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Evaluation of Generic versus Original Prostaglandin Analogues in the Treatment of Glaucoma
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Evaluation of Generic versus Original Prostaglandin Analogues in the Treatment of Glaucoma A Systematic Review and Meta-Analysis Alvilda T. Steensberg, MBBS,1 Olivia O. Müllertz, BSc Pharm,1 Gianni Virgili, MD,2 Augusto Azuara-Blanco, MD, PhD,3 Miriam Kolko, MD, PhD1,4 Topic: An evaluation of the efficacy and tolerability of generic prostaglandin analogues (PGAs) compared with their original counterpart. Clinical Relevance: This systematic review was initiated to enlighten ophthalmologists and patients in the use of original and generic ophthalmic solutions. Methods: A literature search was conducted on PubMed, EMBASE, MEDLINE, Clinicaltrials.gov, and the World Health Organization International Clinical Trials Registry Platform, along with a manual search, from the marketing of the first PGA, latanoprost, in 1995 to the present. Randomized controlled trials comparing an original PGA with its generic counterpart were included. The last literature search was conducted in June 2019. Risk of bias was assessed by 2 independent reviewers using the Cochrane Handbook for Systematic Reviews Tool. The primary outcome was reduction of intraocular pressure (IOP) from baseline. Secondary outcomes included tolerability, ocular surface health, quality of life, disease progression, and cost-effectiveness. Meta-analysis of the primary outcome was planned. Results: Of 385 screened articles, 6 were included in a broad characterization and in the meta-analysis. A total of 619 patients were enrolled. The duration of the studies ranged from 3 to 16 weeks. Meta-analysis of all 6 studies denied any clinically significant difference in efficacy, and the 95% confidence interval included nil (0.50 to 0.04 mmHg). The evidence was of moderate certainty because of unclear or high risk of bias in all studies. There were no reported differences in tolerability. Conclusions: Trials comparing original and generic PGAs did not show a clinically significant difference in IOP-lowering effect or tolerability. However, the quality of the trials is suboptimal. Overall, there is uncertainty, and further research is needed to confirm equivalence. Ophthalmology Glaucoma 2020;3:51-59 ª 2019 by the American Academy of Ophthalmology Supplemental material available at www.ophthalmologyglaucoma.org.
On a global scale, 36 million people are estimated to be blind, and glaucoma is the second leading cause of irreversible vision loss.1,2 No cure exists, but treatments that lower intraocular pressure (IOP) are known to reduce the rate of disease progression in most cases.3 The IOP is a balance between the production of aqueous humor and the uveoscleral outflow and outflow through the trabecular meshwork. The most common treatment strategy is eyedrops that reduce the production of aqueous humor or increase outflow. Among the existing anti-glaucomatous eyedrops, the far most frequently used class of topical glaucomatous drugs, with this effect, are prostaglandin analogues (PGAs). The first PGA used for glaucoma, latanoprost 0.005%, received approval from the European Medicines Evaluation Agency and the US Food and Drug 2019 by the American Academy of Ophthalmology Published by Elsevier Inc.
Administration as a first-line drug in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT).4 The PGAs latanoprost, travoprost, bimatoprost, and tafluprost are all used in the treatment of glaucoma, both as original brand-name drugs and as generic formulaions.5 Generic drugs do not need clinical trials but can be approved by regulators with the use of bioavailability tests. The market cost of generic medications is often reduced, and in some countries the pharmacist is obliged to inform the patient of the cheapest alternative to the prescribed drug. In the United Kingdom, generic latanoprost is recommended as first-line medical treatment for OHT and OAG. An alternative/generic is valued as having the same active ingredient, same dose, and same indication as the originally marketed drug. No claims are made to the excipients in the https://doi.org/10.1016/j.ogla.2019.10.002 ISSN 2589-4196/19
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Ophthalmology Glaucoma Volume 3, Number 1, January/February 2020 eye drop formulation or packaging.6,7 Emerging studies and case reports have found significant differences in physical and chemical properties among original PGAs and generic products.8-10 Because the efficacy and side effects of eyedrops can be dependent on excipients in the formulation, pH, buffer capacity, and viscosity, concerns have been raised on the effectiveness and tolerability of generic eyedrops.11 This study concerns the effectiveness of original and generic PGAs when treating patients of all ages diagnosed with OAG and OHT.
Why Is This Systematic Review Important? The increasing number of generic eyedrops on the market is of great socioeconomic relevance. However, patients and ophthalmologists have raised concern regarding the effectiveness, tolerability, and safety of generic eyedrops. Sparse information is found in the literature on this matter. The studies that do exist have not been assessed for bias, and the results are not clear. To our knowledge, there has not been a systematic review of the evidence pertaining to the efficacy of original PGAs compared with its generic counterpart.
Methods The systematic review protocol was registered at PROSPERO International Prospective Register of Systematic Reviews (https:// www.crd.york.ac.uk/prospero, Registration No. CRD42019125147). This article adheres to the PRISMA statement12 checklist for the preferred reporting of systematic reviews and meta-analysis.
Eligibility Criteria This systematic review focused on studies that investigated the IOP-lowering effect of original PGA and its generic counterparts when treating individuals of all ages diagnosed with OAG or OHT. All PGAs in the treatment of OAG and OHT were included. These are latanoprost, travoprost, bimatoprost, and tafluprost, with no restriction to the final follow-up time. Nonrandomized studies of intervention and cost analysis were excluded, and records not written in Danish, English, or German were also excluded.
Search Method Three databases (PubMed, EMBASE, and MEDLINE) were searched for randomized controlled trials (RCTs) from the marketing of the first PGA (latanoprost) in 1995 to the present date. The following search terms were used to retrieve relevant studies: ((glaucoma (Title/Abstract) OR ocular hypertension (Title/Abstract) OR oht (Title/Abstract)) and generic*). Moreover, clinicaltrials.gov (www.clinicaltrials.gov) and World Health Organization International Clinical Trials Registry Platform were sought for any ongoing or finalized clinical trials that have published results. Then, a manual search was performed by checking the reference lists of the RCTs. For further details regarding the search strategy, see Supplementary 1 (available at www.ophthalmologyglaucoma.org). Two reviewers (ATS and OOM) independently completed the literature search of all databases and screened references of all included studies. The main search was conducted in March 2019, with a follow-up search in June 2019. A flow chart illustrating the article search process is presented in Figure 1.
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Study Selection The abstracts of the records were read by 2 independent review authors (ATS and OOM) and classified as “relevant,” possibly relevant,” or “not relevant.” All relevant or possibly relevant articles were read full length and further divided into “include” or “exclude.” After any disagreements, a third author was asked to arbitrate.
Data Collection and Extraction The following data were extracted from each of the studies: (1) name of the first author, (2) year of publication, (3) trial design, (4) participants, (5) intervention, (6) comparison, (7) outcomes (described later), (8) study setting, and (9) timeframe for follow-up. The primary outcome was change of IOP from baseline. Secondary outcomes included patient preference, any measures of quality of life, costeffectiveness, and tolerability or side effects, when reported.
