Abstract

The need to increase access to medicines, coupled with the limited acceptance of generics has sparked the search for effective interventions to promote it. This systematic review aimed to conduct a survey on interventions to promote the use of generic drugs and its impact. Randomized clinical trials, non-randomized controlled trials, controlled before-after studies and interrupted time series were included. The analysis of the impact of interventions and quality of evidence followed Cochrane’s guidelines. Impact of interventions was rated from “very large” to “very small” and the quality of evidence was rated from “high” to “very low”. Seventeen papers addressing prescribers, pharmacists and users were selected. There were educational, financial incentives and use of electronic prescription and managerial interventions. Interventions applied to prescribers had little to medium impact, with very low-to-low quality evidence. Interventions applied to pharmacists had small impact with very low quality evidence. Interventions applied to users had medium and large impact with very low-to-low quality evidence. Further studies with good quality addressing interventions are required.

Systematic review; Generic drugs; Interventions; Medicines replacement

Introduction

Increasing drug expenditure is a concern of several countries^1-44. Dunn JD, Cannon E, Mitchell MP, Curtiss FR. Utilization and drug cost outcomes of a step-therapy edit for generic antidepressants in an HMO in an integrated health system. J Manag Care Pharm 2006; 12(4):294-302.. Thus, a number of measures such as interventions and campaigns are established to address reduction of this spending, which include the promotion of generic drugs³3. Calvo Alcantara MJ, Inesta Garcia A. The impact of an intervention strategy in the prescription of generic drugs in a primary care area. Aten Primaria 1999; 23(7):419-424.^,55. World Health Organization (WHO). Trade, foreign policy, diplomacy and health: generic drugs 2016. [cited 2016 Feb 22]. Available from: http://www.who.int/trade/glossary/story034/en/.
http://www.who.int/trade/glossary/story0... have been increasingly used to expand access to medicines⁵5. World Health Organization (WHO). Trade, foreign policy, diplomacy and health: generic drugs 2016. [cited 2016 Feb 22]. Available from: http://www.who.int/trade/glossary/story034/en/.
http://www.who.int/trade/glossary/story0... .

The share of generic drugs in the market differs between countries. In the United States and Germany, for example, this share is 60% in volume, while in others, such as Spain, France and Brazil, generic drugs hold between 27% and 42% market share⁶6. Associação Brasileira das Indústrias de Medicamentos Genéricos. Mercado dos Medicamentos Genéricos 2015. [cited 2016 Feb 22. Available from: http://www.progenericos.org.br/index.php/mercado.
http://www.progenericos.org.br/index.php... ^,77. Nardi EP, Ferraz MB, Pinheiro GR, Kowalski SC, Sato EI. Perceptions of the population regarding generic drugs in Brazil: a nationwide survey. BMC Public Health 2015; 15:117..

The main reasons for the low use of generic drugs are the lack of prescription by generic name⁸8. Quintal C, Mendes P. Underuse of generic medicines in Portugal: an empirical study on the perceptions and attitudes of patients and pharmacists. Health policy 2012; 104(1):61-68. and negative perception about them⁹9. Kjoenniksen I, Lindbaek M, Granas AG. Patients’ attitudes towards and experiences of generic drug substitution in Norway. Pharmacy World and Science 2006; 28(5):284-289.. Lack of consumer knowledge is also a hurdle to its use¹⁰10. Fabiano V, Mameli C, Cattaneo D, Fave AD, Preziosa A, Mele G, Clementi E, Zuccotti GV. Perceptions and patterns of use of generic drugs among Italian Family Pediatricians: First round results of a web survey. Health policy 2012; 104(2012):247-252.. A frequent problem is the polysemy of the term “generic drug” due to its different definitions according to each national legislation¹¹11. Alfonso-Cristancho R, Andia T, Barbosa T, Watanabe JH. Definition and Classification of Generic Drugs Across the World. Appl Health Econ Health Policy 2015; 13(1):5-11..

However, most users seem to accept replacement with generic drugs¹²12. Håkonsen H, Toverud E-L. A review of patient perspectives on generics substitution: what are the challenges for optimal drug use. Generics and Biosimilars Initiative Journal 2012; 1(1):28-32.. In recent years, trust and use of generics has increased, especially in developed countries, due to educational efforts, increased monitoring of good manufacturing practices, ensuring quality of medication and the greater communication of users with their caregivers¹³13. Kobayashi E, Karigome H, Sakurada T, Satoh N, Ueda S. Patients’ attitudes towards generic drug substitution in Japan. Health policy 2011; 99(1):60-65.^,1414. Hassali MA, Shafie AA, Jamshed S, Ibrahim MI, Awaisu A. Consumers’ views on generic medicines: a review of the literature. Int J Pharm Pract 2009; 17(2):79-88..

Strategies to encourage the consumption of generic drugs are directed at users, prescribers or pharmacists¹⁵15. Costa-Font J, Rudisill C, Tan S. Brand loyalty, patients and limited generic medicines uptake. Health policy 2014; 116(2-3):224-233. and have been adopted to increase their acceptance and use¹1. Babar Z, Kan S, Scahill S. Interventions promoting the acceptance and uptake of generic medicines: A narrative review of the literature. Health policy 2014; 117(3):285-296.^,88. Quintal C, Mendes P. Underuse of generic medicines in Portugal: an empirical study on the perceptions and attitudes of patients and pharmacists. Health policy 2012; 104(1):61-68.^,1414. Hassali MA, Shafie AA, Jamshed S, Ibrahim MI, Awaisu A. Consumers’ views on generic medicines: a review of the literature. Int J Pharm Pract 2009; 17(2):79-88.. These strategies aim to increase users’ and/or prescribers’ confidence and knowledge about these drugs¹⁴14. Hassali MA, Shafie AA, Jamshed S, Ibrahim MI, Awaisu A. Consumers’ views on generic medicines: a review of the literature. Int J Pharm Pract 2009; 17(2):79-88., since some of these stakeholders are still skeptical about the bioequivalence tests performed.

Most of the interventions observed in the literature focus on the physician’s behavioral change regarding its prescription¹⁶16. Mastura I, Teng CL. The effect of “group detailing” on drug prescribing in primary care. Med J Malaysia 2008; 63(4):315-318.^,1717. Rausell Rausell VJ, Tobaruela Soto M, Najera Perez MD, Iranzo Fernandez MD, Jimenez de Zadava-Lisson Lopez P, Lopez-Picazo Ferrer JJ. Effectiveness of an intervention to improve medical prescription quality in specialized care. Farmacia hospitalaria 2005; 29(2):86-94. to improve its quality and promote the rational use of medicines¹⁸18. Wensing M, Broge B, Riens B, Kaufmann-Kolle P, Akkermans R, Grol R, Szecsenyi J. Quality circles to improve prescribing of primary care physicians. Three comparative studies. Pharmacoepidemiol Drug Saf 2009; 18(9):763-769..

