Rita Isabel Jerónimo Batista

Home , Pharmaceutical policy

Universidade de Lisboa

Faculdade de Farmácia

Evaluation of the generic substitution in Portuguese and Latvian community pharmacies

Mestrado Integrado em Ciências Farmacêuticas

2019 Universidade de Lisboa

Faculdade de Farmácia

Evaluation of the generic substitution in Portuguese and Latvian community pharmacies

Rita Isabel Jerónimo Batista

Monografia de Mestrado Integrado em Ciências Farmacêuticas apresentada à Universidade de Lisboa através da Faculdade de Farmácia

Orientador: Doutora Ana Paula Mecheiro de Almeida Martins Silvestre Correia, Professora Auxiliar Co - Orientador: Doutura Elita Poplavska, Professora Auxiliar

2019

2 Resumo

Objetivo: A política de substituição de medicamentos de marca por medicamentos genéricos, pode ajudar a reduzir os gastos em saúde, baixar os preços dos medicamentos e aumentar o uso do medicamento bioequivalente mais barato. Este estudo teve como principal objetivo descrever e comparar as práticas de substituição genérica dos farmacêuticos comunitários em dois países europeus, Portugal e Letónia, e como políticas diferentes podem influenciar a percentagem e a quota de mercado dos medicamentos genéricos.

Métodos: Um formulário, preenchido por farmacêuticos, foi utilizado para recolher os dados das prescrições médicas. Foi utilizada estatística descritiva para analisar os dados. Para complementar os dados quantitativos, foi criado um questionário de perguntas abertas que foi respondido pelos mesmos farmacêuticos. As respostas foram analisadas por tema em relação às suas diferenças e semelhanças. As farmácias foram escolhidas por conveniência.

Resultados: No total, foram recolhidas 713 prescrições. Em Portugal, a maioria das substâncias ativas foram prescritas através da sua denominação comum internacional, enquanto que na Letónia foram prescritas maioritariamente por marca. A substituição de medicamentos por genéricos foi maior em Portugal (77,78%) do que na Letónia (62,50%). Contudo, o grau de aceitação dos doentes foi maior na Letónia (57,14%) do que em Portugal (47,27%). A maioria farmacêuticos têm conhecimento sobre a política de substituição e reconhecem as suas vantagens e desvantagens.

Conclusão: Continua a existir uma maior preferência pelos medicamentos de marca comparativamente aos medicamentos genéricos em ambos os países. Embora a maioria dos farmacêuticos reconheça a importância da substituição e a taxa de recomendação de substituição seja alta, a aceitação dos medicamentos genéricos, pelos doentes, permanece baixa. Este facto tem vindo a ser associado coma falta de informação e confiança nos medicamentos genéricos e os farmacêuticos concordam que fornecer mais informação deveria estar no foco das autoridades reguladoras. Adicionalmente, uma vez que os profissionais de saúde podem influenciar a opinião dos doentes, é preciso que estes tenham ao seu dispor informação de confiança e que assumam um papel mais ativo na educação do doente.

Palavras-chave: substituição genérica, medicamentos genéricos, medicamento de referência, denominação comum internacional, gastos em saúde

3 Abstract Objective: Generic substitution as a policy can help reduce health expenditures, lead to reduced product prices and increased use of the cheapest interchangeable medicine. This study aimed to describe and compare the generic substitution practices of community pharmacists in two European countries, Portugal and Latvia, and how different country polices can influence the percentage and market share of generic medicines dispensed.

Methods: A data collection form was designed, and pharmacists were asked to fill the form with the details of the prescriptions. Pharmacies were chosen via convenience sample. Descriptive statics was used to analyze the data. In order to complement the quantitative data, a survey with open-ended questions was created and answered by the pharmacists that collected the information. Responses were analyzed by theme for differences and similarities.

Results: In total, 713 prescriptions were collected. In Portugal, most of the active substances were prescribing by its international nonproprietary name, while in Latvia the majority of the active substances where prescribed by brand name. Generic substitution rate slightly higher in Portugal (77,78%) than in Latvia (62,50%). However, patient acceptance of generic medicines is higher in Latvia (57,14%) than in Portugal (47,27%). All pharmacist knew about the generic substitution police and knowledge its advantages and disadvantages.

Conclusion: The results of this study showed that there is still a preference for the branded name medicines over the generic medicines, in both countries. Although the majority of community pharmacists surveyed acknowledged the importance of substitution and considerably high generic substitution recommendation rates, patient acceptance of generic medicines still remains low. This fact has been linked with lack of trust and misconceptions about the generic medicines and pharmacists agreed that information should be at the focus of regulatory authorities. Additionally, healthcare professionals can influence patient’s opinion, they need to be provided with trustworthy information and have to take on a more active role in patient education.

Keywords: generic substitution, generic medicines, reference medicine, international nonproprietary name, health expenditures

4 Acknowledgments

This work marks the end of a journey that began five years ago. I want to use this space to show my heartfelt appreciation to all of those who have been a part of this journey and shaped me throughout these years.

Firstly, I sincerely thank Prof. Elita Poplavska for all the advice, guidance and support, as well as, for believing in me and this project from day one.

To Prof. Ana Paula Martins, for accepting to supervise this project, availability to help me with my many questions and precious reassurance during the final times of writing this project.

Special recognition Dra. Ana Madureira and all the pharmacists of Farmácias Silveira that accepted to participate in this project and took time off their busy schedule to be a part of it. Without all of you, this project would truly have been impossible to accomplish.

To those I have the pleasure to call my friends, specially Beatriz, Sara and Catarina – you are not only my friends, but also my family. I'm utterly grateful to have you in my life. It would not have been the same without you. Your endless love and support have kept me going in the most difficult times of my life.

To Francisco, who in spite of everything, is a big part of this journey and will forever be linked to it. Thank you for always believing and encouraging me. I know I can always count on you no matter what.

To all of those whom I had the opportunity to work during these final months, thank you for teaching me everything you know and make me desire to do and learn more.

Finally, to my amazing parents, a simple thank you will never be enough. Thank you for the friendship, unconditional love and everlasting support you have shown me all my life. I would not be who I am today without you. Thank you for all the opportunities and experiences you enabled me to have.

5 Table of Contents

RESUMO ...... 3 ABSTRACT ...... 4 ACKNOWLEDGMENTS ...... 5 TABLE OF CONTENTS ...... 6 LIST OF TABLES...... 7 LIST OF FIGURES ...... 7 ABBREVIATIONS AND ACRONYMS ...... 8 1. INTRODUCTION ...... 9

1.2 POLICIES USED TO ENCOURAGE THE USE OF GENERIC MEDICINES ...... 10 1.3 GENERIC SUBSTITUTION AS A POLICY TO CONSIDER ...... 11 1.4 ATTITUDES AND VIEWS TOWARDS GENERIC MEDICINES AND GENERIC SUBSTITUTION ...... 12 1.5 OVERVIEW OF GENERIC SUBSTITUTION POLICY IN LATVIA AND PORTUGAL ...... 13 1.5.1 Latvia ...... 13 1.5.2 Portugal ...... 13 1.6 THE ROLE OF COMMUNITY PHARMACISTS ...... 14 2. CONTEXT AND OBJECTIVES ...... 15 3. METHODOLOGY ...... 16 4. RESULTS ...... 18