Risk of Bias Assessment The quality of each included RCT was evaluated individually by the 2 independent review authors. The Cochrane Handbook for Systematic Reviews Tool was used to assess the risk of bias regarding selection bias, performance bias, detection bias, attrition bias, selective outcome reporting bias, and other sources of bias. All studies were divided into “high risk,” “low risk,” or “unknown risk” based on risk of bias. After any disagreements, a third author was asked to arbitrate. If insufficient data were presented to assess the risk of bias, contact was taken to the authors. For crossover studies, another type of bias was considered, the risk of carry-over effect, that is, the effect of the drug used in the first period extends to the second period and influences IOP measured after treatment with the second drug. Although a washout period would be ideal, it was considered potentially unethical in noninferiority studies and accepted as low risk in studies in which IOP was measured at least 3 to 5 weeks after treatment initiation.13 Moreover, average IOP will be considered a stable condition at medium term, so there was no concern regarding period effect in crossover studies. Also, regarding allocation concealment in crossover studies, in which each patient receives both brand and generic treatment with PGAs, and only the period order is randomized if no carry-over effects were suspected, as was the case in all included studies, selection bias was unlikely to happen, and this bias domain was judged as “low risk.”
Data Synthesis A meta-analysis was planned for the primary outcome change of IOP from baseline to final follow-up, per protocol, using a random effect (DerSimonian and Laird) inverse variance meta-analysis to pool data. A difference of 2 mmHg or more was considered post hoc to be clinically significant for the primary outcome. The effect of each study was investigated on the pooled estimate using a leave-1-out technique. The principal summary measures were presented as mean difference (MD) and standard error (SE). To deal with crossover studies and when data were missing for the primary outcome (change in IOP from baseline), recommendations given in the Cochrane Handbook were followed.14 When estimates of the MDs between treatment groups were not available, these were computed from group means to obtain MDs between crossover phases and then between treatments. When SEs of the difference were not available, they were extracted with the following strategy: back-calculation using P values and the correspondent values of the t distribution; when group standard deviations (SDs), but not P values were available, a correlation of 0.8 between crossover phases was assumed, also conducting a sensitivity analysis with 0.5 correlation; when neither P values nor
Steensberg et al
Generic vs Original Prostaglandin Analogues
Figure 1. Article search process.
group SDs were available, the SEs were imputed using the median SE of each treatment group in other studies. To investigate the precision of this meta-analysis and assess the risk of bias regarding different thresholds for the clinically meaningful difference between brand and generic PGAs, the optimal information size (OIS) was computed following Guyatt et al.15 The secondary outcomes were narratively described, and a summary of how the secondary outcomes were reported in the studies. The results of these findings were reported in Table 1.
Results Study Characteristics By using the initial search strategy, 385 articles were identified, and 379 articles were excluded because of irrelevance or study design. Six studies were included in this systematic review and in
the meta-analysis.16-21 Descriptions of participants, follow-up time, and outcome measures are presented in Table 2. All studies evaluated OAG and OHT, and 2 studies evaluated normaltension glaucoma.
Risk of Bias in Included Studies A risk of bias assessment was performed for all RCTs included in this systematic review as per methodology described in the Cochrane Handbook for Systematic Reviews of Interventions. The findings are outlined in Figure 2 divided into proportion of low, high, and unknown risk of bias. For sequence generation, 4 studies were of low risk and 2 studies were of unknown risk of bias. For allocation concealment, 4 studies were of low risk and 2 studies were of unknown risk of bias. For blinding of participants and personnel, 3 studies were of low risk and 3 studies were of unknown risk of bias. For blinding of
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54 Table 1. Number of Reported Adverse Events, Number of Patients Reporting Adverse Events, and Ocular Surface Disease Index Score for the Included Studies Reported AE
OSDI Score
Original e
Generic e
Original e
Generic e
Original 2
12 e 14 e NR
21 e 27 e NR
e 5 e 5 NR
e 2 e 8 NR
e
Golan 2015 Allaire 2012 Narayanaswamy 2007 Digiuni 2013 Kim 2018
e e e
Generic Lataz: 4 Xalaprost: 7 e
TBUT (Mean Decrease, Seconds ± SD) Original 0.47 0.85
e e e
e
Generic Lataz: 0.72 1.21 Xalaprost: 1.03 0.79 e
e e e
e e e
Slit-Lamp Examination (% of Conjunctival Hyperemia) Original e
Generic e
e 18% NR e e
e 15% NR e e
AE ¼ adverse event; NR ¼ not reported; OSDI ¼ Ocular Surface Disease Index; TBUT ¼ tear break-up time.
Table 2. Overview of Details of Included Studies Author Year
Design
Participants; Glaucoma Subtype
Original PGA (Manufacturer)
Follow-up (wks)
Primary Outcome
1. Lataz (Rafarm Pharmaceuticals, Korinthou, Greece) 2. Xalaprost (Cooper Pharmaceuticals, Greece) Glautan (Unipharm, Tel Aviv, Israel) Latanoprost 0.005% (Bausch & Lomb, Berlin, Germany)
16
Mean DIOP
TBUT, OSDI questionnaire
NR/NR
4
Mean DIOP
AE
NR/NR
6
Mean DIOP
Subjective: AE Objective: slit-lamp examination Subjective: AE Objective: slit-lamp examination Local AE Systemic AE AE
NR/Employees of Bausch & Lomb
Generic PGA (Manufacturer)
Diagourtas 2018
RCT
60; OAG or OHT
Xalatan (Pfizer Inc, New York, NY)
Golan 2015
RCT, CO
Xalatan (Pfizer Inc)
Allaire 2012
RCT
19; OAG, OHT, or NTG 257; POAG or OHT
Narayanaswamy 2007
RCT, CO
29; OAG or OHT
Xalatan (Pfizer Inc)
Latoprost (Sun Pharmaceuticals, Mumbai, India)
12
Mean DIOP
Digiuni 2013
RCT
184; OAG or OHT
Xalatan (Pfizer Inc)
12
Mean DIOP
Kim 2018
RCT, CO
70; OAG, OHT, or NTG
Travatan Z (Alcon Inc, Geneva, Switzerland)
0,005% Latanoprost (Galaxia, Alfa Intes srl, Italy) Travoprost (Sandoz Inc, Canada, Boucherville, Quebec, Canada)
3
Mean DIOP
Xalatan (Pfizer Inc)
Secondary Outcome
Sources of Funding/COI
Pfizer Ltd./NR PH&T/(Charlotte, NC)/NR Department of Surgery at University of Sherbrook/NR
AE ¼ adverse event; DIOP ¼ change in IOP from baseline to final visit; CO ¼ cross-over; COI ¼ conflicts of interest; NR ¼ not reported; NTG ¼ normal-tension glaucoma; POAG ¼ primary open-angle glaucoma; OAG ¼ open-angle glaucoma; Obj ¼ Objective; OHT ¼ ocular hypertension; OSDI ¼ Ocular Surface Disease Index; RCT ¼ randomized controlled trial; Subj ¼ Subjective; TBUT ¼ tear breakup time.
Ophthalmology Glaucoma Volume 3, Number 1, January/February 2020
Diagourtas 2018
No. of Patients with AE
Steensberg et al
Generic vs Original Prostaglandin Analogues
Figure 2. Proportion of low, high, and unknown risk of bias.
outcome assessment, 1 study was of low risk and 5 studies were of unknown risk of bias. For incomplete outcome data, 4 studies were of low risk and 2 studies were of unknown risk of bias. For selective reporting, 6 studies were of unknown risk of bias. All of the 3 crossover studies were at low risk, because they used a sufficiently long period of treatment before collecting outcomes (3e5 weeks). Bias domains of greater concern were insufficient details on masking of outcome assessors in 5 of 6 studies and insufficient details on prespecified reporting of outcomes, particularly adverse effects. A detailed risk of bias assessment is shown in Supplement 2 (available at www.ophthalmologyglaucoma.org).