Dunne & Dunne¹⁹19. Dunne SS, Dunne CP. What do people really think of generic medicines? A systematic review and critical appraisal of literature on stakeholder perceptions of generic drugs. BMC medicine 2015; 13(1):1. conducted a review of observational and qualitative studies on the knowledge, acceptance and use of generic drugs from the perspective of physicians, pharmacists and consumers, showing the importance of information and knowledge about the equivalence of generic drugs, but without evaluating the interventions used to improve their prospects and broaden their use. Another narrative review of literature on generic drugs was performed by Babar et al.¹1. Babar Z, Kan S, Scahill S. Interventions promoting the acceptance and uptake of generic medicines: A narrative review of the literature. Health policy 2014; 117(3):285-296., which aimed to describe the strategies and interventions to promote the acceptance of generic drugs, which led to the identification of different types of interventions to increase the use of these drugs, but this study does not show an evaluation of the impact of the observed interventions. Moe-Byrne et al.²⁰20. Moe-Byrne T, Chambers D, Harden M, McDaid C. Behaviour change interventions to promote prescribing of generic drugs: a rapid evidence synthesis and systematic review. BMJ Open 2014; 4:5. reviewed behavioral change interventions to promote the prescription of generic drugs addressing prescriptions.

No revisions were found that had evaluated interventions that aimed to increase the use of generic drugs focused on the three stakeholders (prescriber, user and pharmacists) involved in the generic drug choice. In addition, the aforementioned reviews do not summarize the impact and quality of interventions, which could help the decision-making of managers, aiming at the expansion of generic drugs. Thus, this study aimed to carry out a systematic review of literature on interventions geared to the promotion of the use of generic drugs in order to evaluate their impact.

Methods

Search strategy

Review of literature in the PubMed / Medline, Web of Science and Lilacs databases using the following keywords to identify generic drugs: “generics”; “generic alternatives”; “generic drug”; “drugs, generic”; “generic medicine”; “generic/therapeutic substitution”; “medication substitution”; “generic substitution”; “generic prescription”; “generic dispensing ratio”; “generic dispensing rate”; “generic drugs”; “drug utilization”; “drug substitution”; “nonproprietary drugs”; “non-proprietary drugs”; “generic medication”; “generic medications”; “generic name”; “generic names”.

The following terms were used to characterize the studies as interventions: “intervention”; “educational intervention”; “multiple interventions”; “administrative interventions”; “randomized clinical trials”; “non-randomized controlled trials”; “controlled before-after”; “interrupted times series”; “repeated measures studies”; “interventions”; “pre-post study”; “pre and post”; “before and after”; “controlled trial”; “clinical trial”; “randomized, controlled trial”; “randomized controlled trial”.

Search was performed on February 23, 2016. The strategy included the availability of descriptors / keywords, located in all fields of the paper, without language restriction or year of publication. Papers were searched in open access or in the CAPES journals database, with request to the contact author when not available.

Inclusion criteria

The guidelines that follow the taxonomy and criteria proposed by Cochrane’s Effective Practice and Organization of Care (EPOC)²¹21. Cochrane CI. Manual Cochrane de Revisiones Sistemáticas de Intervenciones, versión 5.1. 0 [actualizada en marzo de 2011]. Barcelona: Centro Cochrane Iberoamericano; 2012. were used as inclusion criteria in the study: randomized controlled trials (RCTs), non-randomized controlled trials (NRCTs), controlled before-after trials (CBA), interrupted time series (ITS) and repeated measures studies (RMS). The target populations of interventions were prescribers, pharmacists and users, with no restriction as to the sample selection location (setting or context).

Exclusion criterion

Papers with clinical trial protocols that did not contain results, papers with different designs than those suggested by Cochrane’s EPOC, before-after studies with no control group, interventions that did not promote the generic drug or that considered the entry of the generic drug in the market as intervention and those whose sum of the evidence quality assessments were left with an overall evidence quality score equal to zero were excluded.

Selection and Extraction Process

The search key was established by two co-authors, and search was conducted in a single day by only one of them. All data selection and extraction was performed by two independent reviewers (MG and MS), with the participation of the other authors in conflicting cases. A database was built in Excel© with papers retrieved to carry out the selection and extraction process. After exclusion of duplicate titles, titles and abstracts were read, excluding those that did not comply with the inclusion criteria.

After reading titles, those who referred to change in prescription, dispensation, perception, acceptance, replacement or use of generic drugs were selected. Subsequently, while reading the abstracts, those whose designs were eligible, original papers and those evaluating interventions of interest were maintained. Figure 1 shows the systematic review flowchart.

Interventions of Interest

Regarding interventions of interest, we considered all those that could increase the use, prescription and/or dispensing of generic drugs. Based on the proposal of Babar et al.¹1. Babar Z, Kan S, Scahill S. Interventions promoting the acceptance and uptake of generic medicines: A narrative review of the literature. Health policy 2014; 117(3):285-296., interventions were classified as: (a) educational, (b) financial incentive, (c) electronic prescription, (d) managerial. When classification categories were overlapped in the same intervention, they were classified under the preponderant category, defined by consensus.

Studies description

The prescriber, pharmacist and/or user’s behavioral change was considered as an outcome. Prescribers were screened for changes in the prescription of generic and reference drugs, pharmacists on the replacement of reference medicines with generic drugs, and users on the change in the relative use of generic drugs over reference medicines and on the replacement of reference medicines with generic drugs.

Studies were described according to the following aspects: year of publication, country of performance, design, intervention type, intervention’s target population, intervention period and outcome measures (Chart 1).

Evidence quality evaluation

The evidence quality score was evaluated by consensus among authors, using the grades of evidence as per the Working Group Grades of Evidence (GRADE), a tool suggested by Cochrane²¹21. Cochrane CI. Manual Cochrane de Revisiones Sistemáticas de Intervenciones, versión 5.1. 0 [actualizada en marzo de 2011]. Barcelona: Centro Cochrane Iberoamericano; 2012.^,2222. Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, Vist GE, Falck-Ytter Y, Meerpohl J, Norris S, Guyatt GH. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011; 64(4):401-406., which assesses design, risk of bias, inconsistency, indirect evidence, inaccuracy and conflict of interest. (Chart 2). Each analyzed characteristic receives a score according to the quality of papers. The sum of scores from each evaluation generates the evidence quality score (classified as very low, low, moderate or high), which was provided to the study group of each intervention for each outcome (Chart 3).

Designs scored from one to four, considering the randomized trials as those with the highest scores (4), and the interrupted time series and repeated measures as studies with the lowest scores (2 or 1).

A realm-based tool was used²¹21. Cochrane CI. Manual Cochrane de Revisiones Sistemáticas de Intervenciones, versión 5.1. 0 [actualizada en marzo de 2011]. Barcelona: Centro Cochrane Iberoamericano; 2012.

22. Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, Vist GE, Falck-Ytter Y, Meerpohl J, Norris S, Guyatt GH. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011; 64(4):401-406.

23. De Carvalho A, Silva V, Grande A. Avaliação do risco de viés de ensaios clínicos randomizados pela ferramenta da colaboração Cochrane. Revista Diagnóstico e Tratamento 2013; 18(1):38-44.^-2424. Collaboration C. Suggested risk of bias criteria for EPOC reviews. Oxford: Cochrane Collaboration; 2013. to assess the risk of bias, where a critical evaluation is performed separately for different aspects of the risk of bias of each design. Nine realms were assessed for RCT, NRCT and CBA, namely: (1) generation of random sequence; (2) concealment of allocation; (3) measure of similar outcome in the intervention and control group; (4) baseline study results similar between control and intervention; (5) blinding participants and professionals regarding the allocation of intervention; (6) blinding outcome evaluators; (7) incomplete outcomes; (8) reporting of selective results; (9) other risks of bias. Seven realms were assessed to evaluate the ITS design,: (1) independent observation in relation to other changes; (2) intervention effect type; (3) probability of intervention affecting data collection; (4) blinding participants and professionals regarding the allocation of intervention; (5) incomplete outcomes; (6) reporting of selective results; (7) other risks of bias. Three possibilities of classification (low, high or uncertain) were considered for each realm of risk of bias analyzed (Table 1). After this realm evaluation, the study group of each intervention, separated by outcomes, received a single classification regarding the severity of the risk of bias²⁴24. Collaboration C. Suggested risk of bias criteria for EPOC reviews. Oxford: Cochrane Collaboration; 2013..

