Round Table Meeting Report the Use of Generic Drugs in Thalassemia

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THE USE OF GENERIC DRUGS IN THALASSEMIA Middle East & North Africa Round Table Meeting

Wednesday, 29th July 2015 Chronic Care Center, Hazmieh - Lebanon

MEETING REPORT Prepared by: Androulla Eleftheriou BSc, MSc, PhD Executive Director, Thalassaemia International Federation Executive Director, Cyprus Alliance for Rare Disorders Head of the World Health Organisation (WHO) Collaborating Centre of the Thalassaemia Centre in Cyprus

with the generous support of EVIDA MEDICAL


TABLE OF CONTENTS Participants list

3

Speakers

4

Programme

5

President’s Message

7

Introduction

8

A. Definitions

11

B. 1. Regulatory Authorities and Generic Drugs

14

B. 2. Haw are generics evaluated

16

B. 3. Ensuring Quality

16

B. 4. Pharmacovigilance

20

C. challenges in the MENA Region

21

D. Conclusion and Action Checklist for Generics

26

APPENDIX I: The results of TIF’s survey on generics

28

APPENDIX II: Useful Website Links

37

EVIDA MEDICAL LIMITED rd 3 Floor 207 Regent street London W1B 2HH United Kingdom

EVIDA MEDICAL DMCC No. R27-14, Reef Tower Plot O1, Jumeirah Lake Towers P.O.Box 392528, Dubai United Arab Emirates

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PARTICIPANTS LIST:Androulla Eleftheriou Executive Director, Thalassaemia International Federation

Michael Angastiniotis Medical Advisor, Thalassaemia International Federation

Ali Taher Professor, American University of Beirut and Chronic Care Center, Lebanon

Suzanne Koussa Attending Physician, Chronic Care Center, Lebanon

Atholl Johnston Professor, Barts and The London School of Medicine and Dentistry, UK

Sarunas Narbutas President, Lithuanian Cancer Patient Coalition, Lithuania

Basem Ali Suleiman Attending Physician, Al Bashir Hospital & Hikma Pharma, Jordan

Amal El-Beshlawy Professor, Cairo University, Egypt

Jalel Gargouri Director, Faculty of Medicine SFAX, Tunisia

Soufiane Zghidi President, Taha Pharma, Tunisia

Houria Boukhelal Professor, University Hospital Center Mustapha Bacha, Algeria

Mahmood Hadipour Dehshal Pharmacist, Iranian Thalassaemia Association, Iran

Mehran Karimi Professor, Shiraz University, Iran

Jawad Abdulabbas Abboud Paediatrician, Diwanyah Maternity & Children’s Hospital, Iraq

Jovarian Mannan Professor, FMH College of Medicine and Dentistry Shadman; Chairperson, Thalassaemia Federation, Pakistan

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SPEAKERS: • • • • • • • • • • • •

Androulla Eleftheriou - Executive Director, Thalassaemia International Federation Michael Angastiniotis - Medical Advisor, Thalassaemia International Federation Ali Taher - Professor, American University of Beirut and Chronic Care Center, Lebanon Atholl Johnston - Professor, Barts and The London School of Medicine and Dentistry, UK Sarunas Narbutas - President, Lithuanian Cancer Patient Coalition, Lithuania Basem Ali Suleiman - Attending Physician, Al Bashir Hospital & Hikma Pharma, Jordan Jalel Gargouri - Director, Faculty of Medicine SFAX, Tunisia Soufiane Zghidi - President, Taha Pharma, Tunisia Houria Boukhelal - Professor, University Hospital Center Mustapha Bacha, Algeria Mahmood Hadipour Dehshal - Pharmacist, Iranian Thalassaemia Association, Iran Mehran Karimi - Professor, Shiraz University, Iran Jovarian Mannan -Professor, FMH College of Medicine and Dentistry Shadman; Chairperson, Thalassaemia Federation, Pakistan

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PROGRAMME:

Session 1: TIME: 09:00 – 11:00

Chairpersons/Moderators: Ali Taher/ Michael Angastiniotis

Androulla Eleftheriou Welcoming Message from TIF Objectives and Expected Outcomes of the meeting Ali Taher 09:15 - 09:25 Message from Meeting Coordinator Mouna Haraoui 09:25 – 09:30 Message from Chronic Care Centre Host Mahmood Hadipour 09:30 – 10:00 Global mapping on the Use of Generic Dehshal Drugs Atholl Johnston 10:00 – 10:30 Generic Drugs: How is their safety and effectiveness being secured in the EU and USA? Mahmood Hadipour 10:30 – 11:0 Quality, access and safety of Generic drugs in the Middle East and North Africa Dehshal Coffee Break: 11:00 – 11:11:15 - Cafeteria level -1 - CCC tour of the different sections with the group - Suzanne Koussa

09:00 – 09:15

Session 2: TIME: 11:15 – 13:30

11:15 – 11:30 11:30 – 11.45 11.45 – 11:55

11.55 – 12:10 12:10 – 12:25 12:25 – 12:40 12:40 – 13:30

Chairpersons/Moderators: Merhan Karimi/ Atholl Johnston Quality, access and safety of Generic drugs in the region:

i. IRAN ii (a) TUNISIA ii (b) How Safety and Efficacy is ensured? The Case of Tunisia iii. ALGERIA iv. JORDAN v. PAKISTAN

Merhan Karimi Jalel Gargouri Soufiane Zghidi Houria Boukhelal Basem Ali Suleiman Jovaria Mannan

Interactive discussion

LUNCH: 13.30 – 14:30 - Cafeteria level -1

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Session 3: TIME: 14:30 – 16:00 14:30 – 15:00 15:00– 15:40

15:40 – 16:00

Chairpersons/Moderators: Narbutas Sarunas/ Mahmood Hadipour Dehshal Sarunas Narbutas Patients’ Perspective on the Use of Generic Drugs Androulla Eleftheriou/ Presenting Data/Results from TIF’s Michael Angastiniotis Questionnaires- 2015: - The physicians’ perspective - The patients’ perspective Interactive Discussion

Coffee Break: 16:00 – 16:15 - Meeting Area

Session 4: TIME: 16:15 – 17:15

Chairpersons/Moderators: Androulla Eleftheriou/Ali Taher/Atholl Johnston/ Mahmood Hadipour Dehshal/ Michael Angastiniotis

16:15 – 17:00

What have we learnt? What we should look out for? What could and should do as next steps.

