Generic Drug Substitution Research Articles

Pharmacists\u2019 views and reported practices in relation to a new generic drug substitution policy in Lebanon: a mixed methods study

BackgroundGovernments in both developed and developing countries have adopted generic drug substitution policies to decrease pharmaceutical expenditures and improve access to medicine. In August 2015, the Ministry of Public Health (MOPH) in Lebanon introduced generic drug substitution and a unified medical prescription form as policy instruments to promote generic drug use. The objective of this exploratory study was to examine the attitudes of community pharmacists and the reported practices in relation to the implementation of the new generic drug substitution policy.MethodsWe used a cross-sectional mixed methods approach composed of self-administered questionnaires and semi-structured interviews. The study population consisted of community pharmacists in Lebanon. We randomly approached one pharmacy personnel from each selected community pharmacy. We conducted descriptive analyses to assess responses to questionnaire and regression analyses to understand associations between responses and respondent demographics. We analyzed qualitative data thematically.ResultsOut of 204 invited community pharmacies, 153 pharmacies participated (75% response rate). The majority of respondents (64%) were in favor of generic drug substitution; however, less than half (40%) indicated they have substituted brand drugs for generic equivalents. Moreover, 57% indicated that the existing pricing system discourages them from performing generic drug substitution. Most respondents indicated that physicians are overusing the “non-substitutable” option (84%) and that there are technical problems with processing the new prescription form (78%). Less than half (47%) reported that the MOPH is performing regular audits on the forms collected by the pharmacy. While 45% of the respondents indicated that consumers have accepted most of the generic substitutions, 21% perceived the increase in generic drug dispensing to be significant. Findings suggested a potentially significant association between being informed about generic drugs and respondents’ support of the policy. Suggested strategies to address implementation challenges included strengthening stewardship function of MOPH, securing full commitment of health care providers, conducting educational and awareness campaigns about generic drugs and generic drug substitution, and aligning incentive systems of the key stakeholders.ConclusionsThe majority of community pharmacists were supportive of generic drug substitution in general but not of the current implementation of the policy in Lebanon. Findings revealed implementation challenges at the provider, patient, and system level which are hindering attainment of the policy objectives. The key lessons derived from this study can be used for continuous improvement of the policy and its implementation.

Impact of substitution among generic drugs on persistence and adherence: A retrospective claims data study from 2 Local Healthcare Units in the Lombardy Region of Italy

BackgroundThe use of generics, equivalent but less expensive drugs, is an important opportunity to reduce healthcare expenditure. MethodsThe purpose of this study was to investigate the effect of substitution between unbranded generics on persistence and adherence to therapy in two Italian Local Health Units (ASL) in real-world clinical practice in 5 therapeutic areas using tracing drugs. Substitution of generic drugs is any change in the name of the manufacturer of the generic drug. The therapeutic areas were: diabetes (metformin); hypertension (amlodipine); dyslipidemia (simvastatin); psychiatry (sertraline); cardiology (propafenone); osteoporosis (alendronate). The retrospective analysis was carried out on the administrative databases of two Local Healthcare Units (ASL – Azienda sanitaria locale Bergamo (BG) and Pavia (PV)) in the Lombardy Region of Italy. The correlation between persistence and adherence with the different cohorts of generic substitution frequency within each therapeutic area was then calculated. ResultsAccording to the inclusion criteria, 23,773 patients were evaluated. Patients were observed for a period of 36 months starting from the first drug delivery (index date). The median age of the overall population was above 61 years in all therapeutic areas. The generic drug substitution occurred in 61.5% of patients (BG: 57.6% and PV: 65.4% respectively); Hypertension was the therapeutic area with the highest percentage of patients with substitutions. Patients' adherence, evaluated by the Medical Possession Rate (MPR) and persistence to the treatment decreases with the increase in the frequency of generic substitutions. This observation was confirmed by a statistically significant negative correlation (p-value of <0.001) between the adherence and persistence and the number of generic substitutions in each therapeutic area and Local Healthcare Units (ASL). DiscussionAdherence is one of the pillars of the patient's health management in the control and prevention of progression of the disease. Several factors, such as ageing, comorbidities, and polypharmacy, may affect adherence and influence the outcome of treatments. These results are in line with studies supporting the possibility that the change of package appearance each time a new prescription is dispensed may create confusion and ultimately reduce patients' adherence. Clinicians and decision makers should consider the impact of frequent generic substitutions on persistence and adherence, which may influence efficacy and/or safety.