The inconsistency evaluation refers to the analysis of the meaning of the results of different studies²⁷27. Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M, Alonso-Coello P, Glasziou P, Jaeschke R, Akl EA, Norris S, Vist G, Dahm P, Shukla VK, Higgins J, Falck-Ytter Y, Schünemann HJ; GRADE Working Group. GRADE guidelines: 7. Rating the quality of evidence inconsistency. J Clin Epidemiol 2011; 64(12):1294-1302.. The evaluation of indirect evidence takes into account studies’ comparability regarding population, intervention and outcome measures²⁸28. Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M, Alonso-Coello P, Falck-Ytter Y, Jaeschke R, Vist G, Akl EA, Post PN, Norris S, Meerpohl J, Shukla VK, Nasser M, Schünemann HJ; GRADE Working Group. GRADE guidelines: 8. Rating the quality of evidence-indirectness. J Clin Epidemiol 2011; 64(12):1303-1310.. The assessment of inaccuracy considers the measures of outcomes studied and their confidence intervals²⁹29. Guyatt GH, Oxman AD, Kunz R, Brozek J, Alonso-Coello P, Rind D, Devereaux PJ, Montori VM, Freyschuss B, Vist G, Jaeschke R, Williams JW Jr, Murad MH, Sinclair D, Falck-Ytter Y, Meerpohl J, Whittington C, Thorlund K, Andrews J, Schünemann HJ. GRADE guidelines 6. Rating the quality of evidence-imprecision. J Clin Epidemiol 2011; 64(12):1283-1293.. Finally, conflict of interest was assessed.

Assessment of risk of bias, inconsistency, indirect evidence and inaccuracy were scored as Not serious (0), Serious (-1) and Very serious (-2).

The summary of the impact of interventions to promote the use of generic drugs was performed according to the Cochrane proposal³⁴34. Cochrane Review Group. Cochrane Effective Practice and Organisation of Care Cochrane Library2016. [cited 2016 Feb 22]. Available from: http://epoc.cochrane.org.
http://epoc.cochrane.org... , where authors, in a consensus, heuristically classified the effects of interventions as very large, large, medium, small or very small, taking into consideration their magnitude.

Studies that showed, in the comparison between intervention and control or in the comparison between before-after in the measurement of post-intervention outcomes, differences smaller than 5 p.p. were of very small impact; greater than or equal to 5 and less than 10 p.p., small impact; greater than or equal to 10 and less than 15 p.p., average impact; greater than or equal to 15 and less than 20 p.p., large impact; and greater than or equal to 20 p.p., very large impact. (Chart 3)

The mathematical summary of findings was not performed because studies showed outcomes with different measures.

Results

There were 14,265 references (9,755 in Web of Science, 3,750 in PubMed / Medline and 760 in Lilacs). Of these, 917 were excluded due to duplication, resulting in 13,348 references for titles reading. Following this stage, the two reviewers read 285 abstracts. Of these, 49 references were selected for full-text reading. After evaluation of full-text papers, 32 were excluded (Figure 1). The 17 articles selected were published between 1993 and 2010, fourteen in English and three in Spanish. All used secondary data from prescription records and drug sales. A study was conducted in a high-middle-income country¹⁶16. Mastura I, Teng CL. The effect of “group detailing” on drug prescribing in primary care. Med J Malaysia 2008; 63(4):315-318. and 16 in high-income countries³3. Calvo Alcantara MJ, Inesta Garcia A. The impact of an intervention strategy in the prescription of generic drugs in a primary care area. Aten Primaria 1999; 23(7):419-424.^,1717. Rausell Rausell VJ, Tobaruela Soto M, Najera Perez MD, Iranzo Fernandez MD, Jimenez de Zadava-Lisson Lopez P, Lopez-Picazo Ferrer JJ. Effectiveness of an intervention to improve medical prescription quality in specialized care. Farmacia hospitalaria 2005; 29(2):86-94.^,2525. Niquille A, Ruggli M, Buchmann M, Jordan D, Bugnon O. The Nine-Year Sustained Cost-Containment Impact of Swiss Pilot Physicians-Pharmacists Quality Circles. Annals of Pharmacotherapy 2010; 44(4):650-657.^,2626. Walker J, Mathers N. The impact of a general practice group intervention on prescribing costs and patterns. Br J Gen Pract 2002; 52(476):181-186.^,3030. Wensing M, Broge B, Kaufmann-Kolle P, Andres E, Szecsenyi J. Quality circles to improve prescribing patterns in primary medical care: what is their actual impact? J Eval Clin Pract 2004; 10(3):457-466.

31. Sicras Mainar A, Pelaez de Lono J. Improving adequacy for drug use and effects in geriatric centers using an intervention program. Farmacia hospitalaria 2005; 29(5):303-311.^-3232. Lopez-Picazo Ferrer JJ, Sanz Moreno JA, Bernal Montanes JM, Sanchez Ruiz JF. Evaluating, improving and monitoring generic drug prescription. Aten Primaria 2002; 29(7):397-406.^,3535. Sedjo RL, Cox ER. The influence of targeted education on medication persistence and generic substitution among consumer-directed health care enrollees. Health Services Research 2009; 44(6):2079-2092.

36. Bhargava V, Greg ME, Shields MC. Addition of generic medication vouchers to a pharmacist academic detailing program: effects on the generic dispensing ratio in a physician-hospital organization. J Manag Care Pharm 2010; 16(6):384-392.

37. Scott AB, Culley EJ, O’Donnell J. Effects of a physician office generic drug sampling system on generic dispensing ratios and drug costs in a large managed care organization. J Manag Care Pharm 2007; 13(5):412-419.

38. Fischer MA, Vogeli C, Stedman M, Ferris T, Brookhart MA, Weissman JS. Effect of electronic prescribing with formulary decision support on medication use and cost. Arch Intern Med 2008; 168(22):2433-2439.

39. Stenner SP, Chen Q, Johnson KB. Impact of generic substitution decision support on electronic prescribing behavior. J Am Med Inform Assoc 2010; 17(6):681-688.

40. Bradlow J, Coulter A. Effect of fundholding and indicative prescribing schemes on general practitioners’ prescribing costs. BMJ 1993; 307(6913):1186-1189.