Ali Taher Atholl Johnston Mahmood Hadipour Dehshal

Meeting Targets:

Androulla Eleftheriou/Michael Angastiniotis

-

-

-

Recommendations/ Declaration on the safe and effective use of Generic Drugs – for Policy making Bodies at National, Regional and International level; Development of Information toolkits for: Health Professionals Patients/Parents The Role of TIF and its medical/scientific advisory panel

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PRESIDENT’S MESSAGE: The Thalassaemia International Federation (TIF) has been, and continues to be, dedicated to ensuring patient access to quality, i.e. safe and effective health care across the world. Although for a plethora of reasons, suboptimal or even no treatment at all is commonly encountered in still many countries, mainly of the ‘developing world’, poor resources and low Governments’ expenditure on health constitute the main ones. As a consequence and more specifically in the context of medicinal drugs, a significant global trend towards the use of more generic drugs, which are (should be) cheaper than the originator drugs, is occurring for some time now with more strengthened efforts in more recent years following the economic recession evidenced across the world. These drugs could play, on account of their better affordability, an essential role in increasing accessibility to patients to life-saving treatments, and this is of immense importance in the case of thalassaemia and other severe haemoglobin disorders (Hb), the management of which is both lifelong and expensive. However, this is an extremely critical turning point, as all stakeholders involved from official health authorities, the medical communities, the drug regulatory bodies, the industry, the academia, to the patients/parents organisations at the national, regional and international level, must become sensitised and committed to ensure that low costs do not compromise safety and efficacy.

Health expectations must be matched with available resources. We do not dismiss generic formulations as many of these are of excellent quality and can deservedly substitute the originator drug…” – Atholl Johnston- Professor of Clinical “

Pharmacology, Barts and the London, School of Medicine and Dentistry, U.K. ‘Round Table Meeting, Beirut, Lebanon, July 2015’.

No cost is greater both in terms of human as well as financial resources than that consequent to a failed or ineffective treatment. As a patient organisation, established and committed to support and strengthen patients’ rights for quality health and life, ensuring drug safety and efficacy for our patients across the world constituted, through the years, and will continue to constitute a major significant pillar of our work and focus. The report that follows is based on a ‘brainstorming’ Round Table meeting of key treating physicians from countries mainly of the MENA region (including Pakistan) and contributed also by patient advocates. Following this report, there will be a series of activities and actions on this critical, for patients and health professionals alike, issue, including the preparation, publication and distribution of a ‘White paper’ and a peer review article. With this opportunity I would like to thank all the members of the faculty, speakers, the Chronic Care Centre and particularly Mrs Mouna Haraoui, Prof Ali Taher-President of the Scientific Committee and Dr Khaled Musallem from the EVIDA DMCC.

Panos Englezos President

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INTRODUCTION: The management of thalassemia, in recent decades, has gone through dramatic advances1 and when such advances have been adopted and implemented by national authorities in a country including full financial coverage of the related services, these have led to impressive decreases in the number of deaths2 as well as significant changes in the causes of mortality and morbidity 2 . Crucial factors contributing to this evidenced success have been (i) the advent of effective blood transfusion and blood safety practices, (ii) the development of effective, almost personalised iron chelation therapy, (iii) the accurate and non-invasive measurement and evaluation of iron overload in vital organs such as the heart (T2*) and liver (LIC) and (iv) the integration of multidisciplinary approach into the care of patients. All these factors contributed immensely to the improved outlook of patients with thalassemia, today. Furthermore, in those countries that such advances in treatment have also been supplemented with the concomitant development and implementation of effective national prevention programmes, the success has been greater. The survival and quality of life of patients have dramatically improved (open-ended survival), and the immense costeffectiveness of such combined strategies (prevention & management) has been proven beyond any doubt3. Sadly, such successes have happened in only very few countries of the world. In the majority of countries where thalassaemia is highly prevalent and where it constitutes an important medical, public health, economic and social challenge, the current state of affairs is very different. Low Governments’ expenditure on health, the absence of prioritization of the disease and hence the existence of sub-optimal services for its management and prevention constitute the average common picture in the majority of the countries, worldwide; and although many countries in the Middle East and North Africa (MENA) region have made significant advances, through the years, albeit more in the management than in the prevention programmes, the situation is still far from optimal and considerable focus and work in this area are still urgently needed. Patients, where optimal and safe management is not secured, go through a painful journey, develop serious and various medical complications, need frequent hospitalisation and subsequently die at early ages; and being a genetic chronic disorder, the close and extended family go through a similar journey of pain, agony and frustration in trying to support, in as many ways as possible their siblings or relatives. It is thus important to focus and strengthen every effort towards improving the quality and safety of care of these patients, in this region and across the world. Focusing on the subject of this report, it is important to focus on the safety and quality of drugs, as a major component of quality care for patients with thalassaemia and other haemoglobin (Hb) disorders; importantly because it is anticipated that in an effort to increase accessibility of patients to life-saving drugs and in the interest of financial/budgetary restrictions, as a consequence of the global economic recession, the use of generic drugs will be actively promoted widely, across the world. The recent surge and global trend towards generic medications may narrow the drug availability and accessibility gap. Many of these of course are of excellent quality and can substitute the safety and effectiveness, of the originator product, particularly those adhering to regulations of recognised official drug regulatory agencies, including USAFDA and EMA. 1

rd

Guidelines for the management of Transfusion Dependent Thalassaemia (TDT) – TIF 3 Edition, 2014 Modell, B & Pennell, D. 2008; Voskaridou, E. 2012 3 Telfer, P. et al 2006 2

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However, with the lack of appropriate regulatory processes or the presence of ‘relaxed’ legal frames pertaining to the manufacturing and/or authorisation and/or monitoring and reporting of adverse reactions or side effects, in still many countries across the world, including in the MENA countries, the safety and effectiveness of generic drugs cannot be ensured. Moreover, in this region of the world, where patency protection is not respected, “copy” or “copied” drugs are produced and which are associated with even greater concerns and risks. In the case of thalassaemia, where, in most of the countries of this region, as well as other regions of the world, appropriate tools to monitor accurately and specifically, iron overload and thus the effectiveness of the iron chelation treatment are lacking, the level of contribution of the generic or “copy” drugs to any treatment ineffectiveness may not be easy to determine or assess. Advocating for changes to happen requires collaborations and knowledge, both on behalf of health professionals, and patients and their families, and certainly of the communities at large, each of which may potentially become a patient to use generic drugs. For the purpose of preparing for this meeting, a survey was conducted by TIF, through the dissemination of two questionnaires, one addressed to patients/parents and the other to the health professionals involved in the care of the disease, on a worldwide basis. The most striking key conclusion stemming from this survey was evidently the very ‘confined’ knowledge on behalf of the patients/parents (relating to the ‘truths’ and ‘myths’) and to a very big extent of the health professionals, across disciplines, on generic drugs and the regulatory policies, binding their manufacturing and authorization. It is thus of utmost importance for health professionals and patients’ organisations to engage, in a very coordinated way, in raising awareness and educational campaigns. In addition, it is also of primal importance to establish close and meaningful collaborations and networks with decision makers and relevant stakeholders at the national, regional and international level. Below, two maps shown underline the spread of drugs with poor quality, raising grave concerns for the patients’ populations: Map 1: The quality of medicines varies greatly, and not just in low- and middle-income countries

Sources: Various Media

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Map 2:

Examples of recent accounts of substandard drugs around the world

Source: Johnston A. & Holt, DW. Br. J Clin. Pharmcol. 2014 Aug; 78(2): 218-243

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The report is divided into four sections: A. Information on various definitions to facilitate better understanding and have consistency in future communication between the participants of this meeting, and by extension, of the project which aims to cover in the next year all regions of the world; B. Explanations given on some key aspects of the regulatory processes in ensuring or promoting safety and efficacy of generic drugs; C. Challenges in the Middle East and North Africa (MENA) region; D. Conclusions and Recommendations for future steps (plan of action 2016-2017)