Generic-to-generic lamotrigine switches in people with epilepsy: the randomised controlled EQUIGEN trial

Patients and clinicians share concerns that generic drug substitution might lead to loss of efficacy or emergence of adverse events. In this trial, we assessed US Food and Drug Administration (FDA) bioequivalence standards by studying the effects of switching between two disparate generic immediate-release lamotrigine products in patients with epilepsy. The Equivalence among Generic Antiepileptic Drugs (EQUIGEN) chronic-dose study was a randomised, double-blind, crossover study that enrolled adults (aged ≥18 years) with epilepsy from six epilepsy centres at academic institutions across the USA who were receiving immediate-release lamotrigine dosed at 100 mg, 200 mg, 300 mg, or 400 mg twice daily. Eligible patients were randomly allocated (1:1) to one of two treatment sequences (sequence 1 or sequence 2), comprising four study periods of 14 days each. During each 14-day treatment period, patients received balanced doses of an oral generic lamotrigine product every 12 h (200-800 mg total, identical to lamotrigine dose prior to study enrolment); after each 14-day period, patients were crossed over to receive the other generic product. Computer-based randomisation was done using random permuted blocks of size two or four for each site to prevent sequence predictability. Both patients and study personnel were masked to the generic products selected, their predicted exposure (ie, "high" vs "low"), and their group allocation. The primary outcome of this trial was bioequivalence between the generic products, which was assessed at the end of the study through a comparison of maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) for each product in the analysis population (all patients who completed all four treatment periods). Bioequivalence was established if the 90% CIs of the ratios of these two parameters for the two products were within equivalence limits (80-125%) in the analysis population. This study is registered with ClinicalTrials.gov\, number NCT01713777. Between April 25, 2013, and Aug 12, 2014, 35 eligible patients were enrolled and randomly assigned to treatment sequence 1 (n=15) or treatment sequence 2 (n=20). 33 patients completed all four treatment periods and were included in the primary outcome analysis. The 90% CIs of the ratios of both Cmax and AUC were within equivalence limits (AUC 90% CI 98-103, Cmax 90% CI 99-105), showing that lamotrigine exposures were equivalent between the generic products. No significant changes in seizure frequency or adverse events were recorded. No deaths, study-related serious adverse events, or changes in clinical laboratory values or vital signs occurred during this study. Disparate generic lamotrigine products in patients with epilepsy showed bioequivalence with no detectable difference in clinical effects, confirming that US Food and Drug Administration bioequivalence standards are appropriate. American Epilepsy Society, Epilepsy Foundation, and US Food and Drug Administration.

In vitro Comparison of Generic and Branded Preparations of Amoxicillin with Potassium Clavulanate.

The Medical Council of India (MCI) has guidelines for physicians to prescribe drugs with generic names. But physicians and patients might have prejudices against generic drug substitution or concerns regarding quality and generics effectiveness. If the drugs are ineffective, they can result in adverse clinical outcomes such as treatment failure. According to WHO, β-lactams are the most common substandard drugs to be produced amongst antibiotics. To evaluate and compare invitro efficacy of generic and branded preparations of Amoxicillin with Potassium Clavulanate. One generic (C) and 5 branded formulations (A,B,D,E,F) of amoxicillin with potassium clavulanate were taken for microbiological assay. Coding was done. Sterile disks were instilled with 10μl of preparations and disk diffusion was screened by Kirby Bauer Method using Mueller Hinton Agar. Bacterial Strains used were Staphylococcus aureus (S.aureus) and Escherichia Coli. Zone of inhibition was measured. Statistical Analysis was done using repeated measures one-way ANOVA followed by Tukey's test. Disk Diffusion test showed that branded Drug F has statistically significant less zone of inhibition (p < 0.001) for S. Aureus and (p < 0.05) for E.coli in comparison with generic drug C. Zone of inhibition of branded Drug A, B & E was comparable with the generic drug C. The results of this study indicate that the generic drug tested was equally effective compared to the tested branded drugs except branded Drug D and F. This suggests that efficacy of generic drug is equivalent to branded drugs and maybe used interchangeably with branded drugs.