41. Dunn JD, Cannon HE, Mitchell MP, Curtiss FR. Utilization and drug cost outcomes of a step-therapy edit for generic antidepressants in an HMO in an integrated health system. J Manag Care Pharm 2006; 12(4):294-302.^-4242. Patel MS, Day S, Small DS, Howell JT, Lautenbach GL, Nierman EH, Volpp KG. Using Default Options Within the Electronic Health Record to Increase the Prescribing of Generic-Equivalent Medications A Quasi-experimental Study. Ann Intern Med 2014; 161(10):S44-S52.. The selected designs were two RCTs, five NRCTs, seven CBAs and three ITS. The interventions were found to be educational³3. Calvo Alcantara MJ, Inesta Garcia A. The impact of an intervention strategy in the prescription of generic drugs in a primary care area. Aten Primaria 1999; 23(7):419-424.^,1616. Mastura I, Teng CL. The effect of “group detailing” on drug prescribing in primary care. Med J Malaysia 2008; 63(4):315-318.

17. Rausell Rausell VJ, Tobaruela Soto M, Najera Perez MD, Iranzo Fernandez MD, Jimenez de Zadava-Lisson Lopez P, Lopez-Picazo Ferrer JJ. Effectiveness of an intervention to improve medical prescription quality in specialized care. Farmacia hospitalaria 2005; 29(2):86-94.^-1818. Wensing M, Broge B, Riens B, Kaufmann-Kolle P, Akkermans R, Grol R, Szecsenyi J. Quality circles to improve prescribing of primary care physicians. Three comparative studies. Pharmacoepidemiol Drug Saf 2009; 18(9):763-769.^,2525. Niquille A, Ruggli M, Buchmann M, Jordan D, Bugnon O. The Nine-Year Sustained Cost-Containment Impact of Swiss Pilot Physicians-Pharmacists Quality Circles. Annals of Pharmacotherapy 2010; 44(4):650-657.^,2626. Walker J, Mathers N. The impact of a general practice group intervention on prescribing costs and patterns. Br J Gen Pract 2002; 52(476):181-186.^,3030. Wensing M, Broge B, Kaufmann-Kolle P, Andres E, Szecsenyi J. Quality circles to improve prescribing patterns in primary medical care: what is their actual impact? J Eval Clin Pract 2004; 10(3):457-466.

31. Sicras Mainar A, Pelaez de Lono J. Improving adequacy for drug use and effects in geriatric centers using an intervention program. Farmacia hospitalaria 2005; 29(5):303-311.^-3232. Lopez-Picazo Ferrer JJ, Sanz Moreno JA, Bernal Montanes JM, Sanchez Ruiz JF. Evaluating, improving and monitoring generic drug prescription. Aten Primaria 2002; 29(7):397-406.^,3535. Sedjo RL, Cox ER. The influence of targeted education on medication persistence and generic substitution among consumer-directed health care enrollees. Health Services Research 2009; 44(6):2079-2092., of financial incentive⁴4. Dunn JD, Cannon E, Mitchell MP, Curtiss FR. Utilization and drug cost outcomes of a step-therapy edit for generic antidepressants in an HMO in an integrated health system. J Manag Care Pharm 2006; 12(4):294-302.^,3232. Lopez-Picazo Ferrer JJ, Sanz Moreno JA, Bernal Montanes JM, Sanchez Ruiz JF. Evaluating, improving and monitoring generic drug prescription. Aten Primaria 2002; 29(7):397-406.^,3636. Bhargava V, Greg ME, Shields MC. Addition of generic medication vouchers to a pharmacist academic detailing program: effects on the generic dispensing ratio in a physician-hospital organization. J Manag Care Pharm 2010; 16(6):384-392.^,3737. Scott AB, Culley EJ, O’Donnell J. Effects of a physician office generic drug sampling system on generic dispensing ratios and drug costs in a large managed care organization. J Manag Care Pharm 2007; 13(5):412-419., electronic prescription³⁸38. Fischer MA, Vogeli C, Stedman M, Ferris T, Brookhart MA, Weissman JS. Effect of electronic prescribing with formulary decision support on medication use and cost. Arch Intern Med 2008; 168(22):2433-2439.^,3939. Stenner SP, Chen Q, Johnson KB. Impact of generic substitution decision support on electronic prescribing behavior. J Am Med Inform Assoc 2010; 17(6):681-688. and managerial⁴⁰40. Bradlow J, Coulter A. Effect of fundholding and indicative prescribing schemes on general practitioners’ prescribing costs. BMJ 1993; 307(6913):1186-1189.. The main characteristics of the studies are summarized in Chart 1.

Table 1 describes the assessment of the risk of bias of the selected studies, according to realms evaluated. Most studies have a high risk of bias because they are not randomized³3. Calvo Alcantara MJ, Inesta Garcia A. The impact of an intervention strategy in the prescription of generic drugs in a primary care area. Aten Primaria 1999; 23(7):419-424.^,44. Dunn JD, Cannon E, Mitchell MP, Curtiss FR. Utilization and drug cost outcomes of a step-therapy edit for generic antidepressants in an HMO in an integrated health system. J Manag Care Pharm 2006; 12(4):294-302.^,1616. Mastura I, Teng CL. The effect of “group detailing” on drug prescribing in primary care. Med J Malaysia 2008; 63(4):315-318.

17. Rausell Rausell VJ, Tobaruela Soto M, Najera Perez MD, Iranzo Fernandez MD, Jimenez de Zadava-Lisson Lopez P, Lopez-Picazo Ferrer JJ. Effectiveness of an intervention to improve medical prescription quality in specialized care. Farmacia hospitalaria 2005; 29(2):86-94.^-1818. Wensing M, Broge B, Riens B, Kaufmann-Kolle P, Akkermans R, Grol R, Szecsenyi J. Quality circles to improve prescribing of primary care physicians. Three comparative studies. Pharmacoepidemiol Drug Saf 2009; 18(9):763-769.^,2525. Niquille A, Ruggli M, Buchmann M, Jordan D, Bugnon O. The Nine-Year Sustained Cost-Containment Impact of Swiss Pilot Physicians-Pharmacists Quality Circles. Annals of Pharmacotherapy 2010; 44(4):650-657.^,2626. Walker J, Mathers N. The impact of a general practice group intervention on prescribing costs and patterns. Br J Gen Pract 2002; 52(476):181-186.^,3030. Wensing M, Broge B, Kaufmann-Kolle P, Andres E, Szecsenyi J. Quality circles to improve prescribing patterns in primary medical care: what is their actual impact? J Eval Clin Pract 2004; 10(3):457-466.

31. Sicras Mainar A, Pelaez de Lono J. Improving adequacy for drug use and effects in geriatric centers using an intervention program. Farmacia hospitalaria 2005; 29(5):303-311.^-3232. Lopez-Picazo Ferrer JJ, Sanz Moreno JA, Bernal Montanes JM, Sanchez Ruiz JF. Evaluating, improving and monitoring generic drug prescription. Aten Primaria 2002; 29(7):397-406.^,3535. Sedjo RL, Cox ER. The influence of targeted education on medication persistence and generic substitution among consumer-directed health care enrollees. Health Services Research 2009; 44(6):2079-2092.^,3737. Scott AB, Culley EJ, O’Donnell J. Effects of a physician office generic drug sampling system on generic dispensing ratios and drug costs in a large managed care organization. J Manag Care Pharm 2007; 13(5):412-419.

38. Fischer MA, Vogeli C, Stedman M, Ferris T, Brookhart MA, Weissman JS. Effect of electronic prescribing with formulary decision support on medication use and cost. Arch Intern Med 2008; 168(22):2433-2439.

