complicated and expensive drug registration procedure. • In recent years, the EAEU has taken steps to unify the pharmaceutical market. This includes the creation of common drug registration procedures, and in the future might include a single pharmaceutical regulator similar to the European Medicines Agency (EMA), which has a 30-year history of successful work.

UKRAINE - CHALLENGES & OPPORTUNITIES

• The government is pushing for serious reforms. Recent positive changes - introduction of reference pricing & simplified fast track registration for drugs registered in countries with strong regulatory regimes. • Public tenders for drugs covered by government-funded programs (state-owned hospitals ≈ 1,800). • Local regulations have replicated GMP and compliance has become mandatory - all manufacturers are required to have either a local or international GMP certificate. • Drugs imported into Ukraine should be compliant with GMP. Manufacturers should also ensure that active ingredients they use in producing their drugs are in compliance with GMP.

Major Changes in Regulatory Requirements

•2000. KGCP revision (enactment in 1995)-Harmonize with ICH guideline E6 •2001. Adoption of the Bridging Concept (E5) •2004. Introduction of Good Review Practice (GRP)-Guarantee quality, efficacy, clarity, transparency, consistency of review results •2008. Change GMP standards (enactment in 1994) -International harmonization of GMP regulation-International collaboration on GMP like PIC/S •2009.Common Technical document(CTD) -Adopted on New Drug •2015.7.Adoption of REMS(Risk Evaluation Mitigation Strategy) 2016.3 CTD

Globally Similar Expectations for Compliance & Ethics Programs

•DOJ-SEC Joint Guidance (2015) -Ten Hallmarks of an Effective Compliance Program -Considerations for opening an investigation & brining charges •UK Ministry of Justice (MOJ) -commentary on the Six Principles of an Adequate Procedures compliance program -Includes importance of risk assessment and top level commitment •Organization of Economic Cooperation and Development (OECD) -Good Practice Guidance on Internal Controls, Ethics, and Compliance

The UK Bribery Act

•Establishes company liability for corrupt acts committed by persons acting on company's behalf. Includes bribery of private entities, not just public officials.•The UK Bribery Act only deals with bribery -not other forms of white collar crimes.•There is a full defense if it can be proved that the organization had "adequate procedures" in place to prevent bribery. •What counts as "adequate" will depend on the bribery risks faced and the nature, size and complexity of the business. •Facilitation payments, which are payments to induce officials to perform routine functions they are otherwise obligated to perform, are bribes. •Paying for legally required administrative fees or fast-tracking services are not facilitation payments.•Any hospitality and promotional, or other business expenditure which seeks to improve the image of a commercial organization, better to present products and services, or establish cordial relations, is recognized as an established and important part of doing business and it is not the intention of the Act to criminalize such behavior.

Issues to consider

•Global Bribery & Corruption Concerns•Healthcare & Regulatory System Differences-Government vs private payers-HCPs as "government officials"•Healthcare-Specific Considerations-Regional Ethics Codes-Clinical Trials & Data Privacy-Spend Transparency •Operationalizing Global Compliance-Language & Communications barriers / word meanings-Cultural differences-Hotline/Helpline

Complex Network of Stakeholders & "Compliance" Concerns

•Interactions with each of these stakeholders creates risks.•Its compliance's job to find a solution for dealing with these risks:•To eliminate the activities is not a practical means of doing business•To add bureaucracy and rigid oversight is often impractical & definitely unpopular•To ignore the potential risk exposure is naïve and can be costly

Pharmaceutical regulation in Mexico

•New synthetic molecules •Generics •Biologics •Bio comparables Orphan drugs were introduced into the General Health Law and the Mexican Pharmacopeia, but there are no specific regulatory requirement applicablE synthetic durgs with API approved in mexico (180 days) synthetic drug with API not approved in mexico but approved abroad (180-240 days) new synthetic drugs (180 days)

Drug Classification

•Origin of Ingredients ➢Chemical, Biological, Herbal •Public Accessibility ➢Prescription, OTC (pharmacy) ➢Safe-and-readily-available drugs (CVS)•Data Requirements (IMD: Incrementally Modified Drug)

Classification on Regulatory pathways

❑Products that Requires Approval New Drug(ND), New Molecular Entity(NME)-An active ingredient never marketed in Korea Incrementally Modified Drugs (IMD)✓New derivative ✓New efficacy✓New formulation✓New combination✓New intended use✓New route of Administration Generic Drugs