Study of regulatory requirements for the conduct of bioequivalence studies in US, Europe, Canada, India, ASEAN and SADC countries: Impact on generic drug substitution

Design of dissolution media for in-vitro bioequivalence testing of Lamivudine Nagiat T Hwisa, Shanta Kumari Adiki, Prakash Katakam, Babu Rao Chandu

Effects of hospital generic drug substitution on diabetes therapy

ObjectivesTo evaluate the effects on physicians’ prescribing behavior and on the therapeutic outcome of non-insulin-dependent diabetes patients of substituting different generic brands of metformin.MethodsWe adopt a retrospective cohort study involving 280 type-2 diabetes patients who regularly used the outpatient services of one medical center and who had changed metformin brands five times between 2003 and 2008. The aim was to examine the effects of switching brands. The generalized estimating equation was used to determine whether drug brand switching affected patient glycated hemoglobin A1c (HbA1c) levels, their prescribed daily dose, or their adherence to medication with metformin.ResultsHbA1c levels increased from 7.91 to 8.34 throughout the study period, although it was found that brand switching did not adversely affect HbA1c levels after controlling for patient characteristics and the time course of the study. Furthermore, the prescribed daily dose of metformin was stable throughout the study period, and was approximately 0.8 of the defined daily dose. Finally, although adherence was significantly higher with the original metformin than with the four generic brands, patients still maintained high levels of adherence of >0.8.ConclusionAlthough switching between different brands of metformin slightly affected the prescribing behavior of the physicians, there was no unfavorable effect on patient HbA1c levels. Thus, the policy of substituting between different generic brands of metformin is a good cost-effective approach that does not adversely affect the quality of diabetes patient care.

Improving the assessment of prescribing: use of a ‘substitution index’

To analyse the current and potential utilization of generic drugs in Japan, to examine the maximum possible cost savings from generic drug use and to develop a fairer measure to assess the level of generic drug substitution. We conducted a cross-sectional retrospective analysis of nine million dispensing records during January to March 2010 in Kyoto Prefecture. Maximum potential quantity-based shares were defined as the quantity of generic drugs used plus the quantity of branded drugs that could have been replaced by generic drugs divided by the quantity of all drugs dispensed. We developed a 'substitution index', defined as the proportion of generic drugs out of the total drugs substitutable with generic drugs (based on quantity rather than cost). Generic drugs had a quantity-based share of 17.9%, a cost-based share of 8.9% and a maximum potential quantity-based share of 50.1%, which is lower than the actual generic drug shares of some other countries. The maximum possible cost savings as a result of generic drug substitution was 16.5%. We also observed wide variations in maximum potential quantity-based shares between health care sectors and health care institutions. Simple comparisons based on quantity-based shares may misrepresent the actual generic drug use. A substitution index that takes into account the maximum potential quantity-based share of generic drugs as a fairer measure may promote more realistic goals and encourage generic drug usage.