The OIS criterion was used to further assess the precision of our estimates using different thresholds for a clinically meaningful difference. Given a median SD of 2 mmHg and 2.5 mmHg in the brand and generic groups, respectively, at final follow-up, a trial with a sample size of 717 was found, such that the total size of this meta-analysis would have 84% power to detect a difference of 0.5 mmHg between groups at an alpha of 0.05 and a power of approximately 100% to detect a difference of 1 mmHg. Thus, it is believed that the OIS criterion is largely met by this meta-analysis, and we did not downgrade the certainty of evidence for imprecision.
Tolerability Effect of Intervention/Meta-Analysis Table 3 presents baseline and final IOP values for each study. Figure 3 presents the meta-analysis results for the primary outcome: the change in IOP from baseline to final visit. The pooled estimate for latanoprost (0.24 mmHg; 95% confidence interval [CI], 0.58 to 0.11 mmHg; I2, 39.5%) was nearly identical to the effect measured by Kim et al,18 the single study on travoprost (0.24 mmHg; 95% CI, 0.75 to 0.27 mmHg). The 95% CI including all 6 studies excluded a clinically meaningful difference and included nil (0.23 mmHg; 95% CI, 0.50 to 0.04 mmHg; I2, 24%). Table 4 presents the results of leave-1-out sensitivity analyses. The exclusion of the study by Narayanaswamy et al,19 which showed only partial overlapping with other studies and a significant difference favoring original PGAs, reduced heterogeneity from 24% to nil. I2 remained between 21% and 40% after exclusion of any other study. The exclusion of the studies by Diagourtas et al17 and Digiuni et al13 made the 95% CI of the pooled estimate approach nominal statistical significance, but the overall interpretation of the results did not change. A sensitivity analysis using a moderate correlation (0.5 rather than 0.8) for SE imputation in the study by Kim et al18 did not change the meta-analytic estimate (0.231 mmHg), whereas 95% CIs widened to a small extent (from 0.50/0.04 to 0.52/0.06).
An overview of adverse events and tolerability outcomes is presented in Table 1. No significant differences in the number of patients with local adverse events were found by Allaire et al16 (chi-square test) and Digiuni et al13 (Fisher exact test). Diagourtas et al17 found no significant difference in tear breakup time (TBUT) calculated by a KruskaleWallis test. Narayanaswamy et al19 found similar hyperemia between the 2 treatment groups when performing a visual comparison by a slitlamp examination. Digiuni et al13 and Kim et al18 suggested that the tolerability of the groups was similar. By using a questionnaire, Golan et al20 and Narayanaswamy et al19 found a greater incidence of local adverse events when treating with generics latanoprost than with Xalatan (Pfizer, New York, NY). However, Golan et al20 did not evaluate this difference as significant (P ¼ 0.06), calculated by a McNemar test for which P < 0.05 was considered statistically significant.
Discussion The meta-analysis, including all 6 studies, suggests no clinically significant difference regarding efficacy between the generic and original PGAs (0.23 mmHg, CI, 0.50 to 0.04 mmHg). The quality of this evidence was moderate because most studies had at least 1 domain of low or unclear
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56
70 5.1 (NR) 70 8.1 (NR) Travatan Z (Alcon Inc) Kim 2018
26.25* (21.88e28.63)y
18.2 (NR)
29 93 8.0 (NR) 6.4 (NR) 14.3 (1.8) 16.5 (2.3) Xalatan (Pfizer Inc) Xalatan (Pfizer Inc) Narayanaswamy 2007 Digiuni 2012
23.1 (2.7) 22.8 (1.8)
130 7.5 (2.8) 16.8 (NR) Xalatan (Pfizer Inc) Allaire 2012
24.4 (1.8)
19 6.4 (NR) 12.3 (NR) 18.8 (NR) Xalatan (Pfizer Inc) Golan 2015
DIOP ¼ change in IOP from baseline to final visit; IOP ¼ intraocular pressure; NR ¼ not reported; PGA ¼ prostaglandin analogue; SD ¼ standard deviation. *Median. y Interquartile interval.
18.4 (3.5) 23.50* (19.00e27.50)y
29 91 7.0 (NR) 6.2 (NR) 16.4 (2.3) 16.4 (2.7) 23.1 (2.7) 22.8 (1.9)
127 7.3 (2.6) 17.2 (NR) 24.5 (1.7)
19 5.4 (NR) 15.6 (NR) 21.1 (NR)
20 16.1 (1.4) 23.1 (1.5)
7.0 (1.0)
20 7.5 (1.0) 15.8 (1.5) 23.3 (1.3)
1. Lataz (Rafarm Pharmaceuticals, Karinthou, Greece) 2. Xalaprost (Cooper Pharmaceuticals, Athens, Greece) Glautan (Unipharm, Tel Aviv, Israel) Latanoprost 0.005% (Bausch & Lomb, Berlin, Germany) Latoprost (Sun Pharmaceuticals) 0.005% Latanoprost (Galaxia, Alfa Intes srl, Casoria, Italy) Travoprost (Sandoz Inc) 20 7.3 (1.0) 15.8 (1.2) 23.1 (1.6) Xalatan (Pfizer Inc) Diagourtas 2018
Final IOP
DIOP
No.
Name (Manufacturer)
Baseline IOP Mean (SD), mmHg Name (Manufacturer)
Original PGA
Baseline IOP Mean (SD), mmHg
Table 3. Baseline and Final Intraocular Pressure Values for Each Study
Generic PGA
Final IOP
DIOP
No.
Ophthalmology Glaucoma Volume 3, Number 1, January/February 2020 risk of bias. The data manipulation and imputation of the primary outcome measures may have had limitations regarding the strength of the evidence; nonetheless, standard Cochrane methods were used for this purpose and suggest that such manipulation caused little risk of bias. There were no significant differences in adverse events. This evidence was of low quality because of risk of bias issues and the heterogeneity in reporting adverse events, which led us to conduct a qualitative synthesis. It is believed that variability in study follow-up is a minor limitation in this review, because treatment duration was sufficient to establish the full treatment effect of PGAs.13 The matter of generic medications is based on a risk/ benefit scale, in which the risks are toxicology and adverse events and the benefits are lower costs and consistent compliance.22 When a drug loses its data exclusivity, other pharmaceutical fabricants are able to formulate a generic version of that drug. This generic drug does not need years of clinical trials but can be marketed on the basis of bioavailability tests. Because there are no means of measuring bioavailability when treating with eyedrops, bioequivalence cannot be determined. Generic eyedrops are marketed on the basis of chemical tests that ensure comparability of the generic drug to the original reference product.7 Because there are fewer tests, the cost of development is less and therefore cheaper for the patient. As for this economic benefit, many patients choose the generic alternative before the original.23 The downside to the generic alternative is that there are no regulations stating that the inactive ingredients should be consistent, so the possibility of different degrees of adverse events is likely to occur.22 However, this study provides no evidence of difference in efficacy and tolerability between the generic and the original PGA. By enlightening the prescriber about the use of generic PGAs, this can be economically beneficial for both the patient and the healthcare system. The IOP-lowering effect of PGAs is reliant on both intrinsic and extrinsic factors, the extrinsic being patient compliance and the intrinsic being the stability and chemical properties of the ophthalmologic solution. In recent years, studies have investigated the physical properties of the plastic container and the chemical properties of the formulation in various generic PGAs and compared these with those of the original formulation.8,10,24-29 Drop size should also be considered because this will determine the actual amount of drug available for administration. Multiple studies show significant variations regarding these properties.8,24 Differences in concentrations of latanoprost, osmolality, pH, and total drop per container have also been suggested.8,24,28 When evaluating the physical and chemical properties of generic and brand-name travoprost, variations were found among drug concentration, osmolality, pH, mean drop size, and volume per container.10 Because of the results of these studies and clinical experience, ophthalmologists have raised concerns regarding the efficacy and safety of the use of generic eyedrops. The pH and osmolarity have an impact on the comfort when installing the drop. When using an eye drop with pH ranging far from that of the ocular tear film (pH ¼ 7.4) and if hypo- or hyperosmolar, discomfort
Steensberg et al
Generic vs Original Prostaglandin Analogues
Figure 3. Meta-analysis of the effect of prostaglandin analogue (PGA) original compared with the generic. CI ¼ confidence interval; ES ¼ effect size.