A. DEFINITIONS: The working group agreed that certain terms needed to be clearly defined in order to avoid confusion, when using them in this text. The participants of the meeting requested to have clear definitions, mainly with regards to the following six different names with which drugs are often met in literature. An effort was made to provide the definitions as described by the World health Organisation (W.H.O.): (1) Brand, Originator, Innovative, Reference, New – (The word originator will be used in this text); (2) Generic drugs; (3) Copy or “copied” drugs-(The word ‘copy’ will be used in this text); (4) Substandard drugs; (5) Counterfeit drugs, and; (6) Bio-similar drugs – (not discussed in this meeting, but only mentioned as a different group of drugs). Group (1) refers to drugs that have been through three or more phases of rigorous clinical trials, over almost two decades, and are authorized by officially established regulatory agencies to be marketed and used by health care professionals (see diagram 1, below). The manufacturing company initially submits a New Drug Application (NDA) to test for safety, efficacy, and post-marketing monitoring. The regulatory authority supervises closely the quality and adherence of the manufacturer to conform to ‘Good Manufacturing Practice’ (GMPs), and to every other procedure and policy set by the regulatory authority. Diagram 1: Original Drug Development Chart

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Group (2) refers to drugs that are similar to those of Group (1), i.e., they contain the same quantity of the same active substances and are administered via the same route and at the same dose. These drugs, however, are not required to undergo through the same rigorous clinical trials, as the originator drug, and are authorized by regulatory agencies after submitting an Abbreviated New Drug Application (ANDA). Usually these drugs only undergo what is referred to as ‘bio-equivalence’ testing, and although this may not be sufficient to guarantee quality and clinical equity, this is, to date, considered as the proof that a generic drug has the same pharmacobio-equivalence, i.e. the same rate and extent of biological availability of the active substance in the body, when administered in the same dose, as an originator drug, to the point that they could be used interchangeably. A generic drug can only be manufactured according to regulations (USAFDA and EMA), when the patency protection and the data exclusivity period of the originator drug have expired.

Group (3) refers to drugs that are manufactured and “copy” the originator drug in violation of international patency laws. These range from good quality and effective drugs to poor quality substandard drugs to counterfeit ones, with consequent concerns and risks. A substandard drug (4) is the one that although is authorized to be used in a country, its manufacturing has not followed quality and safety protocols, as recommended or mandated by national, regional or international drug regulatory authorities, and as such its safety and effectiveness are greatly jeopardised. A sub-standard drug may contain too much or too little of the active ingredient, it may be contaminated, may be poorly packaged or fail to meet quality standards in other ways. A generic or a copy drug, the manufacture of which has not followed quality standards may fall into the category of sub-standard drug with associated risks and consequences. Counterfeit and bio-similar drugs will not constitute the focus of this report, but because they are often found across literature, please see below brief definitions given by W.H.O.4 and FDA5, respectively: (5) A counterfeit drug is one that is deliberately and fraudulently mislabeled with respect to identity and/or source. The active substance of such drugs may range from insufficient in quantity to complete lack thereof. Counterfeiting can apply to both branded and generic products and counterfeit products may include products with the correct ingredients or with

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the wrong ingredients, without active ingredients, with insufficient (inadequate quantities of) active ingredient(s) or with fake packaging4. (6) Bio-similar5 drugs are biological products that are highly similar to a USFDA-licensed originator biological product notwithstanding minor differences in clinically inactive components, and for which it is expected that these are not clinically meaningful differences.

4

Guidelines to develop measures to combat counterfeit drugs http://apps.who.int/iris/bitstream/10665/65892/1/WHO_EDM_QSM_99.1.pdf 5 Bio-similar: Gabionline.net/Biosimilars/General/FDA-definitions-of-generics-and-biosimilars.

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B. 1. REGULATORY AUTHORITIES AND GENERIC DRUGS Regulating agencies, such as the United States Food and Drug Administration (USFDA) and the European Medicines Agency (EMA), two of the most internationally recognised official drug regulatory bodies, require that the generic drugs deliver the same amount of active ingredient, over the same time frame to the patient and that it is of the same quality, strength, purity, stability, safety, and efficacy as the original drug. The USFDA and EMA, as well as other regulatory agencies in other countries (table 1) require that generic drugs undergo bioavailability6 and bioequivalence7 testing with sound scientific methodology (in quality assured laboratories) and ethical committee surveillance. Regulations include the need for (i) evaluation of active ingredient quality including identification and quantification of impurities; (ii) pre- and post-approval when the source of the active ingredient changes; (iii) identification and qualification of degradation production, and (iv) strict Good Manufacturing Practices (GMPs) and field inspection of factories and laboratory testing of the finished product. More illustratively, bio-equivalence 7 describes the rate and extent to which the active ingredient is absorbed from a drug product and becomes available in the general circulation. Two drugs are considered to be bioequivalent if their bio-availabilities after administration in the same dose are similar to the originator drug to such a degree that their effects, with respect to efficacy and safety, are essentially the same. Most countries use and authorize generic drugs that have been tested by recognised drug regulatory authorities (as those indicated in table 1) without requiring further studies of their own. Some countries however require further studies (table 2). Below, table 1 indicates the types of drug regulatory bodies in place, and table 2 designate those countries that require additional studies as part of their generic drugs’ application procedure: Table 1: The Regulatory Authorities as per the country

The regulatory

Source: Int. J. Sci. Rev. Res., 20(2) – 2013 6

Bioavailability: Refers to the extent to which a drug reaches its site of action after administration. For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action- Gabionline.net/Biosimilars/General/FDA-definitions-of-generics-and-biosimilars. 7 Bio-equivalence: Draft Guidance for Industry on Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs Submitted Under an Abbreviated New Drug Application (ANDA) (Dec. 2013).

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Table 2:

2015 European Meeting of ISMPP* International society for Medical Publication

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B. 2. HOW ARE OR SHOULD GENERIC DRUGS BE EVALUATED? Generic drugs, when their manufacturer adheres to quality standards (such as these mentioned by USAFDA and EMA), can potentially address quality management for patients, while at the same time decrease healthcare spending. They can certainly provide patients with access to life-saving medicines, whose costs would have otherwise been prohibitive. In order to achieve, however these goals, it is essential that generics must reach the same standard of quality, safety and efficacy, as those of the originator drugs. In thalassaemia, the use of iron chelators, i.e. the drugs responsible to reduce the toxic iron from the body to desired levels is life-long. In this context, there must be a continued fight (‘advocacy’) for high quality medicines. Safeguarding the quality of drugs constitutes, today and for some time now, not only the responsibility and commitment of regulatory authorities at the national, European (regional) and International level, but also of health professionals across disciplines and patients’ organisations across the world. In particular in countries outside Europe, i.e. in the Middle East, Africa, South East Asia and Western Pacific, where adherence to quality standards in the processes is not regulated or supervised efficiently or even in place at all.