European Society for Organ Transplantation Advisory Committee Recommendations on Generic Substitution of Immunosuppressive Drugs

European Society for Organ Transplantation Advisory Committee Recommendations on Generic Substitution of Immunosuppressive Drugs

Underuse of generic medicines in Portugal: An empirical study on the perceptions and attitudes of patients and pharmacists

Objectives The objectives of this study were to identify: perceptions regarding underuse and characteristics of generic medicines; patients’ attitudes towards drug substitution and pharmacists’ attitudes towards substitution recommendation. Methods Two questionnaires were designed and interviewer-administered – one to patients and another to pharmacists. A binary variable ‘correct understanding’ was created and multiple logistic regression analysis was used to identify factors associated with experience and willingness to accept generic medicine substitution. Statistical analyses were performed by SPSS version 19.0. Results All of the 417 patients knew the term ‘generic medicine’. Level of education, experience and discussion with doctor were significantly associated with correct understanding. 77.5% of respondents had consumed generic medicines and 88.7% (64.5%) were willing to accept drug substitution based on doctor's (pharmacist's) recommendation. Having at least one chronic condition, discussion with doctor and perception that generic drug substitution is cost-saving were significantly associated with experience. In addition to the last two, having correct understanding and having experience were significantly associated with willingness to accept generic drug substitution. 91.6% of pharmacists (95 respondents) said that drug substitution is recommended in their pharmacies. Conclusions More information should be given to patients preferably by doctors and pharmacists. Prescription should be encouraged and experience promoted.

Survey of Patients Attitudes toward Generic Drug Substitution in Community Pharmacies

Survey of Patients Attitudes toward Generic Drug Substitution in Community Pharmacies

Determinants of generic drug substitution in Switzerland.

BackgroundSince generic drugs have the same therapeutic effect as the original formulation but at generally lower costs, their use should be more heavily promoted. However, a considerable number of barriers to their wider use have been observed in many countries. The present study examines the influence of patients, physicians and certain characteristics of the generics' market on generic substitution in Switzerland.MethodsWe used reimbursement claims' data submitted to a large health insurer by insured individuals living in one of Switzerland's three linguistic regions during 2003. All dispensed drugs studied here were substitutable. The outcome (use of a generic or not) was modelled by logistic regression, adjusted for patients' characteristics (gender, age, treatment complexity, substitution groups) and with several variables describing reimbursement incentives (deductible, co-payments) and the generics' market (prices, packaging, co-branded original, number of available generics, etc.).ResultsThe overall generics' substitution rate for 173,212 dispensed prescriptions was 31%, though this varied considerably across cantons. Poor health status (older patients, complex treatments) was associated with lower generic use. Higher rates were associated with higher out-of-pocket costs, greater price differences between the original and the generic, and with the number of generics on the market, while reformulation and repackaging were associated with lower rates. The substitution rate was 13% lower among hospital physicians. The adoption of the prescribing practices of the canton with the highest substitution rate would increase substitution in other cantons to as much as 26%.ConclusionsPatient health status explained a part of the reluctance to substitute an original formulation by a generic. Economic incentives were efficient, but with a moderate global effect. The huge interregional differences indicated that prescribing behaviours and beliefs are probably the main determinant of generic substitution.

Effectiveness, safety and cost of drug substitution in hypertension.

Cost-containment measures in healthcare provision include the implementation of therapeutic and generic drug substitution strategies in patients whose condition is already well controlled with pharmacotherapy. Treatment for hypertension is frequently targeted for such measures. However, drug acquisition costs are only part of the cost-effectiveness equation, and a variety of other factors need to be taken into account when assessing the impact of switching antihypertensives. From the clinical perspective, considerations include maintenance of an appropriate medication dose during the switching process; drug equivalence in terms of clinical effectiveness; and safety issues, including the diverse adverse-event profiles of available alternative drugs, differences in the ‘inactive’ components of drug formulations and the quality of generic formulations. Patients' adherence to and persistence with therapy may be negatively influenced by switching, which will also impact on treatment effectiveness. From the economic perspective, the costs that are likely to be incurred by switching antihypertensives include those for additional clinic visits and laboratory tests, and for hospitalization if required to address problems arising from adverse events or poorly controlled hypertension. Indirect costs and the impact on patients' quality of life also require assessment. Substitution strategies for antihypertensives have not been tested in large outcome trials and there is little available clinical or economic evidence on which to base decisions to switch drugs. Although the cost of treatment should always be considered, careful assessment of the human and economic costs and benefits of antihypertensive drug substitution is required before this practice is recommended.