can occur.24 In this systematic review, it is reported that neither of the studies found a significant difference in regard to tolerability between the original and generic PGAs. This suggests that the pH and osmolarity are within limits of discomfort. Studies included in this systematic review have some limitations. Because relatively many of these have problems with their methodology and the sample size was relatively small, the question regarding efficacy and tolerability for brand-name PGA and their generics is still open. It is important to remember that the generic latanoprost drugs that are compared in this meta-analysis are different drugs from different brands and may have different ingredients. Finally, the studies vary regarding follow-up time. It is assumed that the maximum effect is achieved at all the final IOP measurements because maximum IOP-lowering effect Table 4. Results of Leave-1-Out Sensitivity Analyses Excluded Study All studies Diagourtas 2018 Golan 2015 Allaire 2012 Narayanaswamy 2007 Digiuni 2012 Kim 2018
MD (95% CI) 0.23 0.30 0.20 0.23 0.14 0.30 0.24
(0.50 (0.60 (0.54 (0.56 (0.39 (0.59 (0.58
to to to to to to to
0.04) 0.0) 0.13) 0.09) 0.11) 0.0) 0.11)
CI ¼ confidence interval; MD ¼ mean difference.
I2
P Value for Effect
24.4% 22.4% 35.6% 39.5% 0% 21% 39.5%
0.251 0.049 0.231 0.158 0.263 0.044 0.176
is often achieved 3 to 5 weeks from commencement of treatment.13 The articles included in this systematic review all use change in IOP from baseline as a measure of the efficacy, which made it possible to perform a meta-analysis. A lack of consensus and variability in outcomes and methods to use when comparing effectiveness of glaucoma interventions have been observed.30,31 To address this issue, inspiration can be drawn from the Core Outcome Measures in Effectiveness Trials initiative, a way of identifying the important core outcomes of interest to the patient, clinician, and other stakeholders.30-32 There is also a need for a standardized set of core outcomes when comparing the tolerability and safety of eyedrops, because it is difficult to compare the varying types of outcome measures. An example of this could be measurements of TBUT and a standardized way to report subjective adverse events, for example, the Ocular Surface Disease Index questionnaire. In conclusion, although the physical and chemical differences might indicate a possible influence on the clinical efficacy and safety, this systematic review found no evidence of difference between generic and original formulations of ophthalmic PGAs regarding efficacy. Both generic and original PGAs were well tolerated. This evidence is of moderate quality, but a small number of studies were available, and more randomized trials comparing other generic PGAs with original formulations would be useful to further investigate the robustness and generalizability of these findings. Concerning tolerability and safety, it would be valuable with a set of core outcomes based on
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Ophthalmology Glaucoma Volume 3, Number 1, January/February 2020 standardized methods and patient-reported outcomes in future studies, for example, the Ocular Surface Disease Index questionnaire and measurement of TBUT.
17.
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30.
31. 32.
ocular hypertension and primary open-angle glaucoma. Eur J Ophthalmol. 2012;22:19e27. Diagourtas A, Kagelaris K, Oikonomakis K, et al. Prospective study comparing Xalatan eye drops and two similar generics as to the efficacy and safety profile. Eur J Ophthalmol. 2018;28:378e384. Ta Kim D, Daigle P, Carbonneau M. Randomized crossover trial comparing effectiveness and tolerability of generic and brand-name travoprost. Can J Ophthalmol. 2019;54:223e228. Narayanaswamy A, Neog A, Baskaran M, et al. A randomized, crossover, open label pilot study to evaluate the efficacy and safety of Xalatan in comparison with generic Latanoprost (Latoprost) in subjects with primary open angle glaucoma or ocular hypertension. Indian J Ophthalmol. 2007;55:127e131. Golan S, Rosenfeld E, Shemesh G, Kurtz S. Original and generic latanoprost for the treatment of glaucoma and ocular hypertension: are they really the same? Clin Exp Pharmacol Physiol. 2015;42:220e224. Digiuni M, Manni G, Vetrugno M, et al. An evaluation of therapeutic noninferiority of 0.005% latanoprost ophthalmic solution and Xalatan in patients with glaucoma or ocular hypertension. J Glaucoma. 2013;22:707e712. Zore M, Harris A, Tobe LA, et al. Generic medications in ophthalmology. Br J Ophthalmol. 2013;97:253e257. Stein JD, Shekhawat N, Talwar N, Balkrishnan R. Impact of the introduction of generic latanoprost on glaucoma medication adherence. Ophthalmology. 2015;122:738e747. Angmo D, Wadhwani M, Velpandian T, et al. Evaluation of physical properties and dose equivalency of generic versus branded latanoprost formulations. Int Ophthalmol. 2017;37: 423e428. Dave P, Villarreal Jr G, Friedman DS, et al. Ability of bottle cap color to facilitate accurate patient-physician communication regarding medication identity in patients with glaucoma. Ophthalmology. 2015;122:2373e2379. Kahook MY, Fechtner RD, Katz LJ, et al. A comparison of active ingredients and preservatives between brand name and generic topical glaucoma medications using liquid chromatography-tandem mass spectrometry. Curr Eye Res. 2012;37:101e108. Moore DB, Hammer JD, Akhtari R, et al. Squeeze me if you can: variability in force requirements to extract a drop from common glaucoma bottles. J Glaucoma. 2016;25: 780e784. Queen JH, Feldman RM, Lee DA. Variation in number of doses, bottle volume, and calculated yearly cost of generic and branded latanoprost for glaucoma. Am J Ophthalmol. 2016;163:70e74.e71. Velpandian T, Kotnala A, Halder N, et al. Stability of latanoprost in generic formulations using controlled degradation and patient usage simulation studies. Curr Eye Res. 2015;40: 561e571. Ismail R, Azuara-Blanco A, Ramsay CR. Consensus on outcome measures for glaucoma effectiveness trials: results from a delphi and nominal group technique approaches. J Glaucoma. 2016;25:539e546. Ismail R, Azuara-Blanco A, Ramsay CR. Variation of clinical outcomes used in glaucoma randomised controlled trials: a systematic review. Br J Ophthalmol. 2014;98:464e468. Core Outcome Measures in Effectiveness Trials initiative. http://www.comet-initiative.org/. Published 2019. Accessed September 20, 2019.
