intervenções para promoção do uso de medicamentos genéricos : revisão sistemática Impact of interventions to promote the use of generic drugs : a systematic review

1 Programa de PósGraduação em Epidemiologia, Universidade Federal de Pelotas (UFPel). R. Marechal Deodoro 1160/313, Centro. 96020-220 Pelotas RS Brasil. maguttier@gmail.com 2 Departamento de Fisiologia e Farmacologia, Instituto de Biologia, UFPel. Pelotas RS Brasil. 3 Escola Nacional de Saúde Pública Sérgio Arouca, Fiocruz. Rio de Janeiro RJ Brasil. Impacto de intervenções para promoção do uso de medicamentos genéricos: revisão sistemática


Introduction
Increasing drug expenditure is a concern of several countries [1][2][3][4] .Thus, a number of measures such as interventions and campaigns are established to address reduction of this spending, which include the promotion of generic drugs 3,5 have been increasingly used to expand access to medicines 5 .
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 share 6,7 .
The main reasons for the low use of generic drugs are the lack of prescription by generic name 8 and negative perception about them 9 .Lack of consumer knowledge is also a hurdle to its use 10 .A frequent problem is the polysemy of the term "generic drug" due to its different definitions according to each national legislation 11 .
However, most users seem to accept replacement with generic drugs 12 .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 caregivers 13,14 .
Strategies to encourage the consumption of generic drugs are directed at users, prescribers or pharmacists 15 and have been adopted to increase their acceptance and use 1,8,14 .These strategies aim to increase users' and/or prescribers' confidence and knowledge about these drugs 14 , 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 prescription 16,17 to improve its quality and promote the rational use of medicines 18 .
Dunne & Dunne 19 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. 1 , 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. 20 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.
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) 21 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. 1 , interven-tions 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 Cochrane 21,22 , 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 used [21][22][23][24] 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)   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 bias 24 .
The inconsistency evaluation refers to the analysis of the meaning of the results of different studies 27 .The evaluation of indirect evidence takes into account studies' comparability regarding population, intervention and outcome measures 28 .The assessment of inaccuracy considers the measures of outcomes studied and their confidence intervals 29 .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 proposal 34 , 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  a Randomized controlled trials (RCTs), non-randomized controlled trials (NRCT), controlled before-and-after (CBA), interrupted time series (ITS) and repeated measures studies (RMS); d Lopez-Picazo Ferrer et al. 34 appears twice in the table because it shows two interventions: educational and financial incentive.
Table 1 describes the assessment of the risk of bias of the selected studies, accord- ing to realms evaluated.Most studies have a high risk of bias because they are not randomized 3,4,[16][17][18]25,26,[30][31][32]35,[37][38][39][40]42 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 igh 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 drugs 3,17,18,25,26,[31][32] or reduced prescription by the reference name 16 .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. 18 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. 25 , Wensing et al. 30 , Rausell Rausell et al. 17 , Calvo Alcántara et al. 3  it continues scription 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 & Mathers 26 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. 3 conducted educational sessions, prescribing reports and distrib-uted 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. 31 and Mastura et al. 16 found a significant change in the prescriber's behavior (Chart 1).

Interventions affecting the pharmacist's behavior
Knowton & Knapp 33 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 (7)

Impact b Comments
Prescription of generic drugs 1 CBA 13 Very low Small increase The impact of regulatory interventions on prescriber's behavior is uncertain, since the quality of evidence was very low.( 13) Bradlow et al. 1993   a Quality of evidence general score: Moderate: The true impact value is likely to be close value found, but it could possibility be substantially different.Low: The true impact value could be substantially different from value found.Very low: We are uncertain as to the true impact value.b The impacts of interventions were classified as very large, large, medium, small or very small.Chart 3. continuation 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 & Cox 35 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 = 29.8295% CI: 4.41-201.93)(Chartes 1, 2 and 3).

Interventions affecting the prescriber's behavior
López-Picazo Ferrer et al. 32 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. 36 and Scott et al. 37 made financial interventions on the prescriber.The study subjects of Bhargava et al. 36 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. 37 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. 4 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. 38 and Stenner et al. 39 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. 33 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. 39 , 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).

Interventions affecting the prescriber's behavior
This intervention stemmed from UK's NHS reform 40 , 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. 1 .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 involved 3,17,18,26,31 .
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 prescriptions 43 .
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 others 6 , 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 evidence 3 .Babar et al. 1 performed a narrative review without a quality evaluation.On the other hand, Moe-Byrne et al. 20 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 evaluated 18,30 .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 expenses [44][45][46] .Measures that curb health costs caused by medicines are necessary, and replacement with generic drugs is one of them. 1 Studies such as those of Bhargava et al. 36 and Sedjo & Cox 35 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 definitions 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 drugs [47][48][49] .
In the study by Dunne et al. 50, 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 use 50 .
Regarding the financial incentive applied to users, Schafheutle et al. 51 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 factor 51 .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 drugs [52][53][54][55] .
Two studies evaluated electronic prescription as an intervention to increase the use of ge-nerics 38,39 , 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 review 40 .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 cost 40 .
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 lowand middle-income countries to obtain clearer evidence.

Collaborations
MC Guttier performed the search and selection of the articles and drafted the manuscript.MPT Silveira performed the selection of the articles and reviewed the manuscript.VL Luiza contributed to the selection and helped to draft the manuscript.AD Bertoldi helped to draft the manuscript.All authors read and approved the final manuscript.

Figure 1 .
Figure 1.Flowchart of the process of identification and selection of papers on interventions that promote the use of generic drugs.

a
RCT = Randomized clinical trials; NRCT = Non-Randomized Controlled Trials (NRCT); CBA = Controlled Before-After; ITS = Interrupted Time Series (ITS) b Realms evaluated for RCT, NRCT and CBA: (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.c Realms evaluated for ITS: (1) independent observation in relation to other changes; (2) intervention effect form; (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.

; Country Setting / Specific context Intervention; Intervention's period of implementation Sample Outcome Educational interventions affecting generic prescription NRCT
Description of the selected articles, according to the types of interventions that promote the use of generic drugs.

Educational interventions affecting the pharmacist in the replacement of reference medicines with generic drugs RCT
it continues Chart 1. continuation selected for full-text reading.After evaluation of full-text papers, 32 were excluded (Figure1).The 17 articles selected were published between 1993 and 2010, fourteen in English and three in

Outcome Number of studies Quality of evidence assessment Risk of bias Inconsistency Indirect evidence Inaccuracy Conflict of Interest Change in prescriber's behavior
Assessment of the quality of evidence of interventions geared to the promotion of generic drugs.

Table 1 .
Evaluation of risk of bias of selected studies on interventions that promote the use of generic drugs.