39. Stenner SP, Chen Q, Johnson KB. Impact of generic substitution decision support on electronic prescribing behavior. J Am Med Inform Assoc 2010; 17(6):681-688.^-4040. Bradlow J, Coulter A. Effect of fundholding and indicative prescribing schemes on general practitioners’ prescribing costs. BMJ 1993; 307(6913):1186-1189.^,4242. Patel MS, Day S, Small DS, Howell JT, Lautenbach GL, Nierman EH, Volpp KG. Using Default Options Within the Electronic Health Record to Increase the Prescribing of Generic-Equivalent Medications A Quasi-experimental Study. Ann Intern Med 2014; 161(10):S44-S52. and do not show information about blinding of the intervention group (realm five RCT, NRCT and CBA), classifying as uncertain risk of bias in this area. All of them evidence a high risk of other biases, mainly for selection bias (realm nine for RCT, NRCT and CBA and seven for ITS) and low risk of bias in the realm of blinding outcome assessors (realm 6 for RCT, NRCT and CBA).

Educational Interventions

Intervention affecting the prescriber’s behavior

Among educational interventions, most aimed at changing the prescriber’s behavior in relation to increased prescription of generic drugs³3. Calvo Alcantara MJ, Inesta Garcia A. The impact of an intervention strategy in the prescription of generic drugs in a primary care area. Aten Primaria 1999; 23(7):419-424.^,1717. Rausell Rausell VJ, Tobaruela Soto M, Najera Perez MD, Iranzo Fernandez MD, Jimenez de Zadava-Lisson Lopez P, Lopez-Picazo Ferrer JJ. Effectiveness of an intervention to improve medical prescription quality in specialized care. Farmacia hospitalaria 2005; 29(2):86-94.^,1818. Wensing M, Broge B, Riens B, Kaufmann-Kolle P, Akkermans R, Grol R, Szecsenyi J. Quality circles to improve prescribing of primary care physicians. Three comparative studies. Pharmacoepidemiol Drug Saf 2009; 18(9):763-769.^,2525. Niquille A, Ruggli M, Buchmann M, Jordan D, Bugnon O. The Nine-Year Sustained Cost-Containment Impact of Swiss Pilot Physicians-Pharmacists Quality Circles. Annals of Pharmacotherapy 2010; 44(4):650-657.^,2626. Walker J, Mathers N. The impact of a general practice group intervention on prescribing costs and patterns. Br J Gen Pract 2002; 52(476):181-186.^,3131. Sicras Mainar A, Pelaez de Lono J. Improving adequacy for drug use and effects in geriatric centers using an intervention program. Farmacia hospitalaria 2005; 29(5):303-311.^-3232. Lopez-Picazo Ferrer JJ, Sanz Moreno JA, Bernal Montanes JM, Sanchez Ruiz JF. Evaluating, improving and monitoring generic drug prescription. Aten Primaria 2002; 29(7):397-406. or reduced prescription by the reference name¹⁶16. Mastura I, Teng CL. The effect of “group detailing” on drug prescribing in primary care. Med J Malaysia 2008; 63(4):315-318.. These interventions showed small to average increase in generic prescription and average reduction in the prescription by the reference name, but the quality of evidence of these studies was very low (Chart 3).

Among educational interventions focused on increasing generic prescriptions, Wensing et al.¹⁸18. Wensing M, Broge B, Riens B, Kaufmann-Kolle P, Akkermans R, Grol R, Szecsenyi J. Quality circles to improve prescribing of primary care physicians. Three comparative studies. Pharmacoepidemiol Drug Saf 2009; 18(9):763-769. held periodic meetings with small groups of 8 to 14 prescribers to report generic prescription rates and feedback on good prescribing practices. The intervention group showed a prescription increase of 0.75% (95% CI: 0.40-1.10) of the increase obtained in the control group. While the intervention group increased by 3.2%, the control group increased by 4.3%. (Chart 1)

Niquille et al.²⁵25. Niquille A, Ruggli M, Buchmann M, Jordan D, Bugnon O. The Nine-Year Sustained Cost-Containment Impact of Swiss Pilot Physicians-Pharmacists Quality Circles. Annals of Pharmacotherapy 2010; 44(4):650-657., Wensing et al.³⁰30. Wensing M, Broge B, Kaufmann-Kolle P, Andres E, Szecsenyi J. Quality circles to improve prescribing patterns in primary medical care: what is their actual impact? J Eval Clin Pract 2004; 10(3):457-466., Rausell Rausell et al.¹⁷17. Rausell Rausell VJ, Tobaruela Soto M, Najera Perez MD, Iranzo Fernandez MD, Jimenez de Zadava-Lisson Lopez P, Lopez-Picazo Ferrer JJ. Effectiveness of an intervention to improve medical prescription quality in specialized care. Farmacia hospitalaria 2005; 29(2):86-94., Calvo Alcántara et al.³3. Calvo Alcantara MJ, Inesta Garcia A. The impact of an intervention strategy in the prescription of generic drugs in a primary care area. Aten Primaria 1999; 23(7):419-424., Walker & Mathers²⁶26. Walker J, Mathers N. The impact of a general practice group intervention on prescribing costs and patterns. Br J Gen Pract 2002; 52(476):181-186., López-Picazo Ferrer et al.³²32. Lopez-Picazo Ferrer JJ, Sanz Moreno JA, Bernal Montanes JM, Sanchez Ruiz JF. Evaluating, improving and monitoring generic drug prescription. Aten Primaria 2002; 29(7):397-406., Sicras Mainar & Peláez de Loño³²32. Lopez-Picazo Ferrer JJ, Sanz Moreno JA, Bernal Montanes JM, Sanchez Ruiz JF. Evaluating, improving and monitoring generic drug prescription. Aten Primaria 2002; 29(7):397-406. and Mastura & Teng¹⁶16. Mastura I, Teng CL. The effect of “group detailing” on drug prescribing in primary care. Med J Malaysia 2008; 63(4):315-318. evaluated the effect of continuing education and feedback of prescriptions.

Wensing et al.³⁰30. Wensing M, Broge B, Kaufmann-Kolle P, Andres E, Szecsenyi J. Quality circles to improve prescribing patterns in primary medical care: what is their actual impact? J Eval Clin Pract 2004; 10(3):457-466. evaluated the feedback of prescribing information for 177 prescribers in educational sessions. This intervention had a small impact [OR 1.10 (95% CI: 1.08-1.13)]. Niquille et al.²⁵25. Niquille A, Ruggli M, Buchmann M, Jordan D, Bugnon O. The Nine-Year Sustained Cost-Containment Impact of Swiss Pilot Physicians-Pharmacists Quality Circles. Annals of Pharmacotherapy 2010; 44(4):650-657. evaluated the effect of continuing education and feedback of prescriptions for physicians between 1999 and 2007, however, information on generic drugs was shown only in the last four years (2004-2007), data shown were for five classes of drugs, with no general data on the effect of the intervention (Chart 1).

Rausell Rausell et al.¹⁷17. Rausell Rausell VJ, Tobaruela Soto M, Najera Perez MD, Iranzo Fernandez MD, Jimenez de Zadava-Lisson Lopez P, Lopez-Picazo Ferrer JJ. Effectiveness of an intervention to improve medical prescription quality in specialized care. Farmacia hospitalaria 2005; 29(2):86-94. evaluated the effect of personalized monthly reports containing prescription indicators, one of which was the percentage of generics, showing a significant difference (p = 0.041) between intervention and control groups in the first analyzed period (4-6 months intervention), with a generic prescribing mean of 3.13% (95% CI: 1.79-4.47) in the intervention group and 1.81% (95% CI: 1.08-2.54) in the control group. The results were sustained after 10-12 months intervention and had an average impact, although the overall quality of evidence was very low (Chart 3).

