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FALSIFIED MEDICINES IN PERU: A Retrospective Review (1997-2014).

ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2015-010387

Article Type: Research

Date Submitted by the Author: 27-Oct-2015

Complete List of Authors: Medina, Edwin; University of Barcelona - Faculty of Pharmacy, Department of Pharmacy and Pharmaceutical Technology Bel, Elvira; University of Barcelona - Faculty of Pharmacy, Department of Pharmacy and Pharmaceutical Technology Suñé, Josep María; University of Barcelona - Faculty of Pharmacy, Department of Pharmacy and Pharmaceutical Technology

Primary Subject Public health Heading:

Secondary Subject Heading: Global health, Epidemiology, Health policy, Health services research

Keywords: Safety, Falsified, Medicines, Alerts, counterfeit, Drugs

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BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 FALSIFIED MEDICINES IN PERU: A Retrospective Review (1997-2014). 4 5 6 7 Authors: Edwin Medina1, Elvira Bel1, Josep María Suñé1 8 9 10 11 12 Affiliations: 13 14 15 1. DepartmentFor of peer Pharmacy and review Pharmaceutical only Technology, Faculty of 16 Pharmacy, University of Barcelona, Spain 17 18 19 20 Corresponding author: 21 22 Edwin Salvador Medina Vargas 23 24 Department of Pharmacy and Pharmaceutical Technology 25 Faculty of Pharmacy 26 University of Barcelona 27 Joan XXIII, s/n, 08028 Barcelona 28 29 Spain 30 Email: [email protected] 31 32

33 http://bmjopen.bmj.com/ 34 Keywords: Safety, Falsified, Medicines, Alerts, counterfeit, Drugs 35 36 37 38 39 Word Count 40

41 Abstract: 298 on September 24, 2021 by guest. Protected copyright. 42 Main text: 3440 43 Figures: 4 44 Tables: 2 45 Supplementary: 1 46 References: 56 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 27

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 ABSTRACT 4 5 6 7 Objective: To show the extent of the problem of falsified medicines in Peru. 8 9 10 Design: A retrospective review of drug alerts. 11 12 Setting: The General Directorate of Medicines, Supplies and Drugs (DIGEMID - 13 Ministry of Health of Peru) website search for drug alerts issued between 1997 14 and 2014. 15 For peer review only 16 Eligibility criteria: Drug alerts related to falsified medicines. 17 18 19 Results: A total of 669 Digemid Alerts were issued during the study period, 354 20 (52.91%) of which refer to a total of 1738 cases of falsified medicines (many 21 alerts deal with several cases at a time). Regarding the type of establishment 22 involved in the possession or sale of falsified medicines, 1010 cases (58.11%) 23 involved pharmaceutical establishments; 349 cases (20.08%) involved non- 24 pharmaceutical commercial outlets); in 126 cases (7.23%) the medicines were 25 seized in unauthorized trade (without any marketing authorization), and in 253 26 cases (14.56%) the type of establishment or business related with the seized 27 product is not identified. 28 29 30 The finding of 626 duplicate products/batches in the study period highlights the 31 persistence of falsified medicines on the market, and suggests that the impact 32 of the alert system needs to be revised.

33 http://bmjopen.bmj.com/ 34 Conclusions: In light of the results, there is no doubt that falsified medicines 35 represent a serious public health problem in Peru. A review of the data alone is 36 not enough to conclude whether falsified medicines in Peru have increased 37 38 during the study period, or if the monitoring action of different government 39 health agencies has brought the magnitude of the problem more to the surface 40 by providing more evidence. The problem is clearly structural, since the majority

41 of cases (58.11% of the total) were detected in legitimate supply chains. Most on September 24, 2021 by guest. Protected copyright. 42 falsified medicines involve staple pharmaceutical products and common dosage 43 forms. 44 45 Considerable work remains to be done to control the serious problem of falsified 46 medicines in Peru. 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 27 BMJ Open

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 INTRODUCTION 4 5 The WHO has been receiving reports of falsified medicines since 1982. [1] The 6 phenomenon was first referred to as a problem at the WHO Conference of 7 Experts on the Rational Use of Drugs in Nairobi, Kenya, in 1985. Since then, 8 public awareness of falsified medicines has grown, [2] and it has become a 9 10 major public health issue, as reflected by government initiatives worldwide in 11 response to the problem. 12 13 The issue of falsified medicines is so complex that, for example, even today 14 different definitions are used, or a falsified medicine is confused with one of 15 poor qualityFor (substandard), peer a serious review mistake that hampersonly the exchange of 16 information between countries, and makes it difficult to grasp the true scale of a 17 global problem. The WHO defines falsified medicines as those whose labels 18 19 include, intentionally and fraudulently, false information about their identity and 20 origin. Falsification can affect both branded and generic products, and may 21 include products with the correct or wrong ingredients, without active [2] 22 ingredients, with insufficient active ingredients or with fake packaging. 23 24 According to the WHO, the highest rates of medicine falsification in the world 25 occur in regions with the weakest regulatory and control systems, such as many 26 African, Asian, and Latin American nations and countries in transition. In most 27 industrialized nations, regulatory systems and market control are effective and 28 29 thus the incidence of spurious/falsely-labeled/falsified/counterfeit medicines is low, estimated to be less than 1% of the market value. [3] Medicine falsification 30 [4] 31 involves manufacturing and distribution networks related to organized crime, [5-6] 32 with annual turnovers between 75 and 200 billion dollars and has a [7] 33 significant impact even in large economies like the US. http://bmjopen.bmj.com/ 34 35 In general, the deregulation of any trade or business and the existence of 36 uninformed potential customers constitute a breeding ground for unscrupulous 37 criminal activities, whose sole purpose is to obtain illegitimate profits at the 38 39 expense of harming consumers and, in this case, the health system. In short, 40 this is what has happened with medicines in Peru (according to the World Bank,

41 a country of upper-middle income with a gross national income per capita of $ on September 24, 2021 by guest. Protected copyright. [8] 42 4126 - 12,745). A staple product (medicine) was subjected to the free market 43 by a political decision in the early 1990s without the slightest preliminary 44 analysis of the possible consequences, which have proved disastrous. Attempts 45 to amend certain irregularities have not achieved convincing results so far, as 46 evidenced by this study, despite the efforts and resources invested over the last 47 few years. 48 49 50 The consequences of this illegal phenomenon represent a serious public health [9] 51 problem, including treatment failure, possible cases of added contaminants, 52 and even death. It has also resulted in the deployment and disbursement of 53 often scarce resources, a loss of faith in health systems, distrust of medications 54 and even the failure of major global health policies such as the fight against 55 malaria. [10] 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 27

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 The regulatory authority for medicines in Peru is the General Directorate of 4 Medicines, Supplies and Drugs (DIGEMID), created by the Legislative Decree 5 No. 584 of 16 April 1990, [11] as a linear agency of the Ministry of Health of Peru. 6 In May 1998, the work instigated by the Directorial Resolution No. 367-98-DG- 7 DIGEMID in 1997 was normalized, and the Alerts Committee was created to 8 evaluate and define the actions to take regarding alerts or communications 9 [12] 10 about safety and/or efficacy of pharmaceuticals and related products. 11 12 13 14 OBJECTIVE 15 For peer review only 16 This work seeks to consolidate and assess information on falsified medicines in 17 pharmaceutical alerts issued by the Peruvian medicine agency in a period of 18 18 19 years (1997-2014) of health monitoring and enforcement. The ultimate aim is to 20 draw attention to the situation of falsified medicines in Peru and highlight the 21 efforts of various state institutions headed by DIGEMID. 22 23 24 25 METHOD 26 27 To develop this work, a retrospective and systematic review was carried out of 28 each Digemid alert about falsified medicines, published on the official DIGEMID 29 [13] 30 website from 1997 to December 2014. 31 32 Data from each of the aforementioned Digemid alerts were collected and

33 organized in Microsoft Excel spreadsheets, considering, extracting, and filling in http://bmjopen.bmj.com/ 34 the following information: 35 36 Alerts ordered by year. 37 38 Title of the published Digemid alert. 39 Date of publication. 40 Medicine.

41 Batch number. on September 24, 2021 by guest. Protected copyright. 42 Pharmaceutical dosage form. 43 Presentation. 44 Active ingredient. 45 Classification according to the ATC. 46 Establishment involved. 47 48 Establishment type. 49 Location. 50 Results of the evaluation. 51 Sanction, administrative or penal. 52 Promoter of the inspection. 53 Evaluation. 54 Remarks. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 27 BMJ Open

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 Based on the collected data, the following were determined: 4 5 The number of Digemid alerts issued per year. 6 The number of Digemid alerts about falsified medicines. 7 The number of cases of falsified medicines per year. 8 The number and type of establishments involved in falsified medicines. 9 10 The classification of the falsified medicines according to the ATC system 11 (the main anatomical group and therapeutic/pharmacological subgroups) 12 The classification of the falsified medicines according to their 13 pharmaceutical dosage form. 14 The number of cases of falsified medicines reported by the inspection or 15 controlFor agency. peer review only 16 The number of cases of falsified medicines according to the region where 17 they were seized. 18 The results of the evaluation. 19 20 21 22 23 RESULTS 24 25 In the 18-year period covered by this study (1997-2014), DIGEMID issued a 26 total of 669 alerts, 354 of which (52.91%) concern falsified medicines. It should 27 be mentioned that there is no direct relationship between the number of 28 29 Digemid alerts and the number of falsified medicines, since several alerts refer 30 to more than one medicine or different batches of the same product. In this [14] 31 sense, Digemid alert no. 27 of 2012 particularly stands out, as it deals with 32 74 cases of falsified medicines. Thus, the 354 Digemid alerts concerning

33 falsified medicines include a total of 1738 reported cases (Figure 1 and 2). http://bmjopen.bmj.com/ 34 35 36 37 Figure 1. Flow diagram showing types of Digemid alerts and overall 38 39 results. 40

41 on September 24, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 Figure 2. Digemid alerts and falsified medicines by year 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 27

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 In order to accurately show the origin of the falsified medicines, all the 1738 4 cases were analyzed, since each one was of identical illegality. Regarding the 5 type of outlet/establishment involved in the possession or sale of falsified 6 7 medicines leading to the issue of a DIGEMID alert, 1010 cases (58.11%) of the 8 total involved pharmaceutical establishments (pharmaceutical offices, 9 droguerías, botiquines and laboratories); 349 (20.08%) involved non- 10 11 pharmaceutical establishments (non-pharmaceutical commercial outlets); in 126 12 cases (7.25%) falsified medicines were seized in unauthorized trade (without 13 any marketing authorization), including 10 cases of clandestine laboratories; 14 and finally in 253 (14.56%) cases there is insufficient information to clearly 15 For peer review only 16 identify the type of establishment or business involved. 17 18 Regarding the pharmaceutical establishments, it should be noted that 850 19 (84.16%) of all cases of falsified medicines involved boticas and 130 (12.87%) 20 21 involved pharmacies (Table 1). 22 23 Table 1. Type of establishment or business related with the possession or 24 sale of falsified medicines. 25 26 27 TYPE OF ESTABLISHMENT/OUTLET TOTAL % 28 29 30 PHARMACEUTICAL 1010 58.11% 31 32 PHARMACY

33 Pharmaceutical store dispensing and retailing pharmaceuticals and 130 7.48% http://bmjopen.bmj.com/ 34 related products. Owned by a pharmacist. 35 BOTICA 850 48.91% 36 Pharmaceutical store dispensing and retailing pharmaceuticals and related products. Not owned by a pharmacist. 37 BOTIQUÍN 38 Sells pharmaceuticals and related products included in a restricted list 4 0.23% 39 by the Health Authority. 40 DROGUERÍA

41 Engaged in the import, export, marketing, storage, quality control and / 23 1.32% on September 24, 2021 by guest. Protected copyright. 42 or distribution of pharmaceuticals and related products. 43 LABORATORY 44 Engaged in manufacturing, packaging, bottling, conditioning, 3 0.17% 45 reconditioning, quality control, storage and export of pharmaceuticals 46 and related products. 47 NON-PHARMACEUTICAL 349 20.08% 48 49 50 UNAUTHORIZED TRADE 126 7.25% 51 52 53 NO INFORMATION 253 14.56% 54 55 TOTAL 1738 158.11% 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 27 BMJ Open

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 Regarding the location where falsified medicines were seized, Lima province 4 had the highest number of cases with 582 (33.49%), far outstripping La 5 Libertad, which had 315 (18.12%). Interestingly, no cases were reported in the 6 7 departments of Huanuco and Tumbes. More details are shown in Figure 3. 8 9 10 Figure 3. Number of cases of falsified medicines according to the 11 geographical location where they were seized. 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 Regarding the institution responsible for the surveillance or control activities that 24 led to the falsified medicine alerts during the study period, 1006 of all the cases 25 (57.88%) correspond to initiatives of decentralized health institutions (Health 26 Directorates - DISAs or Regional Health Directorates - DIRESAs), 168 (9.67%) 27 to various agencies formed by the National Police of Peru, the public 28 prosecutor, etc., 151 (8.69%) to DIGEMID itself, and in 413 (23.76%) cases the 29 promoter of the surveillance action is not specified. 30 31 It is very interesting to note the evolution of the monitoring activities during the 32

33 study period, since their decentralization coincided with an increase in http://bmjopen.bmj.com/ 34 inspections. This resulted in greater effectiveness, as can be seen in Figure 4. 35 36 Figure 4. Evolution of inspections according to the promoter. 37 38 39 40

41 on September 24, 2021 by guest. Protected copyright. 42 43 44 45 46 To obtain more precise results regarding the falsified medicines themselves, 47 identical batches (product/batch number) seized in more than one place or 48 mentioned in earlier alerts were excluded, ultimately resulting in a total of 1112 49 50 falsified medicines with different batch numbers, the details of which are shown 51 in Figure 1 and 2. 52 53 The number of falsified medicines classified according to the organ or system 54 on which they act, and the therapeutic and pharmacological subgroups of the 55 ATC code are detailed in Table 2. Among the therapeutic subgroups, painkillers 56 were the most frequently falsified medicines, representing 22.57% of all cases, 57 followed by systemic antibacterials at 19.78%. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 27

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 Table 2. Classification of the falsified medicines according to the ATC 4 Code 5 6 MAIN ANATOMICAL GROUP Nº % 7 N NERVOUS SYSTEM 297 26.71% 8 9 J ANTIINFECTIVES FOR SYSTEMIC USE 220 19.78% 10 G GENITO URINARY SYSTEM AND SEX HORMONES 217 19.51% 11 A ALIMENTARY TRACT AND METABOLISM 188 16.91% 12 R RESPIRATORY SYSTEM 90 8.09% 13 M MUSCULO-SKELETAL SYSTEM 32 2.88% 14 D DERMATOLOGICALS 25 2.25% 15 For peer review only SYSTEMIC HORMONAL PREPARATIONS, EXCL. SEX HORMONES AND H 15 1.35% 16 INSULINS 17 B BLOOD AND BLOOD FORMING ORGANS 15 1.35% 18 C CARDIOVASCULAR SYSTEM 9 0.81% 19 20 P ANTIPARASITIC PRODUCTS, INSECTICIDES AND REPELLENTS 3 0.27% 21 S SENSORY ORGANS 1 0.09% 22 L ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS 0 0.00% 23 V VARIOUS 0 0.00% 24 TOTAL 1112 100.00 25 THERAPEUTIC SUBGROUP Nº % 26 27 N02 ANALGESICS 251 22.57% 28 J01 ANTIBACTERIALS FOR SYSTEMIC USE 220 19.78% 29 G02 OTHER GYNECOLOGICALS 178 16.01% 30 R06 ANTIHISTAMINES FOR SYSTEMIC USE 68 6.12% 31 A11 VITAMINS 65 5.85% 32 A04 ANTIEMETICS AND ANTINAUSEANTS 40 3.60% 33 http://bmjopen.bmj.com/ 34 A07 ANTIDIARRHEALS, INTESTINAL ANTIINFLAMMATORY/ ANTIINFECTIVE AGENTS 36 3.24% 35 M01 ANTIINFLAMMATORY AND ANTIRHEUMATIC PRODUCTS 28 2.52% 36 G03 SEX HORMONES AND MODULATORS OF THE GENITAL SYSTEM 24 2.16% 37 N05 PSYCHOLEPTICS 21 1.89% 38 A03 DRUGS FOR FUNCTIONAL GASTROINTESTINAL DISORDERS 20 1.80% 39 40 OTHERS 161 14.48%

41 TOTAL 1112 100.00 on September 24, 2021 by guest. Protected copyright. 42 PHARMACEUTICAL SUBGROUP Nº % 43 N02B Other analgesics and antipyretics 232 20.86% 44 G02C Other gynecologicals 178 16.01% 45 46 J01E Sulfonamides and trimethoprim 102 9.17% 47 J01C Beta-lactam antibacterials, penicillins 71 6.38% 48 R06A Antihistamines for systemic use 68 6.12% 49 A04A Antiemetics and antinauseants 40 3.60% 50 A11J Other vitamin products, combinations 39 3.51% 51 A07D Antipropulsives 36 3.24% 52 Antiinflammatory and antirheumatic products, M01A 28 2.52% 53 non-steroids 54 N03A Antiepileptics 17 1.53% 55 N05B Anxiolytics 17 1.53% 56 Others 284 25.54% 57 58 TOTAL 1112 100.00 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 27 BMJ Open

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 Regarding the dosage form, 26 different types were found in the study period, 4 the most common being tablets (including coated and chewable), with a total of 5 816 cases (73.38%), followed by injectable dosage forms (injectable solution, 6 powder for injectable suspension, injectable suspension and powder for 7 injectable solution), with a total of 111 cases (9.98%); and 76 cases involving 8 capsules (6.83%). 9 10 11 Among the falsified medicines featured in the alerts of the study period, 164 12 cases (14.75%) had characteristics and/or information that did not correspond 13 to the product specifications, 100 (8.99%) did not contain an active ingredient, 14 12 (1.08%) had a different active ingredient to the one on the label, and 7 15 (0.63%) For had the correctpeer active ingredientreview but with only a different content than 16 authorized. It is noteworthy that in most cases 829 (74.55%) no information was 17 provided, which prevents a significant overall assessment. 18 19 20 21 22 DISCUSSION 23 24 Digemid alerts represent a valuable resource for the transfer of information on 25 the safety of medicines and related products to the general public. To be 26 effective and efficient, the alerts should provide detailed, homogenized and 27 standardized data. A timely assessment of their impact with respect to these 28 29 objectives is recommended. 30 31 This review demonstrates that the problem of falsified medicines in Peru is far 32 from insignificant. On the contrary, in light of the results presented here, the

33 country is facing a serious public health problem, which is even more apparent http://bmjopen.bmj.com/ 34 if these results are compared with those of similar studies in countries of high 35 health surveillance, such as the UK, with 7 cases of falsified medicines in 11 36 years (2001-2011) [15] or Canada with 4 cases in nine years (2005-2013). [16] 37 The difference is overwhelming. 38 39 40 One of the most striking and troubling aspects of the findings of this study is the

41 extent to which the medicine supply chain in Peru is being violated, with the on September 24, 2021 by guest. Protected copyright. 42 highest rate of falsified drugs found in pharmaceutical establishments 43 (pharmacies and boticas): 980 (56.39%) of a total of 1738 cases. This situation 44 is particularly worrying since, according to the Institute of Statistics and 45 Informatics of Peru (INEI), the Peruvian population mainly relies on the 46 pharmacy or botica for health care. [17] As well as a loss of consumer faith in the 47 legal supply chain, the resources, strategies and communication activities that 48 49 promote the responsible acquisition of safe medicines in legally established 50 pharmaceutical establishments are also being undermined. This situation 51 requires the active and joint participation of the regulatory authority and the 52 institutions representing the pharmaceutical establishments; moreover, the 53 cornerstone in solving the problem would be to grant a leading role to the 54 pharmaceutical professionals. [18] 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 27