B. 3. ENSURING QUALITY: Bio-equivalence studies are certainly an important first step but even in countries where this is strictly adhered to, it is by all relevant stakeholders considered that perhaps much more is needed to better safeguard the quality and clinical equivalence of generic drugs. Even under regulated conditions, such as those occurring in countries adhering to USAFDA and/or EMA, many common deficiencies have been reported in ANDA Chemistry reviews, including but not limited, on excipients’ quality, microbe contamination, impurities, drug release composition and formulations (Srinivasan, A et al, 2010)8. One can imagine the grave concerns that exist in countries where even bio-equivalence studies are not mandatory and are not performed or not performed appropriately. Certain pharmacokinetic (Pk) parameters are studied in the context of equivalence testing, including the measurement of the (i) Maximum Concentration of the drug reached in the blood (Cmax); (ii) time taken to reach it (tmax); (iii) how long (i.e. the duration) the drug concentration stays at effective levels in the blood referred to as the ‘Area Under the Curve-AUC), and (iv) the time required for a drug to lose 50% of its concentration in the blood referred to as the ‘halflife’ of the drug (t½) (see diagram 2, below). Diagram 2: Bio-equivalence parameters

C max

900 800

AUC

700 600

n o ti 500 a tr n e400 c n o C300

AUC

200 100 0 0

4

tm a x

8

12

16

20

24

Tim e © A t h oll Joh ns t on

8

Srinivasan A, Iser, R and Gill, DS: Pharmaceutical Technology 34: 45-51 2010

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These pharmacokinetic measurements are taken in the context of simple crossover trial studies, whereby young healthy volunteers who took the originator drug are switched to the generic, under study, after a washout period and vice versa. Typically, today when these studies are undertaken, they include a small sample size of approximately 18 to 24 subjects, who are usually young, healthy volunteers between the age of 18 and 30 years, and current regulations require only one positive study with a single dose comparison from a manufacturer-selected sample of the test drug. Testing of patients, however, is not actually requested and results from such ‘cross-over’ studies may not reflect adequately or represent accurately the evidence required to confirm the clinical equivalence between the two drugs. Such studies are expected to provide an 80% probability of detecting a 20% difference in the average bio-availability of the two formulations. An important example that demonstrates the distinction between clinical (or therapeutic) and pharmaco-equivalence is the one referring to the antidepressant medication Budeprion XL 300 mg, manufactured by Impax and Marketed by Teva, the generic form of Wellbutrin XL 300 mg (Glaxo SmithKline). Budeprion XL was considered, according to pharmacokinetic studies on healthy volunteers by the USFDA as being bioequivalent and thus assumed as therapeutically equivalent to Wellbutrin XL. However, it received 85 post-marketing reports of loss of antidepressant effect and an increase in side effects, when used by patients who were switched from Wellbutrin to Budeprion (its generic formulation). More than half of these patients reported improvement in antidepressant effect and reduction in side effects after switching back to Wellbutrin. Budeprion was eventually (and sadly only 6 years afterwards) withdrawn from the market. In addition, current bioequivalence regulations do not require studies on women, elderly or patients of different racial groups or studies on the influence of nutrition or of different dosage or excipients. It is known, however, that certain medications such as digoxin or verapamil have a different steady-state in elderly patients, who are typical candidates for the drug, versus young patients, while it is known that tacrolimus, an immune modulating drug, has variable serum concentrations in different racial groups; with regards to nutritional interactions, the iron chelator deferasirox provided to patients with thalassaemia and other iron loaded conditions has different concentrations over time between the fasted state and the fed state (high fat breakfast), and some generic forms of cyclosporine were reported to have decreased absorption as compared to the originator, (Neora, Novartis), when taken with apple juice or during the fasting state. Furthermore a generic form of cyclosporine was found to have progressively decreased AUC with higher doses, versus Neora, the originator drug. Excipients, the other chemical ingredients that are used to bind with the ‘active’ ingredient to complete the chemical formulation of the drug also constitute another source of potential problems. In the context of ANDAs protocols, it is not required, by the manufacturers of generic drugs, to include the same excipients, in the generic formulation, as those contained in the originator drug. Several potential problems can occur when generic drugs use different excipients, or even when they use the same but from different sources than those used by the manufacturers of the originator drug. Excipients, on their own may cause hypersensitivity reactions, peripheral neurotoxicity, dyslipidemia, inhibition of drug absorption and/or metabolism or even as serious as carcinogenicity. In addition, and very importantly, although quality assured (or accredited) laboratories; are expected to carry out the bio-equivalence studies, many generic drug manufacturing

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companies, in the developing regions of the world, are not using quality assured laboratories; But also in the ‘developed’ part of the world, in the interest of minimizing costs, manufacturers may outsource these studies to be conducted in laboratories, in developing countries, of unknown or substandard quality. Subsequently, as these do not operate under Good Manufacturing Practices’ (GMPs) policies, the risks and concerns potentially involved are thus many and diverse, and one must not ignore the fact that more than 8-10% of the active ingredients or products are manufactured in developing countries, mainly India and China. This year the EMA, for example, took a decision to suspend the licenses of approximately 700 medicines, produced in India and sold in Europe due to insufficient data to support their safe consumption. This decision was based on an inspection of the facilities in which the studies were conducted and the observation of poor quality laboratories and other facilities (Financial times, August 5, 2015).

COPY DRUGS: Certainly more concerns arise when the drug is “copied”, i.e., it is manufactured at a time when the patency protection of the manufacturer of the originator drug has not expired, and this certainly occurs only in countries outside Europe and USA or in those not accountable to EMA or FDA. In these cases, there is a risk that may vary from low to very high that the copied drug may not be of the quality of the originator, since in addition to the potential absence or “relaxed” measures on quality standards and GM Practices’ relevant information, data and manufacturing steps, as followed in the manufacture of the originator drug are not at the time of the production of the copy drug, yet fully disclosed by the manufacturer of the originator drug. Such information and data from the originator drug registration file is not disclosed to third parties, prior to patency expiration date. In this context, companies producing ‘copy’ drugs may need to invent and develop their own protocols and formulations of a product. Hence, drugs are not manufactured in an identical or near identical manner of those in the manufacture of the originator drug. These drugs are manufactured in countries with sub-optimal regulations and quality assessment policies, and hence, the risks associated with the copy drugs are far greater with regards to their safety and/or effectiveness. Below, the table 3 shows some common issues with substandard therapies and the potential implications for patients:

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Table 3: Common issues with substandard therapies and potential implications for patients

Activ e Ingre dient (API) Prop ertie s

Drug Prod uct Prop ertie s

Source: C. Nalin. 1st Pan-Asian Conference on haemoglobinopathies, Bangkok, Thailand, 2012

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B. 4. PHARMACOVIGILANCE Another major weakness in ensuring safety and effectiveness of drugs in general and even more importantly of generic formulations is the sub-optimal implementation or as on many occasions (in many countries) complete absence of an essential component of the regulations, the post-authorization monitoring of side effects and other unwanted effects such as loss of effectiveness, i.e. the pharmacovigilance programme. Such programmes, although required for both originator and generic formulations, these are poorly implemented, even in the Western world, and very poorly or not at all in many of the developing countries, including the MENA region. Pharmacovigilance is an important process to identify, report, assess and ultimately take corrective actions to promptly reduce the risks of any drug whether originator, generic or copy drug, and whenever drug withdrawals have occurred, these were consequent to information reported in the context of such pharmacovigilance programmes (mainly implemented in the EU and USA). This is a process. which when in place and functioning appropriately, it involves the contribution of all “players”, the national regulatory body, the health care professionals and the patients, and supports and guides official health authorities to decide on corrective measures. It is of utmost significance to underscore one important right, unique to European patients (hoping such rights to be extended across the world): “to report themselves any side effects they encounter or feel that they may be possibly attributed to the drug or drugs, they are receiving. Within or outside Europe, however, the ‘YELLOW CARD’ is or should be made available to ALL patients to report any unwanted side effects”, and health professionals should be sensitised and make every effort to encourage patients to use it and very importantly to utilize it themselves, towards the maximum benefit of the patients.