Walker & Mathers²⁶26. Walker J, Mathers N. The impact of a general practice group intervention on prescribing costs and patterns. Br J Gen Pract 2002; 52(476):181-186. held meetings with prescribers, preceded by reports containing the comparative costs of prescription, number of items and share of generics. There was no significant difference between the groups studied in this study. Calvo Alcántara et al.³3. Calvo Alcantara MJ, Inesta Garcia A. The impact of an intervention strategy in the prescription of generic drugs in a primary care area. Aten Primaria 1999; 23(7):419-424. conducted educational sessions, prescribing reports and distributed the list of selected generic drugs, resulting in a significant change in prescriber behavior.

After implementing their feedback interventions on prescriptions and meetings, Sicras Mainar et al.³¹31. Sicras Mainar A, Pelaez de Lono J. Improving adequacy for drug use and effects in geriatric centers using an intervention program. Farmacia hospitalaria 2005; 29(5):303-311. and Mastura et al.¹⁶16. Mastura I, Teng CL. The effect of “group detailing” on drug prescribing in primary care. Med J Malaysia 2008; 63(4):315-318. found a significant change in the prescriber’s behavior (Chart 1).

These studies³3. Calvo Alcantara MJ, Inesta Garcia A. The impact of an intervention strategy in the prescription of generic drugs in a primary care area. Aten Primaria 1999; 23(7):419-424.^,1616. Mastura I, Teng CL. The effect of “group detailing” on drug prescribing in primary care. Med J Malaysia 2008; 63(4):315-318.

17. Rausell Rausell VJ, Tobaruela Soto M, Najera Perez MD, Iranzo Fernandez MD, Jimenez de Zadava-Lisson Lopez P, Lopez-Picazo Ferrer JJ. Effectiveness of an intervention to improve medical prescription quality in specialized care. Farmacia hospitalaria 2005; 29(2):86-94.^-1818. Wensing M, Broge B, Riens B, Kaufmann-Kolle P, Akkermans R, Grol R, Szecsenyi J. Quality circles to improve prescribing of primary care physicians. Three comparative studies. Pharmacoepidemiol Drug Saf 2009; 18(9):763-769.^,2525. Niquille A, Ruggli M, Buchmann M, Jordan D, Bugnon O. The Nine-Year Sustained Cost-Containment Impact of Swiss Pilot Physicians-Pharmacists Quality Circles. Annals of Pharmacotherapy 2010; 44(4):650-657.^,2626. Walker J, Mathers N. The impact of a general practice group intervention on prescribing costs and patterns. Br J Gen Pract 2002; 52(476):181-186.^,3030. Wensing M, Broge B, Kaufmann-Kolle P, Andres E, Szecsenyi J. Quality circles to improve prescribing patterns in primary medical care: what is their actual impact? J Eval Clin Pract 2004; 10(3):457-466.

31. Sicras Mainar A, Pelaez de Lono J. Improving adequacy for drug use and effects in geriatric centers using an intervention program. Farmacia hospitalaria 2005; 29(5):303-311.^-3232. Lopez-Picazo Ferrer JJ, Sanz Moreno JA, Bernal Montanes JM, Sanchez Ruiz JF. Evaluating, improving and monitoring generic drug prescription. Aten Primaria 2002; 29(7):397-406. showed small to medium impact, always favorable to generic prescription, but with very low quality evidence (Chartes 2 and 3).

Interventions affecting the pharmacist’s behavior

Knowton & Knapp³³33. Knowlton CH, Knapp DA. Community pharmacists help HMO cut drug costs. American pharmacy 1994; 34(1):36-42. evaluated the impact of pharmaceutical meetings on pharmaceutical care, rational use of medicines and guidance in community pharmacies. Meetings were geared to teach pharmacists how to help their patients talk to prescribers about choosing between brand name medicines and generic drugs. The impact of this intervention was small, with a 6.3% increase in the intervention group when compared to the control group. The overall quality of evidence on the pharmacist’s behavioral change was moderate (Chartes 2 and 3).

Interventions affecting the user’s behavior

Sedjo & Cox³⁵35. Sedjo RL, Cox ER. The influence of targeted education on medication persistence and generic substitution among consumer-directed health care enrollees. Health Services Research 2009; 44(6):2079-2092. evaluated the replacement of the reference medicine with the generic drug. This study evaluated educational dissemination, encouraging compliance with the use of drugs for chronic diseases and increasing acceptance of alternatives of generic drugs. While this educational intervention showed a substantial increased impact, the quality of this evidence was low, since the confidence interval of findings was broad (ORadj = 29.82 95% CI: 4.41-201.93) (Chartes 1, 2 and 3).

Financial incentive interventions

Interventions affecting the prescriber’s behavior

López-Picazo Ferrer et al.³²32. Lopez-Picazo Ferrer JJ, Sanz Moreno JA, Bernal Montanes JM, Sanchez Ruiz JF. Evaluating, improving and monitoring generic drug prescription. Aten Primaria 2002; 29(7):397-406. carried out educational and financial incentive intervention. This study indicated an absolute increase of 14.8 p.p. in generic prescriptions after intervention (from 2.79% to 17.63%), with a reported average impact (Chart 3).

Bhargava et al.³⁶36. Bhargava V, Greg ME, Shields MC. Addition of generic medication vouchers to a pharmacist academic detailing program: effects on the generic dispensing ratio in a physician-hospital organization. J Manag Care Pharm 2010; 16(6):384-392. and Scott et al.³⁷37. Scott AB, Culley EJ, O’Donnell J. Effects of a physician office generic drug sampling system on generic dispensing ratios and drug costs in a large managed care organization. J Manag Care Pharm 2007; 13(5):412-419. made financial interventions on the prescriber. The study subjects of Bhargava et al.³⁶36. Bhargava V, Greg ME, Shields MC. Addition of generic medication vouchers to a pharmacist academic detailing program: effects on the generic dispensing ratio in a physician-hospital organization. J Manag Care Pharm 2010; 16(6):384-392. were primary care prescribers who received detailed information and generic drug vouchers to deliver to users. In this study, the estimated effect of the voucher on the dispensing rate was an increase of 1.77 p.p. (p = 0.047), which is a very small impact (Chartes 1 and 2).

Scott et al.³⁷37. Scott AB, Culley EJ, O’Donnell J. Effects of a physician office generic drug sampling system on generic dispensing ratios and drug costs in a large managed care organization. J Manag Care Pharm 2007; 13(5):412-419. evaluated the implementation of an automated system for the supply of samples of generic drugs in clinics, together with detailed information on generics. The intervention group showed a 7.5 p.p. increased rate of generic drugs dispensed, while the control group increased by 6.3 p.p. The difference in the first follow-up year was 1.2 p.p. and fell to 0.8 p.p. in the second year, which is a small impact, despite the overall moderate quality of evidence (Chart 2).