4.2 GENERIC SUBSTITUTION PRACTICES IN PORTUGUESE PHARMACIES AND PATIENT ACCEPTANCE .. 18 4.3 GENERIC SUBSTITUTION PRACTICES IN LATVIAN PHARMACIES AND PATIENT ACCEPTANCE ...... 19 4.4 KNOWLEDGE ON GENERIC SUBSTITUTION POLICY AND ITS ADVANTAGES AND DISADVANTAGES OF PORTUGUESE COMMUNITY PHARMACISTS ...... 21 5. DISCUSSION ...... 26 6. CONCLUSION ...... 30 7. REFERENCES ...... 31 8. ATTACHMENTS ...... 35

6 List of Tables

TABLE 1 | INN PRESCRIPTION AND GENERIC SUBSTITUTION POLICIES IN DIFFERENT EU MEMBER STATES, 2017 [13] ...... 11 TABLE 2 | OVERVIEW OF NATION GENERIC POLICIES IN LATVIA AND PORTUGAL [13] ...... 14

TABLE 3 | GENERIC SUBSTITUTION PRACTISE IN PORTUGUESE PHARMACIES ...... 18

TABLE 4 | OVERVIEW OF GS RECOMMENDATION AND PATIENT ACCEPTANCE RATE BY

PHARMACOTHERAPEUTIC GROUP, PORTUGAL ...... 19 TABLE 5 | GENERIC SUBSTITUTION PRACTICE IN LATVIAN PHARMACIES ...... 19

TABLE 6 | OVERVIEW OF GS RECOMMENDATION AND PATIENT ACCEPTANCE RATE BY

PHARMACOTHERAPEUTIC GROUP, LATVIA ...... 20

TABLE 7 | GENERIC SUBSTITUTION AND PATIENT ACCEPTANCE RATE, COUNTRY COMPARASION. 20

TABLE 8 | DEMOGRAPHIC CHARACTERISTICS OF PHARMACISTS SURVEYED ...... 21 TABLE 9 | OPINION ON THE GENERICS MEDICINES ...... 21

TABLE 10 | KNOWLEDGE ON THE GENERIC SUBSTITUTION POLICY ...... 22

TABLE 11 | KNOWLEDGE ABOUT GENERIC MEDICATION REPLACEMENT BY GENERIC MEDICATION

POLICY ...... 23

List of Figures

FIGURE 1 | SHARE OF GENERICS IN TOTAL PHARMACEUTICAL MARKET, 2016 (OR LATEST YEAR)15

7 Abbreviations and Acronyms

AS Active Substances

EMA European Medicine Agency

EU European Union

INN International Nonproprietary Name

MM Mixed methodology

GM Generic Medicines

GS Generic Substitution

OECD Organization for Economic Co-Operation and Development

RM Reference Medicine

RRP Recommend Retail Price

WHO World Health Organization

NHS National Health Service

8 1. Introduction Providing affordable healthcare at acceptable standards has become one of the biggest challenges for European countries [1]. According to the Organization for Economic Co- Operation and Development (OECD), “one-fifth of the health spending is wasteful and could be minimized or eliminated without undermining health system performance”. Excluding those used in hospitals, pharmaceuticals account for the third biggest source of spending on health care [2]. Not providing patients with adequate medication at the lowest cost to them and their community can be considered irrational use of medicines. Failure to prescribe in accordance with clinical guidelines, non-adherence to dosing regimens or inappropriate use of medication is also considered irrational use of medicines. World Health Organization (WHO) estimates that irrational use of medicines accounts for more than a half of the medicines prescribed, dispensed or sold [3]. The European Medicine Agency (EMA) states that generic medicines (GM) have the same pharmaceutical active substance(s) (AS) as the reference medicine (RM), in the same dosage form, with the route of administration, quality, safety, strength and are used to treat the same disease(s). Nevertheless, the drug’s excipients, appearance (color or shape) and packaging may differ [4]. In order to receive their marketing authorization, GM must demonstrate bioequivalence to the RM. Normally, GM enter the market once the RM’s patent expires and its market price tends to be 20-80% cheaper than the RM because of lower research and development associated costs [5]. Thus, GM play a vital role in healthcare systems, as they can help reduce and control pharmaceutical expenditures, since their market entry may lead to a greater market competition which in turn may lead to lower prices [5], [6]. In 2014, the use of generic medicines saved European payers up to 100 billion euros a year and provided improved access to different therapeutic areas [1]. Although positive knowledge and perception of GM is helpful, by themselves, will not lead to an increased use of GM. In order to promote the use of GM is essential that governments create policies to stimulate its use [7]. Pharmaceutical policies deal with the adequate provision and use of pharmaceuticals, and one of its main goals, is the minimization and cost- containment of pharmaceutical expenditure [8]. Generic substitution (GS), is the act of replacement of a RM for an interchangeable, less expensive medicine, but with the same bioequivalence, safety, quality, effectiveness – the GM. As a police it can be used to help reduce the pharmaceutical expenditure, lead to reduced product prices and increased use of cheapest interchangeable medicine [6], [9]. Given the huge saving potential of GM and GS, the aim of this study is to understand and compare generic substitution practices of community pharmacists in two different European countries, Portugal and Latvia, and how different

9 demand-side polices used to stimulate the penetration of GM, may or may not influence the percentage of GM dispensed.

1.2 Policies used to encourage the use of generic medicines In broad terms, there are two types of policies that can stimulate and encourage the use of GM: demand-side and supply-side policies. Both must complement each other in order to achieve the best results possible [7]. On the one hand, supply-side policies are related to market access, pricing and reimbursement [9]. On the other hand, to have sustainable prices, at competitive levels, the volume of GM on the market is crucial for pharmaceutical industries. Thus, demand-side policies are of upmost importance as they increase the number of packages sold, by increasing demand and encourage the use of GM [10]. These policies are aimed at those who determine the demand for medicines, i.e. prescribers, pharmacists and patients [11]. One of the demand-side policies targeting prescribers is the prescription by International Nonproprietary Name (INN). A medical product can be either identified by a brand-name or by its INN. Normally, GM are identified by the drug’s INN. The INN is a unique name, with characteristic sound and spelling, that identifies the pharmaceutical active ingredient(s). According to the WHO, the main goal of INN system is to “provide health professionals with universally available designated name to identify each pharmaceutical substance”. Considering that INN is recognized worldwide and well established, it should mean a safer prescription and dispensing (avoiding medication-related errors) and make the dialogue between health professionals easier [12]. Prescription by INN enables and supports GS and is mandatory in EU member states, for instance France, Greece, Italy and Portugal [13]. Other demand-side policies targeting prescribers include encourage the use of clinical and prescription guidelines, monitorization/feedback on prescribing patterns, utilization of electronical prescribing, financial incentives and prescribing target and restrictions [7], [11], [14]. As for pharmacists’ policies like implementing a fee-for-performance remuneration system and allow to perform GS are several of the policies implemented [7], [14]. Lastly, it is important to remove any unfounded negative belief that patients may have regarding GM. Media campaign on TV, radio, the internet and press are vital to reach as many people possible, but it is also necessary that pharmacists and prescribers take on a more active role in the demystification of wrong concepts about generics since, for patients, they are the most trustworthy source of information. Moreover, it may be important to add differential co-payments for more expensive medical products since it may drive patients to request GM [7], [14], [15].