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C. CHALLENGES IN THE MIDDLE EAST AND NORTH AFRICA (MENA) REGION: The pharmaceutical market in the MENA region (spanning 18 countries from Morocco o Iran) first began to develop in the 1970s. Government spending, in this region, on health including on drugs is very low as compared to Western European countries and North America, and thus limits access of many patients to a number of originator drugs. The favourable economic environment, limited political risk, falling regulatory barriers and strong market growth potential, however, of the GCC countries make them an exception in the region and some of the most attractive markets in the MENA region (see diagram 3 below).

Significant scope to increase per capita pharmaceutical spend

Per capita drug spending(1) (US $) 900

40

Capital expenditure ($ million)

841 35

33.2

800

+ 41.2%

30

4.3 3.1

700 600

25

23.4

20

2.8 2.2

25.8

18.4 15

500 400

10

370

300

5

299

H1 2010

216

208

MENA

H1 2011

Europe

US

200 133 100

94

118

78 33

32

45

21

20

14

0

(1)

Source: Merrill Lynch Estimates, 2006 Source: Merrill Lynch Estimates

The low level of drug spending in this region (also evidenced in many other parts of the world) constitutes the main reason for the increases occurring, for some time now, in the use of generic formulations; albeit sadly, their prices, on occasions, may not be significantly lower than those of the corresponding originator drug, introducing other factors outside the scenario of benefit vs cost-effectiveness. In the absence of adequate regulatory authorities or the existence of ‘relaxed legal regulatory frameworks’ (fragmented regulatory procedures) in this region, as of course occurs in other regions of the world (mainly outside Europe and the USA), ensuring the safety and quality of generic and copy drugs that are being manufactured and distributed within the region or those imported from other regions is a true challenge. This issue should thus be made a mandatory priority as such current state-of-affairs may put sadly the populations of the regions at high risk. In order to create a trusting environment in the delivery of drugs to patients, there needs to be strong national drug regulatory authorities in every country of the region, which will have the responsibility to oversee the quality of the manufacturing process, the quality of active and excipient ingredients (locally produced or imported from countries within or outside the

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region). National Regulatory agencies need to have processes and policies in place, similar to those exercised by such regulatory bodies that have achieved international recognition for their contribution to the authorisation of safe and effective drugs, such as EMA or USFDA. It is an easy exercise for a National Health Authority or a National Regulatory Agency to set up processes to ensure adherence of local companies to regulations and to identify and recognise whether the country from which a drug is imported has such regulations in place. National Health Authorities (NHAs) can build on what is already working appropriately such as on USAFDA and/or EMA, regulations and guidelines. It requires, however, political commitment and very importantly sufficient knowledge on the part of the health professionals and patients/parents alike to collaborate closely, to bring the matter to the attention of the decision makers and whenever necessary to exert enough pressure to decision makers at the national level to achieve an impact, and make a change. When compared to North America and Europe, almost all the countries of the developing world, including those of the MENA region have a less developed, in some very weak, regulatory framework, including pharmacovigilance policies (tables 4, 5 & 6). Table 4:

Prerequisites for authorisation of generic drugs by USAFDA and/or EMA by some countries of the developing world

Registration requirements for Generics by authorities that are usually used as a reference (examples)

FDA EMA

Some Developing Countries

Bioavailability and bioequivalence testing with sound scientific methodology and ethical committee surveillance

v

Evaluation of active ingredient quality including identification and quantification of impurities (e.g. genotoxicimpurities)

v

v

Pre and post approval when source of active ingredient changes

v

v

Identification and qualification of degradation production in medicines, not just stability testing

v

v

Not a requirement

Strict cGMP and field inspections of plants

v

v

Just a few countries require

Actual laboratory testing of finished product, not stamping and paper work

v

v

Not a requirement in most

v Not a common requirement, in some not required at all

Source: M.H. Dehshal: Round Table meeting, Beirut, July 2015

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Table 5:

Comparison of Key Regulatory Authority of some Developing Countries

Country

Legislative and GMP Quality & Pharmacovigilance Regulatory Framework Complianc Safety Controle

Argentina

Medium-Low

Low-Medium

Medium

Low-Medium

Brazil

Medium-High

Medium

Medium

Medium-High

Egypt

Low-Medium

Low-Medium

Medium

Medium

China

High

Medium

Medium

Low-Medium

India

Low

Low

Low-Medium

Low

Peru

Low-Medium

Low-Medium

Medium

Low-Medium

Russia

Low-Medium

Medium

Low-Medium

Low-Medium

Thailand

Low-Medium

Medium

Low-Medium

Low-Medium

Turkey

Medium

Medium-Low

Medium

Low-Medium

Source: Keeping medicines safe – Extended by Paul Healy and Meir Pugatch

Table 6:

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Table 7 below depicts the current situation that prevails in 3 countries of the MENA region, i.e. KSA, Algeria and Jordan pertaining to the manufacturing, of generic or copy drugs, and Map 3 more specifically for the iron chelation drugs for thalassaemia: Table 7: Leading Manufacturers of generic and ‘copy’ drugs in the MENA region

Map 3:

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Tables 8 and 9 below refer to Deferiprone and Deferasirox, respectively and reflect the global production of their generic and ‘copy’ formulations and the associated levels of increase of side effects reported. Table 8:

Deferiprone Generic formulations:

Trade name

Country of manufacture

Number of centers using it

Increase side effects reported

GPO-L1 Kelfer

Thailand India (Cipla)

5 15

2: 5 centres 7: 15

DFP Aviccena

Iran

2

none

Ferripron

Bangladesh

2

1:2

DFP Meyer

Vietnam

1

1:1

Frinil

Pakistan (Global Pharma)

1

Available

Source: TIF’s Survey 2015 – Appendix I

Table 9: Deferasirox: Copy drug formulations: Trade name

Manufacturer

Country of manufacture

Number of centres using it

Increased side-effects reported

Desirox

Cipla

India

6

2: 6

Defrijet

Sun Pharma

India

4

1: 4

Oderox

AJM Pharma

India

1

No response

Desifer

-

India

1

0: 1

?? No Brand Name*

Shreeji Pharma

India

-

-

Osveral

Osveh Pharma

Iran

2

No response

Eliron

Aburauhan Pharmaceutical

Iran

-

-

?? No Brand Name*

Aviccena

Iran

-

-

Deferox

Hikma company

Jordan

-

_

Defrijet

Sunpharma

India

-

-

Chelaton

Tabuk Pharma

K. Saudi Arabia

1

1: 1

Xefra *

Global Pharma

Pakistan

?? No Brand name*

Taha Company

Tunisia

1:1 under trial

-

-

Source: TIF’s Survey 2015 – Appendix I; * - information obtained in the course of the Round Table meeting