Interventions affecting the user’s behavior

The financial incentive by Dunn et al.⁴4. Dunn JD, Cannon E, Mitchell MP, Curtiss FR. Utilization and drug cost outcomes of a step-therapy edit for generic antidepressants in an HMO in an integrated health system. J Manag Care Pharm 2006; 12(4):294-302. had an average impact, but the quality of evidence was very low (Chart 2). This work evaluated the introduction of a generic incentive program.

Intervention through electronic prescription

Interventions affecting the prescriber’s behavior

Fischer et al.³⁸38. Fischer MA, Vogeli C, Stedman M, Ferris T, Brookhart MA, Weissman JS. Effect of electronic prescribing with formulary decision support on medication use and cost. Arch Intern Med 2008; 168(22):2433-2439. and Stenner et al.³⁹39. Stenner SP, Chen Q, Johnson KB. Impact of generic substitution decision support on electronic prescribing behavior. J Am Med Inform Assoc 2010; 17(6):681-688. evaluated electronic prescription as an intervention. In both studies, electronic prescription system highlighted the generic drug, and the prescriber was able to choose. Fischer et al.³³33. Knowlton CH, Knapp DA. Community pharmacists help HMO cut drug costs. American pharmacy 1994; 34(1):36-42. evaluated the proportion of drugs in each of the three drug co-payment groups of the American health system. The increased proportion of generics prescribed after the intervention was of 4 p.p., which is a very small impact. In the study by Stenner et al.³⁹39. Stenner SP, Chen Q, Johnson KB. Impact of generic substitution decision support on electronic prescribing behavior. J Am Med Inform Assoc 2010; 17(6):681-688., the proportion of generics increased from 32.1% to 54.2% (22 p.p. increase) in the group that used the electronic system and from 29.3% to 31.4% in the control group (Chart 1), with very low quality of evidence (Chart 3).

Managerial intervention

Interventions affecting the prescriber’s behavior

This intervention stemmed from UK’s NHS reform⁴⁰40. Bradlow J, Coulter A. Effect of fundholding and indicative prescribing schemes on general practitioners’ prescribing costs. BMJ 1993; 307(6913):1186-1189., which made it possible for doctors to be responsible for part of the budget, receiving and managing a budget ceiling (Fundholding). The proportion of generic drugs prescribed by clinic doctors who receive this budget ceiling was compared to that of clinics that did not receive it. After the intervention, the intervention group increased 7.6% (95% CI: 7.2-8.0), whereas the control group increased only 0.1% (95% CI: 0.2-0.4) (Chart 1). This intervention had a small impact and the quality of evidence was moderate (Chartes 2 and 3).

Discussion

Educational interventions were the most frequent in this review, as was done by Babar et al.¹1. Babar Z, Kan S, Scahill S. Interventions promoting the acceptance and uptake of generic medicines: A narrative review of the literature. Health policy 2014; 117(3):285-296.. These are widely used to promote behavioral change, but impact was small in the studies analyzed, which may have occurred due to the low quality of evidence. While these interventions showed a significant individual behavior change, the proportions of increase of generic were not significant, not exceeding 22 p.p. increase. The difference in the magnitude of studies may be due to their different settings, user type and medical specialties involved³3. Calvo Alcantara MJ, Inesta Garcia A. The impact of an intervention strategy in the prescription of generic drugs in a primary care area. Aten Primaria 1999; 23(7):419-424.^,1717. Rausell Rausell VJ, Tobaruela Soto M, Najera Perez MD, Iranzo Fernandez MD, Jimenez de Zadava-Lisson Lopez P, Lopez-Picazo Ferrer JJ. Effectiveness of an intervention to improve medical prescription quality in specialized care. Farmacia hospitalaria 2005; 29(2):86-94.^,1818. Wensing M, Broge B, Riens B, Kaufmann-Kolle P, Akkermans R, Grol R, Szecsenyi J. Quality circles to improve prescribing of primary care physicians. Three comparative studies. Pharmacoepidemiol Drug Saf 2009; 18(9):763-769.^,2626. Walker J, Mathers N. The impact of a general practice group intervention on prescribing costs and patterns. Br J Gen Pract 2002; 52(476):181-186.^,3131. Sicras Mainar A, Pelaez de Lono J. Improving adequacy for drug use and effects in geriatric centers using an intervention program. Farmacia hospitalaria 2005; 29(5):303-311..

All studies were performed in high or high middle-income countries and used secondary data. These countries have health records, including prescriptions records, which are reliable and can be quickly used to evaluate and/or monitor interventions. In addition, most work with electronic prescriptions and interconnected dispensing and co-payment systems that facilitate access to intervention outcomes and monitoring of prescriptions⁴³43. Espey J. Data for Development: A Needs Assessment for SDG Monitoring and Statistical Capacity Development. Sustainable Development Solutions Network. [cited 2016 Feb 22]. Available at http://unsdsnorg/wp-content/uploads/2015/04/Data-for-Development-Full-Report.pdf.2015 .
http://unsdsnorg/wp-content/uploads/2015... .

The selected studies were conducted between 1993 and 2010, and showed a lack of current studies addressing increased use of generics, indicating a greater concern with the expanded use of generics when they were implemented. However, some countries still evidence a low proportion of generic drugs in the market when compared to others⁶6. Associação Brasileira das Indústrias de Medicamentos Genéricos. Mercado dos Medicamentos Genéricos 2015. [cited 2016 Feb 22. Available from: http://www.progenericos.org.br/index.php/mercado.
http://www.progenericos.org.br/index.php... , suggesting the need for interventions to increase their use.

The quality of evidence shown by studies was very low or low, evidencing the need for better designed and executed studies to improve the quality of evidence³3. Calvo Alcantara MJ, Inesta Garcia A. The impact of an intervention strategy in the prescription of generic drugs in a primary care area. Aten Primaria 1999; 23(7):419-424.. Babar et al.¹1. Babar Z, Kan S, Scahill S. Interventions promoting the acceptance and uptake of generic medicines: A narrative review of the literature. Health policy 2014; 117(3):285-296. performed a narrative review without a quality evaluation. On the other hand, Moe-Byrne et al.²⁰20. Moe-Byrne T, Chambers D, Harden M, McDaid C. Behaviour change interventions to promote prescribing of generic drugs: a rapid evidence synthesis and systematic review. BMJ Open 2014; 4:5. evaluated the quality of some of these studies, but it was merely a narrative evaluation and did not perform an impact assessment through data summarization, as shown in this review.

Most studies were performed in a hospital environment or primary care clinics, and generic prescription was one of the indicators of the quality of prescription evaluated¹⁸18. Wensing M, Broge B, Riens B, Kaufmann-Kolle P, Akkermans R, Grol R, Szecsenyi J. Quality circles to improve prescribing of primary care physicians. Three comparative studies. Pharmacoepidemiol Drug Saf 2009; 18(9):763-769.^,3030. Wensing M, Broge B, Kaufmann-Kolle P, Andres E, Szecsenyi J. Quality circles to improve prescribing patterns in primary medical care: what is their actual impact? J Eval Clin Pract 2004; 10(3):457-466.. Although there has been no significant increase in generic prescription, this is an important indicator in the hospital setting, since it is also used as an expense indicator and replacement with generic drugs leads to reduced expenses⁴⁴44. Ahluwalia JS, Weisenberger ML, Bernard AM, McNagny SE. Changing physician prescribing behavior: a low-cost administrative policy that reduced the use of brand name nonsteroidal anti-inflammatory drugs. Prev Med 1996; 25(6):668-672.