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 No less worrying are the 349 cases involving non-pharmaceutical outlets, or the 4 126 cases of unauthorized trade, which include 10 cases related to clandestine 5 laboratories. 6 7 Considering the population density of Lima (34.53% of Peru’s 30,475,144 8 inhabitants), [19] it is not surprising that the capital city is the location of 582 9 10 cases in the falsified medicine alerts (33.49%), followed by La Libertad with 315 11 cases (18.12%). As indicated by the WHO, there can be an enormous variation 12 in the incidence of falsified medicines within the same country, whether 13 between rural and urban areas or between different cities. [20] This is an 14 important factor for the planning of appropriate strategies to combat the 15 problem.For peer review only 16 17 In this study, it is especially interesting to note the effect of the decentralization 18 of public health surveillance powers. In 1999, the Ministerial Resolution No. 19 [21] 20 150-99 / DM decreed that the regional and sub-regional health directorates 21 assume the functions of health control and monitoring, although the rules of 22 procedure and operation were not approved until 2003 by the Ministerial 23 Resolution No. 573-2003-SA / DM. [22] After a period of implementation, the 24 results begin to be seen in 2005, when the regional directorates participated in 25 8 cases, which grew to 75 in 2006 and 128 in 2007, reaching a cumulative 1006 26 cases over the study period, representing 57.88% of the total. In parallel, the 27 operational role of the centralized body, DIGEMID, was reduced, replaced by 28 29 coordination functions, among others. 30 31 In the period covered by this review, the alerts alluded to 1112 cases of 32 counterfeit medicines (product/batch). Based on the pharmacological/ [23] 33 therapeutic subgroups (2nd level) of the ATC code allotted to registered http://bmjopen.bmj.com/ 34 products in the DIGEMID database, [24] the most falsified medicines in Peru 35 were Analgesics (251 – 22,57%), followed by Antibacterials for systemic use 36 (220 – 19.78%) and Other gynecologicals (178 – 16.01%), Antihistamines for 37 systemic use (68 – 6.12%), and Vitamins (65 – 5.85%). To some extent, these 38 results reflect the most consumed medicines in Peru, as reported in the 2008 39 [25] 40 study, "The therapeutic value of the best-selling medicines in Peru", which according to the IMS are likely to remain the same in the near future. [26] At this 41 on September 24, 2021 by guest. Protected copyright. 42 point, it is pertinent to raise the issue of implementation of modern technologies 43 to detect falsified medicines [27] and the development of tools for the traceability 44 of pharmaceutical products. Among these are radio frequency technology [28-34] 45 and two-dimensional codes such as the Datamatrix system. Modern analytical 46 methods have been adapted to identify counterfeit medicines, leading to faster 47 and more effective results and allowing more timely action and communication 48 by the health authorities. In this way, the alert system is not only informative, but 49 [35-43] 50 becomes an effective tool. 51 52 The liberalization of the world economy, with fewer commercial borders and a 53 growing impact of the Internet on medicine advertising and trade means that 54 proposals for measures need to be global. Although the Digemid alerts provide 55 no data on the issue, trade in falsified medicines over the Internet is a major 56 global problem (particularly in developed countries). [44-45] Mafias involved in 57 medicine falsification will not have overlooked that the global pharmaceutical 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 27 BMJ Open

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 market is forecast to grow by around 4% per year (21% between 2012 and 4 2017). [46] The concern about falsified medicine is growing worldwide, in 5 developed as well as developing countries; although quantitatively different, its 6 impact on public health and the economy is similar in both. 7 8 Continuing the work of inspection is vital. Due to the magnitude of the problem, 9 10 the measures, activities and behaviors that allow high levels of falsified 11 medicines to enter the Peruvian pharmaceutical market, with a worrying [47] 12 violation of the legal supply chain, require a thorough analysis at an internal 13 (country) and external (global) level (using criteria used by the working groups 14 of the Member States of the WHO to define medical products as substandard, 15 spurious,For falsely-labeled, peer falsified review or counterfeit). only [48] It is necessary to 16 understand why the situation persists, despite the corrective measures in place. 17 All aspects of the problem need to be addressed, from health to economic, [49] 18 legal, [50] technological, social and cultural, which could lead to a renewal of 19 [51-55] 20 viable, effective and efficient strategies to combat this scourge. 21 22 A review based only on the data of the alerts cannot provide a precise 23 conclusion about the extent to which falsified medicines have penetrated the 24 Peruvian pharmaceutical market, or their typology. Nevertheless, the results of 25 this study give an idea of the magnitude of the problem, and suggest that a 26 rethinking of strategies is required to effectively combat the trade in falsified 27 medicines in Peru. Moreover, it is important to recognize that the situation could 28 [56] 29 worsen, as is occurring in many African countries. 30 31 32

33 STRENGTHS AND LIMITATIONS OF THIS STUDY http://bmjopen.bmj.com/ 34 35 Digemid alerts are published systematically, are organized by date, and 36 are readily available on the DIGEMID open access website. 37 The information they provide is not entirely homogenous and 38 39 standardized which is a limitation for an overall analysis. 40 The Digemid alerts do not use a standardized definition of falsified

41 medicines, thereby hindering an overall evaluation of the results. on September 24, 2021 by guest. Protected copyright. 42 The possible health effects resulting from the use of falsified medicines 43 are not addressed or included in the alerts. 44 Graphical reports of counterfeit medicines, which are an illustrative and 45 informative tool, are only provided in 3 alerts (Digemid Alerts 17-2006, 46 35-2005 y 40-2005). 47 48 49 50 51 CONCLUSIONS 52 53 In light of the results, it is clear that the falsification of medicines in Peru is 54 currently a serious public health problem. 55 56 A review based only on the data provided by alerts cannot conclude whether 57 58 falsified medicines have increased in Peru within the study period, or if the 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 27

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 action of different public health surveillance bodies has brought more evidence 4 to the surface about the magnitude of the problem. 5 6 The type of falsified medicines found in Peru is characteristic of developing 7 countries. 8 9 10 The problem is clearly structural or due to pharmaceutical policy, since the 11 highest incidence of cases of falsified medicines leading to DIGEMID alerts 12 involve legal supply chains. 13 14 Most cases of falsified medicines have been found in large cities. 15 For peer review only 16 The decentralization of health management has had a significant impact from 17 the inspection point of view. 18 19 20 Much work remains to be done to address this serious public health concern, 21 both in Peru and worldwide. 22 23 24 25 ACKNOWLEDGMENTS 26 27 We especially thank and dedicate this review to all people that day to day 28 29 fighting the scourge of counterfeit medicines in Peru. 30 31 32

33 FOOTNOTES http://bmjopen.bmj.com/ 34 35 Contributors: 36 37 38 EM drafted the manuscript. EM, EB and JS developed the initial concept and 39 design of the study and contributed to the qualitative analysis. All the authors 40 read and approved the final submitted version of the manuscript and accept

41 accountability for all aspects of the work. on September 24, 2021 by guest. Protected copyright. 42 43 Funding: 44 45 This work was supported by the Bosch i Gimpera Foundation (FBG) – 46 47 University of Barcelona. 48 49 Ethical approval: Not required. 50 51 Competing interests: None declared. 52 53 Provenance and peer review: Not commissioned; externally peer reviewed. 54 55 56 Data sharing statement: No additional data are available. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 27 BMJ Open

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 This is an Open Access article distributed in accordance with the terms of the 4 Creative Commons Attribution (CC BY 4.0) license, which permits others to 5 distribute, remix, adapt and build upon this work, for commercial use, provided 6 the original work is properly cited. 7 See: http://creativecommons.org/licenses/by/4.0/ 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 REFERENCES 4 5 6 7 1. Organización Panamericana de la Salud – OPS. Combate a la Falsificación 8 9 de Medicamentos. Found in file:///C:/Users/Edw/Downloads/GCFM- 10 Antecedentes-esp%20(2).pdf. Accessed on August 5, 2014. 11 12 2. WHO. Programmes – Essential medicines and health products. General 13 information on counterfeit medicines. Found in 14 15 http://www.who.int/medicines/services/counterfeit/overview/en/.For peer review only Accessed on 16 July 4, 2014. 17 18 3. OMS. Medicamentos espurios, de etiquetado engañoso, falsificados o de 19 imitación.Nota descriptiva N°275. Mayo de 2012. Found in 20 21 http://www.who.int/mediacentre/factsheets/fs275/es/. Accessed on August 5, 22 2014. 23 24 4. Dégardin K, Roggo Y, Margot P. Understanding and fighting the medicine 25 counterfeit market. J Pharm Biomed Anal. 2014 Jan;87:167-75. 26 27 5. World Health Organization. Growing threat from counterfeit medicines. Bull 28 29 World Health Organ. Apr 1, 2010; 88(4): 247–248. 30 31 6. Customs group to fight $200 bln bogus drug industry. Found in 32 http://www.reuters.com/article/2010/06/10/us-customs-drugs- 33 idUSTRE65961U20100610. Accessed on September 24, 2014. http://bmjopen.bmj.com/ 34 35 7. Blackstone EA1, Fuhr JP Jr2, Pociask S. The health and economic effects of 36 37 counterfeit drugs. Am Health Drug Benefits. 2014 Jun;7(4):216-24. 38 39 8. The World Bank. Data. Updated Income Classifications. Posted on 40 07/03/2014. Found in http://data.worldbank.org/news/2015-country-

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BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 http://www.digemid.minsa.gob.pe/UpLoad/UpLoaded/PDF/Normatividad/RD_36 4 7-1998.pdf. Accessed on August 11, 2014. 5 6 13. Dirección General de Medicamentos, Insumos y drogas (DIGEMID) – 7 8 ALERTAS – DIGEMID. Found in 9 http://www.digemid.minsa.gob.pe/Main.asp?Seccion=371. Accessed on August 10 12, 2014. 11 12 14. ALERTAS-DIGEMID. Found in 13 http://www.digemid.minsa.gob.pe/UpLoad/UpLoaded/PDF/Alertas/2012/ALERT 14 15 A_27-12.pdf.For Accessed peer on August review24, 2014. only 16 17 15. Almuzaini T, Sammons H, Choonara I. Substandard and falsified medicines 18 in the UK: a retrospective review of drug alerts (2001-2011). BMJ Open. 2013 19 Jul 24;3(7). 20 21 16. Almuzaini T, Sammons H, Choonara I. Quality of medicines in Canada: a 22 23 retrospective review of risk communication documents (2005-2013). BMJ Open. 24 2014 Oct 31;4(10):e006088. 25 26 17. Instituto de Estadística e Informática – INEI. Condiciones de vida en el Perú 27 Enero – Febrero – Marzo 2014. Informe Técnico No 2 – Junio 2014. 28 29 18. Chambliss WG, Carroll WA, Kennedy D. Role of the pharmacist in 30 31 preventing distribution of counterfeit medications. J Am Pharm Assoc (2003). 32 2012 Mar-Apr;52(2):195-9.

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BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 http://www.digemid.minsa.gob.pe/UpLoad/UpLoaded/PDF/RESOLUCIONMINIS 4 TERIALN573-03-SA_DM.pdf. Accessed on October 13, 2014. 5 6 23. WHO Collaborating Centre for Drug Statics Methodology. ATC/DDD Índex 7 8 2014. Found in http://www.whocc.no/atc_ddd_index/. Accessed on August 12, 9 2014. 10 11 24. Dirección General de Medicamentos, Insumos y Drogas (DIGEMID). 12 Registro Sanitario de Productos Farmacéuticos – Base de datos online de 13 productos. Found in 14 15 http://www.digemid.minsa.gob.pe/indexperudis.ASP?seccion=448.For peer review only Accessed 16 on August 12, 2014. 17 18 25. Meza Cornejo E. Valor terapéutico de los medicamentos más vendidos en 19 el Perú. Acción Internacional para la Salud Oficina de Coordinación América 20 21 Latina y el Caribe. Lima – Perú 2010. 22 23 26. Global Outlook for Medicines Through 2018 Exhibits. Found in 24 http://www.imshealth.com/portal/site/imshealth/menuitem.762a961826aad98f53 25 c753c71ad8c22a/?vgnextoid=6011f106fe3c9410VgnVCM10000076192ca2RC 26 27 RD. Accessed on February 2, 2014. 28 29 27. Kovacs S, Hawes SE, Maley SN. Technologies for detecting falsified and 30 substandard drugs in low and middle-income countries. PLoS One. 2014 Mar 31 26;9(3):e90601. 32 33 28. Taylor D . RFID in the pharmaceutical industry: addressing counterfeits with http://bmjopen.bmj.com/ 34 35 technology. J Med Syst. 2014 Nov;38(11):141. 36 37 29. Bansal D, Malla S, Gudala K et al. Anti-counterfeit technologies: a 38 pharmaceutical industry perspective. Sci Pharm. 2013 Mar;81(1):1-13. 39 40 30. Hall C. Technology for combating counterfeit medicine. Pathog Glob Health.

41 2012 May;106(2):73-6. on September 24, 2021 by guest. Protected copyright. 42 43 31. Bussy U, Thibaudeau C, Thomas F, et al. Isotopic finger-printing of active 44 45 pharmaceutical ingredients by 13C NMR and polarization transfer techniques as 46 a tool to fight against counterfeiting. Talanta. 2011 Sep 30;85(4):1909-14. 47 48 32. Sacré PY, Deconinck E, Daszykowski M. Impurity fingerprints for the 49 identification of counterfeit medicines--a feasibility study. Anal Chim Acta. 2011 50 51 Sep 9;701(2):224-31. . 52 53 33. Dipika Bansal, Swathi Malla, Kapil Gudala, et al. Anti-Counterfeit 54 Technologies: A Pharmaceutical Industry Perspective. Sci Pharm. Mar 2013; 55 81(1): 1–13. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 27 BMJ Open

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 34. Nityanand Zadbuke, Sadhana Shahi, Bhushan Gulecha, et al. Recent 4 trends and future of pharmaceutical packaging technology. J Pharm Bioallied 5 Sci. 2013 Apr-Jun; 5(2): 98–110. 6 7 8 35. Ranieri N, Tabernero P, Green MD, et al. Evaluation of a new handheld 9 instrument for the detection of counterfeit artesunate by visual fluorescence 10 comparison. Am J Trop Med Hyg. 2014 Nov 5;91(5):920-4. 11 12 36. Koesdjojo MT, Wu Y, Boonloed A et al. Low-cost, high-speed identification 13 of counterfeit antimalarial drugs on paper. Talanta. 2014 Dec;130:122-7. 14 15 For peer review only 16 37. Lebel P1, Gagnon J2, Furtos A. A rapid, quantitative liquid chromatography- 17 mass spectrometry screening method for 71 active and 11 natural erectile 18 dysfunction ingredients present in potentially adulterated or counterfeit 19 products. J Chromatogr A. 2014 May 23;1343:143-51. 20 21 38. Custers D, Canfyn M, Courselle P. Headspace-gas chromatographic 22 23 fingerprints to discriminate and classify counterfeit medicines. Talanta. 2014 24 Jun;123:78-88. 25 26 39. Anzanello MJ, Ortiz RS, Limbergerb RP et al. A multivariate-based 27 wavenumber selection method for classifying medicines into authentic or 28 29 counterfeitclasses. J Pharm Biomed Anal. 2013 Sep;83:209-14. 30 31 40. McCarthy M. Handheld device for counterfeit drug detection to be tested in 32 Africa. BMJ. 2013 Apr 26;346:f2732.

33 http://bmjopen.bmj.com/ 34 41. Deconinck E, Sacré PY, Courselle P. Chromatography in the detection and 35 characterization of illegal pharmaceutical preparations. J Chromatogr Sci. 2013 36 37 Sep;51(8):791-806. 38 39 42. Mbinze JK, Lebrun P, Debrus B. Application of an innovative design space 40 optimization strategy to the development of liquid chromatographic methods to

41 combat potentially counterfeit nonsteroidal anti-inflammatory drugs. Vols. J on September 24, 2021 by guest. Protected copyright. 42 43 Chromatogr A. 2012 Nov 9;1263:113-24. 44 45 43. Debrus B, Lebrun P, Kindenge JM, et al. Innovative high-performance liquid 46 chromatography method development for the screening of 19 antimalarialdrugs 47 based on a generic approach, using design of experiments, independent 48 49 component analysis and design space. Vols. J Chromatogr A. 2011 Aug 50 5;1218(31):5205-15. 51 52 44. Benton D, Williamson L, Stodart K. Buying medicine online is risky 53 business. Nurs N Z. 2014 May;20(4):27. 54 55 45. Mackey TK, Liang BA. Pharmaceutical digital marketing and governance: 56 57 illicit actors and challenges to global patient safety and public health. Global 58 Health. 2013 Oct 16;9:45. 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 27

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 46. EAE Business School: El Gasto Farmacéutico 2014. Found in 4 http://www.eae.es/news/2014/07/14/el-gasto-farmaceutico-publico-por- 5 habitante-cae-un-7-2-y-se-situa-en-196-52. Accessed on January 15, 2015. 6 7 8 47. Tremblay M. Medicines counterfeiting is a complex problem: a review of key 9 challenges across the supply chain. Curr Drug Saf. 2013 Feb;8(1):43-55. 10 11 48. OMS. Consejo Ejecutivo 134º reunión (EB134/25) del 3 de enero de 2014. 12 Productos médicos de calidad subestándar, espurios, de etiquetado engañoso, 13 falsificados o de imitación. Informe de la Directora General. Found in 14 15 http://apps.who.int/gb/ebwha/pdf_files/WHA67/A67_29-sp.pdf.For peer review only Accessed on 16 January 13, 2015. 17 18 49. Blackstone EA, Fuhr JP Jr, Pociask S. The health and economic effects of 19 counterfeit drugs. Am Health Drug Benefits. 2014 Jun;7(4):216-24. 20 21 50. Lai CW, Chan WK. Legislations combating counterfeit drugs in Hong Kong. 22 23 Hong Kong Med J. 2013 Aug;19(4):286-93. 24 25 51. Committee on Understanding the Global Public Health Implications of 26 Substandard, Falsified, and Counterfeit Medical Products; Board on Global 27 Health;Institute of Medicine; Buckley GJ, Gostin LO, editors. Countering the 28 29 Problem of Falsified and Substandard. Vol. Washington (DC): National 30 Academies Press (US); 2013 May. 31 32 52. Mackey TK, Liang BA. Improving global health governance to combat 33 counterfeit medicines: a proposal for a UNODC-WHO-Interpol trilateral http://bmjopen.bmj.com/ 34 35 mechanism. BMC Med. 2013 Oct 31;11:233. 36 37 53. Weigmann K. Elixirs of death. International organizations are working 38 towards a global solution to address the problem offalsified and substandard 39 medicines, but progress has stagnated. EMBO Rep. 2013 Jul;14(7):597-600. 40

41 54. Seear M. The need for coordinated action against falsified and substandard on September 24, 2021 by guest. Protected copyright. 42 43 medicines. Int J Tuberc Lung Dis. 2013 Mar;17(3):286. 44 45 55. Attaran A, Barry D, Basheer S. How to achieve international action on 46 falsified and substandard medicines. BMJ. 2012 Nov 13;345:e7381. 47 48 56. Newton PN, Tabernero P, Dwivedi P. et al. Falsified medicines in Africa: all 49 talk, no action. Lancet Glob Health. 2014 Sep;2(9):e509-10. 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 27 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

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41 on September 24, 2021 by guest. Protected copyright. 42 43 44 45 46 47 Figure 1. Flow diagram showing types of DIGEMID alerts and overall results. 440x599mm (300 x 300 DPI) 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 27 BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

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41 on September 24, 2021 by guest. Protected copyright. 42 43 44 45 46 47 Figure 2. Digemid alerts and falsified medicines by year 209x297mm (300 x 300 DPI) 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 27 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