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Generic vs Original Prostaglandin Analogues
Footnotes and Financial Disclosures Originally received: June 13, 2019. Final revision: October 8, 2019. Accepted: October 22, 2019. Available online: November 1, 2019.
No animal subjects were used in this study. Author Contributions: Manuscript no. 2019-95.
Conception and design: Steensberg, Müllertz, Azuara-Blanco, Kolko
1
Data collection: Steensberg, Müllertz, Virgili, Azuara-Blanco, Kolko
2
Analysis and interpretation: Steensberg, Müllertz, Virgili, Azuara-Blanco, Kolko
Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark. Department of Neurosciences, Psychology, Drug Research and Child Health, University of Firenze and AOU, Careggi, Italy.
3
Centre for Public Health, Queen’s University Belfast, Belfast, United Kingdom. 4 Department of Ophthalmology, Copenhagen University Hospital, Rigshospitalet e Glostrup, Glostrup, Denmark.
Obtained funding: Not applicable Overall responsibility: Steensberg, Müllertz, Virgili, Azuara-Blanco, Kolko
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Abbreviations and Acronyms: CI ¼ confidence interval; IOP ¼ intraocular pressure; MD ¼ mean difference; OAG ¼ open-angle glaucoma; OHT ¼ ocular hypertension; OIS ¼ optimal information size; PGA ¼ prostaglandin analogue; RCT ¼ randomized controlled trial; SD ¼ standard deviation; SE ¼ standard error.
HUMAN SUBJECTS: No human subjects were included in this study. No Institutional Review Board approval was required. All research adhered to the tenets of the Declaration of Helsinki. The requirement for informed consent was waived because of the retrospective nature of the study.
Correspondence: Alvilda T. Steensberg, MBBS, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Kbh, Denmark. E-mail: [email protected].
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Evaluation of Generic versus Original Prostaglandin Analogues in the Treatment of Glaucoma A Systematic Review and Meta-Analysis Alvilda T. Steensberg, MBBS,1 Olivia O. Müllertz, BSc Pharm,1 Gianni Virgili, MD,2 Augusto Azuara-Blanco, MD, PhD,3 Miriam Kolko, MD, PhD1,4 Topic: An evaluation of the efficacy and tolerability of generic prostaglandin analogues (PGAs) compared with their original counterpart. Clinical Relevance: This systematic review was initiated to enlighten ophthalmologists and patients in the use of original and generic ophthalmic solutions. Methods: A literature search was conducted on PubMed, EMBASE, MEDLINE, Clinicaltrials.gov, and the World Health Organization International Clinical Trials Registry Platform, along with a manual search, from the marketing of the first PGA, latanoprost, in 1995 to the present. Randomized controlled trials comparing an original PGA with its generic counterpart were included. The last literature search was conducted in June 2019. Risk of bias was assessed by 2 independent reviewers using the Cochrane Handbook for Systematic Reviews Tool. The primary outcome was reduction of intraocular pressure (IOP) from baseline. Secondary outcomes included tolerability, ocular surface health, quality of life, disease progression, and cost-effectiveness. Meta-analysis of the primary outcome was planned. Results: Of 385 screened articles, 6 were included in a broad characterization and in the meta-analysis. A total of 619 patients were enrolled. The duration of the studies ranged from 3 to 16 weeks. Meta-analysis of all 6 studies denied any clinically significant difference in efficacy, and the 95% confidence interval included nil (0.50 to 0.04 mmHg). The evidence was of moderate certainty because of unclear or high risk of bias in all studies. There were no reported differences in tolerability. Conclusions: Trials comparing original and generic PGAs did not show a clinically significant difference in IOP-lowering effect or tolerability. However, the quality of the trials is suboptimal. Overall, there is uncertainty, and further research is needed to confirm equivalence. Ophthalmology Glaucoma 2020;3:51-59 ª 2019 by the American Academy of Ophthalmology Supplemental material available at www.ophthalmologyglaucoma.org.
On a global scale, 36 million people are estimated to be blind, and glaucoma is the second leading cause of irreversible vision loss.1,2 No cure exists, but treatments that lower intraocular pressure (IOP) are known to reduce the rate of disease progression in most cases.3 The IOP is a balance between the production of aqueous humor and the uveoscleral outflow and outflow through the trabecular meshwork. The most common treatment strategy is eyedrops that reduce the production of aqueous humor or increase outflow. Among the existing anti-glaucomatous eyedrops, the far most frequently used class of topical glaucomatous drugs, with this effect, are prostaglandin analogues (PGAs). The first PGA used for glaucoma, latanoprost 0.005%, received approval from the European Medicines Evaluation Agency and the US Food and Drug 2019 by the American Academy of Ophthalmology Published by Elsevier Inc.
Administration as a first-line drug in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT).4 The PGAs latanoprost, travoprost, bimatoprost, and tafluprost are all used in the treatment of glaucoma, both as original brand-name drugs and as generic formulaions.5 Generic drugs do not need clinical trials but can be approved by regulators with the use of bioavailability tests. The market cost of generic medications is often reduced, and in some countries the pharmacist is obliged to inform the patient of the cheapest alternative to the prescribed drug. In the United Kingdom, generic latanoprost is recommended as first-line medical treatment for OHT and OAG. An alternative/generic is valued as having the same active ingredient, same dose, and same indication as the originally marketed drug. No claims are made to the excipients in the https://doi.org/10.1016/j.ogla.2019.10.002 ISSN 2589-4196/19
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Ophthalmology Glaucoma Volume 3, Number 1, January/February 2020 eye drop formulation or packaging.6,7 Emerging studies and case reports have found significant differences in physical and chemical properties among original PGAs and generic products.8-10 Because the efficacy and side effects of eyedrops can be dependent on excipients in the formulation, pH, buffer capacity, and viscosity, concerns have been raised on the effectiveness and tolerability of generic eyedrops.11 This study concerns the effectiveness of original and generic PGAs when treating patients of all ages diagnosed with OAG and OHT.
Why Is This Systematic Review Important? The increasing number of generic eyedrops on the market is of great socioeconomic relevance. However, patients and ophthalmologists have raised concern regarding the effectiveness, tolerability, and safety of generic eyedrops. Sparse information is found in the literature on this matter. The studies that do exist have not been assessed for bias, and the results are not clear. To our knowledge, there has not been a systematic review of the evidence pertaining to the efficacy of original PGAs compared with its generic counterpart.
Methods The systematic review protocol was registered at PROSPERO International Prospective Register of Systematic Reviews (https:// www.crd.york.ac.uk/prospero, Registration No. CRD42019125147). This article adheres to the PRISMA statement12 checklist for the preferred reporting of systematic reviews and meta-analysis.
Eligibility Criteria This systematic review focused on studies that investigated the IOP-lowering effect of original PGA and its generic counterparts when treating individuals of all ages diagnosed with OAG or OHT. All PGAs in the treatment of OAG and OHT were included. These are latanoprost, travoprost, bimatoprost, and tafluprost, with no restriction to the final follow-up time. Nonrandomized studies of intervention and cost analysis were excluded, and records not written in Danish, English, or German were also excluded.