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Take Action

D. CONCLUSION AND ACTION CHECKLIST FOR GENERICS: It was concluded that in the absence of reliable regulatory framework in the region, a consolidated plan of action was needed for patients, physicians across disciplines and other health care professionals, and the community at large, to become sensitised and more informed with regards to safety and efficacy of the generic (or copy) drugs, and for national health authorities to take action for high regulatory standards and pharmacovigilance. The participants unanimously agreed upon the following actions (checklist) as designated in table 10: Table 10: Consolidated Actions for developing joint activities:

Interaction and impact cannot occur in the absence of sufficient knowledge of those parameters and those processes that promote the safety and efficacy of non-originator drugs, generic or copy.

o Education of health professionals on the safety and efficacy of drugs: Generics &

o

o

o o

o

Copy drugs: i. Leaflets; ii. Presentations, Integration in workshops/conferences and delegation visits; Education of patients/parents on the safety and efficacy of drugs: Generics & Copy drugs: i. Leaflets; ii. Presentations, Integration in workshops/conferences and delegation visits. Preparation of a ‘White Paper’ to initiate and open official consultations and an on-going line of communication and dialogue with the W.H.O. (and its regional offices) and with every national health authority of each country promoting: i. Development of new or improvements and implementation of existing drug regulatory procedures for ensuring safety and effectiveness of generic/copy drugs; ii. Development of official collaboration with one/two Reference Laboratories (e.g., the WHO Collaborating Centre of Excellence in Uppsala, Sweden) to repeat bio-equivalence testing of generic/copy drugs coming from countries of doubtful regulatory control; Uploading the present report and ensuing ‘White Paper on patients and health professional bodies’ websites; Preparation and publication of an article based on TIF’s survey findings, but also based on the concerns of TIF and the network (of the Round table meeting) on the safety and effectiveness of generic/copy drugs to be published in a peer review journal, and; Establishment of an effective network of collaboration between TIF, health professionals and patients’ organisations in order to monitor events, news, changes etc (starting from the round table meeting participants).

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The Battle for Quality is non-ending… Battle for Quality

“The World Health Organisation estimated that one in five drugs made in India are fakes. A 2010 survey of Delhi pharmacies found 12 percent of sampled drugs were spurious.” ‘Indian Times 2013’ “In one recent example, counterfeit medicines at a paediatric hospital in Kashmir are now suspected of playing a role in hundreds of infant deaths there in recent years.” ‘Indian Times 2013’ “Ranbaxy, one of India’s biggest drug manufacturers’ pleaded guilty to felony charges and paid a $500 million fine last year.”

‘Adnan Abidi – REUTERS – 2013’

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APPENDIX I: The results of TIF’s Survey on Generic drugs Introduction: The Thalassaemia International Federation has recognised that the use of generic drugs is increasing. This is a development which could increase affordability and so accessibility to treatment across the globe. However this depends on the pricing but also the effectiveness, the side effects and the acceptance of these products by the patient community. TIF is also aware that several products are marketed in Middle Eastern countries and Asia which are in fact copy drugs (unlicensed by international agencies since patency protection of the original brand product has not expired. Such preparations are often licensed by the national authorities that are not bound by international agreement. TIF has therefore embarked on an investigation under the title: ‘The use of generic iron chelation drugs in patients with Hb Disorders – A first study of evaluation of their case” with a view to discovering the extent of the use of these formulations globally and to enable us to address the following questions, aiming to clarify the following issues: i. ‘Is the quality, of generic iron chelators similar to or comparable to brand names? ii. Do all generic drugs pass through official authorisation and quality check in every country? iii. Is efficacy and safety of generic drugs assessed by treating specialists when providing these to the patients, and is there feedback to the regulatory authority on these issues? iv. Do patients accept these products? Are they informed about the generic or copy drugs and are they given choices when health authorities decide to switch to these products from brand names (usually for economic reasons) In the field of haemoglobin disorders, patients’ survival and limitation of complications depend on the regular – daily - use of iron chelating agents to minimize the accumulation of toxic iron radicals which result from the need for regular blood transfusions and/or increased absorption from the gut. This life-long need is expensive and expense is a significant factor as to why many patients across the world do not receive adequate treatment, especially in the developing world where the majority of patients live. Non- adherence is also a factor and, if to this difficult regime, a negative view of the prescribed treatment is added, and then optimum treatment is seriously compromised. Even though the lower cost of generic drugs is an important factor influencing the higher rate of the consumption of therapeutic agents, concerns are expressed mainly from the side of patients, but also physicians. The differentiation between subjective impressions and real differences is a difficult exercise, but one which is important for health economics assessment, based on the efficacy of each preparation and the frequency of side effects. The study: The study is divided into two phases: • The first is fact finding from Drug regulatory authorities and physicians in each country or region • The second is an exploration of patients beliefs and feelings about generic drugs The results of these studies are summarised below: The questionnaire to medical centres: The objective of this study was to be informed not only about which preparations are used but also to see if doctors accept and are themselves given the freedom to choose what they

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consider best for their patients. According to a recent review, mandatory switching may lead to unexpected results and doctors should retain the right to request brands. The findings suggested that there may be a negative impact on adherence, poorer clinical outcomes, more adverse events and also that costs increase due to increase in doctors’ visits and hospitalisations [Straka RJ et al. Am J Ther. June 2015]. In another review of the impact of generic switching, involving 40 studies, it was found that in 67% there was no significant difference in clinical outcomes when the switch was made, but also in 64% it was found that generics increased cost. In other words there were similar clinical effects but economic benefits not guaranteed [Gothe H et al. Appl Health Econ Health Policy June 2015] It has also been established that African and East Mediterranean regions have the less developed regulatory framework [Alfonso-Cristancho R et al. Appl Health Econ Health Policy June 2015]. For this reason issues like bioequivalence (monitored in most countries), bioavailability (monitored in few countries) and good manufacturing practices are not well supervised. Results: a questionnaire was sent to 288 treating physicians from centres treating multitransfused patients in 46 countries. Of these, 114 physicians/centres (39.6%) from 42 countries have responded. These centres represent 25776 patients. The countries divided according to the 2014 list for Human Development Index [HDI]: Very High HDI [0.944-0.808] Canada KSA – Kuwait Singapore Israel Argentina Cyprus Hong Kong Germany France Italy Qatar UK USA Taiwan 15 countries

High HDI [0.790-0.700] Bulgaria Malaysia Trinidad & Tobago Sri Lanka Tunisia Algeria Brazil Oman Romania Iran Thailand

Medium HDI [0.698-0.556] Maldives Indonesia Egypt Vietnam Morocco India Cambodia Bangladesh Laos Philippines Iraq

Low HDI [0.540-0.337] Pakistan Myanmar Yemen Nepal Sudan

11 countries

11 countries

5 countries

Thalassaemia patients are not covered or are partially covered by health insurance: Very high HDI: In 3/11 centres insurance is not fully supportive to patients. In Canada only DFP is not covered. In Singapore 99% of thalassaemia patients are not insured and in Argentina 50% are not insured. High HDI: In 3/9 centres, thalassaemia patients have no insurance, while in 2 other centres 10-20% of patients are not covered Medium HDI in 10/16 centres there is no full coverage: in 6 centres there is no coverage for any patients, while in another 4 up to 90% are not covered. Low HDI: there is no coverage for patients in the three centres.