41 on September 24, 2021 by guest. Protected copyright. 42 43 44 45 46 47 Figure 3. Number of cases of falsified medicines according to the geographical location where they were seized. 48 209x297mm (300 x 300 DPI) 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22 of 27 BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Figure 4. Evolution of inspections according to the promoter. 32 297x209mm (300 x 300 DPI)

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SUPPLEMENTARY DATA BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 TOTAL RESULTS 3 4 Table 1. Falsified medicines categorised by promoter of control 5 6 INSTITUTION TOTAL %

7 DIGEMID 151 8,69% 8 9 DISA / DIRESA 1006 57,88% OTHERS (National Police of Peru, Public Prosecutor, 10 168 9,67% 11 Customs, etc. 12 Without information 413 23,76%

13 TOTAL 1738 100% 14 15 Table 2. Falsified medicinesFor according peer to the ATC Code- review pharmacological subgroups only 16

17 SUBGRUPO TERAPÉUTICO TOTAL %

18 N02 ANALGESICS 333 19,15%

19 J01 ANTIBACTERIALS FOR SYSTEMIC USE 315 18,11% 20 G02 OTHER GYNECOLOGICALS 255 14,66% 21 R06 ANTIHISTAMINES FOR SYSTEMIC USE 198 11,39% 22 A11 VITAMINS 124 7,13% A04 ANTIEMETICS AND ANTINAUSEANTS 119 6,84% 23 ANTIDIARRHEALS, INTESTINAL ANTIINFLAMMATORY/ A07 68 3,91% ANTIINFECTIVE AGENTS 24 SEX HORMONES AND MODULATORS OF THE GENITAL G03 37 2,13% SYSTEM 25 M01 ANTIINFLAMMATORY AND ANTIRHEUMATIC PRODUCTS 37 2,13% DRUGS FOR FUNCTIONAL GASTROINTESTINAL 26 A03 25 1,44% DISORDERS 27 N03 ANTIEPILEPTICS 28 1,61% 28 A02 DRUGS FOR ACID RELATED DISORDERS 24 1,38% 29 H02 CORTICOSTEROIDS FOR SYSTEMIC USE 18 1,04% 30 N05 PSYCHOLEPTICS 22 1,27% 31 D08 ANTISEPTICS AND DISINFECTANTS 11 0,63% 32 R05 COUGH AND COLD PREPARATIONS 12 0,69% A10 DRUGS USED IN DIABETES 10 0,58% 33 http://bmjopen.bmj.com/ B03 ANTIANEMIC PREPARATIONS 13 0,75%

34 D02 EMOLLIENTS AND PROTECTIVES 8 0,46% ANTIPRURITICS, INCL. ANTIHISTAMINES, ANESTHETICS, 35 D04 8 0,46% ETC. 36 G04 UROLOGICALS 16 0,92% 37 R01 NASAL PREPARATIONS 13 0,75% 38 R03 DRUGS FOR OBSTRUCTIVE AIRWAY DISEASES 7 0,40% ANTIBIOTICS AND CHEMOTHERAPEUTICS FOR D06 2 0,12% 39 DERMATOLOGICAL USE CORTICOSTEROIDS, DERMATOLOGICAL D07 2 0,12% 40 PREPARATIONS M03 MUSCLE RELAXANTS 2 0,12%

41 on September 24, 2021 by guest. Protected copyright. N06 PSYCHOANALEPTICS 6 0,35%

42 A01 STOMATOLOGICAL PREPARATIONS 1 0,06%

43 A06 DRUGS FOR CONSTIPATION 1 0,06%

44 B01 ANTITHROMBOTIC AGENTS 1 0,06% 45 B05 BLOOD SUBSTITUTES AND PERFUSION SOLUTIONS 1 0,06% 46 C01 CARDIAC THERAPY 1 0,06% 47 C03 DIURETICS 1 0,06% 48 C04 PERIPHERAL VASODILATORS 1 0,06% 49 C08 CALCIUM CHANNEL BLOCKERS 3 0,17% C09 AGENTS ACTING ON THE RENIN-ANGIOTENSIN SYSTEM 1 0,06% 50 M02 TOPICAL PRODUCTS FOR JOINT AND MUSCULAR PAIN 1 0,06%

51 M05 DRUGS FOR TREATMENT OF BONE DISEASES 1 0,06%

52 N04 ANTI-PARKINSON DRUGS 1 0,06%

53 N07 OTHER NERVOUS SYSTEM DRUGS 1 0,06% 54 P01 ANTIPROTOZOALS 1 0,06% 55 P02 ANTHELMINTICS 1 0,06% ECTOPARASITICIDES, INCL. SCABICIDES, INSECTICIDES P03 1 0,06% 56 AND REPELLENTS 57 S01 OPHTHALMOLOGICALS 1 0,06% 58 B06 OTHER HEMATOLOGICAL AGENTS 2 0,12% C05 VASOPROTECTIVES 3 0,17%

59 A05 BILE AND LIVER THERAPY 1 0,06% 60 TOTAL 1738 99,94% For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24 of 27

Table 3. Cases of falsified medicines BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 CÓDIGO ATC MEDICAMENTO Nº % G02CC02 Naproxeno 245 14,10% 2 N02BE51 Paracetamol, combinaciones excl. Psicolépticos 236 13,58% R06AB54 Clorfeniramina, combinaciones 182 10,47% 3 A04AD Otros antieméticos 119 6,85% J01EE01 Sulfametoxazol y trimetoprima 102 5,87% 4 A07DA03 Loperamida 68 3,91% A11JC Vitaminas, otras combinaciones 67 3,86% J01CE02 Fenoximetil penicilina 62 3,57% 5 J01EB52 Sulfametizol, combinaciones 57 3,28% N02BE01 Paracetamol 55 3,16% 6 A11DB Vitamina B1 en combinación con vitamina B6 y/o vitamina B12 36 2,07% M01AE01 Ibuprofeno 20 1,15% 7 N03AB02 Fenitoína 18 1,04% J01AA07 Tetraciclina 17 0,98% G03FA12 Medroxyprogesterone y estrógenos 16 0,92% 8 J01CE Penicilinas sensibles a la betalactamasa 14 0,81% N05BA12 Alprazolam 14 0,81% 9 A11HA52 Piridoxina (vit. B6), combinaciones 14 0,81% A02AA04 Hidróxido de magnesio 13 0,75% 10 A03DB04 Butilescopolamina y analgésicos 13 0,75% J01BA01 Cloranfenicol 12 0,69% B03AB Hierro trivalente, preparados orales 12 0,69% 11 J01FF02 Lincomicina 14 0,81% R06AB04 Clorfenamina 11 0,63% 12 G04BX06 Fenazopiridina 11 0,63% H02AB02 Dexametasona 10 0,58% 13 N02BA51 Ácido acetilsalicílico, combinaciones excl. psicolépticos 10 0,58% A10BB01 Glibenclamida 10 0,58% R01AX Otros preparados nasales 10 0,58% 14 N02CA52 Ergotamina, combinaciones excl. psicolépticos 10 0,58% G02CC01 Ibuprofeno 10 0,58% 15 A02AX Otras combinaciones con antiácidos For peer8 0,46% review only D02AX Otros emolientes y protectores 8 0,46% 16 D04AB51 Lidocaina, combinaciones 8 0,46% D08AJ Compuestos de amonio cuaternario 8 0,46% N02AX52 Tramadol, combinación con 10 0,58% 17 N03AE01 Clonazepam 8 0,46% J01CA04 Amoxicilina 7 0,40% 18 R05DA09 Dextrometorfano 7 0,40% N02BB02 Metamizol sódico (dipirona) 7 0,40% 19 A03AX13 Siliconas 6 0,35% M01AB05 Diclofenaco 6 0,35% H02AB01 Betametasona 5 0,29% 20 J01CA54 Amoxicilina, combinaciones 5 0,29% M01AB15 Ketorolaco 5 0,29% 21 G03AA Progestágenos y estrógenos, preparados de dosis fijas 4 0,23% G03AA07 Levonorgestrel y estrógeno 4 0,23% 22 G03EA03 Prasterona y estrógeno 4 0,23% J01GB06 Amikacina 4 0,23% R03CC52 Salbutamol, combinaciones 4 0,23% 23 A03DC Otros antiespasmódicos en combinación con analgésicos 3 0,17% A11EA Vitaminas del complejo B solas 3 0,17% 24 J01GB03 Gentamicina 3 0,17% J01XE01 Nitrofurantoína 3 0,17% 25 N02AX02 Tramadol 3 0,17% A03FA51 Metoclopramida, combinaciones excl. Psicolépticos 3 0,17% G03AC06 Medroxiprogesterona 3 0,17% 26 N06BX06 Citicolina 3 0,17% G03DA04 Progesterona 3 0,17% 27 G04BX Otros productos urológicos 3 0,17% N06AB06 Sertralina 3 0,17% 28 D07CC01 Betametasona con antibióticos 2 0,12% A02BB01 Misoprostol 2 0,12% A11AA03 Multivitamínicos con otros minerales, incl. combinaciones 2 0,12% 29 D08AG02 Iodo povidona 2 0,12% G03AC03 Levonorgestrel 2 0,12% 30 J01CA01 Ampicilina 2 0,12% J01DA06 Cefuroxima 2 0,12% 31 J01MA02 Ciprofloxacino 2 0,12% N02BG Otros analgésicos y antipiréticos 2 0,12% N03AX11 Topiramato 2 0,12% 32 N05BA06 Lorazepam 2 0,12% R05DA59 Dextrometorfano, combinaciones 2 0,12% 33 R06AB52 Dexchlorpheniramine, combinations 2 0,12% http://bmjopen.bmj.com/ J01MA56 Norfloxacino, combinacion 2 0,12% 34 M01AC06 Meloxicam 2 0,12% R01AA08 Nafazolina 2 0,12% A11BA Multivitamínicos solos 2 0,12% 35 B06AA02 Fibrinolisina y desoxirribonucleasa 2 0,12% C05BA51 Heparinoides, combinaciones 3 0,17% 36 C08CA06 Nimodipino 2 0,12% H02AB07 Prednisona 2 0,12% 37 M01AB55 Diclofenaco, combinaciones 2 0,12% N05CD08 Midazolam 2 0,12% A01AD05 Ácido acetilsalicílico 1 0,06% 38 A06AD11 Lactulosa 1 0,06% B01AB01 Heparina 1 0,06% 39 B03AE10 Varias combinaciones 1 0,06% B05BC01 Manitol 1 0,06% 40 C01DA08 Dinitrato de isosorbida 1 0,06% C03DA01 Espironolactona 1 0,06% C04AD03 Pentoxifilina 1 0,06%

41 C08CA56 Nimodipino, combinaciones 1 0,06% on September 24, 2021 by guest. Protected copyright. C09AA02 Enalapril 1 0,06% 42 D06AX54 Neomicina, combinaciones 1 0,06% D06BA Sulfonamidas 1 0,06% D08AX07 Sodium hypochlorite 1 0,06% 43 G03CA03 Estradiol 1 0,06% G04BD02 Flavoxato 1 0,06% 44 G04BE03 Sildenafilo 1 0,06% H02AB09 Hidrocortisona 1 0,06% 45 J01AA02 Doxiciclina 1 0,06% J01AA56 Oxitetraciclina, combinaciones 1 0,06% J01CF01 Dicloxacilina 1 0,06% 46 J01DH02 Meropenem 1 0,06% J01FA01 Eritromicina 1 0,06% 47 J01FF01 Clindamicina 1 0,06% M01AE02 Naproxeno 1 0,06% 48 M02AC Preparados con ácido salicílico y derivados 1 0,06% M03AB01 Suxametonio 1 0,06% M03BC01 Orfenadrina (citrato) 1 0,06% 49 M05BA06 Ácido ibandrónico 1 0,06% N04BA02 Levodopa con inhibidor de la decarboxilasa 1 0,06% 50 N05AD01 Haloperidol 1 0,06% N05AL05 Amisulprida 1 0,06% 51 N05BA09 Clobazam 1 0,06% N07XX Otras drogas que actúan sobre el sistema nervioso 1 0,06% P01BA01 Cloroquina 1 0,06% 52 P02CA03 Albendazol 1 0,06% P03AX01 Benzoato de bencilo 1 0,06% 53 R01BA52 Pseudoefedrina, combinaciones 1 0,06% R03AC02 Salbutamol 1 0,06% 54 R03BA02 Budesonida 1 0,06% R03CC63 Clenbuterol, combinaciones 1 0,06% R05CB01 Acetilcisteína 1 0,06% 55 R05CB03 Carbocisteína 1 0,06% R05X Otros preparados para el resfriado 1 0,06% 56 R06AE07 Cetirizina 1 0,06% R06AE08 Levocetirizina 1 0,06% 57 R06AX27 Desloratadina 1 0,06% S01AA53 Neomicina, combinaciones 1 0,06% A02AF01 Magaldrato y carminativos 1 0,06% 58 A05AX Otras drogas para terapia biliar 1 0,06% J01MA12 Levofloxacino 1 0,06% 59 M01AH01 Celecoxib 1 0,06% N05BA08 Bromazepam 1 0,06% 60 N02CA Alcaloide ergotamian 0 0,00% TOTAL 1738 100,00% For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 25 of 27 BMJ Open

Table 4. Falsified medicines – Type BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1

2 RESULTS OF THE EVALUATION TOTAL % 3 4 Not contain an active ingredient 183 10,53% 5 6 A different active ingredient to the one on the label 14 0,81% 7 8 Correct active ingredient but with a different content than authorized 7 0,40% 9 Characteristics and/or information that did not correspond to the 279 16,05% 10 product specifications 11 12 Without information 1255 72,21% 13 14 TOTAL 1738 100,00%

15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

TOTAL RESULTS – WITHOUT DUPLICATES BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 Table 5. Cases of falsified medicines 3 CÓDIGO ATC MEDICAMENTO Nº % N02BE51 Paracetamol, combinaciones excl. Psicolépticos 193 17,36% 4 G02CC02 Naproxeno 170 15,29% J01EE01 Sulfametoxazol y trimetoprima 62 5,58% 5 R06AB54 Clorfeniramina, combinaciones 53 4,77% J01CE02 Fenoximetil penicilina 47 4,23% 6 A04AD Otros antieméticos 40 3,60% J01EB52 Sulfametizol, combinaciones 40 3,60% A11JC Vitaminas, otras combinaciones 39 3,51% 7 A07DA03 Loperamida 36 3,24% N02BE01 Paracetamol 24 2,16% 8 N05BA12 Alprazolam 13 1,17% A11DB Vitamina B1 en combinación con vitamina B6 y/o vitamina B12 12 1,08% M01AE01 Ibuprofeno 11 0,99% 9 A03DB04 Butilescopolamina y analgésicos 11 0,99% G04BX06 Fenazopiridina 11 0,99% 10 A11HA52 Piridoxina (vit. B6), combinaciones 10 0,90% J01BA01 Cloranfenicol 10 0,90% B03AB Hierro trivalente, preparados orales 10 0,90% 11 R06AB04 Clorfenamina 10 0,90% J01FF02 Lincomicina 10 0,90% 12 N02AX52 Tramadol, combinación con 10 0,90% J01CE Penicilinas sensibles a la betalactamasa 9 0,81% J01AA07 Tetraciclina 8 0,72% 13 H02AB02 Dexametasona 8 0,72% N03AE01 Clonazepam 8 0,72% 14 N02CA52 Ergotamina, combinaciones excl. psicolépticos 8 0,72% G02CC01 Ibuprofeno 8 0,72% 15 A02AA04 Hidróxido de magnesio 7 0,63% N03AB02 Fenitoína For peer7 review0,63% only G03FA12 Medroxyprogesterone y estrógenos 7 0,63% 16 N02BA51 Ácido acetilsalicílico, combinaciones excl. psicolépticos 7 0,63% A10BB01 Glibenclamida 7 0,63% A02AX Otras combinaciones con antiácidos 7 0,63% 17 D02AX Otros emolientes y protectores 7 0,63% D04AB51 Lidocaina, combinaciones 7 0,63% 18 J01CA04 Amoxicilina 7 0,63% N02BB02 Metamizol sódico (dipirona) 6 0,54% 19 M01AB05 Diclofenaco 6 0,54% J01CA54 Amoxicilina, combinaciones 5 0,45% M01AB15 Ketorolaco 5 0,45% 20 R01AX Otros preparados nasales 4 0,36% D08AJ Compuestos de amonio cuaternario 4 0,36% 21 A03AX13 Siliconas 4 0,36% H02AB01 Betametasona 4 0,36% G03AA07 Levonorgestrel y estrógeno 4 0,36% 22 R05DA09 Dextrometorfano 4 0,36% G03AA Progestágenos y estrógenos, preparados de dosis fijas 3 0,27% 23 J01GB06 Amikacina 3 0,27% R03CC52 Salbutamol, combinaciones 3 0,27% J01GB03 Gentamicina 3 0,27% 24 A03FA51 Metoclopramida, combinaciones excl. Psicolépticos 3 0,27% G03AC06 Medroxiprogesterona 3 0,27% 25 N06BX06 Citicolina 3 0,27% G03DA04 Progesterona 3 0,27% N06AB06 Sertralina 3 0,27% 26 D07CC01 Betametasona con antibióticos 2 0,18% G03EA03 Prasterona y estrógeno 2 0,18% 27 A03DC Otros antiespasmódicos en combinación con analgésicos 2 0,18% J01XE01 Nitrofurantoína 2 0,18% G04BX Otros productos urológicos 2 0,18% 28 A02BB01 Misoprostol 2 0,18% D08AG02 Iodo povidona 2 0,18% 29 J01CA01 Ampicilina 2 0,18% J01MA02 Ciprofloxacino 2 0,18% N02BG Otros analgésicos y antipiréticos 2 0,18% 30 N03AX11 Topiramato 2 0,18% N05BA06 Lorazepam 2 0,18% 31 R05DA59 Dextrometorfano, combinaciones 2 0,18% R06AB52 Dexchlorpheniramine, combinations 2 0,18% 32 J01MA56 Norfloxacino, combinacion 2 0,18% M01AC06 Meloxicam 2 0,18% R01AA08 Nafazolina 2 0,18% http://bmjopen.bmj.com/ 33 A11BA Multivitamínicos solos 2 0,18% B06AA02 Fibrinolisina y desoxirribonucleasa 2 0,18% 34 C08CA06 Nimodipino 2 0,18% H02AB07 Prednisona 2 0,18% M01AB55 Diclofenaco, combinaciones 2 0,18% 35 N05CD08 Midazolam 2 0,18% C05BA51 Heparinoides, combinaciones 2 0,18% 36 A11EA Vitaminas del complejo B solas 1 0,09% N02AX02 Tramadol 1 0,09% A11AA03 Multivitamínicos con otros minerales, incl. combinaciones 1 0,09% 37 G03AC03 Levonorgestrel 1 0,09% J01DA06 Cefuroxima 1 0,09% 38 A01AD05 Ácido acetilsalicílico 1 0,09% A06AD11 Lactulosa 1 0,09% B01AB01 Heparina 1 0,09% 39 B03AE10 Varias combinaciones 1 0,09% B05BC01 Manitol 1 0,09% 40 C01DA08 Dinitrato de isosorbida 1 0,09% C03DA01 Espironolactona 1 0,09% C04AD03 Pentoxifilina 1 0,09% 41 C08CA56 Nimodipino, combinaciones 1 0,09% on September 24, 2021 by guest. Protected copyright. C09AA02 Enalapril 1 0,09% 42 D06AX54 Neomicina, combinaciones 1 0,09% D06BA Sulfonamidas 1 0,09% D08AX07 Sodium hypochlorite 1 0,09% 43 G03CA03 Estradiol 1 0,09% G04BD02 Flavoxato 1 0,09% 44 G04BE03 Sildenafilo 1 0,09% H02AB09 Hidrocortisona 1 0,09% 45 J01AA02 Doxiciclina 1 0,09% J01AA56 Oxitetraciclina, combinaciones 1 0,09% J01CF01 Dicloxacilina 1 0,09% 46 J01DH02 Meropenem 1 0,09% J01FA01 Eritromicina 1 0,09% 47 J01FF01 Clindamicina 1 0,09% M01AE02 Naproxeno 1 0,09% M02AC Preparados con ácido salicílico y derivados 1 0,09% 48 M03AB01 Suxametonio 1 0,09% M03BC01 Orfenadrina (citrato) 1 0,09% 49 M05BA06 Ácido ibandrónico 1 0,09% N04BA02 Levodopa con inhibidor de la decarboxilasa 1 0,09% N05AD01 Haloperidol 1 0,09% 50 N05AL05 Amisulprida 1 0,09% N05BA09 Clobazam 1 0,09% 51 N07XX Otras drogas que actúan sobre el sistema nervioso 1 0,09% P01BA01 Cloroquina 1 0,09% P02CA03 Albendazol 1 0,09% 52 P03AX01 Benzoato de bencilo 1 0,09% R01BA52 Pseudoefedrina, combinaciones 1 0,09% 53 R03AC02 Salbutamol 1 0,09% R03BA02 Budesonida 1 0,09% R03CC63 Clenbuterol, combinaciones 1 0,09% 54 R05CB01 Acetilcisteína 1 0,09% R05CB03 Carbocisteína 1 0,09% 55 R05X Otros preparados para el resfriado 1 0,09% R06AE07 Cetirizina 1 0,09% R06AE08 Levocetirizina 1 0,09% 56 R06AX27 Desloratadina 1 0,09% S01AA53 Neomicina, combinaciones 1 0,09% 57 A02AF01 Magaldrato y carminativos 1 0,09% A05AX Otras drogas para terapia biliar 1 0,09% 58 J01MA12 Levofloxacino 1 0,09% M01AH01 Celecoxib 1 0,09% N05BA08 Bromazepam 1 0,09% 59 TOTAL 1112 100,00% 60

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 27 of 27 BMJ Open

Table 6. Falsified medicines – Type BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 RESULTS OF THE EVALUATION TOTAL % 3 4 Not contain an active ingredient 100 8,99% 5 A different active ingredient to the one on the label 12 1,08% 6 7 Correct active ingredient but with a different content than authorized 7 0,63% Characteristics and/or information that did not correspond to the product 8 164 14,75% 9 specifications 10 Without information 829 74,55% 11 TOTAL 1112 100% 12 13

14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

41 on September 24, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from

Falsified medicines in Peru: A Retrospective Review (1997- 2014).

ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2015-010387.R1

Article Type: Research

Date Submitted by the Author: 22-Dec-2015

Primary Subject Public health Heading:

Secondary Subject Heading: Global health, Epidemiology, Health policy, Health services research

Keywords: Safety, Falsified, Medicines, Alerts, counterfeit, Drugs

http://bmjopen.bmj.com/

on September 24, 2021 by guest. Protected copyright.

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 26 BMJ Open

33 http://bmjopen.bmj.com/ 34 Keywords: Safety, Falsified, Medicines, Alerts, counterfeit, Drugs 35 36 37 38 39 Word Count 40

41 Abstract: 269 on September 24, 2021 by guest. Protected copyright. 42 Main text: 3 965 43 Figures: 3 44 Tables: 3 45 Supplementary data: 1 46 References: 62 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 26

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 ABSTRACT 4 5 Objective: To show the extent of the problem of falsified medicines in Peru. 6 7 Design: A retrospective review of drug alerts. 8 9 10 Setting: The General Directorate of Medicines, Supplies and Drugs (DIGEMID - 11 Ministry of Health of Peru) website search for drug alerts issued between 1997 12 and 2014. 13 14 Eligibility criteria: Drug alerts related to falsified medicines. 15 For peer review only 16 Results: A total of 669 Digemid Alerts were issued during the study period, 354 17 (52.91%) of which refer to a total of 1 738 cases of falsified medicines (many 18 19 alerts deal with several cases at a time). Regarding the type of establishment 20 involved in the possession or sale of falsified medicines, 1 010 cases (58.11%) 21 involved pharmaceutical establishments; 349 cases (20.08%) involved non- 22 pharmaceutical commercial outlets); in 126 cases (7.23%) the medicines were 23 seized in unauthorized trade (without any marketing authorization), and in 253 24 cases (14.56%) the type of establishment or business related with the seized 25 product is not identified. 26 27 Conclusions: In light of the results, there is no doubt that falsified medicines 28 29 represent a serious public health problem in Peru. A review of the data alone is 30 not enough to conclude whether falsified medicines in Peru have increased 31 during the study period, or if the monitoring action of different government 32 health agencies has brought the magnitude of the problem more to the surface

33 by providing more evidence. The problem is clearly structural, since the majority http://bmjopen.bmj.com/ 34 of cases (58.11% of the total) were detected in legitimate supply chains. Most 35 falsified medicines involve staple pharmaceutical products and common dosage 36 forms. 37 38 39 Considerable work remains to be done to control the serious problem of falsified 40 medicines in Peru.

41 on September 24, 2021 by guest. Protected copyright. 42 43 44 STRENGTHS AND LIMITATIONS OF THIS STUDY 45 46 Digemid alerts are published systematically, are organized by date, and 47 48 are readily available on the DIGEMID open access website. 49 The information they provide is not entirely homogenous and 50 standardized which is a limitation for an overall analysis. 51 The Digemid alerts do not use a standardized definition of falsified 52 medicines, thereby hindering an overall evaluation of the results. 53 The possible health effects resulting from the use of falsified medicines 54 are not addressed or included in the alerts. 55 Graphical reports of counterfeit medicines, which are an illustrative and 56 informative tool, are only provided in 3 alerts (Digemid Alerts 17-2006, 57 58 35-2005 y 40-2005). 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 26 BMJ Open

41 a country of upper-middle income with a gross national income per capita of on September 24, 2021 by guest. Protected copyright. [8] 42 $ 4 126 – 12 745). 43 44 In Peru in the early 1990s, with the excuse of an economic crisis, the regulated 45 market for medicines was replaced by an open market, in line with the 46 neoliberal economic model of the moment. For example, ownership of the 47 community pharmacy was no longer the exclusive right of pharmacists, and 48 49 anyone with enough capital could open a pharmaceutical office, in any location, 50 and without rigorous prior control. This change was based on a political decision 51 without a preliminary analysis of the possible consequences, such as the 52 chaotic growth in the number of pharmaceutical establishments, which is 53 currently 23 527 [9] (259 in 1980 - 1989; 3 335 in 1990 – 1999 and 17 071 in 54 2000 - 2008) [10], rendering effective control by the authorities impossible. This 55 is arguably one of the main causes of the high number of cases of counterfeit 56 medicines found in the legal supply chain today. Attempts to resolve this 57 problem include Law No 26842 of 2009, which stipulates mandatory sanitary 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 26

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 authorization for the operation of pharmaceutical establishments, with prior 4 verification of compliance, [11] and more recently a process of registration or 5 special registration under the Temporary Supplementary Provisions of the 6 Supreme Decree No. 033-2014-SA. [12] 7 8 The consequences of this illegal phenomenon represent a serious public health 9 [13] 10 problem, including treatment failure, possible cases of added contaminants, 11 and even death. It has also resulted in the deployment and disbursement of 12 often scarce resources, a loss of faith in health systems, distrust of medications 13 and even the failure of major global health policies such as the fight against 14 malaria. [14] 15 For peer review only 16 The regulatory authority for medicines in Peru is the General Directorate of 17 Medicines, Supplies and Drugs (DIGEMID), created by the Legislative Decree 18 [15] 19 No. 584 of 16 April 1990, as a dependent institution of the Ministry of Health 20 of Peru. In May 1998, the Directorial Resolution No. 367-98-DG-DIGEMID 21 established the Alerts Committee to evaluate and define the actions to take in 22 response to alerts or communications about safety and/or efficacy of 23 pharmaceuticals and related products. [16] 24 25 Inspectors of DIGEMID and regional health institutions carry out inspections 26 and spot checks of pharmaceutical products (in pharmaceutical and non- 27 pharmaceutical establishments), and also receive counterfeit drugs seized by 28 29 other regulatory authorities (National Police, Customs, etc.). Any suspected 30 deficiency or observable abnormality in a product leads to its seizure, and its 31 authenticity is then verified with the holder of the relevant marketing 32 authorization. If the suspected counterfeiting is confirmed, samples are

33 transferred to an Official Control Laboratory to complete the relevant physical- http://bmjopen.bmj.com/ 34 chemical and microbiological analyses. All the documentation and case history 35 is referred to the DIGEMID-Alerts Committee to approve the publication of the 36 corresponding alert in the institutional web page and to initiate internal and 37 external dissemination. [17] 38 39 40

41 on September 24, 2021 by guest. Protected copyright. 42 OBJECTIVE 43 44 This work seeks to consolidate and assess information on falsified medicines in 45 pharmaceutical alerts issued by the Peruvian medicine agency in a period of 18 46 years (1997-2014) of health monitoring and enforcement. The ultimate aim is to 47 draw attention to the situation of falsified medicines in Peru and highlight the 48 49 efforts of various state institutions headed by DIGEMID. 50 51 52 53 METHOD 54 55 To develop this work, a retrospective review was carried out of each Digemid 56 alert about falsified medicines, published on the official DIGEMID website [18] 57 58 from 1997 to December 2014. 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 26 BMJ Open

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 Data from each of the aforementioned Digemid alerts were collected and 4 organized in Microsoft Excel spreadsheets, considering, extracting, and filling in 5 the following information: 6 7 Alerts ordered by year. 8 Title of the published Digemid alert. 9 10 Date of publication. 11 Medicine. 12 Batch number. 13 Pharmaceutical dosage form. 14 Presentation. 15 ActiveFor ingredient. peer review only 16 Classification according to the ATC. 17 Establishment involved. 18 Establishment type. 19 20 Location. 21 Results of the evaluation. 22 Sanction, administrative or penal. 23 Promoter of the inspection. 24 Evaluation. 25 Remarks. 26 27 28 29 Based on the collected data, the following were determined: 30 31 The number of Digemid alerts issued per year. 32 The number of Digemid alerts about falsified medicines.

33 The number of cases of falsified medicines per year. http://bmjopen.bmj.com/ 34 The number and type of establishments involved in falsified medicines. 35 The classification of the falsified medicines according to the ATC system 36 (the main anatomical group and therapeutic/pharmacological subgroups) 37 The classification of the falsified medicines according to their 38 39 pharmaceutical dosage form. 40 The number of cases of falsified medicines reported by the inspection or control agency. 41 on September 24, 2021 by guest. Protected copyright. 42 The number of cases of falsified medicines according to the region where 43 they were seized. 44 The results of the evaluation. 45 46 47 48 49 Of all the DIGEMID-alerts published during the study period, those concerning 50 medical devise, herbal and cosmetic products have been excluded, as have 51 been cases related to quality, general safety or regulation (for example, 52 products without sanitary registration). In each case it is specified the region of 53 Peru where the drug was seized, the authority that instigated the action, and the 54 type of establishment where the counterfeit medicine was found, dividing the 55 latter into 3 groups: 56 57 Pharmaceutical establishments 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 26

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 4 • PHARMACY: Pharmaceutical store dispensing and retailing 5 pharmaceuticals and related products. Owned by a pharmacist. 6 • BOTICA: Pharmaceutical store dispensing and retailing pharmaceuticals 7 and related products. Not owned by a pharmacist. 8 9 • BOTIQUÍN: Sells pharmaceuticals and related products included in a 10 restricted list by the Health Authority. 11 • DROGUERÍA: Engaged in the import, export, marketing, storage, quality 12 control and / or distribution of pharmaceuticals and related products. 13 • LABORATORY: Engaged in manufacturing, packaging, bottling, 14 conditioning, reconditioning, quality control, storage and export of 15 pharmaceuticalsFor peer and related review products. only 16 17 18 Non-pharmaceutical commercial establishments 19 20 Any authorized commercial establishment that is not a pharmaceutical 21 establishment. 22 23 Informal 24 25 26 Unauthorized commercial establishments or places. 27 28 29 30 To be more precise in the analysis of the type of counterfeit medicine, those 31 with a batch number subject of a previous alert are not taken into account. All 32 counterfeit medicines were classified according to the WHO - Anatomical 33 Therapeutic Chemical Classification System (ATC), [19] referring to the main http://bmjopen.bmj.com/ 34 anatomical groups, therapeutic subgroups and pharmacological subgroups. The 35 stated dosage form is in accordance with the DIGEMID alerts or the PERUDIS 36 [20] 37 database. The type of counterfeiting is classified according to the 38 assessment provided by the alerts: features and/or information that do not 39 match the product specifications, containing no active ingredient, containing an 40 active ingredient other than stated on the label, or containing the correct active

41 ingredient but not the authorized content. on September 24, 2021 by guest. Protected copyright. 42 43 All authors have had access to the primary information (DIGEMID-alerts) 44 corresponding to the study period and the evaluation tables (excel); the process 45 46 of analysis and drafting of the work has been carried out by the first author, 47 followed by a process of verification and reconciliation of the results by the other 48 authors. 49 50 51 52 RESULTS 53 54 55 In the 18-year period covered by this study (1997-2014), DIGEMID issued a 56 total of 669 alerts, 354 of which (52.91%) concern falsified medicines. It should 57 be mentioned that there is no direct relationship between the number of 58 Digemid alerts and the number of falsified medicines, since several alerts refer 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 26 BMJ Open

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 to more than one medicine or different batches of the same product. In this 4 sense, Digemid alert no. 27 of 2012 [21] particularly stands out, as it deals with 5 74 cases of falsified medicines. Thus, the 354 Digemid alerts concerning 6 falsified medicines include a total of 1 738 reported cases (Figure 1 and 2). 7 8

9 10 11 Figure 1. Flow diagram showing types of Digemid alerts and overall 12 results. 13 14 15 For peer review only 16 17 18 19 20 21 22 23 Figure 2. Digemid alerts and falsified medicines by year 24 25 26 27 28 29 30 31 32 In the period covered by the study, a total of 1 738 cases of counterfeit 33 medicines were found (see online supplementary file table S1). Regarding the http://bmjopen.bmj.com/ 34 35 type of outlet/establishment involved in the possession or sale of falsified 36 medicines leading to the issue of a DIGEMID alert, 1 010 cases (58.11%) of the 37 total involved pharmaceutical establishments (pharmaceutical offices, 38 droguerías, botiquines and laboratories); 349 (20.08%) involved non- 39 40 pharmaceutical establishments (non-pharmaceutical commercial outlets); in 126

41 cases (7.25%) falsified medicines were seized in unauthorized trade (without on September 24, 2021 by guest. Protected copyright. 42 any marketing authorization), including 10 cases of clandestine laboratories; 43 44 and finally in 253 (14.56%) cases there is insufficient information to clearly 45 identify the type of establishment or business involved. 46 47 Regarding the pharmaceutical establishments, it should be noted that 850 48 (84.16%) of all cases of falsified medicines involved boticas and 130 (12.87%) 49 50 involved pharmacies (Table 1). 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 26

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 Table 1. Type of establishment or business related with the possession or 4 sale of falsified medicines. 5 6 7 8 9 TYPE OF ESTABLISHMENT/OUTLET TOTAL % 10 11 PHARMACEUTICAL 1 010 58.11% 12 13 PHARMACY 14 Pharmaceutical store dispensing and retailing pharmaceuticals 130 7.48% 15 and relatedFor products. Ownedpeer by a pharmacist. review only 16 BOTICA 17 Pharmaceutical store dispensing and retailing pharmaceuticals 850 48.91% 18 and related products. Not owned by a pharmacist. BOTIQUÍN 19 Sells pharmaceuticals and related products included in a 4 0.23% 20 restricted list by the Health Authority. 21 DROGUERÍA 22 Engaged in the import, export, marketing, storage, quality control 23 1.32% 23 and / or distribution of pharmaceuticals and related products. 24 LABORATORY 25 Engaged in manufacturing, packaging, bottling, conditioning, 3 0.17% 26 reconditioning, quality control, storage and export of 27 pharmaceuticals and related products. 28 29 NON-PHARMACEUTICAL 349 20.08% 30 31 UNAUTHORIZED TRADE 126 7.25% 32

33 http://bmjopen.bmj.com/ 34 Without Information 253 14.56% 35 36 37 TOTAL 1 738 100.00% 38 39 40

41 on September 24, 2021 by guest. Protected copyright. 42 Regarding the location where falsified medicines were seized, Lima province 43 had the highest number of cases with 562 (32.34%), far outstripping La 44 45 Libertad, which had 315 (18.12%). Interestingly, no cases were reported in the 46 departments of Huanuco and Tumbes. Taking into account the population in 47 each region and the number of cases of counterfeiting, the province with the 48 highest number of cases of counterfeit medicines per 100 000 inhabitants is 49 50 Madre de Dios, with 19.33 cases, followed by La Libertad with 16.94 cases. 51 More details are shown in Table 2. 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 26 BMJ Open

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 Table 2. Number of cases of falsified medicines according to the 4 geographical location where they were seized and population. 5 6 7 8 9 No. Cases No. Of 10 of Population Cases Per Region % [22] 11 Counterfeit in 2015 100 000 12 Medicines Inhabitants 13 Amazonas 1 0,06% 422 629 0,24 14 Ancash 53 3,05% 1 148 634 4,61 15 ApurimacFor peer review1 0,06% only458 830 0,22 16 Arequipa 93 5,35% 1 287 205 7,22 17 Ayacucho 26 1,50% 688 657 3,78 18 Cajamarca 123 7,08% 1 529 755 8,04 19 Callao 20 1,15% 1 013 935 1,97 20 Cusco 68 3,91% 1 316 729 5,16 21 22 Huancavelica 3 0,17% 494 963 0,61 23 Huánuco 0 0,00% 860 548 0,00 24 Ica 12 0,69% 787 170 1,52 25 Junín 146 8,40% 1 350 783 10,81 26 La libertad 315 18,12% 1 859 640 16,94 27 Lambayeque 56 3,22% 1 260 650 4,44 28 Lima 562 32,34% 9 834 631 5,71 29 Loreto 146 8,40% 1 039 372 14,05 30 Madre de dios 27 1,55% 137 316 19,66 31 Moquegua 24 1,38% 180 477 13,30 32 Pasco 3 0,17% 304 158 0,99 33 Piura 7 0,40% 1 844 129 0,38 http://bmjopen.bmj.com/ 34 Puno 18 1,04% 1 415 608 1,27 35 San Martín 3 0,17% 840 790 0,36 36 Tacna 4 0,23% 341 838 1,17 37 Tumbes 0 0,00% 237 685 0,00 38 Ucayali 11 0,63% 495 511 2,22 39 40 Without Information 16 0,92%

41 on September 24, 2021 by guest. Protected copyright. 42 43 44 Regarding the institution responsible for the surveillance or control activities that 45 led to the falsified medicine alerts during the study period, 1 006 of all the cases 46 (57.88%) correspond to initiatives of decentralized health institutions (Health 47 48 Directorates - DISAs or Regional Health Directorates - DIRESAs), 168 (9.67%) 49 to various agencies formed by the National Police of Peru, the public 50 prosecutor, etc., 151 (8.69%) to DIGEMID itself, and in 413 (23.76%) cases the 51 promoter of the surveillance action is not specified. 52 53 It is very interesting to note the evolution of the monitoring activities during the 54 study period, since their decentralization coincided with an increase in 55 inspections. This resulted in greater effectiveness, as can be seen in Figure 3. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 26

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 4 5 6 7 Figure 3. Evolution of inspections according to the promoter. 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21

22 23 24 25 To obtain more precise results regarding the falsified medicines themselves, 26 identical batches (product/batch number) seized in more than one place or 27 28 mentioned in earlier alerts were excluded, ultimately resulting in a total of 1 112 29 falsified medicines with different batch numbers (see online supplementary file 30 table S2), the details of which are shown in Figure 1 and 2. 626 cases of 31 counterfeit medicines had batch numbers included in more than one alert, many 32 of them in different years.