10 1.3 Generic substitution as a policy to consider In the majority of EU member states, GS is legally allowed, and can be either indicative or mandatory. GS substation is mandatory in countries like Denmark, Estonia, Finland, Germany, Greece, Spain and Sweden. In spite of that, the physician can prevent substitution but has to justify the reason why substitution is forbidden. Furthermore, the patient can refuse the substitution and opt for a more expensive medicine, however, has to cover the price difference or can also receive an additional charge is the they choose a more expensive medicine, which is the case in Greece. In Belgium, GS is only mandatory for antibiotics and antimycotics. Some countries with indicative GS include France, Ireland, Latvia, Portugal and Switzerland. Moreover, Switzerland has even implemented policies to incentivize GS by giving pharmacists a fee for each time GS is performed. Although GS in France is only indicative, if the patient chooses to refuse substitution, the patient only receive the reimbursement after paying the medicine’s full price [13]. Table 1 shows examples of countries and their generic substitution and INN prescription policies As GS helps to generate savings by promoting the use of a less expensive medicines instead of the RM. Moreover, it can not only help to increase the generic market shares, cost- effectiveness and encouragement of generic entry. GS substitution can also boost price competition, by incentivize producers to reduce their prices so they products can be reimbursed by the NHS [6], [16]. Therefore, more should be done to promote and facilitate GS.

Table 1 | INN prescription and generic substitution policies in different EU member states, 2017 [13]

Country Prescription in INN Generic substitution Albania Mandatory Indicative Austria Not allowed Not allowed Belgium Indicative Allowed (mandatory for antibiotics/antimycotics) Bulgaria Indicative Not allowed Croatia Indicative Indicative Denmark Not allowed Mandatory Estonia Mandatory Mandatory Finland Indicative Mandatory France Mandatory Indicative Germany Indicative Mandatory Greece Mandatory Mandatory Ireland Indicative Indicative Latvia Generally indicative. Mandatory only Indicative for newly diagnosed patients Netherlands Indicative Indicative Portugal Mandatory Indicative

11 Spain Mandatory except for non- Mandatory interchangeable medicines Sweden Not allowed Mandatory Switzerland Indicative Indicative United Kingdom Indicative Not allowed

1.4 Attitudes and views towards generic medicines and generic substitution Literature reports that pharmacists hold both positive and negatives perceptions about GM. Although the majority of pharmacists supports and as a full understanding of the definition of generics and regards them as equally safe and effective, there is still some percentage of pharmacists that don’t regard them as effective as the RM [17]–[19]. When it comes to perception about the quality of generics, pharmacists, are amongst the ones that question it the most [18]. Regarding GS, the majority of the pharmacist surveyed were in favor and has a positive attitude towards it. Furthermore, they also believe that GS can help reduce the cost of pharmaceuticals. Some of the GS advantages mentioned were: renewed image and influence within the healthcare system and increased recognition of expertise [17], [19]–[21]. Nonetheless, some pharmacists still show some reluctance as they are afraid that substitution may confuse and worry patients which can translate into poorer health outcomes. Some pharmacists even reported difficulty trying to implement GS due to physicians and patients’ reluctance and therefore, tried to only target only a specific group of patients for substitution [17]. When compared to pharmacists, there are more prescribers thinking that GM are more likely to cause adverse reactions and are less effective. Also, some stated a preference from for RM and older doctors had a worst opinion of GM. In spite of that, the great majority windily accepts GM, however even though physicians may be accepting of GS because of economic and policy pressures they still hold negative concern about the reliability, quality and interchangeability of GM [17], [18]. The biggest challenge has been to try to gain the confidence of patients as there is still a great lack of trust on GM. Reasons presented include: lack of trust in foreign manufactures, the belief that a cheaper medicine means poorer quality and the belief that RM is more effective. Usually, patients easily accept the generics to treat less serious illnesses. Furthermore, literature reports that GS, in some cases, led to medications errors has it led to medication duplication and made it more difficult for patient keep track of their medication because of packaging or appearances issues. However, the level of acceptance, in developed countries, is steadily

12 increasing mainly due information campaigns and a better communication between healthcare professional and patients [17], [18]

1.5 Overview of generic substitution policy in Latvia and Portugal 1.5.1 Latvia

In the Republic of Latvia, the National Health Service (NHS) is the administrative institution in charge of creating a positive reimbursement list and determines which medicines are to be included in the list, as well as, the corresponding reimbursement rate. The reimbursement system is based on the severity of the illness and the need for the chronic use of medication. There are three reimbursement rates – 100%, 75%, 50%. The positive list can be divided in three other different lists: list A (reference price list with interchangeable medicines), list B (non-interchangeable medicines) and list C (non-interchangeable expensive medicines which the annual treatment cost is greater than 4300€) [22]. Several strategies have been used to encourage the use of reference products of list A, such as prescribing by INN and GS. Although INN prescribing is not always mandatory, according to Regulation No. 899 [23], INN is mandatory if a patient is prescribed, for the first time, a medicine that belongs to the list A. In this case, the pharmacist must dispense the lowest priced reimbursable medicine which correspond to the common name, with the same pharmaceutical form and strength. However, if there are two or more pharmaceutical products on the reimbursable list with the cheapest basic reimbursement price, the patient has to be informed that it has the right to choose any of them. Unless the patient doesn’t accept the cheapest medicine or the physician has forbidden substitution, the patient must pay the difference between the reference product and the product chosen or in some cases pay full price.

1.5.2 Portugal

In the case of reimbursement medicines, medical prescriptions must include the INN of the active substance(s) as well as, the pharmaceutical form, the dosage, presentation, quantity and posology of the medicine. Exceptionally, the prescription may include the product’s commercial or the name of the marketing authorization holder, in one of the following situations: 1. There is no reimbursable generic medicine or there are only available branded originals and licenses for the active substance prescribed: 2. The prescriber has a technical justification for not allowing the replacement. All of the exceptions must be identified by the prescriber, in the prescription. The cases where technical justification is acceptable, are the following:

13 a. Prescribe medicine has a narrow therapeutic margin or index, according to the information provided by INFARMED, I.P.; b. Suspected of intolerance of adverse effect, previously reported to INFARMED, I.P., to a drug with the same active substance, but with another commercial name c. Prescribed medicine is intended to ensure continuity of treatment with ta duration of more than 28 days. For non-reimbursed medicines, medical prescription may include the product’s brand name of the name of the marketing authorization holder. During the dispensing act, and in compliance with what has been prescribed, the pharmacist or other qualified person, must inform the patient regarding the medicine that has the lowest price. Pharmacies must have available to dispense at least 3 medicines with the same active substance, pharmaceutical form and dosage of the lowest five prices for each homogenous group. Pharmacies must dispense the lowest priced medicines within these options, unless the patient opposes, or the prescriber prevents it. If the patient opts for a more expensive medicine the difference should be payed out-pf-pocket [24].