45. Bertoldi AD, Barros AJ, Camargo AL, Hallal PC, Vandoros S, Wagner A, Ross-Degnan D. Household expenditures for medicines and the role of free medicines in the Brazilian public health system. Am J Public Health 2011; 101(5):916-921.^-4646. Cameron A, Laing R. Cost savings of switching private sector consumption from originator brand medicines to generic equivalents. Geneva: World health report; 2010.. Measures that curb health costs caused by medicines are necessary, and replacement with generic drugs is one of them.¹1. Babar Z, Kan S, Scahill S. Interventions promoting the acceptance and uptake of generic medicines: A narrative review of the literature. Health policy 2014; 117(3):285-296.

Studies such as those of Bhargava et al.³⁶36. Bhargava V, Greg ME, Shields MC. Addition of generic medication vouchers to a pharmacist academic detailing program: effects on the generic dispensing ratio in a physician-hospital organization. J Manag Care Pharm 2010; 16(6):384-392. and Sedjo & Cox³⁵35. Sedjo RL, Cox ER. The influence of targeted education on medication persistence and generic substitution among consumer-directed health care enrollees. Health Services Research 2009; 44(6):2079-2092. carried out in the U.S., the country that launched generic drugs and showed high rates of use reinforce the quality and reliability of these medicines, contributing to the continued increase of their use.

Another important consideration is the polysemic definition of medicines, since different countries use different definitions¹¹11. Alfonso-Cristancho R, Andia T, Barbosa T, Watanabe JH. Definition and Classification of Generic Drugs Across the World. Appl Health Econ Health Policy 2015; 13(1):5-11. and most of the studies analyzed here do not bring the definition of a generic drug and may lead to a misinterpretation about replacement, use and prescription of generic drugs.

However, by analyzing drug policies and the definitions of generics used in each of the six countries of origin of the studies of this review, it was observed that they use similar definitions, and generic drugs are those that show the same active principle, the same pharmaceutical form, dose, concentration, route of administration as the reference drug, seeking to ensure the quality and safety of these drugs⁴⁷47. Agency EM. Generic medicines 2017. [cited 2017 Jan 18]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/document_listing/document_listing_000335.jsp&mid=WC0b01ac0580514d5c .
http://www.ema.europa.eu/ema/index.jsp?c...

48. Malasya. Ministry of Health. National Pharmaceutical Control Bureau MoHM. Regulatory Control of Generic Medicines in Malaysia. Kuala Lumpur: National Pharmaceutical Control Bureau; 2015.^-4949. U.S. Food & Drug Administration. Understanding Generic Drugs 2017. [cited 2017 Jan 18]. Available from: https://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/UnderstandingGenericDrugs/.
https://www.fda.gov/Drugs/ResourcesForYo... .

In the study by Dunne et al.⁵⁰50. Dunne S, Shannon B, Hannigan A, Dunne C, Cullen W. Physician and pharmacist perceptions of generic medicines: What they think and how they differ. Health policy 2014; 116(2):214-223., knowledge about generics, both for pharmacists and prescribers was surveyed several times in the interviews. Thus, the belief that adequate knowledge by health professionals and the population in general is an essential aspect of acceptance and improvement of their use⁵⁰50. Dunne S, Shannon B, Hannigan A, Dunne C, Cullen W. Physician and pharmacist perceptions of generic medicines: What they think and how they differ. Health policy 2014; 116(2):214-223..

Regarding the financial incentive applied to users, Schafheutle et al.⁵¹51. Schafheutle EI, Hassell K, Noyce PR. Access to medicines: cost as an influence on the views and behaviour of patients. Health & social care in the community 2002; 10(3):187-195. suggest that most users are, to a greater or lesser degree, cost-conscious when it comes to managing their condition and their medications. This would occur especially with those who need to pay for dispensing their prescriptions. Thus, the cost realm becomes an important factor⁵¹51. Schafheutle EI, Hassell K, Noyce PR. Access to medicines: cost as an influence on the views and behaviour of patients. Health & social care in the community 2002; 10(3):187-195.. Interventions that implement financial incentives can promote replacement by increasing the use of generic drugs. However, it should be noted that the pharmaceutical industry and health plans in some countries might have a strong influence on policies favoring the use of generic drugs⁵²52. Königbauer I. Advertising and generic market entry. J Health Economics 2007; 26(2):286-305.

53. Aronsson T, Bergman MA, Rudholm N. The Impact of Generic Drug Competition on Brand Name Market Shares – Evidence from Micro Data. Review of Industrial Organization 2001; 19(4):423-433.

54. Abraham J. The pharmaceutical industry as a political player. Lancet 2002; 360(9344):1498-502.^-5555. King DR, Kanavos P. Encouraging the use of generic medicines: implications for transition economies. Croatian medical journal 2002; 43(4):462-469..

Two studies evaluated electronic prescription as an intervention to increase the use of generics³⁸38. Fischer MA, Vogeli C, Stedman M, Ferris T, Brookhart MA, Weissman JS. Effect of electronic prescribing with formulary decision support on medication use and cost. Arch Intern Med 2008; 168(22):2433-2439.^,3939. Stenner SP, Chen Q, Johnson KB. Impact of generic substitution decision support on electronic prescribing behavior. J Am Med Inform Assoc 2010; 17(6):681-688., the fact that the name of the generic drug is available as the first choice, only requiring selection to compose the prescription, may not only increase the prescription of generics, but also improve its quality. Electronic prescription is available in many hospitals, but without highlighting generic drugs. This seemingly simple and low-cost intervention could be implemented in these health services in order to improve prescription.

Only one study with managerial intervention was included in the review⁴⁰40. Bradlow J, Coulter A. Effect of fundholding and indicative prescribing schemes on general practitioners’ prescribing costs. BMJ 1993; 307(6913):1186-1189.. This type of intervention, despite being applied to prescribers and dispensers, is more comprehensive and can reach more professionals, changing the prescription behavior. This intervention allowed the prescriber to manage part of the costs of the health facility, including medicines. Part of the savings was refunded to the prescriber himself. Thus, this strategy leads to the prescription of generic drugs because of their lower cost⁴⁰40. Bradlow J, Coulter A. Effect of fundholding and indicative prescribing schemes on general practitioners’ prescribing costs. BMJ 1993; 307(6913):1186-1189..

One of the criteria for choosing the analyzed databases was the facilitated access by authors. This may have left out some relevant bases, such as SCOPUS. However, the databases consulted have a broad scope in the subject studied.

Finally, no recalculation of the results for standardization of outcome measures was performed, since the heterogeneous presentation of results facilitated the quantification of findings.

Conclusions

This review lacks studies with a robust methodology to judge the impact of the interventions that have been implemented in order to increase the use, prescription or dispensing of generics. In addition, the few existing studies had small impact and low quality of evidence. Most of the studies analyzed addressed interventions that involved, directly or indirectly, the issue of the lowest price of generics, highlighting concern about drug expenditure. We emphasize the lack of recent studies conducted in middle- and low-income countries. This topic is of interest, since three recent reviews have been identified, although with different approaches, and have shown interest in analyzing what has been done to increase the use of generics. Thus, we highlight the need for well-designed interventions, especially in low- and middle-income countries to obtain clearer evidence.

References

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