33 http://bmjopen.bmj.com/ 34 The number of falsified medicines classified according to the organ or system 35 on which they act, and the therapeutic and pharmacological subgroups of the 36 ATC code are detailed in Table 3. Among the therapeutic subgroups, painkillers 37 were the most frequently falsified medicines, representing 22.57% of all cases, 38 followed by systemic antibacterials at 19.78%. 39 40

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 Table 3. Classification of the falsified medicines according to the ATC 4 Code 5 6 MAIN ANATOMICAL GROUP Nº % 7 N NERVOUS SYSTEM 297 26.71% 8 9 J ANTIINFECTIVES FOR SYSTEMIC USE 220 19.78% 10 G GENITO URINARY SYSTEM AND SEX HORMONES 217 19.51% 11 A ALIMENTARY TRACT AND METABOLISM 188 16.91% 12 R RESPIRATORY SYSTEM 90 8.09% 13 M MUSCULO-SKELETAL SYSTEM 32 2.88% 14 15 D ForDERMATOLOGICALS peer review only 25 2.25% SYSTEMIC HORMONAL PREPARATIONS, EXCL. SEX HORMONES AND H 15 1.35% 16 INSULINS 17 B BLOOD AND BLOOD FORMING ORGANS 15 1.35% 18 C CARDIOVASCULAR SYSTEM 9 0.81% 19 20 P ANTIPARASITIC PRODUCTS, INSECTICIDES AND REPELLENTS 3 0.27% 21 S SENSORY ORGANS 1 0.09% 22 L ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS 0 0.00% 23 V VARIOUS 0 0.00% 24 TOTAL 1 112 100.00 25 26 THERAPEUTIC SUBGROUP Nº % 27 N02 ANALGESICS 251 22.57% 28 J01 ANTIBACTERIALS FOR SYSTEMIC USE 220 19.78% 29 G02 OTHER GYNECOLOGICALS 178 16.01% 30 R06 ANTIHISTAMINES FOR SYSTEMIC USE 68 6.12% 31 32 A11 VITAMINS 65 5.85%

33 A04 ANTIEMETICS AND ANTINAUSEANTS 40 3.60% http://bmjopen.bmj.com/ 34 A07 ANTIDIARRHEALS, INTESTINAL ANTIINFLAMMATORY/ ANTIINFECTIVE AGENTS 36 3.24% 35 M01 ANTIINFLAMMATORY AND ANTIRHEUMATIC PRODUCTS 28 2.52% 36 G03 SEX HORMONES AND MODULATORS OF THE GENITAL SYSTEM 24 2.16% 37 N05 PSYCHOLEPTICS 21 1.89% 38 39 A03 DRUGS FOR FUNCTIONAL GASTROINTESTINAL DISORDERS 20 1.80% 40 OTHERS 161 14.48%

41 TOTAL 1 112 100.00 on September 24, 2021 by guest. Protected copyright. 42 PHARMACEUTICAL SUBGROUP Nº % 43 N02B Other analgesics and antipyretics 232 20.86% 44 45 G02C Other gynecologicals 178 16.01% 46 J01E Sulfonamides and trimethoprim 102 9.17% 47 J01C Beta-lactam antibacterials, penicillins 71 6.38% 48 R06A Antihistamines for systemic use 68 6.12% 49 A04A Antiemetics and antinauseants 40 3.60% 50 A11J Other vitamin products, combinations 39 3.51% 51 52 A07D Antipropulsives 36 3.24% Antiinflammatory and antirheumatic products, 53 M01A 28 2.52% non-steroids 54 N03A Antiepileptics 17 1.53% 55 56 N05B Anxiolytics 17 1.53% 57 Others 284 25.54% 58 TOTAL 1 112 100.00 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 26

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 Regarding the dosage form, 26 different types were found in the study period, 4 the most common being tablets (including coated and chewable), with a total of 5 816 cases (73.38%), followed by injectable dosage forms (injectable solution, 6 powder for injectable suspension, injectable suspension and powder for 7 injectable solution), with a total of 111 cases (9.98%); and 76 cases involving 8 capsules (6.83%). 9 10 11 Among the falsified medicines featured in the alerts of the study period, 164 12 cases (14.75%) had characteristics and/or information that did not correspond 13 to the product specifications, 100 (8.99%) did not contain an active ingredient, 14 12 (1.08%) had a different active ingredient to the one on the label, and 7 15 (0.63%) hadFor the correct peer active ingredient review but not the authorizedonly content of the 16 active ingredient. It is noteworthy that in most cases 829 (74.55%) no 17 information was provided, which prevents a significant overall assessment. 18 19 20 21 22 DISCUSSION 23 24 Digemid alerts represent a valuable resource for the transfer of information on 25 the safety of medicines and related products to the general public. To be 26 effective and efficient, the alerts should provide detailed, homogenized and 27 standardized data. It is worthwhile to make a timely assessment of their impact 28 29 on the goals of controlling and minimizing the risks associated with the trade 30 and use of counterfeit medicines. 31 32 This review demonstrates that the problem of falsified medicines in Peru is far

33 from insignificant. On the contrary, in light of the results presented here, the http://bmjopen.bmj.com/ 34 country is facing a serious public health problem, which is even more apparent 35 if these results are compared with those of similar studies in some countries 36 that are considered in Peru to have a high level of health surveillance, [23] such 37 as the UK, with 7 cases of falsified medicines in 11 years (2001-2011) [24] or 38 [25] 39 Canada with 4 cases in nine years (2005-2013). The difference is 40 overwhelming.

41 on September 24, 2021 by guest. Protected copyright. 42 One of the most striking and troubling aspects of the findings of this study is the 43 extent to which the medicine supply chain in Peru is being violated, with the 44 highest rate of falsified drugs found in pharmaceutical establishments 45 (pharmacies and boticas): 980 (56.39%) of a total of 1 738 cases. This situation 46 is particularly worrying since, according to the Institute of Statistics and 47 Informatics of Peru (INEI), the Peruvian population mainly relies on the 48 [26] 49 pharmacy or botica for health care. As well as a loss of consumer faith in the 50 legal supply chain, the resources, strategies and communication activities that 51 promote the responsible acquisition of safe medicines in legally established 52 pharmaceutical establishments are also being undermined. This situation 53 requires the active and joint participation of the regulatory authority and the 54 institutions representing the pharmaceutical establishments; moreover, the 55 cornerstone in solving the problem would be to grant a leading role to the 56 pharmacist, who should procure medicines from recognized and reliable 57 sources; warn patients against acquiring medicines from informal 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 26 BMJ Open

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 establishments or places (including the internet); confirm that the distributors 4 buy products from approved suppliers; check the alerts on counterfeit medicines 5 issued by the health authority; be alert to products with suspicious features; 6 collaborate with the pharmaceutical industry, distributors and the health 7 authority to establish safety procedures that do not allow violation of the legal 8 supply chain; make use of available technology for the safe management and 9 10 traceability of medicines; receive training and trigger a process of updating 11 safety in the workplace, and report any suspicious activity or product to the [27] 12 health authority. 13 14 No less worrying are the 349 cases involving non-pharmaceutical outlets, or the 15 126 casesFor of unauthorized peer trade, whichreview include 10 cases only related to clandestine 16 laboratories. 17 18 Considering the population density of Lima (31.57% of Peru’s 31 151 643 19 [22] 20 inhabitants), it is not surprising that the capital city is the location of 562 21 cases in the falsified medicine alerts (32.34%), followed by La Libertad with 315 22 cases (18.12%). As indicated by the WHO, there can be an enormous variation 23 in the incidence of falsified medicines within the same country, whether 24 between rural and urban areas or between different cities. [28] This is an 25 important factor for the planning of appropriate strategies to combat the 26 problem. 27 28 29 In this study, it is especially interesting to note the effect of the decentralization of public health surveillance powers. In 1999, the Ministerial Resolution No. 30 [29] 31 150-99 / DM decreed that the regional and sub-regional health directorates 32 assume the functions of health control and monitoring, although the rules of

33 procedure and operation were not approved until 2003 by the Ministerial http://bmjopen.bmj.com/ 34 Resolution No. 573-2003-SA / DM. [30] After a period of implementation, the 35 results begin to be seen in 2005, when the regional directorates participated in 36 8 cases, which grew to 75 in 2006 and 128 in 2007, reaching a cumulative 37 1 006 cases over the study period, representing 57.88% of the total. In parallel, 38 39 the operational role of the centralized body, DIGEMID, was reduced, replaced 40 by coordination functions, among others.

41 on September 24, 2021 by guest. Protected copyright. 42 In the period covered by this review, the alerts alluded to 1 112 cases of 43 counterfeit medicines (product/batch). Based on the pharmacological/ 44 therapeutic subgroups (2nd level) of the ATC code [19] allotted to registered 45 products in the DIGEMID database, [20] the most falsified medicines in Peru 46 were Analgesics (251 – 22,57%), followed by Antibacterials for systemic use 47 (220 – 19.78%) and Other gynecologicals (178 – 16.01%), Antihistamines for 48 49 systemic use (68 – 6.12%), and Vitamins (65 – 5.85%). To some extent, these 50 results reflect the most consumed medicines in Peru, as reported in the 2008 [31] 51 study, "The therapeutic value of the best-selling medicines in Peru", which [32] 52 according to the IMS are likely to remain the same in the near future. At this 53 point, it is recommendable to raise the issue of implementation of modern 54 technologies to detect falsified medicines [33] and the development of tools for 55 the traceability of pharmaceutical products. Among these are radio frequency 56 technology [34-40] and two-dimensional codes such as the Datamatrix system. 57 Modern analytical methods have been adapted to identify counterfeit medicines, 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 26

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 leading to faster and more effective results and allowing more timely action and 4 communication by the health authorities. In this way, the alert system is not only 5 informative, but becomes an effective tool. [41-49] 6 7 The liberalization of the world economy, with fewer commercial borders and a 8 growing impact of the Internet on medicine advertising and trade means that 9 10 proposals for measures need to be global, for example, an internationally 11 accepted standard terminology that allows better information management, 12 transparency and identification of brokers and commercial intermediaries, 13 legislative and regulatory harmonization, the implementation of traceability 14 systems, etc. Although the Digemid alerts provide no data on the issue, trade in 15 falsified medicinesFor overpeer the Internet review is a major global only problem (particularly in 16 developed countries).[50-51] Mafias involved in medicine falsification will not have 17 overlooked that the global pharmaceutical market is forecast to grow by around 18 4% per year (21% between 2012 and 2017).[52] The concern about falsified 19 20 medicine is growing worldwide, in developed as well as developing countries; 21 although quantitatively different, its impact on public health and the economy is 22 similar in both. 23 24 Continuing the work of inspection is vital. The magnitude and nature of the 25 problem require a thorough analysis at two levels: within the region or country 26 as well as globally. It is necessary to evaluate the measures, activities and 27 behaviours (WHO guidelines) [53] responsible for the high levels of counterfeit 28 medicines in the Peruvian pharmaceutical market, with an obvious and worrying 29 [54] 30 violation of the legal supply chain. It is necessary to understand why the 31 situation persists, despite the corrective measures in place. All aspects of the [55] [56] 32 problem need to be addressed, from health to economic, legal,

33 technological, social and cultural, which could lead to a renewal of viable, http://bmjopen.bmj.com/ 34 effective and efficient strategies [57-61] to combat this scourge. 35 36 The finding of 626 duplicate products/batches in the study period highlights the 37 persistence of falsified medicines on the market, and suggests that the impact 38 39 of the alert system needs to be revised. 40

41 A review based only on the data of the alerts cannot provide a precise on September 24, 2021 by guest. Protected copyright. 42 conclusion about the extent to which falsified medicines have penetrated the 43 Peruvian pharmaceutical market, or their typology. Nevertheless, the results of 44 this study give an idea of the magnitude of the problem, and suggest that a 45 rethinking of strategies is required to effectively combat the trade in falsified 46 medicines in Peru. Moreover, it is important to recognize that the situation could 47 worsen, as is occurring in many African countries. [62] 48 49 50 51 52 CONCLUSIONS 53 54 In light of the results, it is clear that the falsification of medicines in Peru is 55 currently a serious public health problem. A review based only on the data 56 provided by alerts cannot conclude whether falsified medicines have increased 57 in Peru within the study period, or if the action of different public health 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 26 BMJ Open

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 surveillance bodies has brought more evidence to the surface about the 4 magnitude of the problem. The type of falsified medicines found in Peru is 5 characteristic of developing countries. The problem is clearly structural or due to 6 pharmaceutical policy, since the highest incidence of cases of falsified 7 medicines leading to DIGEMID alerts involve legal supply chains. Most cases of 8 falsified medicines have been found in large cities. The decentralization of 9 10 health management has had a significant impact from the inspection point of 11 view. It is necessary to establish systems of analysis and risk management 12 related to the counterfeit medicine trade as part of a regional, national and 13 global plan, in which pharmaceutical alerts form part of the communication 14 process and whose impact should be evaluated. Much work remains to be done 15 to addressFor this serious peer public health review concern, both in Peruonly and worldwide. 16 17 18 19 20 ACKNOWLEDGMENTS 21 22 We especially thank and dedicate this review to all people that day to day 23 fighting the scourge of counterfeit medicines in Peru. 24 25 26 27 FOOTNOTES 28 29 30 Contributors: 31 32 EM drafted the manuscript. EM, EB and JS developed the initial concept and

33 design of the study and contributed to the qualitative analysis. All the authors http://bmjopen.bmj.com/ 34 read and approved the final submitted version of the manuscript and accept 35 accountability for all aspects of the work. 36 37 38 Funding: 39 40 This work was supported by the Bosch i Gimpera Foundation (FBG) –

41 University of Barcelona. on September 24, 2021 by guest. Protected copyright. 42 43 Ethical approval: Not required. 44 45 Competing interests: None declared. 46 47 48 Provenance and peer review: Not commissioned; externally peer reviewed. 49 50 Data sharing statement: No additional data are available. 51 52 This is an Open Access article distributed in accordance with the terms of the 53 Creative Commons Attribution (CC BY 4.0) license, which permits others to 54 distribute, remix, adapt and build upon this work, for commercial use, provided 55 56 the original work is properly cited. 57 See: http://creativecommons.org/licenses/by/4.0/ 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 26

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 REFERENCES 4 5 1. Organización Panamericana de la Salud – OPS. Combate a la Falsificación 6 de Medicamentos. Found in 7 8 http://www.paho.org/HQ/index.php?option=com_docman&task=doc_download& 9 gid=20060&Itemid=+&lang=es. Accessed on August 5, 2014. 10 11 2. WHO. Programmes – Essential medicines and health products. General 12 information on counterfeit medicines. Found in 13 14 http://www.who.int/medicines/services/counterfeit/overview/en/. Accessed on 15 July 4, 2014.For peer review only 16 17 3. OMS. Medicamentos espurios, de etiquetado engañoso, falsificados o de 18 imitación.Nota descriptiva N°275. Mayo de 2012. Found in 19 20 http://www.who.int/mediacentre/factsheets/fs275/es/. Accessed on August 5, 21 2014. 22 23 4. Dégardin K, Roggo Y, Margot P. Understanding and fighting the medicine 24 counterfeit market. J Pharm Biomed Anal. 2014 Jan;87:167-75. 25 26 5. World Health Organization. Growing threat from counterfeit medicines. Bull 27 28 World Health Organ. Apr 1, 2010; 88(4): 247–248. 29 30 6. Customs group to fight $200 bln bogus drug industry. Found in 31 http://www.reuters.com/article/2010/06/10/us-customs-drugs- 32 idUSTRE65961U20100610. Accessed on September 24, 2014. 33 http://bmjopen.bmj.com/ 34 7. Blackstone EA, Fuhr JP Jr, Pociask S. The health and economic effects of 35 36 counterfeit drugs. Am Health Drug Benefits. 2014 Jun;7(4):216-24. 37 38 8. The World Bank. Data. Updated Income Classifications. Posted on 39 07/03/2014. Found in http://data.worldbank.org/news/2015-country- 40 classifications. Accessed on August 12, 2014.

41 on September 24, 2021 by guest. Protected copyright. 42 9. Dirección General de Medicamentos, Insumos y Drogas (DIGEMID). Registro 43 Nacional de Establecimientos Farmacéuticos. Found in 44 45 http://observatorio.digemid.minsa.gob.pe/PortalConsultas/Consultas/ConsultaE 46 stablecimientos.aspx?over=1. Accessed on December 12, 2015. 47 48 10. Víctor Dongo. Simposio: Política de Medicamentos. LEY N.º 29459 - ley de 49 los productos farmacéuticos, dispositivos médicos y productos sanitarios. Rev 50 Peru Med Exp Salud Pública. 2009; 26(4): 517-29. 51 52 11. Ley No 29459 Ley de los productos farmacéuticos, dispositivos médicos y 53 productos sanitarios, del 26 de noviembre de 2009. Found in 54 55 http://www.digemid.minsa.gob.pe/UpLoad/UpLoaded/PDF/Ley29459.pdf. 56 Accessed on November 26, 2015. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 26 BMJ Open

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41 2014. Found in http://www.whocc.no/atc_ddd_index/. Accessed on August 12, on September 24, 2021 by guest. Protected copyright. 42 2014. 43 44 20. Dirección General de Medicamentos, Insumos y Drogas (DIGEMID). 45 46 Registro Sanitario de Productos Farmacéuticos – Base de datos online de 47 productos. Found in 48 http://www.digemid.minsa.gob.pe/indexperudis.ASP?seccion=448. Accessed 49 on January 06, 2015. 50 51 21. ALERTAS-DIGEMID. Found in 52 53 http://www.digemid.minsa.gob.pe/UpLoad/UpLoaded/PDF/Alertas/2012/ALERT 54 A_27-12.pdf. Accessed on August 24, 2014. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 26

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 22. National Institute of Statistics and Informatics of Peru. Population in 2000 to 4 2015. Found in http://proyectos.inei.gob.pe/web/poblacion/. Accessed on 5 November 26, 2015. 6 7 23. Decreto Supremo Nº 029-2015-SA. Modifican Reglamento para el 8 Registro, Control y Vigilncia Sanitaria de Productos Farmacéuticos, Dispositivos 9 10 Médico y Productos Sanitarios. Found in 11 http://www.digemid.minsa.gob.pe/UpLoad/UpLoaded/PDF/Normatividad/2015/D 12 S_029-2015.pdf . Accessed on November 26, 2015. 13 14 24. Almuzaini T, Sammons H, Choonara I. Substandard and falsified medicines 15 in the UK:For a retrospective peer review ofreview drug alerts (2001-2011). only BMJ Open. 2013 16 17 Jul 24;3(7). 18 19 25. Almuzaini T, Sammons H, Choonara I. Quality of medicines in Canada: a 20 retrospective review of risk communication documents (2005-2013). BMJ Open. 21 2014 Oct 31;4(10):e006088. 22 23 26. Instituto de Estadística e Informática – INEI. Condiciones de vida en el Perú 24 25 Enero – Febrero – Marzo 2014. Informe Técnico No 2 – Junio 2014. 26 27 27. Chambliss WG, Carroll WA, Kennedy D. Role of the pharmacist in 28 preventing distribution of counterfeit medications. J Am Pharm Assoc (2003). 29 2012 Mar-Apr;52(2):195-9. 30 31 28. Medicamentos espurios, de etiquetado engañoso, falsificados o de 32