Table 2 | Overview of nation generic policies in Latvia and Portugal [13]

GS legally Is generic substitution Is INN Patient can Doctor can allowed? indicative/mandatory? indicative/mandatory? refuse? prevent it? Latvia Yes Indicative Indicative (*) Yes Yes Portugal Yes Indicative Mandatory Yes Yes

(*) Only mandatory if the patient is newly diagnosed

1.6 The role of community pharmacists

Community pharmacies is one of the places where GS policy actually comes into practice. Pharmacists play a vital role when it comes to influence the choice between the RM or GM, as they are the most skilled healthcare professional to assure patients about the quality, safety and effectiveness of generics as well as avoid any confusion that may be caused by substitution. Not only that, but can also contribute to the decrease of pharmaceutical expenditures as they are can advise prescribers and patients on the right GM. Although pharmacies are legally bound to dispense the lowest priced medicine, the patient can always refuse it. Patients who are indifferent may easily take the medicine provided by the pharmacist, whereas those with stronger beliefs about the lack of quality and efficiency of GM may not [25], [26].

14 2. Context and objectives

According to OECD Health Statistics [27], the share of generics in the total pharmaceutical market for Portugal, in the year 2018, was by value (i.e., total expenditure on GM divided by total pharmaceutical expenditures) 20,5% while by volume (i.e., number of packages sold) was 47,6%. However, for the Latvian total pharmaceutical market, in the year of 2016, the share of generics by value was 42% and by volume was 74%, as seen in Figure 1.

Portugal

Latvia

0 10 20 30 40 50 60 70 80

Volume (%) Value (%)

Figure 1 | Share of generics in total pharmaceutical market, 2016 (or latest year) [27]

As stated above, GS can influence the market share of generics. Therefore, is crucial to understand how pharmacists perceive substitution and related policies, since they are the main influencers of GS. Although there are several studies done on the opinion, perceptions and views of GM and GS [17]–[20] there are, to the best of the author’s knowledge, no studies that compare how different policies influence the generic substitution rate and what are the perceptions and knowledge that pharmacists have on the GS policies, barriers pharmacist face daily when trying to perform substitution and what are the similar problems faced in different countries. Latvia and Portugal have different generic policies. In Latvia, prescription by INN is only mandatory in specific cases as opposed to Portugal, where INN is always mandatory. However, in both countries GS on only indicative. Therefore, the aim of this study is to compare policies used to stimulate the use of GM, as well as, GS rates and practices of community pharmacists in two different European countries, Portugal and Latvia. Furthermore, it also aims to assess the rates and patient acceptance of GS, identify barriers that pharmacists face when trying to perform GS and evaluate community pharmacist’s knowledge of GS polices.

15 3. Methodology In order to be able to achieve the mentioned objectives the study took on a mixed methodology approach. Mixed methodology (MM) incorporates “quantitative and qualitative paradigms, approaches, concepts, methods and/or techniques in a single study” [28] For the assessment of the rates of GS a quantitative approach was used. Community pharmacists, in both countries, were asked to fill an anonymous data collection form. The form is based on a form used on a study on generic medicines substitution practices of Malaysian community pharmacists [29]. The form was provided to the pharmacists, in the corresponding language. Pharmacists were asked to fill the form with the first three prescriptions at the start of every hour throughout eight hours for three days. This was done in order to avoid bias related to the working hours of the pharmacies, since is more likely that certain populations only come to the pharmacy at a certain time. In the form, pharmacists were asked to register: hour of which the medicine was dispensed, whether or not the patient asked for the generic, whether or not GS was suggested, whether or not patient refused substitution, prescription details (drug name, form, dosage, quantity) and medical product dispensed (drug name, form, dosage, quantity); Due to limited time and resources, convenience sampling was used. Convenience sampling is a nonprobability sampling technique was used. Unlike probability sampling, in nonprobability sampling all elements of the populations don’t stand the same change of being picked and randomization is not applied [30]. Therefore, the sample population only has to meet certain preestablished criteria, like availability, easy access and willingness to participate [30], [31]. Therefore, three pharmacies and two pharmacists per pharmacy in three different regions of Lisbon were selected. Since it is desired to determine the frequency at which substitution happens, OpenEpi [32] used to calculate the sample size for a frequency in a population. The population size used for this calculation was based on the minimum requirement of people in an area for the opening of a pharmacy, which is minimum of 3500 people, in Portugal [33]. Therefore, for three pharmacies the population size was 10500. In order to achieve a confidence level of 95%, is was estimated that it was necessary to collect 371 prescriptions. The same methodology was applied in Latvian community pharmacies, with the necessary alterations. The data gathered from the forms was entered into Excel version 16.29.1 for analysis and descriptive statistic was used. To identify possible barriers/challenges that pharmacists are confronted with during their daily activities, as well as, their knowledge of the GS substitution polices, a survey with open-ended questions was designed. Although this survey was done for both countries, at the time of writing the results from the surveys from Latvia were not available, since the Latvian pharmacist were not available to answer them in the agreed time . In questionnaire four

16 different sections where established: demographic characteristic of the pharmacists (age and numbers of years working as a community pharmacist), their opinion on GM, knowledge and opinions on generic drug substitution policy and barriers faced when trying to perform GS. This type of questionnaire helps to complement the quantitative data obtained and makes possible to capture the views and opinions of the pharmacists. Furthermore, doesn’t allow the responder to drift from the initial question, doesn’t pressure the responder to feel like has to give the right answer and has no time constraints [34]. The answers were transcribed verbatim and were analyzed by theme for their difference and similarities.

17 4. Results In the following section the results for GS recommendation and patient acceptance rate are presented for both countries. However, at the time of writing the data from the surveys to Latvian pharmacist was not available.

4.2 Generic substitution practices in Portuguese pharmacies and patient acceptance

Analysis of the prescriptions (table 3) revealed that in 371 prescriptions, 345 of the active substances (AS) were prescribed by its INN. Moreover, the cases where prescribing by INN wasn’t used are small. In 15 prescriptions INN was missing and in 11 prescriptions both the INN and the commercial name was used. In some cases (29,65%) patients asked for the generic directly. Recommendation of substitution of a branded-name medicine for a generic was done in the majority of the cases (83,91%). The cases where substitution was not suggested it was either because a GM wasn’t available (8,43%) or pharmacist didn’t ask (7,66%). When the recommendation of substitution was performed the majority of the patient refused the GM (52,97%).

Table 3 | Generic substitution practice in Portuguese pharmacies

Number of cases Percentage (%) Yes 345 92,99

Prescription in INN? No 15 4,04 Both 11 2,96

Did patient ask for the Yes 110 29,65 generic? No 261 70,35 Yes 219 83,91 Was substitution No 20 7,66 recommended? No – GM not 22 8,43 available Did patient refuse Yes 116 52,97 substitution? No 103 47,03

The three most prevalent pharmacotherapeutic groups were the medicines used in anti- infectious, central nervous and cardiovascular disorders. The GS recommendation rate for these groups were 95,24%, 88,71% and 81,41%, respectively. However, patient acceptance was highest (52,27%) in medicines that belonged to the medicines used to treat cardiovascular diseases and lowest (37,5%) in medicines used to treat anti-infectious diseases. Table 4 shows GS recommendation and patient acceptance rate for all the pharmacotherapeutic groups that were prescribed in this study

18 Table 4 | Overview of GS recommendation and patient acceptance rate by pharmacotherapeutic group, Portugal

Pharmacotherapeutic Group Number of GS recommendation Patient acceptance rate prescriptions rate (%) (%) Anti - infectious medicines 54 95,24 37,50 Central nervous system 97 88,71 47,27 Cardiovascular system 91 81,41 52,27 Blood 9 66,67 66,67 Respiratory system 10 42,86 66,67 Digestive system 22 91,67 45,45 Genito-urinary system 5 75,00 66,67 Hormones and medicines used to 26 63,64 57,14 treat endocrine disorders Musculo-skeletal system 40 94,29 45,45 Antiallergic mediation 11 77,78 28,57 Medication used in 6 60,00 33,33 otorhinolaryngological disorders

4.3 Generic substitution practices in Latvian pharmacies and patient acceptance Analysis of the prescriptions (table 5) revealed that in 342 prescriptions, only 62 of the active substances (AS) were prescribed by its INN. In the majority of the cases INN was not use and the commercial name was used instead. There is only one case where both designations were used. Recommendation of substitution of a branded-name medicine for a generic was done in the majority of the cases (45,03%). The cases where substitution was not suggested it was either because a GM wasn’t available (29,82%) or pharmacist didn’t ask (25,15%). When the recommendation of substitution was performed the majority of the patient accepted the GM (64,94%).