Patients’ attitudes towards generic drug substitution in Japan

The aim of this study was to evaluate the understanding and attitude of Japanese patients towards generic drug substitutions. The subjects were male and female patients, who purchased their prescription medications at a pharmacy. A questionnaire was created to assess their attitudes towards generic drugs. Of 1215 respondents, 68.4% knew the term "generic drugs." The majority of them had the correct understanding only on the following two points: generic drugs are less expensive than the brand name drugs (86.0%) and generic drugs contain the same active ingredients as brand name drugs (71.1%). However, their understanding was poor in other aspects of generic substitution: the availability and accessibility of generic drugs, etc. Only the experience of a previous generic drug substitution was significantly associated with the increased willingness for generic substitution (OR=2.93, CI 1.93-4.44). The main reasons for accepting generic substitutions were recommendations by physicians (48.6%) and by pharmacists (33.1%). The public awareness program on generic drugs should be expanded to include more detailed information so that patients obtain the correct understanding of generic substitution. It is critical that physicians and pharmacists have the proper understanding of generic drug substitution and provide the correct information to patients.

Understanding Therapeutic Equivalence in Epilepsy

The issues surrounding generic drug substitution in patients with epilepsy are complex. The substitution of one formulation of an antiepileptic drug (AED) for another is controversial. Well-reasoned and defensible cases can be made both for and against such substitution. Although regulatory agencies require that generic and proprietary drugs have similar pharmacokinetic bioequivalence data, their therapeutic efficacy may not necessarily be identical. The paroxysmal nature of epilepsy, the narrow therapeutic index of some AEDs, the need to individualize therapy to achieve seizure control, and the negative consequences of uncontrolled epilepsy distinguishes epilepsy from other clinical conditions. Epilepsy management with AEDs requires careful dose titration and consistent drug exposure at the optimal level for each patient, which can be altered if a different formulation of the AED is substituted. Unexpected variability in plasma concentrations could occur when a patient who has been receiving one formulation of an AED (generic or brand) receives an alternate formulation. Thus, no substitutions should be made for people with epilepsy without the knowledge and approval of the prescribing physician. Patients should be consulted about the substitution, with all risks and benefits carefully explained.

The Effect of Introducing Rebate Contracts to Promote Generic Drug Substitution, on Doctors’ Prescribing Practices

As of 1 April 2007, pharmacists in Germany filling prescriptions covered by the statutory health insurance system (Gesetzliche Krankenversicherung, GKV) are required, whenever possible, to dispense a preparation that contains the same active substance and for which a rebate contract is in effect. The physician can block drug substitution by crossing out "aut idem" ("or the like") on the prescription form. The latter option has existed since 2002. We studied the possible effect of the introduction of rebate contracts on the use of the no-substitution option. Three independent random samples were taken from the routine data of the Gmünder ErsatzKasse (GEK, a statutory health insurance carrier). The samples consisted of 0.5% of the insured adult population in the month of October in the years 2006, 2007, and 2008 (n = 6195; n = 6300; n = 6845). Within these sample groups, all medication orders in which the physician could potentially have exercised a no-substitution option were selected, and the corresponding prescriptions were examined. The percentage of no-substitution prescriptions rose from October 2006 to October 2007, and then rose still further to October 2008 (14.4%, 18.4%, 19.0%; p for trend < 0.0001). Considerable differences were seen between physicians belonging to different regional Associations of Statutory Health Insurance Physicians (Kassenärztliche Vereinigungen). In about one-quarter of the no-substitution prescriptions for 2007 and 2008 (25.1%, 25.7%), the prescribed medication was itself included in a rebate contract. The use of the no-substitution option is not uniform across Germany at present. Rebate contracts and the no-substitution option require further evaluation. Moreover, the dispensing of medications urgently needs a more stable regulatory framework.

Generic substitution: are antiepileptic drugs different?