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BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 c753c71ad8c22a/?vgnextoid=6011f106fe3c9410VgnVCM10000076192ca2RC 4 RD. Accessed on February 2, 2014. 5 6 33. Kovacs S, Hawes SE, Maley SN. Technologies for detecting falsified and 7 8 substandard drugs in low and middle-income countries. PLoS One. 2014 Mar 9 26;9(3):e90601. 10 11 34. Taylor D . RFID in the pharmaceutical industry: addressing counterfeits with 12 technology. J Med Syst. 2014 Nov;38(11):141. 13 14 35. Bansal D, Malla S, Gudala K et al. Anti-counterfeit technologies: a 15 For peer review only 16 pharmaceutical industry perspective. Sci Pharm. 2013 Mar;81(1):1-13. 17 18 36. Hall C. Technology for combating counterfeit medicine. Pathog Glob Health. 19 2012 May;106(2):73-6. 20 21 37. Bussy U, Thibaudeau C, Thomas F, et al. Isotopic finger-printing of active 22 pharmaceutical ingredients by 13C NMR and polarization transfer techniques as 23 24 a tool to fight against counterfeiting. Talanta. 2011 Sep 30;85(4):1909-14. 25 26 38. Sacré PY, Deconinck E, Daszykowski M. Impurity fingerprints for the 27 identification of counterfeit medicines--a feasibility study. Anal Chim Acta. 2011 28 Sep 9;701(2):224-31. . 29 30 39. Dipika Bansal, Swathi Malla, Kapil Gudala, et al. Anti-Counterfeit 31 32 Technologies: A Pharmaceutical Industry Perspective. Sci Pharm. Mar 2013;

33 81(1): 1–13. http://bmjopen.bmj.com/ 34 35 40. Nityanand Zadbuke, Sadhana Shahi, Bhushan Gulecha, et al. Recent 36 trends and future of pharmaceutical packaging technology. J Pharm Bioallied 37 Sci. 2013 Apr-Jun; 5(2): 98–110. 38 39 40 41. Ranieri N, Tabernero P, Green MD, et al. Evaluation of a new handheld

41 instrument for the detection of counterfeit artesunate by visual fluorescence on September 24, 2021 by guest. Protected copyright. 42 comparison. Am J Trop Med Hyg. 2014 Nov 5;91(5):920-4. 43 44 42. Koesdjojo MT, Wu Y, Boonloed A et al. Low-cost, high-speed identification 45 of counterfeit antimalarial drugs on paper. Talanta. 2014 Dec;130:122-7. 46 47 48 43. Lebel P1, Gagnon J2, Furtos A. A rapid, quantitative liquid chromatography- 49 mass spectrometry screening method for 71 active and 11 natural erectile 50 dysfunction ingredients present in potentially adulterated or counterfeit 51 products. J Chromatogr A. 2014 May 23;1343:143-51. 52 53 44. Custers D, Canfyn M, Courselle P. Headspace-gas chromatographic 54 55 fingerprints to discriminate and classify counterfeit medicines. Talanta. 2014 56 Jun;123:78-88. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 26

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 45. Anzanello MJ, Ortiz RS, Limbergerb RP et al. A multivariate-based 4 wavenumber selection method for classifying medicines into authentic or 5 counterfeitclasses. J Pharm Biomed Anal. 2013 Sep;83:209-14. 6 7 8 46. McCarthy M. Handheld device for counterfeit drug detection to be tested in 9 Africa. BMJ. 2013 Apr 26;346:f2732. 10 11 47. Deconinck E, Sacré PY, Courselle P. Chromatography in the detection and 12 characterization of illegal pharmaceutical preparations. J Chromatogr Sci. 2013 13 Sep;51(8):791-806. 14 15 For peer review only 16 48. Mbinze JK, Lebrun P, Debrus B. Application of an innovative design space 17 optimization strategy to the development of liquid chromatographic methods to 18 combat potentially counterfeit nonsteroidal anti-inflammatory drugs. Vols. J 19 Chromatogr A. 2012 Nov 9;1263:113-24. 20 21 49. Debrus B, Lebrun P, Kindenge JM, et al. Innovative high-performance liquid 22 23 chromatography method development for the screening of 19 antimalarialdrugs 24 based on a generic approach, using design of experiments, independent 25 component analysis and design space. Vols. J Chromatogr A. 2011 Aug 26 27 5;1218(31):5205-15. 28 29 50. Benton D, Williamson L, Stodart K. Buying medicine online is risky 30 business. Nurs N Z. 2014 May;20(4):27. 31 32 51. Mackey TK, Liang BA. Pharmaceutical digital marketing and governance: 33 illicit actors and challenges to global patient safety and public health. Global http://bmjopen.bmj.com/ 34 35 Health. 2013 Oct 16;9:45. 36 37 52. EAE Business School: El Gasto Farmacéutico 2014. Found in 38 http://www.eae.es/news/2014/07/14/el-gasto-farmaceutico-publico-por- 39 habitante-cae-un-7-2-y-se-situa-en-196-52. Accessed on January 15, 2015. 40

41 53. Tremblay M. Medicines counterfeiting is a complex problem: a review of key on September 24, 2021 by guest. Protected copyright. 42 43 challenges across the supply chain. Curr Drug Saf. 2013 Feb;8(1):43-55. 44 45 54. OMS. Consejo Ejecutivo 134º reunión (EB134/25) del 3 de enero de 2014. 46 Productos médicos de calidad subestándar, espurios, de etiquetado engañoso, 47 falsificados o de imitación. Informe de la Directora General. Found in 48 49 http://apps.who.int/gb/ebwha/pdf_files/WHA67/A67_29-sp.pdf. Accessed on 50 January 13, 2015. 51 52 55. Blackstone EA, Fuhr JP Jr, Pociask S. The health and economic effects of 53 counterfeit drugs. Am Health Drug Benefits. 2014 Jun;7(4):216-24. 54 55 56. Lai CW, Chan WK. Legislations combating counterfeit drugs in Hong Kong. 56 57 Hong Kong Med J. 2013 Aug;19(4):286-93. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 26 BMJ Open

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 57. Committee on Understanding the Global Public Health Implications of 4 Substandard, Falsified, and Counterfeit Medical Products; Board on Global 5 Health;Institute of Medicine; Buckley GJ, Gostin LO, editors. Countering the 6 7 Problem of Falsified and Substandard. Vol. Washington (DC): National 8 Academies Press (US); 2013 May. 9 10 58. Mackey TK, Liang BA. Improving global health governance to combat 11 counterfeit medicines: a proposal for a UNODC-WHO-Interpol trilateral 12 13 mechanism. BMC Med. 2013 Oct 31;11:233. 14 15 59. WeigmannFor K. Elixirs peer of death. Internationalreview organizations only are working 16 towards a global solution to address the problem offalsified and substandard 17 medicines, but progress has stagnated. EMBO Rep. 2013 Jul;14(7):597-600. 18 19 60. Seear M. The need for coordinated action against falsified and substandard 20 21 medicines. Int J Tuberc Lung Dis. 2013 Mar;17(3):286. 22 23 61. Attaran A, Barry D, Basheer S. How to achieve international action on 24 falsified and substandard medicines. BMJ. 2012 Nov 13;345:e7381. 25 26 62. Newton PN, Tabernero P, Dwivedi P. et al. Falsified medicines in Africa: all 27 28 talk, no action. Lancet Glob Health. 2014 Sep;2(9):e509-10. 29 30 31 32

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41 on September 24, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22 of 26 BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

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41 on September 24, 2021 by guest. Protected copyright. 42 43 44 45 46 47 Figure 1. Flow diagram showing types of Digemid alerts and overall results. 440x599mm (300 x 300 DPI) 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 26 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

41 on September 24, 2021 by guest. Protected copyright. 42 43 44 45 46 47 Figure 2. Digemid alerts and falsified medicines by year 209x297mm (300 x 300 DPI) 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24 of 26 BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Figure 3. Evolution of inspections according to the promoter. 297x209mm (300 x 300 DPI) 32 33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

Supplementary file table 1: Total results - Cases of falsified medicines BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 CÓDIGO ATC MEDICAMENTO Nº % G02CC02 Naproxeno 245 14,10% 2 N02BE51 Paracetamol, combinaciones excl. Psicolépticos 236 13,58% R06AB54 Clorfeniramina, combinaciones 182 10,47% 3 A04AD Otros antieméticos 119 6,85% J01EE01 Sulfametoxazol y trimetoprima 102 5,87% 4 A07DA03 Loperamida 68 3,91% A11JC Vitaminas, otras combinaciones 67 3,86% J01CE02 Fenoximetil penicilina 62 3,57% 5 J01EB52 Sulfametizol, combinaciones 57 3,28% N02BE01 Paracetamol 55 3,16% 6 A11DB Vitamina B1 en combinación con vitamina B6 y/o vitamina B12 36 2,07% M01AE01 Ibuprofeno 20 1,15% 7 N03AB02 Fenitoína 18 1,04% J01AA07 Tetraciclina 17 0,98% G03FA12 Medroxyprogesterone y estrógenos 16 0,92% 8 J01CE Penicilinas sensibles a la betalactamasa 14 0,81% N05BA12 Alprazolam 14 0,81% 9 A11HA52 Piridoxina (vit. B6), combinaciones 14 0,81% A02AA04 Hidróxido de magnesio 13 0,75% 10 A03DB04 Butilescopolamina y analgésicos 13 0,75% J01BA01 Cloranfenicol 12 0,69% B03AB Hierro trivalente, preparados orales 12 0,69% 11 J01FF02 Lincomicina 14 0,81% R06AB04 Clorfenamina 11 0,63% 12 G04BX06 Fenazopiridina 11 0,63% H02AB02 Dexametasona 10 0,58% 13 N02BA51 Ácido acetilsalicílico, combinaciones excl. psicolépticos 10 0,58% A10BB01 Glibenclamida 10 0,58% R01AX Otros preparados nasales 10 0,58% 14 N02CA52 Ergotamina, combinaciones excl. psicolépticos 10 0,58% G02CC01 Ibuprofeno 10 0,58% 15 A02AX Otras combinaciones con antiácidosFor peer8 0,46% review only D02AX Otros emolientes y protectores 8 0,46% 16 D04AB51 Lidocaina, combinaciones 8 0,46% D08AJ Compuestos de amonio cuaternario 8 0,46% N02AX52 Tramadol, combinación con 10 0,58% 17 N03AE01 Clonazepam 8 0,46% J01CA04 Amoxicilina 7 0,40% 18 R05DA09 Dextrometorfano 7 0,40% N02BB02 Metamizol sódico (dipirona) 7 0,40% 19 A03AX13 Siliconas 6 0,35% M01AB05 Diclofenaco 6 0,35% H02AB01 Betametasona 5 0,29% 20 J01CA54 Amoxicilina, combinaciones 5 0,29% M01AB15 Ketorolaco 5 0,29% 21 G03AA Progestágenos y estrógenos, preparados de dosis fijas 4 0,23% G03AA07 Levonorgestrel y estrógeno 4 0,23% 22 G03EA03 Prasterona y estrógeno 4 0,23% J01GB06 Amikacina 4 0,23% R03CC52 Salbutamol, combinaciones 4 0,23% 23 A03DC Otros antiespasmódicos en combinación con analgésicos 3 0,17% A11EA Vitaminas del complejo B solas 3 0,17% 24 J01GB03 Gentamicina 3 0,17% J01XE01 Nitrofurantoína 3 0,17% 25 N02AX02 Tramadol 3 0,17% A03FA51 Metoclopramida, combinaciones excl. Psicolépticos 3 0,17% G03AC06 Medroxiprogesterona 3 0,17% 26 N06BX06 Citicolina 3 0,17% G03DA04 Progesterona 3 0,17% 27 G04BX Otros productos urológicos 3 0,17% N06AB06 Sertralina 3 0,17% 28 D07CC01 Betametasona con antibióticos 2 0,12% A02BB01 Misoprostol 2 0,12% A11AA03 Multivitamínicos con otros minerales, incl. combinaciones 2 0,12% 29 D08AG02 Iodo povidona 2 0,12% G03AC03 Levonorgestrel 2 0,12% 30 J01CA01 Ampicilina 2 0,12% J01DA06 Cefuroxima 2 0,12% 31 J01MA02 Ciprofloxacino 2 0,12% N02BG Otros analgésicos y antipiréticos 2 0,12% N03AX11 Topiramato 2 0,12% 32 N05BA06 Lorazepam 2 0,12% R05DA59 Dextrometorfano, combinaciones 2 0,12% 33 R06AB52 Dexchlorpheniramine, combinations 2 0,12% http://bmjopen.bmj.com/ J01MA56 Norfloxacino, combinacion 2 0,12% 34 M01AC06 Meloxicam 2 0,12% R01AA08 Nafazolina 2 0,12% A11BA Multivitamínicos solos 2 0,12% 35 B06AA02 Fibrinolisina y desoxirribonucleasa 2 0,12% C05BA51 Heparinoides, combinaciones 3 0,17% 36 C08CA06 Nimodipino 2 0,12% H02AB07 Prednisona 2 0,12% 37 M01AB55 Diclofenaco, combinaciones 2 0,12% N05CD08 Midazolam 2 0,12% A01AD05 Ácido acetilsalicílico 1 0,06% 38 A06AD11 Lactulosa 1 0,06% B01AB01 Heparina 1 0,06% 39 B03AE10 Varias combinaciones 1 0,06% B05BC01 Manitol 1 0,06% 40 C01DA08 Dinitrato de isosorbida 1 0,06% C03DA01 Espironolactona 1 0,06% C04AD03 Pentoxifilina 1 0,06%

Supplementary file table 2: Without duplicates - Cases of falsified medicines BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 CÓDIGO ATC MEDICAMENTO Nº % 2 N02BE51 Paracetamol, combinaciones excl. Psicolépticos 193 17,36% G02CC02 Naproxeno 170 15,29% J01EE01 Sulfametoxazol y trimetoprima 62 5,58% 3 R06AB54 Clorfeniramina, combinaciones 53 4,77% J01CE02 Fenoximetil penicilina 47 4,23% 4 A04AD Otros antieméticos 40 3,60% J01EB52 Sulfametizol, combinaciones 40 3,60% A11JC Vitaminas, otras combinaciones 39 3,51% 5 A07DA03 Loperamida 36 3,24% N02BE01 Paracetamol 24 2,16% 6 N05BA12 Alprazolam 13 1,17% A11DB Vitamina B1 en combinación con vitamina B6 y/o vitamina B12 12 1,08% M01AE01 Ibuprofeno 11 0,99% 7 A03DB04 Butilescopolamina y analgésicos 11 0,99% G04BX06 Fenazopiridina 11 0,99% 8 A11HA52 Piridoxina (vit. B6), combinaciones 10 0,90% J01BA01 Cloranfenicol 10 0,90% B03AB Hierro trivalente, preparados orales 10 0,90% 9 R06AB04 Clorfenamina 10 0,90% J01FF02 Lincomicina 10 0,90% 10 N02AX52 Tramadol, combinación con 10 0,90% J01CE Penicilinas sensibles a la betalactamasa 9 0,81% 11 J01AA07 Tetraciclina 8 0,72% H02AB02 Dexametasona 8 0,72% N03AE01 Clonazepam 8 0,72% 12 N02CA52 Ergotamina, combinaciones excl. psicolépticos 8 0,72% G02CC01 Ibuprofeno 8 0,72% 13 A02AA04 Hidróxido de magnesio 7 0,63% N03AB02 Fenitoína 7 0,63% G03FA12 Medroxyprogesterone y estrógenos 7 0,63% 14 N02BA51 Ácido acetilsalicílico, combinaciones excl. psicolépticos 7 0,63% A10BB01 Glibenclamida 7 0,63% 15 A02AX Otras combinaciones con antiácidos 7 0,63% D02AX Otros emolientes y protectores For peer7 review0,63% only D04AB51 Lidocaina, combinaciones 7 0,63% 16 J01CA04 Amoxicilina 7 0,63% N02BB02 Metamizol sódico (dipirona) 6 0,54% 17 M01AB05 Diclofenaco 6 0,54% J01CA54 Amoxicilina, combinaciones 5 0,45% M01AB15 Ketorolaco 5 0,45% 18 R01AX Otros preparados nasales 4 0,36% D08AJ Compuestos de amonio cuaternario 4 0,36% 19 A03AX13 Siliconas 4 0,36% H02AB01 Betametasona 4 0,36% G03AA07 Levonorgestrel y estrógeno 4 0,36% 20 R05DA09 Dextrometorfano 4 0,36% G03AA Progestágenos y estrógenos, preparados de dosis fijas 3 0,27% 21 J01GB06 Amikacina 3 0,27% R03CC52 Salbutamol, combinaciones 3 0,27% J01GB03 Gentamicina 3 0,27% 22 A03FA51 Metoclopramida, combinaciones excl. Psicolépticos 3 0,27% G03AC06 Medroxiprogesterona 3 0,27% 23 N06BX06 Citicolina 3 0,27% G03DA04 Progesterona 3 0,27% N06AB06 Sertralina 3 0,27% 24 D07CC01 Betametasona con antibióticos 2 0,18% G03EA03 Prasterona y estrógeno 2 0,18% 25 A03DC Otros antiespasmódicos en combinación con analgésicos 2 0,18% J01XE01 Nitrofurantoína 2 0,18% 26 G04BX Otros productos urológicos 2 0,18% A02BB01 Misoprostol 2 0,18% D08AG02 Iodo povidona 2 0,18% 27 J01CA01 Ampicilina 2 0,18% J01MA02 Ciprofloxacino 2 0,18% 28 N02BG Otros analgésicos y antipiréticos 2 0,18% N03AX11 Topiramato 2 0,18% N05BA06 Lorazepam 2 0,18% 29 R05DA59 Dextrometorfano, combinaciones 2 0,18% R06AB52 Dexchlorpheniramine, combinations 2 0,18% 30 J01MA56 Norfloxacino, combinacion 2 0,18% M01AC06 Meloxicam 2 0,18% R01AA08 Nafazolina 2 0,18% 31 A11BA Multivitamínicos solos 2 0,18% B06AA02 Fibrinolisina y desoxirribonucleasa 2 0,18% 32 C08CA06 Nimodipino 2 0,18% H02AB07 Prednisona 2 0,18%

M01AB55 Diclofenaco, combinaciones 2 0,18% http://bmjopen.bmj.com/ 33 N05CD08 Midazolam 2 0,18% C05BA51 Heparinoides, combinaciones 2 0,18% 34 A11EA Vitaminas del complejo B solas 1 0,09% N02AX02 Tramadol 1 0,09% A11AA03 Multivitamínicos con otros minerales, incl. combinaciones 1 0,09% 35 G03AC03 Levonorgestrel 1 0,09% J01DA06 Cefuroxima 1 0,09% 36 A01AD05 Ácido acetilsalicílico 1 0,09% A06AD11 Lactulosa 1 0,09% B01AB01 Heparina 1 0,09% 37 B03AE10 Varias combinaciones 1 0,09% B05BC01 Manitol 1 0,09% 38 C01DA08 Dinitrato de isosorbida 1 0,09% C03DA01 Espironolactona 1 0,09% 39 C04AD03 Pentoxifilina 1 0,09% C08CA56 Nimodipino, combinaciones 1 0,09% C09AA02 Enalapril 1 0,09% 40 D06AX54 Neomicina, combinaciones 1 0,09% D06BA Sulfonamidas 1 0,09% D08AX07 Sodium hypochlorite 1 0,09% 41 on September 24, 2021 by guest. Protected copyright. G03CA03 Estradiol 1 0,09% G04BD02 Flavoxato 1 0,09% 42 G04BE03 Sildenafilo 1 0,09% H02AB09 Hidrocortisona 1 0,09% 43 J01AA02 Doxiciclina 1 0,09% J01AA56 Oxitetraciclina, combinaciones 1 0,09% J01CF01 Dicloxacilina 1 0,09% 44 J01DH02 Meropenem 1 0,09% J01FA01 Eritromicina 1 0,09% 45 J01FF01 Clindamicina 1 0,09% M01AE02 Naproxeno 1 0,09% M02AC Preparados con ácido salicílico y derivados 1 0,09% 46 M03AB01 Suxametonio 1 0,09% M03BC01 Orfenadrina (citrato) 1 0,09% 47 M05BA06 Ácido ibandrónico 1 0,09% N04BA02 Levodopa con inhibidor de la decarboxilasa 1 0,09% N05AD01 Haloperidol 1 0,09% 48 N05AL05 Amisulprida 1 0,09% N05BA09 Clobazam 1 0,09% 49 N07XX Otras drogas que actúan sobre el sistema nervioso 1 0,09% P01BA01 Cloroquina 1 0,09% P02CA03 Albendazol 1 0,09% 50 P03AX01 Benzoato de bencilo 1 0,09% R01BA52 Pseudoefedrina, combinaciones 1 0,09% 51 R03AC02 Salbutamol 1 0,09% R03BA02 Budesonida 1 0,09% 52 R03CC63 Clenbuterol, combinaciones 1 0,09% R05CB01 Acetilcisteína 1 0,09% R05CB03 Carbocisteína 1 0,09% 53 R05X Otros preparados para el resfriado 1 0,09% R06AE07 Cetirizina 1 0,09% 54 R06AE08 Levocetirizina 1 0,09% R06AX27 Desloratadina 1 0,09% S01AA53 Neomicina, combinaciones 1 0,09% 55 A02AF01 Magaldrato y carminativos 1 0,09% A05AX Otras drogas para terapia biliar 1 0,09% 56 J01MA12 Levofloxacino 1 0,09% M01AH01 Celecoxib 1 0,09% 57 N05BA08 Bromazepam 1 0,09% TOTAL 1112 100,00% 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from

Falsified medicines in Peru: A Retrospective Review (1997- 2014).

ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2015-010387.R2

Article Type: Research

Date Submitted by the Author: 04-Feb-2016

Primary Subject Public health Heading:

Secondary Subject Heading: Global health, Epidemiology, Health policy, Health services research

Keywords: Safety, Falsified, Medicines, Alerts, counterfeit, Drugs

http://bmjopen.bmj.com/

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33 http://bmjopen.bmj.com/ 34 Keywords: Safety, Falsified, Medicines, Alerts, counterfeit, Drugs 35 36 37 38 39 Word Count 40

41 Abstract: 283 on September 24, 2021 by guest. Protected copyright. 42 Main text: 4 482 43 Figures: 3 44 Tables: 3 45 Supplementary data: 1 46 References: 63 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 28

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 ABSTRACT 4 5 Objective: Consolidate and assess information on falsified medicines in 6 pharmaceutical alerts issued by the Peruvian Medicines Regulatory Authority in 7 a period of 18 years (1997-2014) of health monitoring and enforcement. 8 9 10 Design: A retrospective review of drug alerts. 11 12 Setting: The General Directorate of Medicines, Supplies and Drugs (DIGEMID - 13 Ministry of Health of Peru) website search for drug alerts issued between 1997 14 and 2014. 15 For peer review only 16 Eligibility criteria: Drug alerts related to falsified medicines. 17 18 19 Results: A total of 669 DIGEMID Alerts were issued during the study period, 20 354 (52.91%) of which refer to a total of 1 738 cases of falsified medicines 21 (many alerts deal with several cases at a time). Regarding the type of 22 establishment involved in the possession or sale of falsified medicines, 1 010 23 cases (58.11%) were pharmaceutical establishments; 349 cases (20.08%) were 24 non-pharmaceutical commercial outlets; in 126 cases (7.23%) the medicines 25 were seized in unauthorized trade (without any marketing authorization), and in 26 253 cases (14.56%) the type of establishment or business related with the 27 seized product is not identified. 28 29 30 Conclusions: In light of the results, there is no doubt that falsified medicines 31 represent a serious public health problem in Peru. A review of the data alone is 32 not enough to conclude whether falsified medicines in Peru have increased

33 during the study period, or if the monitoring action of different government http://bmjopen.bmj.com/ 34 health agencies has brought the magnitude of the problem more to the surface 35 by providing more evidence. The problem is clearly structural, since the majority 36 of cases (58.11% of the total) were detected in legitimate supply chains. Most 37 falsified medicines involve staple pharmaceutical products and common dosage 38 39 forms. 40

41 Considerable work remains to be done to control the serious problem of falsified on September 24, 2021 by guest. Protected copyright. 42 medicines in Peru. 43 44 STRENGTHS AND LIMITATIONS OF THIS STUDY 45 46 DIGEMID alerts are published systematically, are organized by date, and 47 48 are readily available on the DIGEMID open access website. 49 The information they provide is not entirely homogenous and 50 standardized which is a limitation for an overall analysis. 51 In most cases, the DIGEMID alerts do not provide information on the 52 results of the evaluation, thereby hindering an overall evaluation. 53 The possible health effects resulting from the use of falsified medicines 54 are not addressed or included in the alerts. 55 Graphical reports of counterfeit medicines, which are an illustrative and 56 informative tool, are only provided in three alerts (DIGEMID Alerts 17- 57 58 2006, 35-2005 and 40-2005). 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 28 BMJ Open

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 INTRODUCTION 4 5 The WHO has been receiving reports of falsified medicines since 1982. [1] The 6 phenomenon was first referred to as a problem at the WHO Conference of 7 Experts on the Rational Use of Drugs in Nairobi, Kenya, in 1985. Since then, 8 public awareness of falsified medicines has grown, [2] and it has become a 9 10 major public health issue, as reflected by government initiatives worldwide in 11 response to the problem. 12 13 The issue of falsified medicines is so complex that, for example, even today 14 different definitions are used, or a falsified medicine is confused with one of 15 poor qualityFor (substandard), peer a serious review mistake that hampersonly the exchange of 16 information between countries, and makes it difficult to grasp the true scale of a 17 global problem. The WHO defines falsified medicines as those whose labels 18 19 include, intentionally and fraudulently, false information about their identity and 20 origin. Falsification can affect both branded and generic products, and may 21 include products with the correct or wrong ingredients, without active [2] 22 ingredients, with insufficient active ingredients or with fake packaging. 23 24 According to the WHO, the highest rates of medicine falsification in the world 25 occur in regions with the weakest regulatory and control systems, such as many 26 African, Asian, and Latin American nations and countries in transition. In most 27 industrialized nations, regulatory systems and market control are effective and 28 29 thus the incidence of spurious/falsely-labelled/falsified/counterfeit medicines is low, estimated to be less than 1% of the market value. [3] Medicine falsification 30 [4] 31 involves manufacturing and distribution networks related to organized crime, [5-6] 32 with annual turnovers between 75 and 200 billion dollars and has a [7] 33 significant impact even in large economies like the US. http://bmjopen.bmj.com/ 34 35 In general, the deregulation of any trade or business and the existence of 36 uninformed consumers facilitate criminal activities of unscrupulous people, 37 whose sole purpose is to obtain illegitimate profits, at the expense of harming 38 39 consumers and the health system. This is the case of the medicine market in 40 Peru (according to the World Bank, a country of upper-middle income with a [8]

41 gross national income per capita of $ 4 126 – 12 745). on September 24, 2021 by guest. Protected copyright. 42 43 In Peru, in the early 1990s, with the excuse of an economic crisis, the regulated 44 market for medicines was replaced by an open market, in line with the 45 neoliberal economic model of the moment. For example, ownership of the 46 community pharmacy was no longer the exclusive right of pharmacists, and 47 anyone with enough capital could open a pharmaceutical office (store 48 49 dispensing and retailing pharmaceuticals and related products; with the same 50 function, can be pharmacies, where the owner is a pharmacist; or boticas, 51 where the owner is not a pharmacist), in any location, and without rigorous prior 52 control. This change was based on a political decision without a preliminary 53 analysis of the possible consequences, such as the chaotic growth in the 54 number of pharmaceutical establishments, which is currently 23 527 [9] (259 in 55 1980 - 1989; 3 335 in 1990 – 1999 and 17 071 in 2000 - 2008) [10], rendering 56 effective control by the authorities impossible. This is arguably one of the main 57 causes of the high number of cases of counterfeit medicines found in the legal 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 28

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 supply chain today. Attempts to resolve this problem include Law No 26842 of 4 2009, which stipulates mandatory sanitary authorization for the operation of 5 pharmaceutical establishments, with prior verification of compliance, [11] and 6 more recently a process of registration or special registration under the 7 Temporary Supplementary Provisions of the Supreme Decree No. 033-2014- 8 SA. [12] 9 10 11 The consequences of this illegal phenomenon represent a serious public health [13] 12 problem, including treatment failure, possible cases of added contaminants, 13 and even death. It has also resulted in the deployment and disbursement of 14 often scarce resources, a loss of faith in health systems, distrust of medications 15 and evenFor the failure peer of major global review health policies suchonly as the fight against 16 malaria. [14] 17 18 19 The regulatory authority for medicines in Peru is the General Directorate of Medicines, Supplies and Drugs (DIGEMID), created by the Legislative Decree 20 [15] 21 No. 584 of 16 April 1990, as a dependent institution of the Ministry of Health 22 of Peru. In May 1998, the Alerts Committee was established by the Directorial 23 Resolution No. 367-98-DG-DIGEMID to evaluate and define which actions 24 should be taken in response to alerts or communications about safety and/or 25 efficacy of pharmaceuticals and related products. [16] 26 27 Inspectors of DIGEMID and regional health institutions carry out inspections 28 29 and spot checks of pharmaceutical products (in pharmaceutical and non- 30 pharmaceutical establishments), and also receive counterfeit drugs seized by 31 other regulatory authorities (National Police, Customs, etc.). Any suspected 32 deficiency or observable abnormality in a product leads to its seizure, and its

33 authenticity is then verified with the holder of the relevant marketing http://bmjopen.bmj.com/ 34 authorization. If the suspected counterfeiting is confirmed, samples are 35 transferred to an Official Control Laboratory to complete the relevant physical- 36 chemical and microbiological analyses. All the documentation and case history 37 is referred to the DIGEMID-Alerts Committee to approve the publication of the 38 corresponding alert in the institutional web page and to initiate internal and 39 [17] 40 external dissemination.

41 on September 24, 2021 by guest. Protected copyright. 42 43 44 OBJECTIVE 45 46 This work seeks to consolidate and assess information on falsified medicines in 47 pharmaceutical alerts issued by the Peruvian Medicines Regulatory Authority in 48 49 a period of 18 years (1997-2014) of health monitoring and enforcement. The 50 ultimate aim is to draw attention to the situation of falsified medicines in Peru 51 and highlight the efforts of various state institutions headed by DIGEMID. 52 53 54 55 METHODS 56 57 58 Inclusion and exclusion criteria 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 28 BMJ Open

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 A falsified medicine is a product improperly manufactured, in a deliberate and 4 fraudulent manner with respect to its identity or its origin. They may include 5 products with right ingredients or with wrong ingredients, without active 6 pharmaceutical ingredients (APIs), with insufficient or wrong active 7 pharmaceutical ingredients (APIs) or with packaging or labelling falsified. [18] 8 9 10 A DIGEMID Alert is a document issued by the National Authority of 11 Pharmaceutical Products and Medical Devices, as a measure of health safety, 12 through which the regulatory actions and other actions, on the safety, 13 falsification, critical quality results, among others, related to pharmaceutical 14 products and medical devices are made known to the national scientific 15 communityFor and to thepeer public in general, review with the ultimate only objective of controlling 16 and minimising the risk related to the commercialisation and its respective use. 17 [17] 18 19 20 To be eligible for inclusion in the retrospective review, DIGEMID-alerts had to 21 include falsified medicines. The resulting DIGEMID alerts were compiled and 22 exclusion criteria included the following: medical devices, herbal products and 23 cosmetic products have been excluded, as have been cases related to quality, 24 general safety or regulation (for example, products without sanitary registration). 25 26 Data sources and searches 27 28 29 A search for DIGEMID-alerts related to falsified medicines products was carried 30 out. This was performed through the official DIGEMID website using the section 31 allocated for DIGEMID-alerts. [19] The first DIGEMID-alert published on the 32 DIGEMID website was in the year 1997; thus, all drug alerts issued between 33 1997 and 2014 were included. http://bmjopen.bmj.com/ 34 35 Data collection 36 37 38 All available DIGEMID alerts were reviewed, to make a final choice and to 39 determine their inclusion in the review. A structured Excel spreadsheet was 40 used to record relevant information and ensure uniformity of evaluation for each

41 DIGEMID alert. The following data were extracted from these alerts: on September 24, 2021 by guest. Protected copyright. 42 43 • Publication date of DIGEMID alert: It allows a temporary location of each 44 45 case of medicinal products falsification and display their periodic impact. 46 • Medicinal product: It discloses which medicaments are being falsified, on 47 a regular basis, to which therapeutic groups they belong to, etc. 48 • Batch number: It allows to identify over time which batches of the same 49 medicinal product have been seized more than once. 50 • Pharmaceutical dosage form: We can observe which pharmaceutical 51 dosage forms are being falsified more regularly, for instance. 52 53 • Establishment data or place where seizure took place: It allows to know 54 the types of establishments involved in the commercialisation of falsified 55 medicinal products and geographically establish the incidence of cases 56 in the different regions of the country. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 28

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 • Seizure promoter: It points out which authority has permitted through its 4 activity to seize a falsified medicinal product. 5 • Assessment result: it allows to know the characteristics of the falsification 6 that the medicinal product has suffered. 7 8 9 10 11 Data analysis 12 13 Based on the collected data, the total number of DIGEMID alerts issued per 14 year, the number of DIGEMID alerts about falsified medicines and the number 15 of cases Forof falsified peermedicines was review determined (there onlyare DIGEMID alerts with 16 17 more than one case of falsified medicinal product as we shall further see in the 18 results); which gives us an idea of the magnitude of the problem. 19 20 Moreover, with the data of the establishment involved, it is possible to 21 determine the type of establishment where the counterfeit medicine was found 22 were determined, dividing the latter into three groups: 23 24 1. Pharmaceutical establishments (pharmaceutical offices (pharmacy and 25 botica), pharmacy of health establishments, botiquín, droguería, specialty stores 26 [18] 27 and laboratory). 28 29 Pharmaceutical offices (Pharmacies and Boticas): 30 31 • Pharmacy, pharmaceutical store dispensing and retailing 32 pharmaceuticals and related products. Owned by a pharmacist. 33 http://bmjopen.bmj.com/ • Botica, pharmaceutical store dispensing and retailing 34 35 pharmaceuticals and related products. Not owned by a 36 pharmacist. 37 38 Pharmacy of Health Establishments, which belongs to a health 39 establishment, public or private. 40 Botiquín, sells pharmaceuticals and related products included in a

41 restricted list by the Health Authority. on September 24, 2021 by guest. Protected copyright. 42 Droguería: Engaged in the import, export, marketing, storage, quality 43 control and / or distribution of pharmaceuticals and related products. 44 45 Specialty Stores, infrastructure of a public health establishment for the 46 storage and distribution of pharmaceuticals and related products. 47 Laboratory, engaged in manufacturing, packaging, bottling, conditioning, 48 reconditioning, quality control, storage and export of pharmaceuticals 49 and related products. 50 51 2. Non-pharmaceutical commercial establishments, any authorised commercial 52 establishment that is not a pharmaceutical establishment. 53 54 55 3. Informal, unauthorised commercial establishments or places. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 28 BMJ Open

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 To view a geographical relationship with the problem of the falsification of 4 medicinal products in Peru, the results are distributed on the basis of the 24 5 Departments of Peru and the Constitutional Province of Callao. 6 7 It will also be taken into account for the analysis to the corresponding promoter 8 of the audit activity which led to the seizure of the falsified medicinal product to 9 10 which Alert DIGEMID makes reference (General Directorate of Medicines, 11 Supplies and Drugs – DIGEMID, Health Directorates – DISAs, Regional Health 12 Directorates – DIRESAs, National police of Peru, Public Prosecutor, customs, 13 etc.). 14 15 All counterfeitFor medicines peer were classified review according toonly the WHO - Anatomical 16 Therapeutic Chemical Classification System (ATC), where medicines are 17 classified in groups at five different levels and the first three levels were used in 18 19 this section. The first level classifies medicine according to the system or organ 20 on which it acts; the second level classifies medicine according to its 21 therapeutic subgroup and the third level classifies medicine according to its [20] 22 pharmacological subgroup. The stated dosage form is in accordance with 23 the DIGEMID alerts or the database of the registration of pharmaceutical 24 products of the regulatory authority of medicinal products of Peru (PERUDIS). 25 [21] This was performed to highlight the most frequent therapeutic classes and 26 dosage forms affected by counterfeit drugs. The type of counterfeiting is 27 classified according to the assessment provided by the alerts: features and/or 28 29 information that do not match the product specifications, containing no active 30 ingredient, containing an active ingredient other than stated on the label, or 31 containing the correct active ingredient but not the authorised content. To be 32 more precise in the analysis of the type of counterfeit medicine, those with a

33 batch number subject of a previous alert are not taken into account. http://bmjopen.bmj.com/ 34 35 The result of the assessment of each one of the falsified medicinal products can 36 be divided into four groups: do not contain any active ingredient, contain active 37 ingredients other that those stated on the label, contain the active ingredient but 38 39 in in different dosage to the label claim or the result of the assessment does not 40 exist.

41 on September 24, 2021 by guest. Protected copyright. 42 Quality assessment 43 44 All authors have had access to the primary information (DIGEMID-alerts) 45 corresponding to the study period and the evaluation tables (excel); the process 46 of analysis and drafting of the work has been carried out by the first author, 47 followed by a process of verification and reconciliation of the results by the other 48 49 authors. 50 51 52 53 RESULTS 54 55 In the 18-year period covered by this study (1997-2014), DIGEMID issued a 56 total of 669 alerts, 354 of which (52.91%) concern falsified medicines. It should 57 58 be mentioned that there is no direct relationship between the number of 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 28

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 DIGEMID alerts and the number of falsified medicines, since several alerts refer 4 to more than one medicine or different batches of the same product. In this 5 sense, DIGEMID alert No. 27 of 2012 [22] particularly stands out, as it deals with 6 74 cases of falsified medicines. Thus, the 354 DIGEMID alerts concerning 7 falsified medicines include a total of 1 738 reported cases (Figure 1 and 2). 8 9 10 11 12 Figure 1. Flow diagram showing types of DIGEMID alerts and overall 13 results. 14 15 For peer review only 16 17 18 19 20 21 22 23 24 Figure 2. DIGEMID alerts and falsified medicines by year. 25 26 27 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 In the period covered by the study, a total of 1 738 cases of counterfeit 39 medicines were found (see online supplementary file table S1). Regarding the 40 type of outlet/establishment involved in the possession or sale of falsified 41 medicines leading to the issue of a DIGEMID alert, 1 010 cases (58.11%) of the on September 24, 2021 by guest. Protected copyright. 42 43 total involved pharmaceutical establishments (pharmaceutical offices, 44 droguerías, botiquines and laboratories); 349 (20.08%) involved non- 45 pharmaceutical establishments (non-pharmaceutical commercial outlets); in 126 46 47 cases (7.25%) falsified medicines were seized in unauthorized trade (without 48 any marketing authorization), including 10 cases of clandestine laboratories; 49 and finally in 253 (14.56%) cases there is insufficient information to clearly 50 identify the type of establishment or business involved. 51 52 53 Regarding the pharmaceutical establishments, it should be noted that 850 54 (84.16%) of all cases of falsified medicines involved boticas and 130 (12.87%) 55 involved pharmacies (Table 1). 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 28 BMJ Open

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 Table 1. Type of establishment or business related with the possession or 4 sale of falsified medicines. 5 6 7 TYPE OF ESTABLISHMENT/OUTLET TOTAL % 8 9 PHARMACEUTICAL 1 010 58.11% 10 11 PHARMACY 12 Pharmaceutical store dispensing and retailing pharmaceuticals 130 7.48% 13 and related products. Owned by a pharmacist. BOTICA 14 Pharmaceutical store dispensing and retailing pharmaceuticals 850 48.91% 15 and relatedFor products. Notpeer owned by a pharmacist. review only 16 BOTIQUÍN 17 Sells pharmaceuticals and related products included in a 4 0.23% 18 restricted list by the Health Authority. 19 DROGUERÍA 20 Engaged in the import, export, marketing, storage, quality control 23 1.32% 21 and / or distribution of pharmaceuticals and related products. 22 LABORATORY 23 Engaged in manufacturing, packaging, bottling, conditioning, 3 0.17% 24 reconditioning, quality control, storage and export of 25 pharmaceuticals and related products. 26 NON-PHARMACEUTICAL 349 20.08% 27 28 29 UNAUTHORIZED TRADE 126 7.25% 30 31 32 Without Information 253 14.56%