Search Method Three databases (PubMed, EMBASE, and MEDLINE) were searched for randomized controlled trials (RCTs) from the marketing of the first PGA (latanoprost) in 1995 to the present date. The following search terms were used to retrieve relevant studies: ((glaucoma (Title/Abstract) OR ocular hypertension (Title/Abstract) OR oht (Title/Abstract)) and generic*). Moreover, clinicaltrials.gov (www.clinicaltrials.gov) and World Health Organization International Clinical Trials Registry Platform were sought for any ongoing or finalized clinical trials that have published results. Then, a manual search was performed by checking the reference lists of the RCTs. For further details regarding the search strategy, see Supplementary 1 (available at www.ophthalmologyglaucoma.org). Two reviewers (ATS and OOM) independently completed the literature search of all databases and screened references of all included studies. The main search was conducted in March 2019, with a follow-up search in June 2019. A flow chart illustrating the article search process is presented in Figure 1.
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Study Selection The abstracts of the records were read by 2 independent review authors (ATS and OOM) and classified as “relevant,” possibly relevant,” or “not relevant.” All relevant or possibly relevant articles were read full length and further divided into “include” or “exclude.” After any disagreements, a third author was asked to arbitrate.
Data Collection and Extraction The following data were extracted from each of the studies: (1) name of the first author, (2) year of publication, (3) trial design, (4) participants, (5) intervention, (6) comparison, (7) outcomes (described later), (8) study setting, and (9) timeframe for follow-up. The primary outcome was change of IOP from baseline. Secondary outcomes included patient preference, any measures of quality of life, costeffectiveness, and tolerability or side effects, when reported.
Risk of Bias Assessment The quality of each included RCT was evaluated individually by the 2 independent review authors. The Cochrane Handbook for Systematic Reviews Tool was used to assess the risk of bias regarding selection bias, performance bias, detection bias, attrition bias, selective outcome reporting bias, and other sources of bias. All studies were divided into “high risk,” “low risk,” or “unknown risk” based on risk of bias. After any disagreements, a third author was asked to arbitrate. If insufficient data were presented to assess the risk of bias, contact was taken to the authors. For crossover studies, another type of bias was considered, the risk of carry-over effect, that is, the effect of the drug used in the first period extends to the second period and influences IOP measured after treatment with the second drug. Although a washout period would be ideal, it was considered potentially unethical in noninferiority studies and accepted as low risk in studies in which IOP was measured at least 3 to 5 weeks after treatment initiation.13 Moreover, average IOP will be considered a stable condition at medium term, so there was no concern regarding period effect in crossover studies. Also, regarding allocation concealment in crossover studies, in which each patient receives both brand and generic treatment with PGAs, and only the period order is randomized if no carry-over effects were suspected, as was the case in all included studies, selection bias was unlikely to happen, and this bias domain was judged as “low risk.”
Data Synthesis A meta-analysis was planned for the primary outcome change of IOP from baseline to final follow-up, per protocol, using a random effect (DerSimonian and Laird) inverse variance meta-analysis to pool data. A difference of 2 mmHg or more was considered post hoc to be clinically significant for the primary outcome. The effect of each study was investigated on the pooled estimate using a leave-1-out technique. The principal summary measures were presented as mean difference (MD) and standard error (SE). To deal with crossover studies and when data were missing for the primary outcome (change in IOP from baseline), recommendations given in the Cochrane Handbook were followed.14 When estimates of the MDs between treatment groups were not available, these were computed from group means to obtain MDs between crossover phases and then between treatments. When SEs of the difference were not available, they were extracted with the following strategy: back-calculation using P values and the correspondent values of the t distribution; when group standard deviations (SDs), but not P values were available, a correlation of 0.8 between crossover phases was assumed, also conducting a sensitivity analysis with 0.5 correlation; when neither P values nor
Steensberg et al
Generic vs Original Prostaglandin Analogues
Figure 1. Article search process.
group SDs were available, the SEs were imputed using the median SE of each treatment group in other studies. To investigate the precision of this meta-analysis and assess the risk of bias regarding different thresholds for the clinically meaningful difference between brand and generic PGAs, the optimal information size (OIS) was computed following Guyatt et al.15 The secondary outcomes were narratively described, and a summary of how the secondary outcomes were reported in the studies. The results of these findings were reported in Table 1.
Results Study Characteristics By using the initial search strategy, 385 articles were identified, and 379 articles were excluded because of irrelevance or study design. Six studies were included in this systematic review and in
the meta-analysis.16-21 Descriptions of participants, follow-up time, and outcome measures are presented in Table 2. All studies evaluated OAG and OHT, and 2 studies evaluated normaltension glaucoma.
Risk of Bias in Included Studies A risk of bias assessment was performed for all RCTs included in this systematic review as per methodology described in the Cochrane Handbook for Systematic Reviews of Interventions. The findings are outlined in Figure 2 divided into proportion of low, high, and unknown risk of bias. For sequence generation, 4 studies were of low risk and 2 studies were of unknown risk of bias. For allocation concealment, 4 studies were of low risk and 2 studies were of unknown risk of bias. For blinding of participants and personnel, 3 studies were of low risk and 3 studies were of unknown risk of bias. For blinding of
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54 Table 1. Number of Reported Adverse Events, Number of Patients Reporting Adverse Events, and Ocular Surface Disease Index Score for the Included Studies Reported AE
OSDI Score
Original e
Generic e
Original e
Generic e
Original 2
12 e 14 e NR
21 e 27 e NR
e 5 e 5 NR
e 2 e 8 NR
e
Golan 2015 Allaire 2012 Narayanaswamy 2007 Digiuni 2013 Kim 2018
e e e
Generic Lataz: 4 Xalaprost: 7 e
TBUT (Mean Decrease, Seconds ± SD) Original 0.47 0.85
e e e
e
Generic Lataz: 0.72 1.21 Xalaprost: 1.03 0.79 e
e e e
e e e
Slit-Lamp Examination (% of Conjunctival Hyperemia) Original e
Generic e
e 18% NR e e
e 15% NR e e
AE ¼ adverse event; NR ¼ not reported; OSDI ¼ Ocular Surface Disease Index; TBUT ¼ tear break-up time.
Table 2. Overview of Details of Included Studies Author Year
Design
Participants; Glaucoma Subtype
Original PGA (Manufacturer)
Follow-up (wks)
Primary Outcome
1. Lataz (Rafarm Pharmaceuticals, Korinthou, Greece) 2. Xalaprost (Cooper Pharmaceuticals, Greece) Glautan (Unipharm, Tel Aviv, Israel) Latanoprost 0.005% (Bausch & Lomb, Berlin, Germany)
16
Mean DIOP
TBUT, OSDI questionnaire
NR/NR
4
Mean DIOP
AE
NR/NR
6
Mean DIOP
Subjective: AE Objective: slit-lamp examination Subjective: AE Objective: slit-lamp examination Local AE Systemic AE AE
NR/Employees of Bausch & Lomb
Generic PGA (Manufacturer)
Diagourtas 2018
RCT
60; OAG or OHT
Xalatan (Pfizer Inc, New York, NY)
Golan 2015
RCT, CO
Xalatan (Pfizer Inc)
Allaire 2012
RCT
19; OAG, OHT, or NTG 257; POAG or OHT
Narayanaswamy 2007
RCT, CO
29; OAG or OHT
Xalatan (Pfizer Inc)
Latoprost (Sun Pharmaceuticals, Mumbai, India)
12
Mean DIOP
Digiuni 2013
RCT
184; OAG or OHT
Xalatan (Pfizer Inc)
12
Mean DIOP
Kim 2018
RCT, CO
70; OAG, OHT, or NTG
Travatan Z (Alcon Inc, Geneva, Switzerland)
0,005% Latanoprost (Galaxia, Alfa Intes srl, Italy) Travoprost (Sandoz Inc, Canada, Boucherville, Quebec, Canada)
3
Mean DIOP
Xalatan (Pfizer Inc)
Secondary Outcome
Sources of Funding/COI
Pfizer Ltd./NR PH&T/(Charlotte, NC)/NR Department of Surgery at University of Sherbrook/NR
AE ¼ adverse event; DIOP ¼ change in IOP from baseline to final visit; CO ¼ cross-over; COI ¼ conflicts of interest; NR ¼ not reported; NTG ¼ normal-tension glaucoma; POAG ¼ primary open-angle glaucoma; OAG ¼ open-angle glaucoma; Obj ¼ Objective; OHT ¼ ocular hypertension; OSDI ¼ Ocular Surface Disease Index; RCT ¼ randomized controlled trial; Subj ¼ Subjective; TBUT ¼ tear breakup time.
