Evergreening refers to owners of pharmaceutical products using numerous strategies, such as patent laws and minor drug modifications, to extend their monopoly privileges with their products 123. Typically, these strategies are developed before expiry of the patent of an original drug, usually a high-revenue drug 456. If they succeed, they result in an extension of the patent protection period or a new patent for a minimally modified version of the drug.

A consequence of evergreening is delayed entry of generic drugs into the market with extension of the original drug patent or competition between the patent-protected minimally modified version of the drug and generic drugs 7. This situation might increase drug reimbursement costs by keeping the cheaper generic versions completely or partly out of the market 8. Pharmaceutical companies defend evergreening practices and claim that revised formulas benefit patients (for example, by improving adherence) and the drug industry (for example, by providing incentives for companies to engage in incremental innovation) 91011.

Minimal modifications used in evergreening include use of a different salt or molecule as an additive to the main drug components, change in formulation, modified release or change in route of administration 1213. An enantiomer patent is another form of evergreening based on a chiral switch (that is, from a chiral drug developed as a racemic mixture to a single enantiomer) 14. Single-enantiomer drugs represent more than 50% of the top-selling 100 drugs worldwide 15.

A typical example of this strategy was the case of citalopram/escitalopram, two antidepressants. The Lundbeck company's patent on citalopram has run out in many countries 15. The company launched a single-enantiomer drug, escitalopram, before the patent on the original drug expired and significantly increased its advertising campaigns to promote the new form 16. However, the clinical superiority of escitalopram over citalopram is still debated 15. Moreover, previous evergreening's societal burden analyses, dedicated to other evergreening examples, were based on projections of market shares and health insurance reimbursement costs 417.

We aimed to evaluate the impact of evergreening citalopram with the chiral switch form escitalopram on efficacy and treatment acceptability for patients, as well as health insurance costs for society.

We investigated the relative efficacy and acceptability of citalopram and escitalopram by performing meta-analyses for direct evidence (meta-analyses of results of head-to-head trials) and indirect evidence (adjusted indirect comparison of results of placebo-controlled trials). Health insurance costs were analyzed through reimbursement data for citalopram, its generic forms and escitalopram from the French national health insurance information system.

We performed a large-scale systematic review to evaluate the impact of evergreening of citalopram with the chiral switch form escitalopram on efficacy, treatment acceptability and health insurance costs. We found substantial discrepancy between the direct and indirect comparisons of citalopram and escitalopram for short-term treatment efficacy and acceptability. The direct comparison showed clinical superiority of escitalopram over citalopram, but the indirect comparison showed no evidence of difference between the two. Our analysis of reimbursement costs for a large representative sample of French health insurance beneficiaries, showed that escitalopram took a large share of the market, with citalopram substantially lower. The generic forms of citalopram started to gain an expected share of the market, but the uptake was suppressed by escitalopram competition. Moreover, escitalopram consumption overcame citalopram and its generic forms combined.

Network meta-analysis can be used to combine direct and indirect estimates of efficacy or acceptability. The analysis borrows strength from all the available evidence and increases statistical power and precision of estimates. However, we could not perform such a network meta-analysis because of the observed discrepancy between direct and indirect evidence. A possible explanation for the discrepancy is dose difference among trials; however, sensitivity analysis for comparable dosages showed consistent results. Another possible explanation could be bias in the direct comparison or the indirect comparison 2731. Head-to-head trials are usually considered the gold standard. However, such trials may favor the sponsored treatment 3334 or the newest treatment 353637. In our analysis, most head-to-head trials, except two, were sponsored by the manufacturer (Lundbeck/Forest Lab). One of the two trials was sponsored by Arbacom, a Russian company with potential conflict of interest with the Danish manufacturer Lundbeck 38. The trial results contained outlying results, with strong superiority of escitalopram over citalopram. The second trial was an institutional funded trial 32, and did not find any evidence of difference between the two drugs. Escitalopram was superior to citalopram in a network multiple-drug treatments meta-analysis of efficacy without placebo controlled trials 22. However, citalopram was superior to escitalopram, with a statistical non-significance, in an extensive multiple-drug treatments meta-analysis that considered the entire network of second-generation antidepressant drugs and including placebo-controlled trials 21.

Our indirect comparison may have been biased. For instance, the characteristics of citalopram and escitalopram placebo-controlled trials may have greatly differed, which would have invalidated the adjusted indirect comparison. However, we found no evidence of unequal distribution of potential treatment effect modifiers. Placebo-controlled trials may have exhibited reporting bias. Nevertheless, this bias is unlikely because as compared with active comparator trials, placebo-controlled trials are frequently registered with the FDA, which is considered a gold standard for placebo-controlled trials in the antidepressant field 39 and when we searched the FDA database, we identified five trials with unpublished data. As well, the indirect comparison may have had low statistical power 40. However, we ensured a balance in the number of included trials, with at least 10 randomized comparisons for both citalopram and escitalopram versus placebo.

Our study has some limitations. In the comparative effectiveness analysis, we assessed treatment acceptability only and did not assess safety outcomes 2122. Our findings could not be generalized to other patent-extended medications using chiral switch or other indications for citalopram/escitalopram usage. Second, we examined the EGB sample 29, although the EGB is a representative sample of the SNIIR-AM database 30. The EGB data limited our analysis to begin with 2003, so we were not able to look at the cost and consumption trends earlier than 2003.

We found strong uncertainty about the clinical benefits of escitalopram over citalopram. Given the likelihood of sponsorship bias for head-to-head trials and the absence of reporting bias for placebo-controlled trials 41, our adjusted indirect comparison may be less biased than the direct comparison. However, the market share of escitalopram increased substantially and suppressed that of the generic forms, which may have prevented a substantial cost savings for health insurance, especially if we assumed prescriptions shifted from escitalopram to generic citalopram. Finally, as evergreened medications are typically launched to the market before the patent of the original product expires - in the expectation of generic competition - it might be suitable to base the new product costs on the estimated price of the generic form, rather than on the current price of the originator. Moreover, health technology assessment agencies could redefine product innovation to reflect actual added benefits to patients and society. This might effectively make the evergreened product less cost effective and might help discourage this practice 42.

CI: confidence interval; DDD: defined daily dose; EGB: Echantillon généraliste de bénéficiaires; MADRS: Montgomery-Åsberg depression rating scale; NNT: number needed to treat; OR: odds ratio; RCTs: randomized controlled trials; SNIIR-AM: French National Health Insurance Inter-regime Information System

The authors declare that they have no competing interests.

AA contributed to the study design and performed the literature search, data collection and data interpretation. AA was also involved in drafting the manuscript. LT substantially contributed to the design, data collection and data analysis, and was also involved in the manuscript drafting and revising its intellectual content. GB contributed in gathering reimbursement data and its analysis, and also critically revised the manuscript for intellectual content. MD contributed to the conception and design of the study, and also was involved in the manuscript revision and approving its intellectual content. PR contributed substantially to the conception, design of the evergreening study and the interpretation of data, and was involved in revising the manuscript critically for intellectual content and has given the final approval of the version to be published. All authors have read and approved the manuscript for publication.