Generic drug substitution can markedly decrease the cost of health care. For conditions where agents have a relatively narrow therapeutic index, notably epilepsy, financial savings through generic substitution might be offset by increases in patient complications and related costs. Results from a study with topiramate support this view, particularly when a patient receives a drug from multiple manufacturers.

GENERICS AND COST-EFFECTIVE PRESCRIBING IN BELGIUM: DOES BIOEQUIVALENCE ALWAYS TRANSLATE IN THERAPEUTIC EQUIVALENCE?

As many other countries, Belgium has a policy to promote the use of generic pharmaceutical products. In order to protect consumers, these generic products must be demonstrated to be essentially similar to the previously approved product, typically an innovator product. The therapeutic equivalence of a generic and an innovator product is most commonly based on the demonstration of bioequivalence, i.e. clinically insignificant differences in the rate and extent of drug absorption usually assessed from pharmacokinetic measurements, in a normal and healthy population. This article reviews the bioequivalence requirements for generic products and examines whether bioequivalence always adequately substantiates therapeutic equivalence and interchangeability. Clinical practice has identified a number of drug classes for which generic substitution should be approached with caution. Current bioequivalence requirements are based on a measure of average bioequivalence. There are fears that use of this measure may be inappropriate in the case of a drug with a narrow therapeutic range or high intrasubject or intersubject variability. Under these circumstances, measures of individual and population bioequivalence are proposed to be more accurate than measures of average bioequivalence. Bioequivalence issues are discussed together with more general concerns about generic drug substitution, such as differences in product and packaging appearance and differences in excipients.

Switches of antiepileptic drug products come under fire

A patient advocacy group’s campaign and the media’s recent focus on generic drug substitution have increased the need for pharmacists to judge FDA-declared bioequivalent products by more than just price, say two pharmacists who work at epilepsy clinics. “At the dispensing end . . . there’s

Understanding patients' perspective in the use of generic antiepileptic drugs: compelling lessons for physicians to improve physician/patient communication

BackgroundEpilepsy is a condition in which consistency of treatment is paramount to successful management and for most patients, effective seizure control can be achieved. Given the severe consequences of even a single breakthrough seizure, patients should be afforded every opportunity to succeed on their given regimens.DiscussionSome experts argue that global policy on generic antiepileptic drug substitution in epilepsy should be limited – occurring at the discretion of and with careful monitoring by the physician. While the debate continues, physicians still have daily responsibilities to their patients to help them best manage their epilepsy within the context of the current environment – the reality of which may involve switching to a generic antiepileptic drug or navigating various formulations between generics.SummaryTo provide context, this paper first reviews the main "hot button" issues fueling the ongoing generic debate, including a broad overview of the current state of the literature. The main goal however is to provide physicians with a patient perspective on generic antiepileptic drug use in epilepsy as a source of clinically useful, everyday advice to improve communication and increase patient self-advocacy, both of which are necessary for optimal patient outcome.

Hidden Paradoxes in Generic Drug Substitution Affecting Pharmacotherapy

The issue of the generic versus brand-name drug interchangeability is an intensely debated theme historically focused on whether bioequivalence testing can guarantee therapeutic efficacy. The controversy is supported by reports of the lack of therapeutic equivalence between some generic medicinal products and brand-name drugs, as well as by a great deal of editorials expressing a negative view on generic drug substitution. This could be of particular concern for critical therapeutic categories such as psychotropic, cardiovascular, and metabolic/endocrine drugs as well as for special subpopulations such as elderly, debilitated/psychoneurotic patients, infants and children [1, 2]. To deal with this issue, large, prospective controlled evaluations have been proposed, providing information on how current bioequivalence and pharmacological equivalence translate into clinical equivalence [3]. In our opinion, however, although on one hand this strategy could be suitable in clinical trials to ascertain the “essential similarity” requirement in drug substitution—in terms of active ingredient (amount and type), route of administration, and therapeutic effectiveness—on the other hand, it might be insufficient in real practice to support the therapeutic equivalence for the general population. This could also be due to the possible influence of the marketing to patient's response.