Ophthalmology Glaucoma Volume 3, Number 1, January/February 2020
Diagourtas 2018
No. of Patients with AE
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Generic vs Original Prostaglandin Analogues
Figure 2. Proportion of low, high, and unknown risk of bias.
outcome assessment, 1 study was of low risk and 5 studies were of unknown risk of bias. For incomplete outcome data, 4 studies were of low risk and 2 studies were of unknown risk of bias. For selective reporting, 6 studies were of unknown risk of bias. All of the 3 crossover studies were at low risk, because they used a sufficiently long period of treatment before collecting outcomes (3e5 weeks). Bias domains of greater concern were insufficient details on masking of outcome assessors in 5 of 6 studies and insufficient details on prespecified reporting of outcomes, particularly adverse effects. A detailed risk of bias assessment is shown in Supplement 2 (available at www.ophthalmologyglaucoma.org).
The OIS criterion was used to further assess the precision of our estimates using different thresholds for a clinically meaningful difference. Given a median SD of 2 mmHg and 2.5 mmHg in the brand and generic groups, respectively, at final follow-up, a trial with a sample size of 717 was found, such that the total size of this meta-analysis would have 84% power to detect a difference of 0.5 mmHg between groups at an alpha of 0.05 and a power of approximately 100% to detect a difference of 1 mmHg. Thus, it is believed that the OIS criterion is largely met by this meta-analysis, and we did not downgrade the certainty of evidence for imprecision.
Tolerability Effect of Intervention/Meta-Analysis Table 3 presents baseline and final IOP values for each study. Figure 3 presents the meta-analysis results for the primary outcome: the change in IOP from baseline to final visit. The pooled estimate for latanoprost (0.24 mmHg; 95% confidence interval [CI], 0.58 to 0.11 mmHg; I2, 39.5%) was nearly identical to the effect measured by Kim et al,18 the single study on travoprost (0.24 mmHg; 95% CI, 0.75 to 0.27 mmHg). The 95% CI including all 6 studies excluded a clinically meaningful difference and included nil (0.23 mmHg; 95% CI, 0.50 to 0.04 mmHg; I2, 24%). Table 4 presents the results of leave-1-out sensitivity analyses. The exclusion of the study by Narayanaswamy et al,19 which showed only partial overlapping with other studies and a significant difference favoring original PGAs, reduced heterogeneity from 24% to nil. I2 remained between 21% and 40% after exclusion of any other study. The exclusion of the studies by Diagourtas et al17 and Digiuni et al13 made the 95% CI of the pooled estimate approach nominal statistical significance, but the overall interpretation of the results did not change. A sensitivity analysis using a moderate correlation (0.5 rather than 0.8) for SE imputation in the study by Kim et al18 did not change the meta-analytic estimate (0.231 mmHg), whereas 95% CIs widened to a small extent (from 0.50/0.04 to 0.52/0.06).
An overview of adverse events and tolerability outcomes is presented in Table 1. No significant differences in the number of patients with local adverse events were found by Allaire et al16 (chi-square test) and Digiuni et al13 (Fisher exact test). Diagourtas et al17 found no significant difference in tear breakup time (TBUT) calculated by a KruskaleWallis test. Narayanaswamy et al19 found similar hyperemia between the 2 treatment groups when performing a visual comparison by a slitlamp examination. Digiuni et al13 and Kim et al18 suggested that the tolerability of the groups was similar. By using a questionnaire, Golan et al20 and Narayanaswamy et al19 found a greater incidence of local adverse events when treating with generics latanoprost than with Xalatan (Pfizer, New York, NY). However, Golan et al20 did not evaluate this difference as significant (P ¼ 0.06), calculated by a McNemar test for which P < 0.05 was considered statistically significant.
Discussion The meta-analysis, including all 6 studies, suggests no clinically significant difference regarding efficacy between the generic and original PGAs (0.23 mmHg, CI, 0.50 to 0.04 mmHg). The quality of this evidence was moderate because most studies had at least 1 domain of low or unclear
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70 5.1 (NR) 70 8.1 (NR) Travatan Z (Alcon Inc) Kim 2018
26.25* (21.88e28.63)y
18.2 (NR)
29 93 8.0 (NR) 6.4 (NR) 14.3 (1.8) 16.5 (2.3) Xalatan (Pfizer Inc) Xalatan (Pfizer Inc) Narayanaswamy 2007 Digiuni 2012
23.1 (2.7) 22.8 (1.8)
130 7.5 (2.8) 16.8 (NR) Xalatan (Pfizer Inc) Allaire 2012
24.4 (1.8)
19 6.4 (NR) 12.3 (NR) 18.8 (NR) Xalatan (Pfizer Inc) Golan 2015
DIOP ¼ change in IOP from baseline to final visit; IOP ¼ intraocular pressure; NR ¼ not reported; PGA ¼ prostaglandin analogue; SD ¼ standard deviation. *Median. y Interquartile interval.
18.4 (3.5) 23.50* (19.00e27.50)y
29 91 7.0 (NR) 6.2 (NR) 16.4 (2.3) 16.4 (2.7) 23.1 (2.7) 22.8 (1.9)
127 7.3 (2.6) 17.2 (NR) 24.5 (1.7)
19 5.4 (NR) 15.6 (NR) 21.1 (NR)
20 16.1 (1.4) 23.1 (1.5)
7.0 (1.0)
20 7.5 (1.0) 15.8 (1.5) 23.3 (1.3)
1. Lataz (Rafarm Pharmaceuticals, Karinthou, Greece) 2. Xalaprost (Cooper Pharmaceuticals, Athens, Greece) Glautan (Unipharm, Tel Aviv, Israel) Latanoprost 0.005% (Bausch & Lomb, Berlin, Germany) Latoprost (Sun Pharmaceuticals) 0.005% Latanoprost (Galaxia, Alfa Intes srl, Casoria, Italy) Travoprost (Sandoz Inc) 20 7.3 (1.0) 15.8 (1.2) 23.1 (1.6) Xalatan (Pfizer Inc) Diagourtas 2018
Final IOP
DIOP
No.
Name (Manufacturer)
Baseline IOP Mean (SD), mmHg Name (Manufacturer)
Original PGA
Baseline IOP Mean (SD), mmHg
Table 3. Baseline and Final Intraocular Pressure Values for Each Study
Generic PGA
Final IOP
DIOP
No.