Table 5 | Generic substitution practice in Latvian pharmacies

Number of cases Percentage (%) Yes 62 21,58

Prescription in INN? No 279 81,58 Both 1 0,29 Yes 154 45,03 Was substitution No 86 25,15 recommended? No – GM not 102 29,82 available Did patient refuse Yes 55 35,71 substitution? No 99 64,29

The two most prevalent pharmacotherapeutic groups were the medicines used in central nervous and cardiovascular disorders. The GS recommendation rate for these groups were 80,0% and 75,8%, respectively. However, patient acceptance was highest (80,0%) in medicines that belonged to the medicines used to treat central nervous system diseases and lowest (42%) in medicines that belong to the cardiovascular system group. Overall, the mean value for the GS recommendation rate was 72,7% and for patient acceptance rate 57,1%. Table 6 shows GS recommendation and patient acceptance rate for all the pharmacotherapeutic groups that were prescribed in this study.

Table 6 | Overview of GS recommendation and patient acceptance rate by pharmacotherapeutic group, Latvia

Pharmacotherapeutic Group Number of GS recommendation Patient acceptance rate prescriptions rate (%) (%) Anti - infectious medicines 25 62,50 86,67 Central nervous system 50 71,43 84,00 Cardiovascular system 111 70,83 55,88 Others 39 26,67 100,00 Respiratory system 22 54,55 50,00 Digestive system 12 70,00 42,86 Skin condition 14 55,56 60,00 Hormones and medicines used to 18 70,00 57,14 treat endocrine disorders Musculo-skeletal system 25 45,00 44,44

Diabetes 14 50,00 0,00 Eye conditions 12 87,50 85,71

Overall, the value for the GS recommendation rate was slightly bigger in Portugal than in Latvia. However, in Latvia, patients are more willing to accept substitution. (table 7).

Table 7 | Generic substitution and patient acceptance rate, country comparison

Portugal (mean value) Latvia (mean value) Generic substitution rate 77,78 62,50 Patient acceptance rate 47,27 57,14

20 4.4 Knowledge on generic substitution policy and its advantages and disadvantages of Portuguese community pharmacists In total six pharmacists were asked to respond to the survey. Respondents’ aged varied between 26 to 40 years and the extent of experience working in community pharmacy also varies significantly (see table 8).

Table 8 | Demographic characteristics of pharmacists surveyed

Characteristics Value Age, mean (range) 30,5 (26-40) Working experience in community pharmacy, mean (range) 6,5 (1-16)

The answers of the surveyed were transcribed verbatim and the answers to the three main themes can be read bellow:

Table 9 | Opinion on the generics medicines

Bioequivalent medication to brand medication Medication equivalent to the original, but usually cheaper

than the original. Medication with the same active substance as the original In your opinion, generic It is medication which contains the same active principle and medication is: the same dosage as the original. Medication with equivalent properties to the brand medication A bioequivalent medication to the original In those that have their own production and don’t just to buy from other laboratories.

Sandoz, ratiopharm and generis Which generic medication Original medication, due to the years of usage in patients manufacturing which present alterations regarding the study phase groups. laboratories do you trust I trust more in generic medication made in the same the most? Why? laboratory as the original, because the bioavailability must be closer to the original. Generis, Sandoz, Ratiopharm. Because of the experience/feedback I have.

21 Generis, Farmoz, Sandoz, Aurovitas I trust them because the “mother houses” of these generic medications are well known laboratories and because I know they are produced in certifies laboratories with high accuracy and control standards.

Table 10 | Knowledge on the generic substitution policy

Decrease health spending by replacing brand medication with cheaper and same quality generic medication, leading

to a lowering of the prices, including brand medication due to the decrease in reference prices; What do you consider is Decrease health spending for the generic medication taking the goal for replacing users. brand medication by Give the patient decision power

generic medication? Give a cheaper and equally effective and safe alternative for users and SNS (Portuguese Nation Health Service). Reduce user spending Economic savings for the user Profitable purposes for the company There are many laboratories for each molecule "producing" generic medicines, with very different RRP, which pressures

pharmacies to stock all brands, many of them with little rotation.

In many prescriptions, doctors prescribe a certain generic

laboratory and often patients do not do this laboratory and Do you feel this policy is that we can’t replace. fulfilling its purpose? Yes, to the extent that the majority of patients know what Explain. generic medication is and accept or not replacement when suggested. I don't know the policy so I can't answer. Not in all situations. Many people still think that because it's cheaper, the effect is not quite the same. I think we need more knowledge about the laboratories and their products to make sure they are trustworthy and credible.

22 The SNS could only reimburse generic RRP5 for example. This would force the remaining laboratories to reduce the

RRP of their brands to be reimbursed as well. Doctors prescribing by active substance and not mentioning

generic laboratories.

More information and training aimed at the user and provided by doctors, as the generic replacement policy exists due to Which strategies would the information or disinformation the doctor provides the you wish to see user. implemented to ensure More available information on televisions and newspapers. this policy is successful? So that the majority of the population could acquire knowledge about generic medication. More information to users. More training and information with scientific studies to support information

Table 11 | Knowledge about generic medication replacement by generic medication policy

Cheaper for the patient, better profitability for the pharmacy.

Give the user power of decision

Always give the patient a choice, as there is often a non- In your opinion, what adherence to therapy because the patient does not have are the advantages to enough income to purchase it. generic substitution? Save the client’s money The user can pay less. To be cheaper for the user, benefits for the SNS, financial advantages for the company. When the patient is loyal to a generic brand that does not exist in the pharmacy’s stock and they do not want to switch brand, which requires ordering if the client waits or losing the dispensing. Creates doubts in the users. Many of them don’t trust generic medication.

23 To give the power of decision to the user who is not trained/well-informed on the issue, making them more

confused and doubt-filled relating their therapy.

Changing the medication in situations where the doctor doesn’t agree, if the patient is finding it difficult to stabilize In your opinion, what therapeutic goals. are the disadvantages Lower bioavailability. And different taste or aroma, which the to generic replacement? patient may not be able to handle. Often, when the patient doesn’t improve, they associate the lack of improvement with the fact that the medication was generic. Generic medication is unreliable and does not have the same effect as the reference medication. Patient loyalty to certain generic laboratories with low rotation, doubts regarding the price of the generic that the patient will pay.

Not relying on generic to brand equivalence and the price of prescription medication (often these prices are out of date).