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Countries that stated that non-brand products are used: Country Desferrioxamine Deferiprone DFP DFO Algeria Kelfer Bangladesh Feripron, GPO-L1 Brazil DFO Brazil Cambodia GPO-L1 Canada DFO Canada Cyprus Hospira, Noritem Egypt Kelfer India Kelfer, Iran Italy Laos Malaysia Morocco Myanmar Nepal Pakistan Saudi Arabia Sri Lanka Taiwan Thailand UK USA Vietnam

Desfonak, DFO Jaber L1 Avesina Deferoxir DFO Italy GPO-L1 GPO-L1, Kelfer Kelfer Kelfer Kelfer Feripro Demoferidon, Talifer

Deferasirox DFX Derasirox

Desirox, Defrijet Osveral, (Exir)

Desifer, Defersirox

Desirox, Desifer Oderox Pakistan DFX Chelaton ?

Kelfer Kelfer GPO-L1, Kelfer

Hospira Mesylate Kelfer, DFP Vietnam

Notes: 1. Most very high HDI countries report only Desferrioxamine generic products – since the patent is long expired, it is expected that most countries will use generics. However Taiwan and Saudi Arabia state the use of other generics 2. Most of the less developed economies use ‘copy’ drugs produced either in India or locally in each country. These are mainly copies of Deferasirox. Deferiprone is not patented even though FDA and EMA have registered only Ferriprox. The manufacture of Kelfer preceded Ferriprox by many years. 3. Deferiprone products for the purposes of this paper are regarded as generic drugs while those of Deferasirox are regarded as copy drugs. 4. The centres of Yemen and Sudan have not any registered iron chelating drugs and report no generics 37 of the 114 (32.5%) report using non-brand products Trends from the doctors’ survey Medium /low HDI countries are more likely to use generics Very high/high HDI countries are more likely to have all 3 iron chelating agents registered Out of pocket contribution is necessary in 12/17 countries that use generics: 85% of these are medium/low HDI countries

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Out of pocket contribution is necessary in 6/20 countries that do not use generics: 83% of these are Very high/high HDI countries The patients’ awareness and attitude towards the use of non-brand products The patients’ views were sought via the support associations who circulated the questionnaire to their members. In addition an online version was provided. 96 patients responded, with the following characteristics: •

The countries of origin of the patients did not coincide with the countries from which we received reports from centres/physicians, although there was overlap:

Very High HDI [0.944-0.808] Country

Number of Patients

Canada KSA Kuwait

2 0 0

Singapore Israel Argentina Cyprus Hong Kong Germany France Italy

0 0 1 1 0 0 0 4

Qatar UK USA Taiwan Malta Australia

0 2 33 0 1 8 1 3 1 58

Netherlands

Greece UAE Total number of patients

High HDI [0.790-0.700] Country

Number of Patients

Bulgaria Malaysia

Medium HDI [0.698-0.556] Country

2 0 0

Maldives

Tunisia Algeria Brazil Oman Romania Mauritius Turkey

0 0 0 0 0 0 3 1

Vietnam Morocco India

Iran Thailand

10 2

Trinidad & Tobago Sri Lanka

18

Number of Patients

Indonesia

Egypt

Cambodia Bangladesh

Laos Philippines

South Africa Palestine

Low HDI [0.540-0.337] Country

Number of Patients

0 2 0

Pakistan Myanmar Yemen

4 0 0

0 0 6 0 3 0 0 1

Nepal Sudan Yemen

0 0 1 1

Afghanistan

2

14

6

• The average age was 33.7 years, the oldest was 58 years old • 34 were male and 61 female (ratio approx 1M:1.8F) • Their educational level is manly college graduates: College graduates 58 (60.4%) Some college education 13 (13.5%), therefore 71 (74%) have had some higher education High school graduation was achieved by 13 (13.5%) Elementary education in 9 patients (9.4%) One patient did not answer this question

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• The health status of the respondents described as at least good: Excellent 12 (12.5%) Very good 32 (33.3%) Good 40 (41.7%) Fair 9 (9.4%) Poor 3 (3.1%) Comments : The patients that have responded to this questionnaire have a self selection bias, in that they highly educated respondents from very high and high HDI countries. This is probably due to a language barrier in that the English speaking world and the educated of the nonEnglish speakers are more likely to respond. In the low HDI countries also the support associations who were asked to distribute the questionnaires to their patients have a weaker infrastructure and may have failed to sensitize their members. This bias has to be considered especially since the primary target was to target the countries where generics are most used. Another comment concerns the responses from the patients living in the USA. These patients have less contact with the international thalassaemia community, and their willingness to respond, along with the Australian responders may be a demonstration of the need to communicate. The questions concerning patient knowledge: 1. Do patients know the phases of drug development? • The responses were almost equally divided between the yes I know (45.8%) and an admission of ignorance (47%), with 5 patients (5.2%) not answering. • Were the responses related to HDI category? V High HDI High HDI Medium HDI Low HDI Yes I know 51.7% 38.9% 28.6% 50% No 44.8% 61.1% 71.4% 50% The relationship between country development and knowledge of the drug development process seems poor except in the medium HDI countries. The Low HDI group is small and the patients probably self selected. • Are responses related to educational level? College & Some High school Elementary Education not college education stated Yes I know 35 (49.3%) 6 (46.1%) 3 (33.3%) 2 Do not know 33 (46.4%) 7 (53.9%) 4 (44.4%) 1 No answer 3 (4.3%) 2 (22.2%) Total 71 (100%) 13 (100%) 9 3 There is no statistical difference in the two main categories, while the sample of those with elementary education is too small to give a meaningful conclusion. 2. 80 patients stated that they knew what a generic drug is. This is 83.3% of the sample 3. Must a generic go through clinical trials? The majority, 68 (70.8%) answered yes and only 23 (24%) answered correctly. Of those correct answers, 17/23 (74%) had reached college level education. Also 74% were from very high HDI countries (most from the USA) 4. Do you know what tests should be carried out before a generic drug is authorized?