Ophthalmology Glaucoma Volume 3, Number 1, January/February 2020 risk of bias. The data manipulation and imputation of the primary outcome measures may have had limitations regarding the strength of the evidence; nonetheless, standard Cochrane methods were used for this purpose and suggest that such manipulation caused little risk of bias. There were no significant differences in adverse events. This evidence was of low quality because of risk of bias issues and the heterogeneity in reporting adverse events, which led us to conduct a qualitative synthesis. It is believed that variability in study follow-up is a minor limitation in this review, because treatment duration was sufficient to establish the full treatment effect of PGAs.13 The matter of generic medications is based on a risk/ benefit scale, in which the risks are toxicology and adverse events and the benefits are lower costs and consistent compliance.22 When a drug loses its data exclusivity, other pharmaceutical fabricants are able to formulate a generic version of that drug. This generic drug does not need years of clinical trials but can be marketed on the basis of bioavailability tests. Because there are no means of measuring bioavailability when treating with eyedrops, bioequivalence cannot be determined. Generic eyedrops are marketed on the basis of chemical tests that ensure comparability of the generic drug to the original reference product.7 Because there are fewer tests, the cost of development is less and therefore cheaper for the patient. As for this economic benefit, many patients choose the generic alternative before the original.23 The downside to the generic alternative is that there are no regulations stating that the inactive ingredients should be consistent, so the possibility of different degrees of adverse events is likely to occur.22 However, this study provides no evidence of difference in efficacy and tolerability between the generic and the original PGA. By enlightening the prescriber about the use of generic PGAs, this can be economically beneficial for both the patient and the healthcare system. The IOP-lowering effect of PGAs is reliant on both intrinsic and extrinsic factors, the extrinsic being patient compliance and the intrinsic being the stability and chemical properties of the ophthalmologic solution. In recent years, studies have investigated the physical properties of the plastic container and the chemical properties of the formulation in various generic PGAs and compared these with those of the original formulation.8,10,24-29 Drop size should also be considered because this will determine the actual amount of drug available for administration. Multiple studies show significant variations regarding these properties.8,24 Differences in concentrations of latanoprost, osmolality, pH, and total drop per container have also been suggested.8,24,28 When evaluating the physical and chemical properties of generic and brand-name travoprost, variations were found among drug concentration, osmolality, pH, mean drop size, and volume per container.10 Because of the results of these studies and clinical experience, ophthalmologists have raised concerns regarding the efficacy and safety of the use of generic eyedrops. The pH and osmolarity have an impact on the comfort when installing the drop. When using an eye drop with pH ranging far from that of the ocular tear film (pH ¼ 7.4) and if hypo- or hyperosmolar, discomfort
Steensberg et al
Generic vs Original Prostaglandin Analogues
Figure 3. Meta-analysis of the effect of prostaglandin analogue (PGA) original compared with the generic. CI ¼ confidence interval; ES ¼ effect size.
can occur.24 In this systematic review, it is reported that neither of the studies found a significant difference in regard to tolerability between the original and generic PGAs. This suggests that the pH and osmolarity are within limits of discomfort. Studies included in this systematic review have some limitations. Because relatively many of these have problems with their methodology and the sample size was relatively small, the question regarding efficacy and tolerability for brand-name PGA and their generics is still open. It is important to remember that the generic latanoprost drugs that are compared in this meta-analysis are different drugs from different brands and may have different ingredients. Finally, the studies vary regarding follow-up time. It is assumed that the maximum effect is achieved at all the final IOP measurements because maximum IOP-lowering effect Table 4. Results of Leave-1-Out Sensitivity Analyses Excluded Study All studies Diagourtas 2018 Golan 2015 Allaire 2012 Narayanaswamy 2007 Digiuni 2012 Kim 2018
MD (95% CI) 0.23 0.30 0.20 0.23 0.14 0.30 0.24
(0.50 (0.60 (0.54 (0.56 (0.39 (0.59 (0.58
to to to to to to to
0.04) 0.0) 0.13) 0.09) 0.11) 0.0) 0.11)
CI ¼ confidence interval; MD ¼ mean difference.
I2
P Value for Effect
24.4% 22.4% 35.6% 39.5% 0% 21% 39.5%
0.251 0.049 0.231 0.158 0.263 0.044 0.176
is often achieved 3 to 5 weeks from commencement of treatment.13 The articles included in this systematic review all use change in IOP from baseline as a measure of the efficacy, which made it possible to perform a meta-analysis. A lack of consensus and variability in outcomes and methods to use when comparing effectiveness of glaucoma interventions have been observed.30,31 To address this issue, inspiration can be drawn from the Core Outcome Measures in Effectiveness Trials initiative, a way of identifying the important core outcomes of interest to the patient, clinician, and other stakeholders.30-32 There is also a need for a standardized set of core outcomes when comparing the tolerability and safety of eyedrops, because it is difficult to compare the varying types of outcome measures. An example of this could be measurements of TBUT and a standardized way to report subjective adverse events, for example, the Ocular Surface Disease Index questionnaire. In conclusion, although the physical and chemical differences might indicate a possible influence on the clinical efficacy and safety, this systematic review found no evidence of difference between generic and original formulations of ophthalmic PGAs regarding efficacy. Both generic and original PGAs were well tolerated. This evidence is of moderate quality, but a small number of studies were available, and more randomized trials comparing other generic PGAs with original formulations would be useful to further investigate the robustness and generalizability of these findings. Concerning tolerability and safety, it would be valuable with a set of core outcomes based on
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Ophthalmology Glaucoma Volume 3, Number 1, January/February 2020 standardized methods and patient-reported outcomes in future studies, for example, the Ocular Surface Disease Index questionnaire and measurement of TBUT.
17.
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Steensberg et al
Generic vs Original Prostaglandin Analogues
Footnotes and Financial Disclosures Originally received: June 13, 2019. Final revision: October 8, 2019. Accepted: October 22, 2019. Available online: November 1, 2019.
No animal subjects were used in this study. Author Contributions: Manuscript no. 2019-95.
Conception and design: Steensberg, Müllertz, Azuara-Blanco, Kolko
1
Data collection: Steensberg, Müllertz, Virgili, Azuara-Blanco, Kolko
2
Analysis and interpretation: Steensberg, Müllertz, Virgili, Azuara-Blanco, Kolko
Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark. Department of Neurosciences, Psychology, Drug Research and Child Health, University of Firenze and AOU, Careggi, Italy.
3
Centre for Public Health, Queen’s University Belfast, Belfast, United Kingdom. 4 Department of Ophthalmology, Copenhagen University Hospital, Rigshospitalet e Glostrup, Glostrup, Denmark.
Obtained funding: Not applicable Overall responsibility: Steensberg, Müllertz, Virgili, Azuara-Blanco, Kolko
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Abbreviations and Acronyms: CI ¼ confidence interval; IOP ¼ intraocular pressure; MD ¼ mean difference; OAG ¼ open-angle glaucoma; OHT ¼ ocular hypertension; OIS ¼ optimal information size; PGA ¼ prostaglandin analogue; RCT ¼ randomized controlled trial; SD ¼ standard deviation; SE ¼ standard error.
HUMAN SUBJECTS: No human subjects were included in this study. No Institutional Review Board approval was required. All research adhered to the tenets of the Declaration of Helsinki. The requirement for informed consent was waived because of the retrospective nature of the study.
Correspondence: Alvilda T. Steensberg, MBBS, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Kbh, Denmark. E-mail: [email protected].
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