Lack of information on the subject; the pharmacy does not have the generic that the patient What are the most usually takes; common difficulties you the doctor "locking" the prescription and not allowing the face? patient’s preferred generic; no generic stock in the pharmacy with the patient’s preferred price. Fear / doubts of patients regarding generic medication. The doctor telling the patient to not switch medication. The low confidence of some users in "generic drugs". Patients do not always want to replace their medication with the generic version. Make the RRP more homogeneous and closer to the reference price. In the new prescriptions, there should be no reference to prices (because they are often incorrect and raise problems for the pharmacy).

24 Training / informing to patients about generic medication; patients should be more informed and responsible with

their medication.

What suggestions do Giving the patient better information about the difference between generics and originals. you have for solving There should be more information regarding the effects of these difficulties? brand vs generic medication accessible to the general public. Provide more training to healthcare professionals More information available for patients, debunking the lack of quality and efficacy of generic medication.

The doctors give more information to their patients more,

What do you think as they trust them with their therapy. encourages generic Greater consistency in the efficacy of generics. And more information available to patients medication acceptance? There should be more information regarding the effects of brand vs generic medication available to the general public. There should be more control, rigor in the manufacturing of the generic medication.

25 5. Discussion The promotion of the generic drug market and the use of GM has been one of the principal goals of Portugal and Latvia’s drug policy and its increased use has been one of the most relevant cost-control measures. In order to increase market share, mandatory INN and allowing pharmacist to perform substitution of prescribed medicines by the generics have been introduced, in Portugal, in 2012 [35], [36]. Although the use of GM has been promoted throughout the years, in Portugal, its market share is still bellow OECD average [37]. Conversely, in the year of 2016, Latvia presented a high penetration rate of GM [37]. Measures like INN prescribing, GS and information campaign were also introduced in Latvia to stimulate and promote the use of GM [38]. The combination of GS and INN prescribing has been adopted by many European countries to help reduce pharmaceutical expenditures [39]. Portuguese legislation states that medical prescription must include the INN except under certain conditions, yet, Latvian legislation states that prescribing by INN is only mandatory if the patient is prescribed a medicine, from list A, for the first time. The results revealed that in the Portuguese case the majority of the medicines were prescribed through INN, however, in Latvia the opposite occurred. This finding is somehow expected because in Portugal, prescribing by INN it’s a legal obligation for all reimbursed medicines, while in Latvia is not. The use of INN in prescriptions is said to improve patient acceptance of GM, since it can enhance patient familiarity with the generic names instead of the brand name and reduce confusion with the difference of appearance/packing when generics are dispensed [17]. When substitution was suggested, more patients accepted the GM in Latvia than in Portugal. A study done on the use of GM in Latvia showed that the people in Latvia considered themselves to be well informed on the GM and its availability, nevertheless the majority of the respondents said, if they had to make a choice, they would prefer not using the GM [38]. Lack of acceptance of the GM may be associated with the patient’s lack of trust in generics which in turn is caused by a lack of information and education. Studies have shown that it is crucial to educate and inform patients in order to demystify unfounded beliefs in order to gain people’s confidence and improve generics acceptance [40]. Additionally, it is important to consider where this information is coming from [40]. In Latvia, physicians were shown to provide negative information about GM. This may be due to close relations with the pharmaceutical industry since payments from the pharmaceutical industry have been associated with preference for brand-name medicines or lack of knowledge about the concept of bioequivalence [38]. In Portugal, the underuse of GM was also associated with patients’ lack of trust in GM and information. Quintal et. al [41] stated more should be done in terms of information and the main massage should be centered on the positive financial aspect that GS can have on patient’s finances; this factor was associated with enhanced willingness to accept substitution [42].

26 Results from this study also showed that pharmacists agreed that patients still trust physician’s opinion the most and they can easily influence patients’ opinion on GM. Therefore, it is vital to make sure that physicians are also provided with correct and trustworthy information, because their negative opinions and beliefs may incorrectly influence patients [40]. Not only that, but respondents also agreed that in order to improve substitution acceptance and GM, more should be done in terms of information not only to the patients but also to all healthcare professionals. When it comes to the knowledge on GS policy findings from this study revelated that the majority of the respondents knew about the policy and pharmacists believed that the main goal of the GS policy is to lower pharmaceutical related expenditures by replacing a more expensive medicine with a cheaper alternative, which is equally safe and effective. However, they believed this policy fails to achieve its intended purpose and there are still many problems that should be addressed. Reasons mentioned for failure where: too many generics for the same molecule with very different recommended retail prices (RRP), patient lack of trust in generics and failure to substitute because physicians prescribed a certain generic laboratory and unable substitution. In spite of this, the majority agreed that as a policy helps to reduce pharmaceutical expenditures for the NHS and the patients. All the pharmacists had a clear understanding of what a GM is, which is consistent with literature [43], however there are doubts about the laboratories where the generic is produced and some considered that the laboratories where the RM is also produced are more reliable. Five out six respondents agreed that there are laboratories more reliable than others and a study done by Josef Maly et. al [43] found that some pharmacists think that good manufacturing practices requirements are not followed by some GM laboratories. This fact may be worrisome because some generics may be preferred over others during the dispensing act. Regarding the GS policy, half of the respondents said they would like to receive more information and/or training about the policy as they didn’t fully understand the policy and its main goals. This fact may lead to infrequent application of GS due to lack of confidence in performing substitution. Some of the reasons pharmacists may have not to suggest substitution include fear of adverse drug reaction and risk of medication errors like duplication of medication [43]. Another reason that should be considered is pharmacists’ lack of trust in generic also highlighted by this study. Some pharmacists believe that the generic may not be bioequivalent and are not as safe as the RF. Although this is uncommon, literature reports [19], [43], [44] that some pharmacists holds negative beliefs and opinions about GM. It would be important to have more in-depth knowledge about the reasons why pharmacist may not always suggest substitution and the reasons some consider generics to be of low inferiority.

27 All the pharmacists surveyed claimed that they suggest substitution every time it’s possible to substitute the RF and only a few face problems during substitution. However, this is not consistent with data from this study. Even though GS was suggested most of the time, there are cases where substitution is not suggested, either because the GM was not available or because it was not suggested. Moreover, it is important to consider whether or not the substitution recommendation rate is that high because pharmacists might have felt pressure to suggest substitution more frequently. Once again, the main problem is the patient’s lack of trust in the GM and information. Also, doctors telling the patients not to change generics or “lock” the prescription to make it impossible to dispense the generic the patient wants is regarded as an issue. Other problems reported include the “loyalty” some patient have to certain generic manufacturer which may arise problems in the cases the pharmacy does not have the generic available and the patient does not want to substitute. Doubts about the prices shown is the prescriptions have also been mentioned since sometimes that prices are incorrect and causes problems in the pharmacy. It was suggested that the new prescriptions should not show the prices of the medication. The advantages and disadvantages of GS have also been acknowledged. According to the respondents, the main advantage is the financial aspect of substitution. Furthermore, it was mentioned that substitution for a cheaper medicine improves patient’s therapeutic adherence, because sometimes patient’s may not have the financial means to acquire all the medication. However, some recognize that substitution may confuse patients about their medication. Some respondents also question the reliability of generics stating that one of the downsides of substitution is that the medicine dispensed has inferior efficacy. It is also important to notice the Portuguese pharmacists were picked through convenience sampling and only them answered the surveys. Therefore, we cannot extrapolate these findings to the general population. Additionally, because of the sampling method, there is potential bias related to under-representation of the population and therefore, the power to detect differences within the is limited [45]. Since it was not possible to include the answers of the Latvian pharmacists it is important to consider that we are missing relevant issues that the Portuguese pharmacists are also facing and forgot to address, as well as, different issues that Portuguese pharmacist are not being faced with. The qualitative results (i.e. views and opinions on GS policy) were obtained through a survey with open-ended questions, instead of interviews or a focus group, mostly due to time constrains. Although it allows to complement the quantitative data of this study and it gives the change for pharmacists to answer the surveys when they are available, the views, opinions and issues addressed are limited to the questions being asked. Moreover, although they don’t drift from the initial question, other issues they may be facing will not be addressed. Therefore, additional research using interviews, or a focus group would be relevant to consider it would

28 provide a deeper understanding of the issues and detailed insight into their experiences and opinions.