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The majority 58.3% answered that they do know and 6.3% gave no answer and can also be presumed not to know, bringing those do not know up to 63.6%. This result is in agreement with the expression of ignorance to the previous question. 5. Is approval of generic drug necessary by a) a national authority? b) the EMA c) the FDA? 59.4% believe that national approval is necessary –however 35.4% did not know or did not answer 22.9% believe that EMA approval is needed – 63.6% did not know or did not answer 56.25% believe that FDA approval is needed –35.4% did not know or did not answer Only a minority stated that no authorization is needed in each category. Comment: Concerning patient knowledge generic drugs, overall in the analysis by the University, there was no statistical difference related to the level of education or age of the patients or the HDI of the country The questions regarding patient acceptance of generics 1. I would rather take a generic than a brand name product: • Strongly or somewhat disagree (taken to mean that they would not prefer a generic) was recorded by 20 and 13 respectively, a total of 33 (34.4%) • Neither agree or disagree (taken to mean that no opinion has been formed) was recorded by 34 patients (35.4%) • 13 (13.5%) of patients somewhat agreed with the statement (taken to mean that they would consider a generic over a brand name) • Only 9 patients (9.4%) would agree that they would rather take a generic 2. I would rather take a generic than no drug at all: • Strongly disagree (meaning that if a brand name product is not available it is better to avoid generics) – 9 patients (9.4%) • Somewhat disagree – 4 patients (4.2%) • Neither agree or disagree – 9 (9.4%) • The majority agreed and would prefer to take a generic somewhat agreeing 15 (15.6%) or strongly agreeing 52 (54.2%) • 7 patients did not respond (7.3%) 3. A brand product would be more effective: • Strongly disagree: 14 (14.6%) and somewhat disagree 23 patients (24%) – this group feels that effectiveness is equal or almost equal between generics and brands • 32 (33.3%) could not agree or disagree • Agreement that a brand product is more effective was agreed somewhat by 10 and strongly by another 10 patients – a total of 20 (20.8%) • 7 patients did not respond Overall there seems to be uncertainty among the patients on this issue and this seems to open the door to accepting generics as effective if there is adequate information. 4. A generic drug would cause more side effects: • Strongly disagree (= a generic is just as safe) was stated by 13 (13.5%) while another 13 somewhat disagreed. Overall this statement is rejected by 27% • 36 (37.5%) felt that they could neither agree or disagree • Agreement with the statement was somewhat in 15 (15.6%) and strong in 12 (12.5%). Overall this statement was accepted by 28% • 7 patients (7.3%) did not respond

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5. Generics are less expensive: Disagreement was expressed by only 2 patients and another 3 had no opinion. The vast majority agree that generics are cheaper – 31 somewhat agree and 52 strongly, making a total of 86.5% (8 abstained) Questions about the information provided by doctors concerning generic preparations and patient participation in decisions 1. The doctor talks about generics: • Never: 44 (45.8%) • Seldom 20 (20.8%) • Sometimes 13 (13.5%) • Most of the time 4 (4.2%) • Always 3 (3.1%) • No response from 12 patients (12.5%) In over 66.6% patients hardly ever hear fro doctors about generics 2. The doctor informs if a generic is available when the brand product runs out • Never 46 (47.9%) • Seldom 17 (17.7%) • Sometimes 11 (11.5%) • Most of the time 5 (5.2%) • Always 4 (4.2%) • No response 13 (13.5%) 3. Are you interested to know why your doctor decides to switch to a generic preparation? • Never 8 (8.3%) • Seldom 5 (5.2%) • Sometimes 7 (7.3%) • Most of the time 8 (8.3%) • Always 51 (53.1%) • No response 17 (17.7%) This desire of patients, according to the previous and the following responses is only partially satisfied 4. Does the doctor inform of his decision to switch? • Never 27 (28%) • Seldom 11 (11.5%) • Sometimes 9 (9.4%) • Most of the time 12 (12.5%) • Always 21 (21.8%) • No response 16 (16.6%) 5. Are you given a choice between a brand product and a generic? • Never 34 (35.4%) • Seldom 14 (14.6%) • Sometimes 11 (11.5%) • Most of the time 10 (10.4%) • Always 12 (12.5%) • No response 15 (15.6%) 6. Do you feel comfortable asking the doctor to change a generic to brand product? • Strongly disagree 5 (this means what? No I do not feel comfortable) • Somewhat disagree 5 (I feel somewhat uncomfortable?) • Neither (comfortable or uncomfortable?) 22 • Somewhat agree (? I feel somehow comfortable?) 25 • I strongly agree ( I am quite comfortable to ask?) 27 • No response 12

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7. Do you report side effects (either from brand or generics) to your doctor? 75% answered positively 11.5% answered that that they do not report 13.5% did not respond 8. Do you know if the doctor reports side effects? • Yes 29 (30.2%) • No 54 (56.3%) • No response 13 (13.5%) Comment: Whether the doctor provides information is not statistically related to the level of patient education (p= 0.137) or the HDI of the country (p= 0.164). However there is a statistically significant relationship of doctor reporting side effects to the relevant authorities according to the HDI from which patients originated – Very high HDI believe that their doctor does report side effects (p= 0.004). This relationship does hold in the question whether patients report side effects. Questions related the patient / doctor relationship 1. How would you describe the quality of treatment from your doctor: • Very poor 2 (2%) • Poor 4 (4.2%) • Satisfactory 29 (30.2%) • Very good 23 (24%) • Excellent 25 (26%) • No response 13 (13.5%) Comment: This is a satisfactory result with very few exceptions. 2. • • • • • •

Patient relationship with the doctor Very poor 1 (1%) Poor 2 (2%) Satisfactory 25 (26%) Very good 28 (29.2%) Excellent 28 (29.2%) No response 12 (12.5%)

Comment: In all questions which relate to the relationship with doctors there is an abstention 12-15 % Questions related to the reimbursement policy 1. The reimbursement policy of the country • Patient pays completely out – of pocket 18 (18.7%) • Full reimbursement 9 (9.4%) • Some copayment necessary 48 (40%) • No response 21 (21.9%) The lack of response by 22% of patients is surprising. The countries of origin of these non-responders: Malta 1 UAE 1 Australia 2 Bulgaria 1 Mauritius 2 Pakistan 1 UK 1 USA 2 Italy 2 Afghanistan 1 Yemen 1 Greece 1 Argentina 1 Iran 4

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Of these we know that free drugs are provided by at least 10 of these counties so possibly the question was not understood. Only a patient from Yemen gave a explanation for his lack of response (government pays through the society. Questions related to patient preferences concerning generics 1. If you could pay or co-pay, would you buy a brand or a generic preparation: • I would buy a generic 20 (20.8%) • I would buy either 28 (29.2%) • I would buy a brand 31 (32.3%) • No response 17 (17.7%) 2. I would never buy a generic iron chelating agent • No 60 (62.5%) • Yes 19 (19.8%) • No answer 17 (17.7%) 3. I would accept a generic if it was free • No 32 (33.3%) • Yes 46 (47.9%) • No answer 18 (18.8%) 4. I trust whatever my doctor prescribes • No 62 (64.6%) • Yes 19 (19.8%) • No answer 15 (15.6%) From these responses a good proportion of patients (around 50%) would accept a generic if necessary but about one third would definitely demand a brand product. Comment : Overall acceptance of generic drugs is not related to the educational level but the Higher HDI countries seem more likely to accept (p= 0.022)

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APPENDIX II: Useful Information for Further reading: 1. http://ec.europa.eu/health/documents/eudralex/index_en.htm 2. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3555014/ 3. http://www.who.int/medicines/publications/druginformation/DI_28-1_RegulatoryHarmonization.pdf 4. http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=celex:32004R0726

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