33 http://bmjopen.bmj.com/ 34 TOTAL 1 738 100.00% 35 36 37 38 39 40 Regarding the location where falsified medicines were seized, Lima province

41 had the highest number of cases with 562 (32.34%), far outstripping La on September 24, 2021 by guest. Protected copyright. 42 Libertad, which had 315 (18.12%). Interestingly, no cases were reported in the 43 44 departments of Huanuco and Tumbes. Taking into account the population in 45 each region and the number of cases of counterfeiting, the province with the 46 highest number of cases of counterfeit medicines per 100 000 inhabitants is 47 48 Madre de Dios, with 19.33 cases, followed by La Libertad with 16.94 cases. 49 More details are shown in Table 2. 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 28

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 Table 2. Number of cases of falsified medicines according to the 4 geographical location where they were seized and population. 5 6 7 8 9 No. Cases No. Of 10 of Population Cases Per Region % [23] 11 Counterfeit in 2015 100 000 12 Medicines Inhabitants 13 Amazonas 1 0,06% 422 629 0,24 14 Ancash 53 3,05% 1 148 634 4,61 15 ApurimacFor peer review1 0,06% only458 830 0,22 16 Arequipa 93 5,35% 1 287 205 7,22 17 Ayacucho 26 1,50% 688 657 3,78 18 Cajamarca 123 7,08% 1 529 755 8,04 19 Callao 20 1,15% 1 013 935 1,97 20 Cusco 68 3,91% 1 316 729 5,16 21 22 Huancavelica 3 0,17% 494 963 0,61 23 Huánuco 0 0,00% 860 548 0,00 24 Ica 12 0,69% 787 170 1,52 25 Junín 146 8,40% 1 350 783 10,81 26 La libertad 315 18,12% 1 859 640 16,94 27 Lambayeque 56 3,22% 1 260 650 4,44 28 Lima 562 32,34% 9 834 631 5,71 29 Loreto 146 8,40% 1 039 372 14,05 30 Madre de dios 27 1,55% 137 316 19,66 31 Moquegua 24 1,38% 180 477 13,30 32 Pasco 3 0,17% 304 158 0,99 33 Piura 7 0,40% 1 844 129 0,38 http://bmjopen.bmj.com/ 34 Puno 18 1,04% 1 415 608 1,27 35 San Martín 3 0,17% 840 790 0,36 36 Tacna 4 0,23% 341 838 1,17 37 Tumbes 0 0,00% 237 685 0,00 38 Ucayali 11 0,63% 495 511 2,22 39 40 Without Information 16 0,92%

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 Figure 3. Evolution of inspections according to the promoter. 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 To obtain more precise results regarding the falsified medicines themselves, 27 identical batches (product/batch number) seized in more than one place or 28 mentioned in earlier alerts were excluded, ultimately resulting in a total of 1 112 29 30 falsified medicines with different batch numbers (see online supplementary file 31 table S2), the details of which are shown in Figure 1 and 2. 626 cases of 32 counterfeit medicines had batch numbers included in more than one alert, many

33 of them in different years. http://bmjopen.bmj.com/ 34 35 The number of falsified medicines classified according to the organ or system 36 on which they act, and the therapeutic and pharmacological subgroups of the 37 ATC code are detailed in Table 3. Among the therapeutic subgroups, painkillers 38 were the most frequently falsified medicines, representing 22.57% of all cases, 39 followed by systemic antibacterials at 19.78%. 40

41 on September 24, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50

51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 28

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 Table 3. Classification of the falsified medicines according to the ATC 4 Code. 5 6 MAIN ANATOMICAL GROUP Nº % 7 N NERVOUS SYSTEM 297 26.71% 8 9 J ANTIINFECTIVES FOR SYSTEMIC USE 220 19.78% 10 G GENITO URINARY SYSTEM AND SEX HORMONES 217 19.51% 11 A ALIMENTARY TRACT AND METABOLISM 188 16.91% 12 R RESPIRATORY SYSTEM 90 8.09% 13 M MUSCULO-SKELETAL SYSTEM 32 2.88% 14 15 D ForDERMATOLOGICALS peer review only 25 2.25% SYSTEMIC HORMONAL PREPARATIONS, EXCL. SEX HORMONES AND H 15 1.35% 16 INSULINS 17 B BLOOD AND BLOOD FORMING ORGANS 15 1.35% 18 C CARDIOVASCULAR SYSTEM 9 0.81% 19 20 P ANTIPARASITIC PRODUCTS, INSECTICIDES AND REPELLENTS 3 0.27% 21 S SENSORY ORGANS 1 0.09% 22 L ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS 0 0.00% 23 V VARIOUS 0 0.00% 24 TOTAL 1 112 100.00 25 26 THERAPEUTIC SUBGROUP Nº % 27 N02 ANALGESICS 251 22.57% 28 J01 ANTIBACTERIALS FOR SYSTEMIC USE 220 19.78% 29 G02 OTHER GYNECOLOGICALS 178 16.01% 30 R06 ANTIHISTAMINES FOR SYSTEMIC USE 68 6.12% 31 32 A11 VITAMINS 65 5.85%

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 Regarding the dosage form, 26 different types were found in the study period, 4 the most common being tablets (including coated and chewable), with a total of 5 816 cases (73.38%), followed by injectable dosage forms (injectable solution, 6 powder for injectable suspension, injectable suspension and powder for 7 injectable solution), with a total of 111 cases (9.98%); and 76 cases involving 8 capsules (6.83%). 9 10 11 Among the falsified medicines featured in the alerts of the study period, 164 12 cases (14.75%) had characteristics and/or information that did not correspond 13 to the product specifications, 100 (8.99%) did not contain an active ingredient, 14 12 (1.08%) had a different active ingredient to the one on the label, and 7 15 (0.63%) hadFor the correct peer active ingredient review but not the authorizedonly content of the 16 active ingredient. It is noteworthy that in most cases 829 (74.55%) no 17 information was provided, which prevents a significant overall assessment. 18 19 20 21 22 DISCUSSION 23 24 Regarding the type of establishment involved in the possession or sale of 25 falsified medicines, 1 010 cases (58.11%) involved pharmaceutical 26 establishments; 349 cases (20.08%) involved non-pharmaceutical commercial 27 outlets); in 126 cases (7.23%) the medicines were seized in unauthorized trade 28 29 (without any marketing authorization), and in 253 cases (14.56%) the type of 30 establishment or business related with the seized product is not identified. 31 32 DIGEMID alerts represent a valuable resource for the transfer of information on

33 the safety of medicines and related products to the general public. To be http://bmjopen.bmj.com/ 34 effective and efficient, the alerts should provide detailed, homogenized and 35 standardized data. It is worthwhile to make a timely assessment of their impact 36 on the goals of controlling and minimizing the risks associated with the trade 37 and use of counterfeit medicines. 38 39 This review demonstrates that the problem of falsified medicines in Peru is far 40 from insignificant. On the contrary, in light of the results presented here, the

41 on September 24, 2021 by guest. Protected copyright. 42 country is facing a serious public health problem, which is even more apparent 43 if these results are compared with those of similar studies in some countries [24] 44 that are considered in Peru to have a high level of health surveillance, such 45 as the UK, with seven cases of falsified medicines in 11 years (2001-2011) [25] 46 or Canada with four cases in nine years (2005-2013); [26] reveals an 47 overwhelming difference. 48 49 One of the most striking and troubling aspects of the findings of this study is the 50 51 extent to which the medicine supply chain in Peru is being violated, with the 52 highest rate of falsified drugs found in pharmaceutical establishments 53 (pharmacies and boticas): 980 (56.39%) of a total of 1 738 cases. This situation 54 is particularly worrying since, according to the Institute of Statistics and 55 Informatics of Peru (INEI), the Peruvian population mainly relies on the 56 pharmacy or botica for health care. [27] As well as a loss of consumer faith in the 57 legal supply chain, the resources, strategies and communication activities that 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 28

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 promote the responsible acquisition of safe medicines in legally established 4 pharmaceutical establishments are also being undermined. This situation 5 requires the active and joint participation of the regulatory authority and the 6 institutions representing the pharmaceutical establishments. Moreover, the 7 cornerstone in solving the problem would be to grant a leading role to the 8 pharmacist, who should procure medicines from recognized and reliable 9 10 sources; warn patients against acquiring medicines from informal 11 establishments or places (including the internet); confirm that the distributors 12 buy products from approved suppliers; check the alerts on counterfeit medicines 13 issued by the health authority; be alert to products with suspicious features; 14 collaborate with the pharmaceutical industry, distributors and the health 15 authority Forto establish peer safety procedures review that do not allowonly violation of the legal 16 supply chain; make use of available technology for the safe management and 17 traceability of medicines; receive training and trigger a process of updating 18 safety in the workplace, and report any suspicious activity or product to the 19 [28] 20 health authority. The pharmacists must be prepared to succeed in 21 confronting the challenge of the falsified medicines. 22 23 No less worrying are the 349 cases involving non-pharmaceutical outlets, or the 24 126 cases of unauthorized trade, which include 10 cases related to clandestine 25 laboratories. 26 27 Considering the population density of Lima (31.57% of Peru’s 31 151 643 28 [23] 29 inhabitants), it is not surprising that the capital city is the location of 562 30 cases in the falsified medicine alerts (32.34%), followed by La Libertad with 315 31 cases (18.12%). As indicated by the WHO, there can be an enormous variation 32 in the incidence of falsified medicines within the same country, whether [29] 33 between rural and urban areas or between different cities. This is an http://bmjopen.bmj.com/ 34 important factor for the planning of appropriate strategies to combat the 35 problem. 36 37 In this study, it is especially interesting to note the effect of the decentralization 38 of public health surveillance powers. In 1999, the Ministerial Resolution No. 39 [30] 40 150-99 / DM decreed that the regional and sub-regional health directorates assume the functions of health control and monitoring, although the rules of 41 on September 24, 2021 by guest. Protected copyright. 42 procedure and operation were not approved until the Ministerial Resolution No. 43 573-2003-SA / DM of 2003. [31] After a period of implementation, the results 44 began to be seen in 2005, when the regional directorates participated in 8 45 cases, which grew to 75 in 2006 and 128 in 2007, reaching a cumulative 1 006 46 cases over the study period, representing 57.88% of the total. In parallel, the 47 operational role of the centralized body, DIGEMID, was reduced, as it 48 49 concentrated more on coordination, among other functions. 50 51 In the period covered by this review, the alerts alluded to 1 112 cases of 52 counterfeit medicines (product/batch). Based on the pharmacological/ 53 therapeutic subgroups (2nd level) of the ATC code [20] allotted to registered 54 products in the DIGEMID database, [21] the most falsified medicines in Peru 55 were analgesics (251 – 22,57%), followed by antibacterials for systemic use 56 (220 – 19.78%) and other gynecologicals (178 – 16.01%), antihistamines for 57 systemic use (68 – 6.12%), and vitamins (65 – 5.85%). To some extent, these 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 28 BMJ Open

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 results reflect the most consumed medicines in Peru, as reported in the 2008 4 study, "The therapeutic value of the best-selling medicines in Peru", [32] which 5 according to the IMS are likely to remain the same in the near future.[33] At this 6 point, it is recommendable to raise the issue of implementation of modern 7 technologies to detect falsified medicines [34] and the development of tools for 8 the traceability of pharmaceutical products. Among these are radio frequency 9 [35-41] 10 technology and two-dimensional codes such as the Datamatrix system. 11 Modern analytical methods have been adapted to identify counterfeit medicines, 12 leading to faster and more effective results and allowing more timely action and 13 communication by the health authorities. In this way, the alert system is not only 14 informative, but becomes an effective tool. [42-50] 15 For peer review only 16 The liberalization of the world economy, with fewer commercial borders and a 17 growing impact of the Internet on medicine advertising and trade means that 18 proposals for measures against falsified medicines need to be global. Solutions 19 20 include an internationally accepted standard terminology for improved 21 information management, transparency and identification of brokers and 22 commercial intermediaries, legislative and regulatory harmonization, the 23 implementation of traceability systems, etc. Although the DIGEMID alerts 24 provide no data on the issue, trade in falsified medicines over the Internet is a 25 major global problem (particularly in developed countries). [51-52] Mafias involved 26 in medicine falsification will not have overlooked that the global pharmaceutical 27 market is forecast to grow by around 4% per year (21% between 2012 and 28 2017). [53] The concern about falsified medicine is growing worldwide, in 29 30 developed as well as developing countries; although quantitatively different, its 31 impact on public health and the economy is similar in both. 32

33 Continuing the work of inspection is vital. The magnitude and nature of the http://bmjopen.bmj.com/ 34 problem require a thorough analysis at two levels: within the region or country 35 as well as globally. It is necessary to evaluate the measures, activities and 36 behaviours (WHO guidelines) [54] responsible for the high levels of counterfeit 37 medicines in the Peruvian pharmaceutical market, with an obvious and worrying 38 [55] 39 violation of the legal supply chain. It is necessary to understand why the 40 situation persists, despite the corrective measures in place. All aspects of the problem need to be addressed, from health to economic, [56] legal, [57] 41 on September 24, 2021 by guest. Protected copyright. 42 technological, social and cultural, which could lead to a renewal of viable, 43 effective and efficient strategies to combat this scourge. [58-62] 44 45 The finding of 626 duplicate products/batches in the study period highlights the 46 persistence of falsified medicines on the market, and suggests that the impact 47 of the alert system needs to be revised. 48 49 50 A review based only on the data of the alerts cannot provide a precise 51 conclusion about the extent to which falsified medicines have penetrated the 52 Peruvian pharmaceutical market, or their typology. Nevertheless, the results of 53 this study give an idea of the magnitude of the problem, and suggest that a 54 rethinking of strategies is required to effectively combat the trade in falsified 55 medicines in Peru. Moreover, it is important to recognize that the situation could 56 worsen, as is occurring in many African countries. [63] 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 28

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 4 5 CONCLUSIONS 6 7 In light of the results, it is clear that the falsification of medicines in Peru is 8 currently a serious public health problem. A review based only on the data 9 10 provided by alerts cannot conclude whether falsified medicines have increased 11 in Peru within the study period, or if the action of different public health 12 surveillance bodies has brought more evidence to the surface about the 13 magnitude of the problem. The type of falsified medicines found in Peru is 14 characteristic of developing countries. The problem is clearly structural or due to 15 pharmaceuticalFor policy, peer since the review highest incidence only of cases of falsified 16 medicines leading to DIGEMID alerts involve legal supply chains. Most cases of 17 falsified medicines have been found in large cities. The decentralization of 18 19 health management has had a significant impact from the inspection point of 20 view. It is necessary to establish systems of analysis and risk management 21 related to the counterfeit medicine trade as part of a regional, national and 22 global plan, in which pharmaceutical alerts form part of the communication 23 process and whose impact should be evaluated. Much work remains to be done 24 to address this serious public health concern, both in Peru and worldwide. 25 26 27 28 29 ACKNOWLEDGMENTS 30 31 We especially thank and dedicate this review to all those who day to day are 32 fighting the scourge of counterfeit medicines in Peru.

33 http://bmjopen.bmj.com/ 34 35 36 FOOTNOTES 37 38 39 Contributors: 40

41 EM drafted the manuscript. EM, EB and JS developed the initial concept and on September 24, 2021 by guest. Protected copyright. 42 design of the study and contributed to the qualitative analysis. All the authors 43 read and approved the final submitted version of the manuscript and accept 44 accountability for all aspects of the work. 45 46 Funding 47 : 48 49 This work was supported by the Bosch i Gimpera Foundation (FBG) – 50 University of Barcelona. 51 52 Ethical approval: Not required. 53 54 Competing interests: None declared. 55 56 57 Provenance and peer review: Not commissioned; externally peer reviewed. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 28 BMJ Open

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 Data sharing statement: No additional data are available. 4 5 This is an Open Access article distributed in accordance with the terms of the 6 Creative Commons Attribution (CC BY 4.0) license, which permits others to 7 distribute, remix, adapt and build upon this work, for commercial use, provided 8 9 the original work is properly cited. 10 See: http://creativecommons.org/licenses/by/4.0/ 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

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41 illicit actors and challenges to global patient safety and public health. Global on September 24, 2021 by guest. Protected copyright. 42 43 Health. 2013 Oct 16;9:45. 44 45 53. EAE Business School: El Gasto Farmacéutico 2014. Found in 46 http://www.eae.es/news/2014/07/14/el-gasto-farmaceutico-publico-por- 47 habitante-cae-un-7-2-y-se-situa-en-196-52. Accessed on January 15, 2015. 48 49 54. Tremblay M. Medicines counterfeiting is a complex problem: a review of key 50 51 challenges across the supply chain. Curr Drug Saf. 2013 Feb;8(1):43-55. 52 53 55. OMS. Consejo Ejecutivo 134º reunión (EB134/25) del 3 de enero de 2014. 54 Productos médicos de calidad subestándar, espurios, de etiquetado engañoso, 55 falsificados o de imitación. Informe de la Directora General. Found in 56 57 http://apps.who.int/gb/ebwha/pdf_files/WHA67/A67_29-sp.pdf. Accessed on 58 January 13, 2015. 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 28 BMJ Open

BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 56. Blackstone EA, Fuhr JP Jr, Pociask S. The health and economic effects of 4 counterfeit drugs. Am Health Drug Benefits. 2014 Jun;7(4):216-24. 5 6 57. Lai CW, Chan WK. Legislations combating counterfeit drugs in Hong Kong. 7 8 Hong Kong Med J. 2013 Aug;19(4):286-93. 9 10 58. Committee on Understanding the Global Public Health Implications of 11 Substandard, Falsified, and Counterfeit Medical Products; Board on Global 12 Health;Institute of Medicine; Buckley GJ, Gostin LO, editors. Countering the 13 Problem of Falsified and Substandard. Vol. Washington (DC): National 14 15 AcademiesFor Press (US); peer 2013 May. review only 16 17 59. Mackey TK, Liang BA. Improving global health governance to combat 18 counterfeit medicines: a proposal for a UNODC-WHO-Interpol trilateral 19 mechanism. BMC Med. 2013 Oct 31;11:233. 20 21 60. Weigmann K. Elixirs of death. International organizations are working 22 23 towards a global solution to address the problem offalsified and substandard 24 medicines, but progress has stagnated. EMBO Rep. 2013 Jul;14(7):597-600. 25 26 61. Seear M. The need for coordinated action against falsified and substandard 27 medicines. Int J Tuberc Lung Dis. 2013 Mar;17(3):286. 28 29 62. Attaran A, Barry D, Basheer S. How to achieve international action on 30 31 falsified and substandard medicines. BMJ. 2012 Nov 13;345:e7381. 32 33 63. Newton PN, Tabernero P, Dwivedi P. et al. Falsified medicines in Africa: all http://bmjopen.bmj.com/ 34 talk, no action. Lancet Glob Health. 2014 Sep;2(9):e509-10. 35 36 37 38 39 40

41 on September 24, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24 of 28 BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

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41 on September 24, 2021 by guest. Protected copyright. 42 43 44 45 46 47 Figure 1. Flow diagram showing types of DIGEMID alerts and overall results. 440x599mm (300 x 300 DPI) 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 25 of 28 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

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41 on September 24, 2021 by guest. Protected copyright. 42 43 44 45 46 47 Figure 2. DIGEMID alerts and falsified medicines by year. 297x420mm (300 x 300 DPI) 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 26 of 28 BMJ Open: first published as 10.1136/bmjopen-2015-010387 on 4 April 2016. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Figure 3. Evolution of inspections according to the promoter. 32 297x209mm (300 x 300 DPI)

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