29 6. Conclusion The results of this study showed branded name medicines are still preferred over the GM. Although the majority of community pharmacist surveyed acknowledged the importance of substitution and considerably high GS recommendation rates, patient acceptance of GM still remains low. This fact has been linked with lack of trust and misconceptions about the GM. If patients are ill-informed about the equivalence of GM it is more likely that brand-named medicines will always be preferred and the possible savings from the use of GM will not be generated [18]. There is a need to do more in terms of information, not only to the patients but also to healthcare professionals. By preferring a certain type of medication, healthcare professionals can influence patient’s choices, thus making the acceptance of GM more difficult. Moreover, the information should target not only concepts of quality, safety, efficacy but also explain why GM are cheaper and regulatory process that GM have to go through in order to enter the market. Correct knowledge and understanding of GM are regarded as vital factors to increase the acceptance and use of GM [46]. Both pharmacist and physicians have a vital role in the promotion of GM, GS and patient acceptance. Therefore, it is crucial that they have a more active role in educating and recommending the GM more often. Also, it is important to considerate prescribing by INN may not be affective as is, in Latvia. Since it is not always mandatory, the physician can opt out of it and prescribe by brand name instead. Therefore, healthcare authorities should reconsider their correct legislation, as it has been seen that INN prescribing can help with better acceptance of GM. This study had the following limitations - due to the reduce number of pharmacists surveyed and the fact that the sample was generate through convivence sample, it is not possible to consider this sample as representative of the population. Consequently, is not possible to extrapolate the results to the general population. However, this study provides meaningful insight to GS rates and patient acceptance of GM, as well pharmacist’s opinion on generic substitution. Thus, this study can serve as preliminary study and be valuable as a starting point for further research. Also, may be interesting to considerer focus-group or semi-structured interviews to pharmacists in order to expand on the issues reported.

30 7. References

[1] IMS Institute for Healthcare Informatic, “The Role of Generic Medicines in Sustaining Healthcare Systems: A European Perspective,” 2015. [2] OECD/EU, “Health at a Glance: Europe 2018 : State of Health in the EU Cycle,” OECD Publishing, Paris, 2018. [3] W. H. Organization, “Promoting rational use of medicines: core components,” 2002. [4] European Medicines Agency, “Questions and answers on generic medicines,” Questions and answers on generic medicines, London, pp. 1–3, 2012. [5] P. Dylst and S. Simoens, “Does the market share of generic medicines influence the price level?: A European analysis,” Pharmacoeconomics, vol. 29, no. 10, pp. 875–882, 2011. [6] S. Simoens, “Sustainable Provision of Generic Medicines in Europe,” 2013. [7] P. Dylst, A. Vulto, and S. Simoens, “Demand-side policies to encourage the use of generic medicines: An overview,” Expert Rev. Pharmacoeconomics Outcomes Res., vol. 13, no. 1, pp. 59–72, 2013. [8] A. B. Almarsdóttir and J. M. Traulsen, “Studying and evaluating pharmaceutical policy - Becoming a part of the policy and consultative process,” Int. J. Clin. Pharm., vol. 28, no. 1, pp. 6–12, 2006. [9] G. Carone, C. Schwierz, and A. Xavier, “Cost-containment policies in public pharmaceutical spending in the EU,” Econ. Pap., vol. 461, no. September, 2012. [10] P. Kawalec et al., “Pharmaceutical regulation in Central and Eastern European countries: A current review,” Front. Pharmacol., vol. 8, no. DEC, 2017. [11] J. R. J. Espin, “Analysis of differences and commonalities in pricing and reimbursement systems in Europe,” 2007. [12] W. H. Organization, Guidance on the use of international nonproprietary names (INNs) for pharmaceutical substances. Geneva, World Health Organization, 2017. [13] S. Vogler, M. A. Haasis, G. Dedet, J. Lam, and H. B. Pedersen, “Medicines reimbursement policies in Europe,” 2018. [14] P. Dylst, A. Vulto, B. Godman, and S. Simoens, “Generic medicines: Solutions for a sustainable drug market?,” Appl. Health Econ. Health Policy, vol. 11, no. 5, pp. 437– 443, 2013. [15] S. Simoens and S. De Coster, “Sustaining generic medicines markets in Europe,” 2006. [16] F. von der Schulenburg, S. Vandoros, and P. Kanavos, “The effects of drug market regulation on pharmaceutical prices in Europe: Overview and evidence from the market of ace Inhibitors,” Health Econ. Rev., vol. 1, no. 1, pp. 1–8, 2011. [17] S. S. Dunne and C. P. Dunne, “What do people really think of generic medicines? A

31 systematic review and critical appraisal of literature on stakeholder perceptions of generic drugs,” BMC Med., vol. 13, no. 1, 2015. [18] S. Colgan, K. Faasse, L. R. Martin, M. H. Stephens, A. Grey, and K. J. Petrie, “Perceptions of generic medication in the general population, doctors and pharmacists: A systematic review,” BMJ Open, vol. 5, no. 12, 2015. [19] A. Drozdowska and T. Hermanowski, “Exploring factors underlying the attitude of community pharmacists to generic substitution: a nationwide study from Poland,” Int. J. Clin. Pharm., vol. 38, no. 1, pp. 162–170, Feb. 2016. [20] E. Olsson and S. Kälvemark Sporrong, “Pharmacists experiences and attitudes regarding generic drugs and generic substitution: Two sides of the coin,” Int. J. Pharm. Pract., vol. 20, no. 6, pp. 377–383, 2012. [21] B. Allenet and H. Barry, “Opinion and behaviour of pharmacists towards the substitution of branded drugs by generic drugs: Survey of 1,000 French community pharmacists,” Pharm. World Sci., vol. 25, no. 5, pp. 197–202, 2003. [22] J. Silins and M. Szkultecka-Dębek, “Drug Policy in Latvia,” Value Heal. Reg. Issues, vol. 13, pp. 73–78, 2017. [23] C. of M. R. of Latvia, “Regulation No. 889 Procedures for Reimbursement of Expenditures for Acquisition of Medical Products and Medical Devices Intended for Outpatient Medical Treatment.” [Online]. Available: https://likumi.lv/ta/en/id/147522- procedures-for-the-reimbursement-of-expenditures-for-the-acquisition-of-medicinal- products-and-medical-devices-intended-for-the-outpatient-medical-treatment. [Accessed: 22-Oct-2019]. [24] “Portaria 224/2015, Diário da República, 1a Série, No 144/2015.” [Online]. Available: https://dre.pt/home/-/dre/69879391/details/maximized?p_auth=Ev8uUQ6y. [Accessed: 22-Oct-2019]. [25] N. Yousefi, G. Mehralian, F. Peiravian, and F. Noee, “Generic substitution policy implementation: A pharmacists’ perspective survey,” J. Generic Med., vol. 12, no. 1, pp. 17–25, 2015. [26] P. Lewek, J. Śmigielski, I. Banaś, and P. Kardas, “Pharmacist’s age affect information provided for pharmacy clients about generic substitution,” J. Med. Sci., vol. 86, no. 2, p. 163, 2017. [27] OECD Health Statistics, “Pharmaceutical Market: Generic Market.” [Online]. Available: https://stats.oecd.org/index.aspx?DataSetCode=HEALTH_STAT. [Accessed: 22-Oct- 2019]. [28] Zina O’Leary, The Essential Guide To Doing Your Research Project, 3rd Editio. SAGE Publication, Ltd., 2017. [29] C. C. Ping, M. B. Bahari, and M. A. Hassali, “A pilot study on generic medicine

32 substitution practices among community pharmacists in the Sate of Penang, Makaysia,” Pharmacoepidemiol. Drug Saf., no. 17, pp. 82–89, 2008. [30] I. Etikan, S. A. Musa, and R. S. Alkassim, “Comparison of Convenience Sampling and Purposive Sampling,” Am. J. Theor. Appl. Stat., vol. 5, no. January 2016, pp. 1–5, 2016. [31] L. M. Given, The SAGE Encyclopedia of Qualitative Research Methods. London: SAGE Publication, Ltd., 2008. [32] Kevin M. Sullivan, “OpenEpi - Sample Size for % Frequency in a Population (Random Sample).” [Online]. Available: http://www.openepi.com/SampleSize/SSPropor.htm. [Accessed: 22-Oct-2019]. [33] “Portaria 352/2012, Diário da República, 1a Série, No 210/2012.” [Online]. Available: https://dre.pt/pesquisa/-/search/191539/details/maximized. [Accessed: 22-Oct-2019]. [34] N. Harland and E. Holey, “Including open-ended questions in quantitative questionnaires-theory and practice,” Int. J. Ther. Rehabil., vol. 18, no. 9, pp. 482–486, 2011. [35] J. de A. G. F. A. I. F. Simões and C. Hernández-Quevedo, “Health Systems in Transition Portugal,” Port. Heal. Syst. Rev., vol. 19, no. 2, 2017. [36] “Lei 11/2012, Diário da República, 1a Série, No 49/2012.” [Online]. Available: https://dre.pt/pesquisa/-/search/542271/details/maximized. [Accessed: 22-Oct-2019]. [37] OECD, Health at a Glance 2017: OECD Indicators, vol. 49, no. 6. Paris: OECD Publishing, 1997. [38] I. Salmane Kulikovska, E. Poplavska, M. Ceha, and S. Mezinska, “Use of generic medicines in Latvia: awareness, opinions and experiences of the population,” J. Pharm. Policy Pract., vol. 12, no. 1, pp. 1–7, 2019. [39] E. Van Bever, M. Elseviers, M. Plovie, L. Vandeputte, L. Van Bortel, and R. Vander Stichele, “Attitudes of physicians and pharmacists towards international non-proprietary name prescribing in Belgium,” Basic Clin. Pharmacol. Toxicol., vol. 116, no. 3, pp. 264– 272, 2015. [40] S. S. Dunne, “What Do Users of Generic Medicines Think of Them? A Systematic Review of Consumers’ and Patients’ Perceptions of, and Experiences with, Generic Medicines,” Patient, vol. 9, no. 6, pp. 499–510, 2016. [41] C. Quintal and P. Mendes, “Underuse of generic medicines in Portugal: An empirical study on the perceptions and attitudes of patients and pharmacists,” Health Policy (New. York)., vol. 104, no. 1, pp. 61–68, 2012. [42] R. Heikkilä, P. Mäntyselkä, K. Hartikainen-Herranen, and R. Ahonen, “Customers’ and physicians’ opinions of and experiences with generic substitution during the first year in Finland,” Health Policy (New. York)., vol. 82, no. 3, pp. 366–374, 2007. [43] J. Maly, M. Dosedel, and A. Kubena, “Analysis of pharmacists’ opinions, attitudes and

33 experiences with generic drugs and generic substitution in the Czech Republic,” Acta Pol. Pharm. - Drug Res., vol. 70, no. 5, pp. 923–931, 2013. [44] C. P. Chong, M. A. Hassali, M. B. Bahari, and A. A. Shafie, “Exploring community pharmacists’ views on generic medicines: A nationwide study from Malaysia,” Int. J. Clin. Pharm., vol. 33, no. 1, pp. 124–131, 2011. [45] M. H. Bornstein, J. Jager, and D. L. Putnick, “Sampling in Developmental Science: Situations, Shortcomings, Solutions, and Standards.,” Dev. Rev., vol. 33, no. 4, pp. 357– 370, Dec. 2013. [46] K. Stewart et al., “Patient knowledge, perceptions, and acceptance of generic medicines: a comprehensive review of the current literature,” Patient Intell., no. January 2016, p. 1, 2014.

34 8. Attachments

Survey instruments – Prescription data collection form

Prescription in Patient Substitution for Patient refused Prescription Medicine INN? asked for a GM the GM? details (drug dispensed (Yes/No/Both) the GM? suggested? (Yes/No) name, form, (drug name, (Yes/No) (Yes/No) dosage, form, dosage, quantity) quantity)

Survey instruments – Survey Evaluating Pharmacists Perceptions: How Do They Think and How Do They Act Regarding Medication Replacement

This questionnaire aims to discover the daily practices, difficulties and perceptions of pharmacists regarding generic replacement. Generic replacement consists of the replacement of brand medication by a generic version with the same bioequivalence, safety, quality and efficacy. In this way, and considering the pharmacist is the main connection between medication and patients, it is important we understand how these health professionals may influence the practice of generic replacement. Lastly, we aim to understand the pharmacist’s perceptions and attitudes regarding the replacement, and which challenges they face when applying the concept.

Age: Professional experience (no. of years working as a pharmacist)

Opinion Regarding Generic Medication 1. In your opinion, generic medication is: 2. Do you agree some generic medication manufacturing laboratories are more trustworthy than others? (Agree, Don’t Agree) 3. Which ones do you trust the most? Why?

Knowledge About Brand Medication Replacement by Generic Medication Policy 1. What do you consider is the goal for replacing brand medication by generic medication?

35 2. Have you ever received any training or information regarding the generic replacement policy? (Yes/No). 3. Explain where you obtained this information or training 4. Do you agree more training or information regarding this policy and its goals is necessary? Explain. 5. Do you feel this policy is fulfilling its purpose? (Yes/No) Explain. 6. Which strategies would you wish to see implemented to ensure this policy is successful?

Challenges Faced During the Replacement 1. Do you suggest replacement when it’s possible to replace brand medication by generic medication? (Yes/No). 2. In your opinion, what are the advantages to generic replacement? 3. In your opinion, what are the disadvantages to generic replacement? 4. Do you face difficulties when you apply this policy? (Yes/No). 5. What are the most common difficulties you face? 6. What suggestions do you have for solving these difficulties? 7. What do you think encourages generic medication acceptance?